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d58c081b8e85f0de659d8a351ba8f00d440175bd | wikidoc | Colin Butler | Colin Butler
Dr Colin Butler is a Director of the Benevolent Organisation for Development, Health and Insight (BODHI) and Visiting Fellow at the National Centre for Epidemiology and Population Health, ANU. He is a former Senior Research Fellow of the School of Health and Social Development at Deakin University. His work lies at the intersection of globalisation, health and sustainability. Globalisation includes social, economic, cultural and environmental changes, at scales from the microscopic to the planetary. His main research interest lies in trying to find ways to advance sustainable global health for all, including people who are marginalized and oppressed.
His interests include agriculture, climatology, demography, development, ecology, economics, environmental change, epidemiology, ethics, future studies, general practice, global change, global health, health promotion, human rights, inequality, infectious diseases, nutrition, poverty, public health, social justice, sociology and sustainability. He is particularly interested in ecosocial systems and the relationship between human conflict and resource scarcity.
He also works part time in rural general practice in Tasmania. He holds post graduate qualifications from the London School of Hygiene and Tropical Medicine and in 2002 he completed a multidisciplinary PhD at the Australian National University. This thesis argued that the unequal distribution of global political and economic influence facilitates "environmental brinkmanship" whereby the wealthy and powerful risk global environmental change of such degree that it threatens the fabric of civilisation. He was extensively involved with the Millennium Ecosystem Assessment, and has published over 100 letters, papers and chapters.
In 1989 Colin and his wife Susan co-founded BODHI, an NGO which works in the field of international health and primary health care. | Colin Butler
Dr Colin Butler is a Director of the Benevolent Organisation for Development, Health and Insight (BODHI) [1] and Visiting Fellow at the National Centre for Epidemiology and Population Health, ANU. He is a former Senior Research Fellow of the School of Health and Social Development at Deakin University. His work lies at the intersection of globalisation, health and sustainability. [2] Globalisation includes social, economic, cultural and environmental changes, at scales from the microscopic to the planetary. His main research interest lies in trying to find ways to advance sustainable global health for all, including people who are marginalized and oppressed.
His interests include agriculture, climatology, demography, development, ecology, economics, environmental change, epidemiology, ethics, future studies, general practice, global change, global health, health promotion, human rights, inequality, infectious diseases, nutrition, poverty, public health, social justice, sociology and sustainability. He is particularly interested in ecosocial systems and the relationship between human conflict and resource scarcity.
He also works part time in rural general practice in Tasmania. He holds post graduate qualifications from the London School of Hygiene and Tropical Medicine and in 2002 he completed a multidisciplinary PhD at the Australian National University. This thesis argued that the unequal distribution of global political and economic influence facilitates "environmental brinkmanship" whereby the wealthy and powerful risk global environmental change of such degree that it threatens the fabric of civilisation. He was extensively involved with the Millennium Ecosystem Assessment, and has published over 100 letters, papers and chapters. [3]
[4]
In 1989 Colin and his wife Susan co-founded BODHI, an NGO which works in the field of international health and primary health care. | https://www.wikidoc.org/index.php/Colin_Butler | |
15ee65259d909252f038b4c5bc8d7f30fca64e8b | wikidoc | Colin Carrie | Colin Carrie
Colin Carrie (born April 11, 1962 in Hamilton, Ontario is a Canadian politician. He is a current member of the Canadian House of Commons, representing the riding of Oshawa (electoral district) in the province of Ontario for the Conservative Party of Canada.
Colin Carrie was elected to the House of Commons in June 2004. He was re-elected in January 2006, and once again in October 2008. On February 7, 2006, Prime Minister Stephen Harper appointed Carrie to the post of Parliamentary Secretary to the Minister of Industry, at that time the Honourable Maxime Bernier, and since August 2007 the Honourable Jim Prentice.
Carrie is the son of a late Royal Canadian Navy officer, and lived in several Canadian cities before settling in Oshawa, Ontario at age fifteen. He has a Bachelor's Degree in Kinesiology from the University of Waterloo, and was awarded a Doctor of Chiropractic in 1989 from the Canadian Memorial Chiropractic College in 1989. He has worked as a chiropractor in private life, and is co-owner of the Lakeview Chiropractic and Wellness Clinic. He is past executive member of the Durham Chiropractic Society and former chair of Spinal Health Week in Durham Region, and has been financial secretary of the Oshawa Knights of Columbus.
Carrie was a director of the Oshawa Progressive Conservative Party of Canada Association, before that party's 2004 merger with the Canadian Alliance to form the Conservative Party. He was elected for Oshawa in the Canadian federal election, 2004, defeating New Democratic Party candidate Sid Ryan and Liberal Party of Canada Louise Parkes in a close three-way race. In a close two-way race with returning NDP challenger Sid Ryan, Carrie retained his seat in the 2006 election as part of the first Conservative government to be elected in Canada in almost 13 years.
In the 38th Parliament, Carrie served as a member of the House of Commons Standing Committee on Health. After his election in 2004, he reintroduced Private Member's Bill C-420 (previously introduced by James Lunney) to end the listing of vitamins, minerals and related products as drugs under the Canadian Food and Drugs Act. This measure, endorsed and largely designed by Freedom Party of Ontario activist Trueman Tuck, has been criticized by some as removing a safety provision from the regulation of natural health products. Supporters of the bill argued that it would benefit the position of small producers relative to the pharmaceutical industry. Carrie has served as Chair of the Conservative Party of Canada’s (CPC) Automotive Caucus and was a member of the CPC's Energy Caucus and Seniors Caucus.
On January 19, 2007, Elections Canada charged Alan Clarke, a former activist in Carrie's 2004 federal election campaign over an alleged defamation against Oshawa NDP candidate, Sid Ryan. Ryan, who is Ontario President of the Canadian Union of Public Employees (CUPE), also launched a one million dollar libel suit against Clarke. Carrie's campaign manager, Andrew Morin, suggested that the leaflet is a product of union squabbling over an endorsement by the Canadian Auto Workers, and stated that Ryan and Carrie were on good terms. In May 2008, a judge rejected the Crown's arguments and acquitted Clarke on all charges. matter.
On June 3, 2008 General Motors of Canada announced it would stop producing light duty pick-up trucks at its Oshawa truck assembly plant in 2009. Carrie, along with Whitby-Oshawa MP and Minister of Finance Jim Flaherty, were criticized by some members of CAW Local 222 for not having visited a union-initiated illegal blockade of GM's corporate headquarters in Oshawa, when many other federal, provincial, and municipal politicians had done so. Carrie also came under repeated fire from Local 222 President Chris Buckley, who told union members that Carrie had neglected to call until nearly two full days after GM's announcement. | Colin Carrie
Template:Infobox CanadianMP
Colin Carrie (born April 11, 1962 in Hamilton, Ontario[citation needed] is a Canadian politician. He is a current member of the Canadian House of Commons, representing the riding of Oshawa (electoral district) in the province of Ontario for the Conservative Party of Canada.
Colin Carrie was elected to the House of Commons in June 2004. He was re-elected in January 2006, and once again in October 2008. On February 7, 2006, Prime Minister Stephen Harper appointed Carrie to the post of Parliamentary Secretary to the Minister of Industry, at that time the Honourable Maxime Bernier, and since August 2007 the Honourable Jim Prentice.
Carrie is the son of a late Royal Canadian Navy officer, and lived in several Canadian cities before settling in Oshawa, Ontario at age fifteen. He has a Bachelor's Degree in Kinesiology from the University of Waterloo, and was awarded a Doctor of Chiropractic in 1989 from the Canadian Memorial Chiropractic College in 1989. He has worked as a chiropractor in private life, and is co-owner of the Lakeview Chiropractic and Wellness Clinic. He is past executive member of the Durham Chiropractic Society and former chair of Spinal Health Week in Durham Region, and has been financial secretary of the Oshawa Knights of Columbus.
Carrie was a director of the Oshawa Progressive Conservative Party of Canada Association, before that party's 2004 merger with the Canadian Alliance to form the Conservative Party. He was elected for Oshawa in the Canadian federal election, 2004, defeating New Democratic Party candidate Sid Ryan and Liberal Party of Canada Louise Parkes in a close three-way race. In a close two-way race with returning NDP challenger Sid Ryan, Carrie retained his seat in the 2006 election as part of the first Conservative government to be elected in Canada in almost 13 years.
In the 38th Parliament, Carrie served as a member of the House of Commons Standing Committee on Health. After his election in 2004, he reintroduced Private Member's Bill C-420 (previously introduced by James Lunney) to end the listing of vitamins, minerals and related products as drugs under the Canadian Food and Drugs Act. This measure, endorsed and largely designed by Freedom Party of Ontario activist Trueman Tuck, has been criticized by some as removing a safety provision from the regulation of natural health products. Supporters of the bill argued that it would benefit the position of small producers relative to the pharmaceutical industry.[1] Carrie has served as Chair of the Conservative Party of Canada’s (CPC) Automotive Caucus and was a member of the CPC's Energy Caucus and Seniors Caucus.
On January 19, 2007, Elections Canada charged Alan Clarke, a former activist in Carrie's 2004 federal election campaign over an alleged defamation against Oshawa NDP candidate, Sid Ryan. Ryan, who is Ontario President of the Canadian Union of Public Employees (CUPE), also launched a one million dollar libel suit against Clarke. Carrie's campaign manager, Andrew Morin, suggested that the leaflet is a product of union squabbling over an endorsement by the Canadian Auto Workers, and stated that Ryan and Carrie were on good terms.[2] In May 2008, a judge rejected the Crown's arguments and acquitted Clarke on all charges. matter.[3]
On June 3, 2008 General Motors of Canada announced it would stop producing light duty pick-up trucks at its Oshawa truck assembly plant in 2009.[4] Carrie, along with Whitby-Oshawa MP and Minister of Finance Jim Flaherty, were criticized by some members of CAW Local 222 for not having visited a union-initiated illegal blockade of GM's corporate headquarters in Oshawa, when many other federal, provincial, and municipal politicians had done so.[5] Carrie also came under repeated fire from Local 222 President Chris Buckley, who told union members that Carrie had neglected to call until nearly two full days after GM's announcement. | https://www.wikidoc.org/index.php/Colin_Carrie | |
5cbcf3e254dcf99139a6573aba080c805ea998e1 | wikidoc | Collagenases | Collagenases
Collagenases are enzymes that break the peptide bonds in collagen.
They assist in destroying extracellular structures in pathogenesis of bacteria such as Clostridium. They are an exotoxin (a virulence factor) and help to facilitate the spread of gas gangrene. They normally target the connective tissue in muscle cells and other body organs.
Collagen, a key component of the animal extracellular matrix, is made through cleavage of pro-collagen by collagenase once it has been secreted from the cell. This stops large structures from forming inside the cell itself.
Collagenase production can be induced during an immune response, by cytokines which stimulate cells such as fibroblasts and osteoblasts, and cause indirect tissue damage.
SANTYL Ointment, a Healthpoint, Ltd. product, is the only FDA approved product containing Collagenase as its primary ingredient.
They are categorized under EC number 3.4.24. | Collagenases
Collagenases are enzymes that break the peptide bonds in collagen.
They assist in destroying extracellular structures in pathogenesis of bacteria such as Clostridium. They are an exotoxin (a virulence factor) and help to facilitate the spread of gas gangrene. They normally target the connective tissue in muscle cells and other body organs.[1]
Collagen, a key component of the animal extracellular matrix, is made through cleavage of pro-collagen by collagenase once it has been secreted from the cell. This stops large structures from forming inside the cell itself.
Collagenase production can be induced during an immune response, by cytokines which stimulate cells such as fibroblasts and osteoblasts, and cause indirect tissue damage.[citation needed]
SANTYL Ointment, a Healthpoint, Ltd. product, is the only FDA approved product containing Collagenase as its primary ingredient.
They are categorized under EC number 3.4.24. | https://www.wikidoc.org/index.php/Collagenases | |
4a09679a2430c38eed4693127b6d37169ea1696f | wikidoc | Color vision | Color vision
Color vision is the capacity of an organism or machine to distinguish objects based on the wavelengths (or frequencies) of the light they reflect or emit. The nervous system derives color by comparing the responses to light from the several types of cone photoreceptors in the eye. These cone photoreceptors are sensitive to different portions of the visible spectrum. For humans, the visible spectrum ranges approximately from 380 to 750 nm, and there are normally three types of cones. The visible range and number of cone types differ between species.
A 'red' apple does not emit red light. Rather, it simply absorbs all the frequencies of visible light shining on it except for a group of frequencies that is perceived as red, which are reflected. An apple is perceived to be red only because the human eye can distinguish between different wavelengths. Three things are needed to see color: a light source, a detector (e.g. the eye) and a sample to view.
The advantage of color, which is a quality constructed by the visual brain and not a property of objects as such, is the better discrimination of surfaces allowed by this aspect of visual processing.
In order for animals to respond accurately to their environments, their visual systems need to correctly interpret the form of objects around them. A major component of this is perception of colors.
# Physiology of color perception
Perception of color is achieved in mammals through color receptors containing pigments with different spectral sensitivities. In most primates closely related to humans there are three types of color receptors (known as cone cells). This confers trichromatic color vision, so these primates, like humans, are known as trichromats. Many other primates and other mammals are dichromats, and many mammals have little or no color vision.
In the human eye, the cones are maximally receptive to short, medium, and long wavelengths of light and are therefore usually called S-, M-, and L-cones. L-cones are often referred to as the red receptor, but while the perception of red depends on this receptor, microspectrophotometry has shown that its peak sensitivity is in the greenish-yellow region of the spectrum. Similarly, the S- and M-cones do not directly correspond to blue and green, although they are often depicted as such (such as in the graph to the right). It is important to note that the RGB color model is merely a convenient means for representing color, and is not directly based on the types of cones in the human eye.
The peak response of human color receptors varies, even amongst individuals with 'normal' color vision;
in non-human species this polymorphic variation is even greater, and it may well be adaptive.
## Cone cells in the human eye
A range of wavelengths of light stimulates each of these receptor types to varying degrees. Yellowish-green light, for example, stimulates both L and M cones equally strongly, but only stimulates S-cones weakly. Red light, on the other hand, stimulates L cones much more than M cones, and S cones hardly at all; blue-green light stimulates M cones more than L cones, and S cones a bit more strongly, and is also the peak stimulant for rod cells;
and violet light stimulates almost exclusively S-cones. The brain combines the information from each type of receptor to give rise to different perceptions of different wavelengths of light.
The pigments present in the L and M cones are encoded on the X chromosome; defective encoding of these leads to the two most common forms of color blindness. The OPN1LW gene, which codes for the pigment that responds to yellowish light, is highly polymorphic (a recent study by Verrelli and Tishkoff, 2004, found 85 variants in a sample of 236 men), so up to ten percent of women have an extra type of color receptor, and thus a degree of tetrachromatic color vision. Variations in OPN1MW, which codes for the bluish-green pigment, appear to be rare, and the observed variants have no effect on spectral sensitivity.
## Color in the human brain
Color processing begins at a very early level in the visual system (even within the retina) through initial color opponent mechanisms. Opponent mechanisms refer to the opposing color effect of red-green, blue-yellow, and light-dark. Visual information is then sent back via the optic nerve to the optic chiasm: a point where the two optic nerves meet and information from the temporal (contralateral) visual field crosses to the other side of the brain. After the optic chiasm the visual fiber tracts are referred to as the optic tracts, which enter the thalamus to synapse at the lateral geniculate nucleus (LGN). The LGN is segregated into six layers: two magnocellular (large cell) achromatic layers (M cells) and four parvocellular (small cell) chromatic layers (P cells). Within the LGN P-cell layers there are two chromatic opponent types: red vs. green and blue vs. green/red.
After synapsing at the LGN, the visual tract continues on back toward the primary visual cortex (V1) located at the back of the brain within the occipital lobe. Within V1 there is a distinct band (striation). This is also referred to as "striate cortex", with other cortical visual regions referred to collectively as "extrastriate cortex".It is at this stage that color processing becomes much more complicated.
In V1 the simple three-color segregation begins to break down. Many cells in V1 respond to some parts of the spectrum better than others, but this "color tuning" is often different depending on the adaptation state of the visual system. A given cell that might respond best to long wavelength light if the light is relatively bright might then become responsive to all wavelengths if the stimulus is relatively dim. Because the color tuning of these cells is not stable, some believe that a different, relatively small, population of neurons in V1 is responsible for color vision. These specialized "color cells" often have receptive fields that can compute local cone ratios. Such "double-opponent" cells were initially described in the goldfish retina by Nigel Daw; their existence in primates was suggested by David Hubel and Torsten Wiesel and subsequently proven by Bevil Conway. As Margaret Livingstone and David Hubel showed, double opponent cells are clustered within localized regions of V1 called blobs, and are thought to come in two flavors, red-green and blue-yellow. Red-green cells compare the relative amounts of red-green in one part of a scene with the amount of red-green in an adjacent part of the scene, responding best to local color contrast (red next to green). Modeling studies have shown that double-opponent cells are ideal candidates for the neural machinery of color constancy explained by Edwin H. Land in his retinex theory.
From the V1 blobs, color information is sent to cells in the second visual area, V2. The cells in V2 that are most strongly color tuned are clustered in the "thin stripes" that, like the blobs in V1, stain for the enzyme cytochrome oxidase (separating the thin stripes are interstripes and thick stripes, which seem to be concerned with other visual information like motion and high-resolution form). Neurons in V2 then synapse onto cells in area V4. Area V4 is a relatively large visual area, the largest by far cortical area outside V1, encompassing almost as much cortex as V1. Neurons in V4 were originally proposed by Semir Zeki to be exclusively dedicated to color, but this has since been shown not to be the case. Quantitative studies have argued that there is no higher concentration of color cells in V4 than in primary visual cortex, although this remains controversial. Independent of color sensitivity, V4 neurons have been shown to be very sensitive to the shape of stimuli, curvature, and stereo-scopic depth. V4 neurons have also been shown to be modulated by attention. The role of V4 neurons in color vision remains to be better characterized: indeed the vast majority of scientific papers examining the function of V4 do not concern color processing.
Anatomical studies have shown that neurons in V4 provide input to the inferior temporal lobe . "IT" cortex is thought to integrate color information with shape and form, although it has been difficult to define the appropriate criteria for this claim. Despite this murkiness, it has been useful to characterize this pathway (V1 > V2 > V4 > IT) as the ventral stream or the "what pathway", distinguished from the dorsal stream ("where pathway") that is thought to analyze motion, among many other features.
## In other animals
Other animals may have more complex color vision systems than humans (for review see Kelber et al. 2003). These are many tropical fish and birds. In the latter case tetrachromacy is achieved through up to four cone types, depending on species. Brightly colored oil droplets inside the cones shift or narrow the spectral sensitivity of the cell. It has been suggested that it is likely that pigeons are pentachromats. Mammals other than primates generally have less effective two-receptor color perception systems, allowing only dichromatic color vision; marine mammals have only a single cone type and are thus monochromats. Many invertebrates have color vision. Honey- and bumblebees have trichromatic color vision, which is insensitive to red but sensitive in ultraviolet to a color called bee purple. Papilio butterflies apparently have tetrachromatic color vision despite possessing six photoreceptor types (Arikawa 2003). The most complex color vision system in animal kingdom has been found in stomatopods with up to 12 different spectral receptor types (Cronin & Marshall 1989) which are thought to work as multiple dichromatic units.
# Evolution
Color perception mechanisms are highly dependent on evolutionary factors, of which the most prominent is thought to be satisfactory recognition of food sources. In herbivorous primates, color perception is essential for finding proper (mature) leaves. In hummingbirds, particular flower types are often recognized by color as well. On the other hand, nocturnal mammals have less-developed color vision, since adequate light is needed for cones to function properly. There is evidence that ultraviolet light plays a part in color perception in many branches of the animal kingdom, especially insects.
Trichromatic color vision evolved in the ancestors of modern monkeys, apes, and humans as they switched to diurnal (daytime) activity and consumption of fruits from flowering plants.
# Mathematics of color perception
A "physical color" is a combination of pure spectral colors (in the visible range). Since there are, in principle, infinitely many distinct spectral colors, the set of all physical colors may be thought of as an infinite-dimensional vector space, in fact a Hilbert space. We call this space Hcolor. More technically, the space of physical colors may be considered to be the (mathematical) cone over the simplex whose vertices are the spectral colors.
An element C of Hcolor is a function from the range of visible wavelengths—considered as an interval of real numbers —to the real numbers, assigning to each wavelength w in its intensity C(w).
A humanly perceived color may be modeled as three numbers: the extents to which each of the 3 types of cones is stimulated. Thus a humanly perceived color may be thought of as a point in 3-dimensional Euclidean space. We call this space R3color.
Since each wavelength w stimulates each of the 3 types of cone cells to a known extent, these extents may be represented by 3 functions s(w), m(w), l(w) corresponding to the response of the S, M, and L cone cells, respectively.
Finally, since a beam of colored light can be composed of many different wavelengths, to determine the extent to which a physical color C in Hcolor stimulates each cone cell, we must calculate the integral (with respect to w), over the interval , of C(w)*s(w), of C(w)*m(w), and of C(w)*b(w). The triple of resulting numbers associates to each physical color C (which is a region in Hcolor) to a particular perceived color (which is a single point in R3color). This association is easily seen to be linear. It may also easily be seen that many different regions in the "physical" space Hcolor can all result in the same single perceived color in R3color, so a perceived color is not unique to one physical color.
Thus human color perception is determined by a specific, non-unique linear mapping from the infinite-dimensional Hilbert space Hcolor to the 3-dimensional Euclidean space R3color.
Technically, the image of the (mathematical) cone over the simplex whose vertices are the spectral colors, by this linear mapping, is also a (mathematical) cone in R3color. Moving directly away from the vertex of this cone represents maintaining the same chromaticity while increasing its intensity. Taking a cross-section of this cone yields a 2D chromaticity space. Both the 3D cone and its projection or cross-section are convex sets; that is, any mixture of spectral colors is also a color.
In practice, it would be quite difficult to measure an individual's cones' three responses to various physical color stimuli. So instead, three specific benchmark test lights are typically used; let us call them S, M, and L. In order to calibrate human perceptual space, scientists allowed human subjects to try to match any physical color by turning dials to create specific combinations of intensities (IS, IM, IL) for the S, M, and L lights, resp., until a match was found. This needed only to be done for physical colors that are spectral (since a linear combination of spectral colors will be matched by the same linear combination of their (IS, IM, IL) matches). Note that in practice, often at least one of S, M, L would have to be added with some intensity to the physical test color, and that combination matched by a linear combination of the remaining 2 lights. Across different individuals (without color blindness), the matchings turned out to be nearly identical.
By considering all the resulting combinations of intensities (IS, IM, IL) as a subset of 3-space, a model for human perceptual color space is formed. (Note that when one of S, M, L had to be added to the test color, its intensity was counted as negative.) Again, this turns out to be a (mathematical) cone—not a quadric, but rather all rays through the origin in 3-space passing through a certain convex set. Again, this cone has the property that moving directly away from the origin corresponds to increasing the intensity of the S, M, L lights proportionately. Again, a cross-section of this cone is a planar shape that is (by definition) the space of "chromaticities" (informally: distinct colors); one particular such cross section, corresponding to constant X+Y+Z of the CIE 1931 color space, gives the CIE chromaticity diagram.
It should be noted that this system implies that for any hue or non-spectral color, there are infinitely many distinct physical spectra that are all perceived as that hue or color. So, in general there is no such thing as the combination of spectral colors that we perceive as (say) yellow-green; instead there are infinitely many possibilities.
The CIE chromaticity diagram is horseshoe-shaped, with its curved edge corresponding to all spectral colors (the spectral locus), and the remaining straight edge corresponding to the most saturated purples—mixtures of red and violet.
# Chromatic adaptation
An object may be viewed under various conditions. For example, it may be illuminated by sunlight, the light of a fire, or a harsh electric light. In all of these situations, human vision perceives that the object has the same color: an apple always appears red, whether viewed at night or during the day. On the other hand, a camera with no adjustment for light may register the apple as having varying color. This feature of the visual system is called chromatic adaptation, or color constancy; when the correction occurs in a camera it is referred to as white balance.
Chromatic adaptation is one aspect of vision that may fool someone into observing a color-based optical illusion, such as the same color illusion.
Though the human visual system generally does maintain constant perceived color under different lighting, there are situations where the relative brightness of two different stimuli will appear reversed at different illuminance levels. For example, the bright yellow petals of flowers will appear dark compared to the green leaves in dim light while the opposite is true during the day. This is known as the Purkinje effect, and arises because the peak sensitivity of the human eye shifts toward the blue end of the spectrum at lower light levels.
## Von Kries transform
The von Kries chromatic adaptation method is a technique that is sometimes used in camera image processing. The method is to apply a gain to each of the human cone cell spectral sensitivity responses so as to keep the adapted appearance of the reference white constant. The application of Johannes von Kries's idea of adaptive gains on the three cone cell types was first explicitly applied to the problem of color constancy by Herbert E. Ives, and the method is sometimes referred to as the Ives tranform or the von Kries–Ives adaptation.
The von Kries coefficient rule rests on the assumption that color constancy is achieved by individually adapting the gains of the three cone responses, the gains depending on the sensory context, that is, the color history and surround. Thus, the cone responses c' from two radiant spectra can be matched by appropriate choice of diagonal adaptation matrices D_1 and D_2:
where S is the cone sensitivity matrix and f is the spectrum of the conditioning stimulus. This leads to the von Kries transform for chromatic adaptation in LMS color space (responses of long-, medium-, and short-wavelength cone response space):
This diagonal matrix D maps cone responses, or colors, in one adaptation state to corresponding colors in another; when the adaptation state is presume to be determined by the illuminant, this matrix is useful as an illuminant adaptation transform. The elements of the diagonal matrix D are the ratios of the cone responses (Long, Medium, Short) for the illuminant's white point.
The more complete von Kries transform, for colors represented in XYZ or RGB color space, includes matrix transformations into and out of LMS space, with the diagonal transform D in the middle. | Color vision
Color vision is the capacity of an organism or machine to distinguish objects based on the wavelengths (or frequencies) of the light they reflect or emit. The nervous system derives color by comparing the responses to light from the several types of cone photoreceptors in the eye. These cone photoreceptors are sensitive to different portions of the visible spectrum. For humans, the visible spectrum ranges approximately from 380 to 750 nm, and there are normally three types of cones. The visible range and number of cone types differ between species.
A 'red' apple does not emit red light. Rather, it simply absorbs all the frequencies of visible light shining on it except for a group of frequencies that is perceived as red, which are reflected. An apple is perceived to be red only because the human eye can distinguish between different wavelengths. Three things are needed to see color: a light source, a detector (e.g. the eye) and a sample to view.
The advantage of color, which is a quality constructed by the visual brain and not a property of objects as such, is the better discrimination of surfaces allowed by this aspect of visual processing.
In order for animals to respond accurately to their environments, their visual systems need to correctly interpret the form of objects around them. A major component of this is perception of colors.
# Physiology of color perception
Perception of color is achieved in mammals through color receptors containing pigments with different spectral sensitivities. In most primates closely related to humans there are three types of color receptors (known as cone cells). This confers trichromatic color vision, so these primates, like humans, are known as trichromats. Many other primates and other mammals are dichromats, and many mammals have little or no color vision.
In the human eye, the cones are maximally receptive to short, medium, and long wavelengths of light and are therefore usually called S-, M-, and L-cones. L-cones are often referred to as the red receptor, but while the perception of red depends on this receptor, microspectrophotometry has shown that its peak sensitivity is in the greenish-yellow region of the spectrum. Similarly, the S- and M-cones do not directly correspond to blue and green, although they are often depicted as such (such as in the graph to the right). It is important to note that the RGB color model is merely a convenient means for representing color, and is not directly based on the types of cones in the human eye.
The peak response of human color receptors varies, even amongst individuals with 'normal' color vision;[1]
in non-human species this polymorphic variation is even greater, and it may well be adaptive.[2]
## Cone cells in the human eye
A range of wavelengths of light stimulates each of these receptor types to varying degrees. Yellowish-green light, for example, stimulates both L and M cones equally strongly, but only stimulates S-cones weakly. Red light, on the other hand, stimulates L cones much more than M cones, and S cones hardly at all; blue-green light stimulates M cones more than L cones, and S cones a bit more strongly, and is also the peak stimulant for rod cells;
and violet light stimulates almost exclusively S-cones. The brain combines the information from each type of receptor to give rise to different perceptions of different wavelengths of light.
The pigments present in the L and M cones are encoded on the X chromosome; defective encoding of these leads to the two most common forms of color blindness. The OPN1LW gene, which codes for the pigment that responds to yellowish light, is highly polymorphic (a recent study by Verrelli and Tishkoff, 2004, found 85 variants in a sample of 236 men), so up to ten percent of women[5] have an extra type of color receptor, and thus a degree of tetrachromatic color vision.[6] Variations in OPN1MW, which codes for the bluish-green pigment, appear to be rare, and the observed variants have no effect on spectral sensitivity.
## Color in the human brain
Color processing begins at a very early level in the visual system (even within the retina) through initial color opponent mechanisms. Opponent mechanisms refer to the opposing color effect of red-green, blue-yellow, and light-dark. Visual information is then sent back via the optic nerve to the optic chiasm: a point where the two optic nerves meet and information from the temporal (contralateral) visual field crosses to the other side of the brain. After the optic chiasm the visual fiber tracts are referred to as the optic tracts, which enter the thalamus to synapse at the lateral geniculate nucleus (LGN). The LGN is segregated into six layers: two magnocellular (large cell) achromatic layers (M cells) and four parvocellular (small cell) chromatic layers (P cells). Within the LGN P-cell layers there are two chromatic opponent types: red vs. green and blue vs. green/red.
After synapsing at the LGN, the visual tract continues on back toward the primary visual cortex (V1) located at the back of the brain within the occipital lobe. Within V1 there is a distinct band (striation). This is also referred to as "striate cortex", with other cortical visual regions referred to collectively as "extrastriate cortex".It is at this stage that color processing becomes much more complicated.
In V1 the simple three-color segregation begins to break down. Many cells in V1 respond to some parts of the spectrum better than others, but this "color tuning" is often different depending on the adaptation state of the visual system. A given cell that might respond best to long wavelength light if the light is relatively bright might then become responsive to all wavelengths if the stimulus is relatively dim. Because the color tuning of these cells is not stable, some believe that a different, relatively small, population of neurons in V1 is responsible for color vision. These specialized "color cells" often have receptive fields that can compute local cone ratios. Such "double-opponent" cells were initially described in the goldfish retina by Nigel Daw; their existence in primates was suggested by David Hubel and Torsten Wiesel and subsequently proven by Bevil Conway. As Margaret Livingstone and David Hubel showed, double opponent cells are clustered within localized regions of V1 called blobs, and are thought to come in two flavors, red-green and blue-yellow. Red-green cells compare the relative amounts of red-green in one part of a scene with the amount of red-green in an adjacent part of the scene, responding best to local color contrast (red next to green). Modeling studies have shown that double-opponent cells are ideal candidates for the neural machinery of color constancy explained by Edwin H. Land in his retinex theory.
From the V1 blobs, color information is sent to cells in the second visual area, V2. The cells in V2 that are most strongly color tuned are clustered in the "thin stripes" that, like the blobs in V1, stain for the enzyme cytochrome oxidase (separating the thin stripes are interstripes and thick stripes, which seem to be concerned with other visual information like motion and high-resolution form). Neurons in V2 then synapse onto cells in area V4. Area V4 is a relatively large visual area, the largest by far cortical area outside V1, encompassing almost as much cortex as V1. Neurons in V4 were originally proposed by Semir Zeki to be exclusively dedicated to color, but this has since been shown not to be the case. Quantitative studies have argued that there is no higher concentration of color cells in V4 than in primary visual cortex, although this remains controversial. Independent of color sensitivity, V4 neurons have been shown to be very sensitive to the shape of stimuli, curvature, and stereo-scopic depth. V4 neurons have also been shown to be modulated by attention. The role of V4 neurons in color vision remains to be better characterized: indeed the vast majority of scientific papers examining the function of V4 do not concern color processing.
Anatomical studies have shown that neurons in V4 provide input to the inferior temporal lobe . "IT" cortex is thought to integrate color information with shape and form, although it has been difficult to define the appropriate criteria for this claim. Despite this murkiness, it has been useful to characterize this pathway (V1 > V2 > V4 > IT) as the ventral stream or the "what pathway", distinguished from the dorsal stream ("where pathway") that is thought to analyze motion, among many other features.
## In other animals
Other animals may have more complex color vision systems than humans (for review see Kelber et al. 2003). These are many tropical fish and birds. In the latter case tetrachromacy is achieved through up to four cone types, depending on species. Brightly colored oil droplets inside the cones shift or narrow the spectral sensitivity of the cell. It has been suggested that it is likely that pigeons are pentachromats. Mammals other than primates generally have less effective two-receptor color perception systems, allowing only dichromatic color vision; marine mammals have only a single cone type and are thus monochromats. Many invertebrates have color vision. Honey- and bumblebees have trichromatic color vision, which is insensitive to red but sensitive in ultraviolet to a color called bee purple. Papilio butterflies apparently have tetrachromatic color vision despite possessing six photoreceptor types (Arikawa 2003). The most complex color vision system in animal kingdom has been found in stomatopods with up to 12 different spectral receptor types (Cronin & Marshall 1989) which are thought to work as multiple dichromatic units.
# Evolution
Color perception mechanisms are highly dependent on evolutionary factors, of which the most prominent is thought to be satisfactory recognition of food sources. In herbivorous primates, color perception is essential for finding proper (mature) leaves. In hummingbirds, particular flower types are often recognized by color as well. On the other hand, nocturnal mammals have less-developed color vision, since adequate light is needed for cones to function properly. There is evidence that ultraviolet light plays a part in color perception in many branches of the animal kingdom, especially insects.
Trichromatic color vision evolved in the ancestors of modern monkeys, apes, and humans as they switched to diurnal (daytime) activity and consumption of fruits from flowering plants.[7]
# Mathematics of color perception
A "physical color" is a combination of pure spectral colors (in the visible range). Since there are, in principle, infinitely many distinct spectral colors, the set of all physical colors may be thought of as an infinite-dimensional vector space, in fact a Hilbert space. We call this space Hcolor. More technically, the space of physical colors may be considered to be the (mathematical) cone over the simplex whose vertices are the spectral colors.
An element C of Hcolor is a function from the range of visible wavelengths—considered as an interval of real numbers [Wmin,Wmax]—to the real numbers, assigning to each wavelength w in [Wmin,Wmax] its intensity C(w).
A humanly perceived color may be modeled as three numbers: the extents to which each of the 3 types of cones is stimulated. Thus a humanly perceived color may be thought of as a point in 3-dimensional Euclidean space. We call this space R3color.
Since each wavelength w stimulates each of the 3 types of cone cells to a known extent, these extents may be represented by 3 functions s(w), m(w), l(w) corresponding to the response of the S, M, and L cone cells, respectively.
Finally, since a beam of colored light can be composed of many different wavelengths, to determine the extent to which a physical color C in Hcolor stimulates each cone cell, we must calculate the integral (with respect to w), over the interval [Wmin,Wmax], of C(w)*s(w), of C(w)*m(w), and of C(w)*b(w). The triple of resulting numbers associates to each physical color C (which is a region in Hcolor) to a particular perceived color (which is a single point in R3color). This association is easily seen to be linear. It may also easily be seen that many different regions in the "physical" space Hcolor can all result in the same single perceived color in R3color, so a perceived color is not unique to one physical color.
Thus human color perception is determined by a specific, non-unique linear mapping from the infinite-dimensional Hilbert space Hcolor to the 3-dimensional Euclidean space R3color.
Technically, the image of the (mathematical) cone over the simplex whose vertices are the spectral colors, by this linear mapping, is also a (mathematical) cone in R3color. Moving directly away from the vertex of this cone represents maintaining the same chromaticity while increasing its intensity. Taking a cross-section of this cone yields a 2D chromaticity space. Both the 3D cone and its projection or cross-section are convex sets; that is, any mixture of spectral colors is also a color.
In practice, it would be quite difficult to measure an individual's cones' three responses to various physical color stimuli. So instead, three specific benchmark test lights are typically used; let us call them S, M, and L. In order to calibrate human perceptual space, scientists allowed human subjects to try to match any physical color by turning dials to create specific combinations of intensities (IS, IM, IL) for the S, M, and L lights, resp., until a match was found. This needed only to be done for physical colors that are spectral (since a linear combination of spectral colors will be matched by the same linear combination of their (IS, IM, IL) matches). Note that in practice, often at least one of S, M, L would have to be added with some intensity to the physical test color, and that combination matched by a linear combination of the remaining 2 lights. Across different individuals (without color blindness), the matchings turned out to be nearly identical.
By considering all the resulting combinations of intensities (IS, IM, IL) as a subset of 3-space, a model for human perceptual color space is formed. (Note that when one of S, M, L had to be added to the test color, its intensity was counted as negative.) Again, this turns out to be a (mathematical) cone—not a quadric, but rather all rays through the origin in 3-space passing through a certain convex set. Again, this cone has the property that moving directly away from the origin corresponds to increasing the intensity of the S, M, L lights proportionately. Again, a cross-section of this cone is a planar shape that is (by definition) the space of "chromaticities" (informally: distinct colors); one particular such cross section, corresponding to constant X+Y+Z of the CIE 1931 color space, gives the CIE chromaticity diagram.
It should be noted that this system implies that for any hue or non-spectral color, there are infinitely many distinct physical spectra that are all perceived as that hue or color. So, in general there is no such thing as the combination of spectral colors that we perceive as (say) yellow-green; instead there are infinitely many possibilities.
The CIE chromaticity diagram is horseshoe-shaped, with its curved edge corresponding to all spectral colors (the spectral locus), and the remaining straight edge corresponding to the most saturated purples—mixtures of red and violet.
# Chromatic adaptation
An object may be viewed under various conditions. For example, it may be illuminated by sunlight, the light of a fire, or a harsh electric light. In all of these situations, human vision perceives that the object has the same color: an apple always appears red, whether viewed at night or during the day. On the other hand, a camera with no adjustment for light may register the apple as having varying color. This feature of the visual system is called chromatic adaptation, or color constancy; when the correction occurs in a camera it is referred to as white balance.
Chromatic adaptation is one aspect of vision that may fool someone into observing a color-based optical illusion, such as the same color illusion.
Though the human visual system generally does maintain constant perceived color under different lighting, there are situations where the relative brightness of two different stimuli will appear reversed at different illuminance levels. For example, the bright yellow petals of flowers will appear dark compared to the green leaves in dim light while the opposite is true during the day. This is known as the Purkinje effect, and arises because the peak sensitivity of the human eye shifts toward the blue end of the spectrum at lower light levels.
Template:Splitsection
## Von Kries transform
The von Kries chromatic adaptation method is a technique that is sometimes used in camera image processing. The method is to apply a gain to each of the human cone cell spectral sensitivity responses so as to keep the adapted appearance of the reference white constant. The application of Johannes von Kries's idea of adaptive gains on the three cone cell types was first explicitly applied to the problem of color constancy by Herbert E. Ives,[8][9] and the method is sometimes referred to as the Ives tranform[10] or the von Kries–Ives adaptation.[11]
The von Kries coefficient rule rests on the assumption that color constancy is achieved by individually adapting the gains of the three cone responses, the gains depending on the sensory context, that is, the color history and surround. Thus, the cone responses <math>c'</math> from two radiant spectra can be matched by appropriate choice of diagonal adaptation matrices <math>D_1</math> and <math>D_2</math>[12]:
where <math>S</math> is the cone sensitivity matrix and <math>f</math> is the spectrum of the conditioning stimulus. This leads to the von Kries transform for chromatic adaptation in LMS color space (responses of long-, medium-, and short-wavelength cone response space):
This diagonal matrix D maps cone responses, or colors, in one adaptation state to corresponding colors in another; when the adaptation state is presume to be determined by the illuminant, this matrix is useful as an illuminant adaptation transform. The elements of the diagonal matrix D are the ratios of the cone responses (Long, Medium, Short) for the illuminant's white point.
The more complete von Kries transform, for colors represented in XYZ or RGB color space, includes matrix transformations into and out of LMS space, with the diagonal transform D in the middle.[13] | https://www.wikidoc.org/index.php/Color_perception | |
9290d1d1a2d22599ace58219a1499ed31f65f038 | wikidoc | Vaginoplasty | Vaginoplasty
# Overview
Vaginoplasty is any surgical procedure whose purpose is to treat vaginal structural defects, affect aesthetic considerations, or to partially or totally construct or reconstruct a vagina. The term vaginoplasty is used to describe any such vaginal surgery, while the term neovaginoplasty is more specifically used to refer to procedures of partial or total construction or reconstruction of the vulvovaginal complex.
There are many different vaginoplasty techniques. Some involve the use of autologous biological tissue from other parts of the body of the patient to construct areas of vagina. Areas that may be used include oral mucosa, skin flaps, skin grafts, the vaginal labia, penile skin and/or tissue, scrotal skin, intestinal mucosa, and others.
# Neovaginoplasty
Neovaginoplasty is a reconstructive surgery procedure used to construct or reconstruct a vaginal canal and mucous membrane. These may be absent in a woman, due either to congenital disease such as vaginal atresia or to an acquired cause, such as trauma or cancer. Some transwomen opt for vaginoplasty as part of their gender transition.
The outcome of neovaginoplasty is variable. It usually allows sexual intercourse, although sensation is not always present. In genetic women, menstruation and fertilization are assured when the uterus and ovaries have preserved a normal function. In a few cases, vaginal childbirth is possible.
# Male-to female transsexual patients
Most neovaginoplasty procedures are performed on transsexual women. The penile inversion technique was perfected by the late Georges Burou during his pioneering work in sex reassignment surgery.
For the creation of the male-to-female neovagina, there is also the possibility of using penile skin flaps (so-called penile inversion), as well as the "Suporn technique" and "Wilson method".
In the 1990s and continuing to the present, neovaginal construction has been further advanced by Toby R. Meltzer, M.D., whose technique involves the use of both penile and scrotal tissue to form the vaginal vault, and has yielded more reliable sexual sensation, maintenance of vaginal depth, and a stronger pelvic floor by maintaining a nearly intact levitor ani muscle complex.
Meltzer creates a neurologically sensate clitoris, constructed from a penile glans pedicle, with its attached blood supply and nerves. During a secondary procedure using Meltzer's technique, he forms a labia hood for the clitoris using the inverted Y plasty suturing method, leaving only a single midline incision scar.
When the transwoman is ready, there are two steps to Sexual Reassignment Surgery. The first procedure is called Vaginoplasty. Vaginoplasty is the procedure that essentially turns the penis into the vagina. It is often followed several months later by the Labiaplasty. The Labiaplasty refines the labia or external female genitalia.
During Vaginoplasty "the right spermatic cord is clamped and ligated. The primary incision is continued up the ventral side of the shaft of the penis. the anterior flap is developed from the skin of the penis. The urethra is dissected from the shaft. The corpora cavernosa are separated to assure a minimal stump. the anterior flap perforated to position the urethral meatus. The skin flaps are sutured and placed in position in the vaginal cavity. , the preservation of the vaginal cavity is assured by the use of a suitable vaginal form." Finally the vagina is complete.
When a patient receives Labiaplasty, a frequently used procedure, labia and a clitoral hood are created. This is often performed a few months after the first part of the procedure. In some cases, labiaplasty is an elective procedure to improve appearance after a one-stage Vaginoplasty. Labiaplasty (2000).
Even after SRS there are many complications that range from minor to major. There are the minor complications which include infections, bleeding and loss of grafted skin. "The more serious complications include major infections or bleeding, and damage to the bladder. There is a possibility of damage to the prostate or major nerves during the dissection to form the vagina."
While undergoing this surgery the most severe complication is the formation of a vaginal-rectal fistula. This occurs when the doctor accidentally cuts through the rectal wall during vaginal cavity dissection. As a result, excrement bypasses the anal stricture and exits through the vagina. This prevents proper healing. This process can be remedied through a long process of surgeries and many months of wearing of a colostomy bag. Because of the embarrassment, the complication often goes untreated, leading to serious infections.
# The Vecchietti procedure
The Vecchietti procedure is a laparoscopic procedure that has been shown to result in a vagina that is comparable to a normal vagina in patients with Mullerian agenesis.
# Colovaginoplasty
With colovaginoplasty, sometimes called a colon section, a vagina is created by cutting away a section of the sigmoid colon and using it to form a vaginal lining.
This surgery is performed on females with androgen insensitivity syndrome, congenital adrenal hyperplasia, vaginal agenesis, Müllerian agenesis, and other intersexed conditions, where non-invasive forms of lengthening the vagina cannot be done and, mostly, on male-to-female transsexuals as an alternative to penile inversion with or without an accompanying skin graft (usually from either the thigh or abdomen).
Due to numerous potential complications (such as diversion colitis) most surgeons will recommend a colovaginoplasty only when there is no alternative.
# Penile inversion
Penile inversion is a surgical technique for genital reassignment (sex change) used to construct a neo-vagina from a penis for transwomen, sometimes also for intersex people. It is one of two main sorts of vaginoplasty, along with colovaginoplasty.
The erectile tissue of the penis is removed, and the skin, with its blood and nerve supplies still attached (a flap technique first used by Sir Harold Gillies in 1951), is used to create a vestibule area and labia minora, and inverted into a cavity created in the pelvic tissue. Part of the tip (glans) of the penis, still connected to its blood and nerve supplies, is usually used to construct a clitoris, the urethra is shortened to end at a place that is appropriate for a female anatomy.
# Neoclitoris
There are two ways to create a clitoris for a transsexual woman. The most common method is to remove the head or glans of the penis, and use some of that tissue to function in the position of a biological woman's clitoris. Some transsexual women have the entire penis head used as their clitoris. Some transsexual women have spongiform from their urethras to function as the neoclitoris. The success rate for the creation of a clitoris for transsexual women varies greatly. If the relocation of the glans penis is successful then the transsexual woman may have a sensate neoclitoris capable of orgasm. The glans penis tissue does not resemble a biological woman's clitoris. Most transsexual women's bodies readily accept the relocation of glans penile tissue in the area of a biological woman's clitoris. However, as with all surgeries nothing is perfect and there have been cases of the glans penis neoclitoris bleeding and even falling off entirely. There are many SRS surgeons who do not attempt any creation of a neoclitoris for their transsexual patients. Instead they allow the transwoman to orgasm with the penile lined vagina. Some SRS surgeons do not agree with using the head of the penis to create a neoclitoris. They prefer to either use urethral spongiform or make no attempt at the creation of a clitoris at all. Some SRS surgeons take the head of the penis and surgically place it inside the body in the position of a cervix. The late Stanley Biber preferred this method. Many transsexual women like the glans penis being inside their bodies because it can be greatly stimulated during vaginal penetration. The transsexual activist and playwright Kate Bornstein has indicated in her book 'Gender Outlaw: On Men, Women and The Rest Of Us' that her glans penis was placed inside her body in the position of a cervix. She reports enjoying vaginal penetration and that the use of dildos greatly stimulates her now internalized penis head.
# Related procedures
## Labioplasty
Labiaplasty is a plastic surgery procedure involving the labia, any of four folds of tissue of the vulva. Labiaplasty may be performed alone or as part of vaginoplasty.
Labiaplasty - Cosmetic Vaginal Surgery (sometimes spelled labioplasty ) is plastic surgery of the Labia majora and/or the Labia minora, the external folds of the female genital organs (Vulva). The procedure involves reshaping or reduction of the labia. Labiaplasty is a plastic surgery procedure involving the labia, any of four folds of tissue of the vulva . Labiaplasty may be performed alone or as part of vaginoplasty.
Labiaplasty may be undertaken for functional reasons, aesthetic reasons, or a combination of the two, although the cosmetic surgery's definition of "functional reasons" has yet to be explained to the rest of society: having large labia does not prevent the "function" of the vagina, and in fact because labiaplasty can make sex painful and prevent orgasm, labiaplasty can actually decrease the functionality of the vagina for sexual pleasure. The procedure is frequently performed to reduce the size of one or both sets of labia. It may also be used to repair the labia following disease or injury, or to reshape after childbirth. Labiaplasty does not improve the "function" of the vagina, but can in fact decrease or eliminate sensory perception of the genitals. Complications from the surgery, outside of those complications from any surgery (scarring, infection), include a loss of sensation of the clitoris, an inability to achieve orgasm, and pain from intercourse.
Labia Majora (outer lips) Reduction - This common anatomical variation may be worsened by childbirth or by weight gain or loss. The Labia Majora may become stretched out, most commonly in the shape of flaps or "wings".
Labia Minora (inner lips) Reduction - Cosmetic surgeons say that overly large labia minora can also result in constant irritation in tight pants, though this has largely been descried as myth by medical professionals.
Women are often pressured into having labiaplasty by partners who are confused about the realistic proportions of unique women; because the side effects can be so devastating (including loss of sensation or pain during sex), most medical professionals who do not have a financial stake in cosmetic surgery advise against the procedure at all costs.
## "Vaginal rejuvenation"
Non-reconstructive vaginoplasty or "vaginal rejuvenation" is used to restore vaginal tone and appearance, largely by removing excess tissue and tightening supportive structures. The popularity of surgery to improve the cosmetic appearance of a female's genitalia has increased in North America over the last few years. The term "designer vagina" refers to an idealized image of female sex organs attained through vaginoplasty. In recent years laser has been introduced to assist in the procedure. The rejuvenation procedure is intended to reduce or undo effects of age and childbearing. The American College of Obstetricians and Gynecologists, however, warns that this procedure lacks supporting data regarding safety and efficacy. Indeed, vaginal rejuvenation surgery can lead to decreased sensory perception of the clitoris and the rest of the genital area, potentially to such an extent as to prevent the possibility of orgasm, and can lead to complications such as infection, adhesions, and scarring.
# Terminology
The term vaginoplasty has also been applied to:
- Hymenotomy, a surgical procedure to create an opening in an imperforate hymen
- Hymenorrhaphy, a surgical procedure to recreate a ruptured hymen. | Vaginoplasty
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2]
# Overview
Vaginoplasty is any surgical procedure whose purpose is to treat vaginal structural defects, affect aesthetic considerations, or to partially or totally construct or reconstruct a vagina. The term vaginoplasty is used to describe any such vaginal surgery, while the term neovaginoplasty is more specifically used to refer to procedures of partial or total construction or reconstruction of the vulvovaginal complex.
There are many different vaginoplasty techniques. Some involve the use of autologous biological tissue from other parts of the body of the patient to construct areas of vagina. Areas that may be used include oral mucosa, skin flaps, skin grafts, the vaginal labia, penile skin and/or tissue, scrotal skin, intestinal mucosa, and others.
# Neovaginoplasty
Neovaginoplasty is a reconstructive surgery procedure used to construct or reconstruct a vaginal canal and mucous membrane. These may be absent in a woman, due either to congenital disease such as vaginal atresia or to an acquired cause, such as trauma or cancer. Some transwomen opt for vaginoplasty as part of their gender transition.
The outcome of neovaginoplasty is variable. It usually allows sexual intercourse, although sensation is not always present. In genetic women, menstruation and fertilization are assured when the uterus and ovaries have preserved a normal function. In a few cases, vaginal childbirth is possible.
# Male-to female transsexual patients
Most neovaginoplasty procedures are performed on transsexual women. The penile inversion technique was perfected by the late Georges Burou during his pioneering work in sex reassignment surgery.
For the creation of the male-to-female neovagina, there is also the possibility of using penile skin flaps (so-called penile inversion), as well as the "Suporn technique" and "Wilson method".
In the 1990s and continuing to the present, neovaginal construction has been further advanced by Toby R. Meltzer, M.D., whose technique involves the use of both penile and scrotal tissue to form the vaginal vault, and has yielded more reliable sexual sensation, maintenance of vaginal depth, and a stronger pelvic floor by maintaining a nearly intact levitor ani muscle complex.[1]
Meltzer creates a neurologically sensate clitoris, constructed from a penile glans pedicle, with its attached blood supply and nerves. During a secondary procedure using Meltzer's technique, he forms a labia hood for the clitoris using the inverted Y plasty suturing method, leaving only a single midline incision scar.[2][3]
When the transwoman is ready, there are two steps to Sexual Reassignment Surgery. The first procedure is called Vaginoplasty. Vaginoplasty is the procedure that essentially turns the penis into the vagina. It is often followed several months later by the Labiaplasty. The Labiaplasty refines the labia or external female genitalia.
During Vaginoplasty "the right spermatic cord is clamped and ligated. The primary incision is continued up the ventral side of the shaft of the penis. [Then] the anterior flap is developed from the skin of the penis. The urethra is dissected from the shaft. The corpora cavernosa are separated to assure a minimal stump. [After that] the anterior flap [is] perforated to position the urethral meatus. The skin flaps are sutured and placed in position in the vaginal cavity. [When that is completed], the preservation of the vaginal cavity is assured by the use of a suitable vaginal form." Finally the vagina is complete.
When a patient receives Labiaplasty, a frequently used procedure, labia and a clitoral hood are created. This is often performed a few months after the first part of the procedure. In some cases, labiaplasty is an elective procedure to improve appearance after a one-stage Vaginoplasty. Labiaplasty (2000).
Even after SRS there are many complications that range from minor to major. There are the minor complications which include infections, bleeding and loss of grafted skin. "The more serious complications include major infections or bleeding, and damage to the bladder. There is a possibility of damage to the prostate or major nerves during the dissection to form the vagina."
While undergoing this surgery the most severe complication is the formation of a vaginal-rectal fistula. This occurs when the doctor accidentally cuts through the rectal wall during vaginal cavity dissection. As a result, excrement bypasses the anal stricture and exits through the vagina. This prevents proper healing. This process can be remedied through a long process of surgeries and many months of wearing of a colostomy bag. Because of the embarrassment, the complication often goes untreated, leading to serious infections.[3]
# The Vecchietti procedure
The Vecchietti procedure is a laparoscopic procedure that has been shown to result in a vagina that is comparable to a normal vagina in patients with Mullerian agenesis.[4][5]
# Colovaginoplasty
With colovaginoplasty, sometimes called a colon section, a vagina is created by cutting away a section of the sigmoid colon and using it to form a vaginal lining.
This surgery is performed on females with androgen insensitivity syndrome, congenital adrenal hyperplasia, vaginal agenesis, Müllerian agenesis, and other intersexed conditions, where non-invasive forms of lengthening the vagina cannot be done and, mostly, on male-to-female transsexuals as an alternative to penile inversion with or without an accompanying skin graft (usually from either the thigh or abdomen).
Due to numerous potential complications (such as diversion colitis) most surgeons will recommend a colovaginoplasty only when there is no alternative.
# Penile inversion
Penile inversion is a surgical technique for genital reassignment (sex change) used to construct a neo-vagina from a penis for transwomen, sometimes also for intersex people. It is one of two main sorts of vaginoplasty, along with colovaginoplasty.
The erectile tissue of the penis is removed, and the skin, with its blood and nerve supplies still attached (a flap technique first used by Sir Harold Gillies in 1951), is used to create a vestibule area and labia minora, and inverted into a cavity created in the pelvic tissue. Part of the tip (glans) of the penis, still connected to its blood and nerve supplies, is usually used to construct a clitoris, the urethra is shortened to end at a place that is appropriate for a female anatomy.
# Neoclitoris
There are two ways to create a clitoris for a transsexual woman. The most common method is to remove the head or glans of the penis, and use some of that tissue to function in the position of a biological woman's clitoris. Some transsexual women have the entire penis head used as their clitoris. Some transsexual women have spongiform from their urethras to function as the neoclitoris. The success rate for the creation of a clitoris for transsexual women varies greatly. If the relocation of the glans penis is successful then the transsexual woman may have a sensate neoclitoris capable of orgasm. The glans penis tissue does not resemble a biological woman's clitoris. Most transsexual women's bodies readily accept the relocation of glans penile tissue in the area of a biological woman's clitoris. However, as with all surgeries nothing is perfect and there have been cases of the glans penis neoclitoris bleeding and even falling off entirely. There are many SRS surgeons who do not attempt any creation of a neoclitoris for their transsexual patients. Instead they allow the transwoman to orgasm with the penile lined vagina. Some SRS surgeons do not agree with using the head of the penis to create a neoclitoris. They prefer to either use urethral spongiform or make no attempt at the creation of a clitoris at all. Some SRS surgeons take the head of the penis and surgically place it inside the body in the position of a cervix. The late Stanley Biber preferred this method. Many transsexual women like the glans penis being inside their bodies because it can be greatly stimulated during vaginal penetration. The transsexual activist and playwright Kate Bornstein has indicated in her book 'Gender Outlaw: On Men, Women and The Rest Of Us' that her glans penis was placed inside her body in the position of a cervix. She reports enjoying vaginal penetration and that the use of dildos greatly stimulates her now internalized penis head.
# Related procedures
## Labioplasty
Labiaplasty is a plastic surgery procedure involving the labia, any of four folds of tissue of the vulva. Labiaplasty may be performed alone or as part of vaginoplasty.
Labiaplasty - Cosmetic Vaginal Surgery (sometimes spelled labioplasty ) is plastic surgery of the Labia majora and/or the Labia minora, the external folds of the female genital organs (Vulva). The procedure involves reshaping or reduction of the labia. Labiaplasty is a plastic surgery procedure involving the labia, any of four folds of tissue of the vulva . Labiaplasty may be performed alone or as part of vaginoplasty.
Labiaplasty may be undertaken for functional reasons, aesthetic reasons, or a combination of the two, although the cosmetic surgery's definition of "functional reasons" has yet to be explained to the rest of society: having large labia does not prevent the "function" of the vagina, and in fact because labiaplasty can make sex painful and prevent orgasm, labiaplasty can actually decrease the functionality of the vagina for sexual pleasure. The procedure is frequently performed to reduce the size of one or both sets of labia. It may also be used to repair the labia following disease or injury, or to reshape after childbirth. Labiaplasty does not improve the "function" of the vagina, but can in fact decrease or eliminate sensory perception of the genitals. Complications from the surgery, outside of those complications from any surgery (scarring, infection), include a loss of sensation of the clitoris, an inability to achieve orgasm, and pain from intercourse.
Labia Majora (outer lips) Reduction - This common anatomical variation may be worsened by childbirth or by weight gain or loss. The Labia Majora may become stretched out, most commonly in the shape of flaps or "wings".
Labia Minora (inner lips) Reduction - Cosmetic surgeons say that overly large labia minora can also result in constant irritation in tight pants, though this has largely been descried as myth by medical professionals.
Women are often pressured into having labiaplasty by partners who are confused about the realistic proportions of unique women; because the side effects can be so devastating (including loss of sensation or pain during sex), most medical professionals who do not have a financial stake in cosmetic surgery advise against the procedure at all costs.
## "Vaginal rejuvenation"
Non-reconstructive vaginoplasty or "vaginal rejuvenation" is used to restore vaginal tone and appearance, largely by removing excess tissue and tightening supportive structures. The popularity of surgery to improve the cosmetic appearance of a female's genitalia has increased in North America over the last few years. The term "designer vagina" refers to an idealized image of female sex organs attained through vaginoplasty. In recent years laser has been introduced to assist in the procedure. The rejuvenation procedure is intended to reduce or undo effects of age and childbearing. The American College of Obstetricians and Gynecologists, however, warns that this procedure lacks supporting data regarding safety and efficacy.[6] Indeed, vaginal rejuvenation surgery can lead to decreased sensory perception of the clitoris and the rest of the genital area, potentially to such an extent as to prevent the possibility of orgasm, and can lead to complications such as infection, adhesions, and scarring.[7]
# Terminology
The term vaginoplasty has also been applied to:
- Hymenotomy, a surgical procedure to create an opening in an imperforate hymen
- Hymenorrhaphy, a surgical procedure to recreate a ruptured hymen. | https://www.wikidoc.org/index.php/Colovaginoplasty | |
f66b696ae7d82421193590472418d0a1c2ba37dd | wikidoc | Nasal septum | Nasal septum
The nasal septum separates the left and right airways in the nose, dividing the two nostrils.
It is depressed by the Depressor septi nasi muscle.
# Composition
The fleshy external end of the nasal septum is sometimes also called columella.
The nasal septum is composed of three structures:
- ethmoid bone
- vomer bone
- quadrangular cartilage
# Clinical significance
The nasal septum can depart from the centreline of the nose; this condition is known as a deviated septum. Trauma, excessive nose-picking and cocaine usage can cause septum perforations, or holes developing in the septum.
An operation to the nasal septum is known as a septoplasty.
# Additional images
- Horizontal section of nasal and orbital cavities.
- Left orbicularis oculi, seen from behind.
- Cartilages of the nose, seen from below.
- Coronal section of nasal cavities.
- Front of nasal part of pharynx, as seen with the laryngoscope.
- MRI image showing nasal septum. | Nasal septum
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The nasal septum separates the left and right airways in the nose, dividing the two nostrils.
It is depressed by the Depressor septi nasi muscle.
# Composition
The fleshy external end of the nasal septum is sometimes also called columella.
The nasal septum is composed of three structures:
- ethmoid bone
- vomer bone
- quadrangular cartilage
# Clinical significance
The nasal septum can depart from the centreline of the nose; this condition is known as a deviated septum. Trauma, excessive nose-picking and cocaine usage can cause septum perforations, or holes developing in the septum.
An operation to the nasal septum is known as a septoplasty.
# Additional images
- Horizontal section of nasal and orbital cavities.
- Left orbicularis oculi, seen from behind.
- Cartilages of the nose, seen from below.
- Coronal section of nasal cavities.
- Front of nasal part of pharynx, as seen with the laryngoscope.
- MRI image showing nasal septum. | https://www.wikidoc.org/index.php/Columella | |
c45e5974c092463786b9d1db22c46f6df87c092b | wikidoc | Combat medic | Combat medic
A combat medic is a trained soldier who is responsible for providing first aid and frontline trauma care on the battlefield. Also responsible for providing continuing medical care in the absence of a readily available physician, including care for disease and non battle injury. Combat medics are normally co-located with the combat troops they serve in order to easily move with the troops and monitor ongoing health.
Combat medics are officially known by a variety of names. In the United States Army, medics have often been called 68Ws since December of 2005. In the United States Navy, they are known as Corpsmen and fill the combat medic role of the United States Marine Corps, which does not have its own medical personnel. Combat Medical Technicians (CMTs) in the British Army are members of the Royal Army Medical Corps.
In most armies, medics wear specific insignia, with a prominent Red Cross on a white background. Islamic countries use a red crescent instead while Israeli medics wear the Magen David Adom (a red star of David on a white background). These symbols signify to enemy soldiers that the medic is a noncombatant, providing medical care. For many years, most medics have carried at least a side arm like the handgun and knife (and now, frequently a rifle, carbine or submachine gun), to be used as a defensive weapon. Medical personnel may be armed, but may only use their weapons to protect themselves or the wounded and sick in their care. If they use their arms offensively (i.e. attacking or assaulting), or carry arms that qualify as offensive (such as a sniper rifle, machine gun or grenade launcher), they then sacrifice their protection under the Geneva Conventions. Generally, a medic holding his/her weapon is considered to be an armed, military threat. According to the Geneva Convention, knowingly firing at a medic wearing clear insignia is a war crime.
# History
During World War II (and before the implementation of the 1949 revision to the Geneva Convention made it illegal), there was an unwritten law of ethics between Allied and German forces whereby soldiers would not knowingly fire at a medic treating a wounded comrade. This was in stark contrast to the policy of the Japanese forces, who regarded medics as primary targets, resulting in Allied medics removing or covering their insignia. | Combat medic
A combat medic is a trained soldier who is responsible for providing first aid and frontline trauma care on the battlefield. Also responsible for providing continuing medical care in the absence of a readily available physician, including care for disease and non battle injury. Combat medics are normally co-located with the combat troops they serve in order to easily move with the troops and monitor ongoing health.
Combat medics are officially known by a variety of names. In the United States Army, medics have often been called 68Ws since December of 2005. In the United States Navy, they are known as Corpsmen and fill the combat medic role of the United States Marine Corps, which does not have its own medical personnel. Combat Medical Technicians (CMTs) in the British Army are members of the Royal Army Medical Corps.
In most armies, medics wear specific insignia, with a prominent Red Cross on a white background. Islamic countries use a red crescent instead while Israeli medics wear the Magen David Adom (a red star of David on a white background). These symbols signify to enemy soldiers that the medic is a noncombatant, providing medical care. For many years, most medics have carried at least a side arm like the handgun and knife (and now, frequently a rifle, carbine or submachine gun), to be used as a defensive weapon. Medical personnel may be armed, but may only use their weapons to protect themselves or the wounded and sick in their care. If they use their arms offensively (i.e. attacking or assaulting), or carry arms that qualify as offensive (such as a sniper rifle, machine gun or grenade launcher), they then sacrifice their protection under the Geneva Conventions. Generally, a medic holding his/her weapon is considered to be an armed, military threat. According to the Geneva Convention, knowingly firing at a medic wearing clear insignia is a war crime.
# History
During World War II (and before the implementation of the 1949 revision to the Geneva Convention made it illegal), there was an unwritten law of ethics between Allied and German forces whereby soldiers would not knowingly fire at a medic treating a wounded comrade. This was in stark contrast to the policy of the Japanese forces, who regarded medics as primary targets, resulting in Allied medics removing or covering their insignia. | https://www.wikidoc.org/index.php/Combat_medic | |
e9f62171a73f7a2dc3bbc34d4861d1996ea28263 | wikidoc | Commensalism | Commensalism
Commensalisms is a term employed in ecology to describe a relationship between two living organisms where one benefits and the other is not significantly harmed or helped (like a bird living in a tree). It is derived from the English word commensal, meaning the sharing of food, and used of human social interaction. The word derives from the Latin com mensa, meaning sharing a table.
As with all ecological interactions, commensalisms vary in strength and duration from intimate, long-lived symbioses to brief, weak interactions through intermediaries. Originally it was used to describe the use of waste food by second animals, like the carcass eaters that follow hunting animals, but wait until they have finished their meal. Other forms of commensalism include:
- Phoresy: One animal attaching to another animal for transportation only. This concerns mainly arthropods, examples of which are mites on insects (such as beetles, flies, or bees), pseudoscorpions on mammals and millipedes on birds. Phoresy can be either obligate or facultative (induced by environmental conditions).
- Inquilinism: Using a second organism for housing. Examples are epiphytic plants (such as many orchids) which grow on trees, or birds that live in holes in trees.
- Metabiosis: A more indirect dependency, in which the second organism uses something the first created, however after the death of the first. An example is the hermit crabs that use gastropod shells to protect their bodies.
The question of whether the relationship between humans and some types of our gut flora is commensal or mutualistic is still unanswered.
Some biologists argue that any close interaction between two organisms is unlikely to be completely neutral for either party, and that relationships identified as commensal are likely mutualistic or parasitic in a subtle way that has not been detected. For example, epiphytes are "nutritional pirates" that may intercept substantial amounts of mineral nutrients that would otherwise go to the host plant. Large numbers of epiphytes can also cause tree limbs to break or shade the host plant and reduce its rate of photosynthesis. Similarly, the phoretic mites in the image above may hinder their host by making flight more difficult, which may affect its aerial hunting ability or cause it to expend extra energy while carrying these passengers. | Commensalism
Commensalisms is a term employed in ecology to describe a relationship between two living organisms where one benefits and the other is not significantly harmed or helped (like a bird living in a tree). It is derived from the English word commensal, meaning the sharing of food, and used of human social interaction. The word derives from the Latin com mensa, meaning sharing a table.
As with all ecological interactions, commensalisms vary in strength and duration from intimate, long-lived symbioses to brief, weak interactions through intermediaries. Originally it was used to describe the use of waste food by second animals, like the carcass eaters that follow hunting animals, but wait until they have finished their meal. Other forms of commensalism include:
- Phoresy: One animal attaching to another animal for transportation only. This concerns mainly arthropods, examples of which are mites on insects (such as beetles, flies, or bees), pseudoscorpions on mammals[1] and millipedes on birds.[2] Phoresy can be either obligate or facultative (induced by environmental conditions).
- Inquilinism: Using a second organism for housing. Examples are epiphytic plants (such as many orchids) which grow on trees, or birds that live in holes in trees.
- Metabiosis: A more indirect dependency, in which the second organism uses something the first created, however after the death of the first. An example is the hermit crabs that use gastropod shells to protect their bodies.
The question of whether the relationship between humans and some types of our gut flora is commensal or mutualistic is still unanswered.
Some biologists argue that any close interaction between two organisms is unlikely to be completely neutral for either party, and that relationships identified as commensal are likely mutualistic or parasitic in a subtle way that has not been detected. For example, epiphytes are "nutritional pirates" that may intercept substantial amounts of mineral nutrients that would otherwise go to the host plant.[3] Large numbers of epiphytes can also cause tree limbs to break or shade the host plant and reduce its rate of photosynthesis. Similarly, the phoretic mites in the image above may hinder their host by making flight more difficult, which may affect its aerial hunting ability or cause it to expend extra energy while carrying these passengers. | https://www.wikidoc.org/index.php/Commensal | |
91ed6e1cdd3c3594e1805280ece5b392acfa8435 | wikidoc | Common Lilac | Common Lilac
The Common Lilac (Syringa vulgaris) is a deciduous plant in the olive family (Oleaceae), native to the Balkan Peninsula in southeastern Europe, where it grows in the wild on rocky hills.
It is a large shrub or small tree, growing 6-7 m high. The smooth bark is grey to grey-brown. The shrubs are multi-stemmed, producing secondary shoots from the base or roots.
The leaves are simple, light green to glaucous, oval to cordate, with pinnate leaf venation, a mucronate apex and an entire margin, reaching a length of 5-10 cm. They are arranged opposite pairs or occasionally in whorls of three.
The four-petaled flowers are cup-shaped with a four-lobed corolla, usually lilac to mauve. They are arranged in a dense, terminal panicle 8-18 cm long. The fruit is a dry, smooth brown capsule, about 1 cm long.
# Cultivation
Common Lilac is a very common ornamental plant in gardens and parks, because of the attractive, sweet smell of its flowers. Most garden plants are cultivars with flowers varying in color from white to dark lilac. The majority of garden cultivars do not exceed 4-5 m tall.
Syringa vulgaris is the state flower of the state of New Hampshire, because it "is symbolic of that hardy character of the men and women of the Granite State" (New Hampshire Revised Statute Annotated (RSA) 3:5).
- flowers and leaves
flowers and leaves
- Syringa vulgaris 'Alba'
Syringa vulgaris 'Alba'
- Syringa vulgaris 'Charles Joly'
Syringa vulgaris 'Charles Joly'
- Syringa vulgaris 'Corondel'
Syringa vulgaris 'Corondel'
- Syringa vulgaris 'Etna'
Syringa vulgaris 'Etna'
- Syringa vulgaris 'Mme. Francisque Morel'
Syringa vulgaris 'Mme. Francisque Morel'
- Syringa vulgaris 'Maréchal Foch'
Syringa vulgaris 'Maréchal Foch'
- File:Jorgovan-pcela4.JPG | Common Lilac
The Common Lilac (Syringa vulgaris) is a deciduous plant in the olive family (Oleaceae), native to the Balkan Peninsula in southeastern Europe, where it grows in the wild on rocky hills.
It is a large shrub or small tree, growing 6-7 m high. The smooth bark is grey to grey-brown. The shrubs are multi-stemmed, producing secondary shoots from the base or roots.
The leaves are simple, light green to glaucous, oval to cordate, with pinnate leaf venation, a mucronate apex and an entire margin, reaching a length of 5-10 cm. They are arranged opposite pairs or occasionally in whorls of three.
The four-petaled flowers are cup-shaped with a four-lobed corolla, usually lilac to mauve. They are arranged in a dense, terminal panicle 8-18 cm long. The fruit is a dry, smooth brown capsule, about 1 cm long.
## Cultivation
Common Lilac is a very common ornamental plant in gardens and parks, because of the attractive, sweet smell of its flowers. Most garden plants are cultivars with flowers varying in color from white to dark lilac. The majority of garden cultivars do not exceed 4-5 m tall.
Syringa vulgaris is the state flower of the state of New Hampshire, because it "is symbolic of that hardy character of the men and women of the Granite State" (New Hampshire Revised Statute Annotated (RSA) 3:5).
- flowers and leaves
flowers and leaves
- Syringa vulgaris 'Alba'
Syringa vulgaris 'Alba'
- Syringa vulgaris 'Charles Joly'
Syringa vulgaris 'Charles Joly'
- Syringa vulgaris 'Corondel'
Syringa vulgaris 'Corondel'
- Syringa vulgaris 'Etna'
Syringa vulgaris 'Etna'
- Syringa vulgaris 'Mme. Francisque Morel'
Syringa vulgaris 'Mme. Francisque Morel'
- Syringa vulgaris 'Maréchal Foch'
Syringa vulgaris 'Maréchal Foch'
- File:Jorgovan-pcela4.JPG | https://www.wikidoc.org/index.php/Common_Lilac | |
8cba2f77315df13f550e01783ab1e1634680b4b1 | wikidoc | Connie Eaves | Connie Eaves
# Overview
Connie Eaves née Gregory FRSC PhD, Director and co-founder of Terry Fox Laboratory, Vancouver, Canada is internationally recognized for her pioneering research in basic blood stem cell biology, which led to a breakthrough in treatment for leukemia. She is one of the world leaders in the field of hematopoietic stem cell biology. Her major contributions are the development of stem cell assays, the molecular regulation of stem cell fate decisions, and studies of leukemogensis. She also has an interest in studies in progenitor and stem cells in normal a malignant breast tissue. Her recent independent discovery of breast stem cells has been a breakthrough understanding in the field of breast cancer.
Currently she is researching the unique properties of normal and cancerous stem cells in a variety of tissues, believed to be key in the development of definitive anti-cancer treatments, for breast cancer as well as leukemia.
# Education
Eaves received a BA in Biology and Chemistry and a MSc in Biology (Genetics) from Queen's University in 1964 and 1966. She then pursued doctoral training under the supervision of Dr. Lazlo Lajtha - one of the founders of modern hematology - at the Paterson Laboratories of the Christie Hospital and Holt Radium Institute and obtained a PhD from the University of Manchester in Great Britain in 1969.
After an additional year of post-doctoral work in radiobiology at the same lab, she returned to Canada to undertake further post-doctoral studies at the Ontario Cancer Institute in Toronto where she worked with Dr. James Till and Dr. Ernest McCulloch from 1970-73.
# Career
In 1973 she was recruited to the British Columbia Cancer Institute (now the BC Cancer Agency) as its second full-time scientist and National Cancer Institute of Canada Scholar to help develop the preclinical pius-meson radiobiology research program. At the same time she was appointed Assistant Professor in the Department of Medical Genetics at the University of British Columbia. In 1980 she became a co-founder of the Terry Fox Laboratory at the BC Cancer Agency and was appointed its Deputy Director in 1986, an appointment she continues to hold. Throughout her training and subsequent productive scientific career she has received numerous awards and scholarships. She was elected a Fellow of the Royal Society of Canada in 1993 and, in 2003, she received the prestigious Robert L. Noble Prize for Excellence in Cancer Research from the National Cancer Institute of Canada.
Her PhD studies provided the first evidence that two distinct cell populations contribute to the generation of antibody responses, heralding the discovery soon thereafter of B and T lymphocytes. This seminal work was published in Nature in 1967. As a postdoctoral fellow, Eaves’ studies contributed to the definition of the earliest stages of the red blood cell differentiation process. Her initial work as an independent investigator followed from this, laying the groundwork for the concept of a hierarchy of progenitor classes within different lineages in the blood-forming system, whose members can be distinguished by evolving biological properties and different regulatory mechanisms. She is widely recognized as a world authority on the stem cells of the blood-forming system and their regulation in both normal and perturbed states, with a particular emphasis on chronic myeloid leukemia (CML). Since the early 1990’s she has extended her contributions in understanding stem cell behaviour to normal and malignant breast cells.
Over the last 25 years Eaves has played a major role in the recruitment and education of many talented undergraduate and graduate students as well as post-doctoral fellows, particularly those with a clinical background, and has directly supervised more than 50 trainees at the post-graduate level. Many of these individuals have since become internationally recognized scientists in their own right in Canada, the U.S. and Europe. She remains particularly interested in the training of young investigators and continues to lead a dynamic research group at the Terry Fox Laboratory, with a publication record of more than 340 full papers including peer-reviewed articles, conference proceedings and book chapters.
Eaves has also devoted much energy to the successful development of collaborative research programs locally, nationally and internationally. She is currently involved in such activities within Genome BC, the Stem Cell Network (a Canadian NCE Program for which she served as the Associate Scientific Director for 4 years), a still active NCIC Program Project (started under her leadership in 1981) and an NIH-funded Program Project in Gene Therapy, now in its 10th year, that links investigators in Vancouver, New York, Boston and Chicago.
From 1996-99 she served an elected 3-year term as a Councillor of the American Society of Hematology and from 2000-2003 she was the elected Vice President, President-Elect and President of the International Society for Experimental Hematology. She continues to offer her services to grants panels, committees, NIH study sections and site review teams, reviews many papers each year for a variety of leading journals and has been an Associate Editor and/or member of the Editorial Board of most of the lead journals in hematology and stem cell biology including the recently started Cell Stem Cell.
Eaves is an active member of numerous national and international scientific societies and has held senior executive offices in the American Society of Hematology and the International Society for Experimental Hematology. She was one of the first Co-Chairs of the Canadian Breast Cancer Research Initiative and later served as President of the National Cancer Institute of Canada (1996-98). Dr. Eaves is a member of several editorial boards and the Associate Editor of Blood as well as the Biology of Blood and Marrow Transplantation.
# Personal life
Eaves is the mother of 4 children - all of whom are university graduates now developing successful careers in business, politics and academia. Besides her work and her family, her passions are music, art and gardening. | Connie Eaves
# Overview
Connie Eaves née Gregory FRSC PhD, Director and co-founder of Terry Fox Laboratory, Vancouver, Canada is internationally recognized for her pioneering research in basic blood stem cell biology, which led to a breakthrough in treatment for leukemia. She is one of the world leaders in the field of hematopoietic stem cell biology. Her major contributions are the development of stem cell assays, the molecular regulation of stem cell fate decisions, and studies of leukemogensis. She also has an interest in studies in progenitor and stem cells in normal a malignant breast tissue. Her recent independent discovery of breast stem cells has been a breakthrough understanding in the field of breast cancer.
Currently she is researching the unique properties of normal and cancerous stem cells in a variety of tissues, believed to be key in the development of definitive anti-cancer treatments, for breast cancer as well as leukemia.
# Education
Eaves received a BA in Biology and Chemistry and a MSc in Biology (Genetics) from Queen's University in 1964 and 1966. She then pursued doctoral training under the supervision of Dr. Lazlo Lajtha - one of the founders of modern hematology - at the Paterson Laboratories of the Christie Hospital and Holt Radium Institute and obtained a PhD from the University of Manchester in Great Britain in 1969.
After an additional year of post-doctoral work in radiobiology at the same lab, she returned to Canada to undertake further post-doctoral studies at the Ontario Cancer Institute in Toronto where she worked with Dr. James Till and Dr. Ernest McCulloch from 1970-73.
# Career
In 1973 she was recruited to the British Columbia Cancer Institute (now the BC Cancer Agency) as its second full-time scientist and National Cancer Institute of Canada Scholar to help develop the preclinical pius-meson radiobiology research program. At the same time she was appointed Assistant Professor in the Department of Medical Genetics at the University of British Columbia. In 1980 she became a co-founder of the Terry Fox Laboratory at the BC Cancer Agency and was appointed its Deputy Director in 1986, an appointment she continues to hold. Throughout her training and subsequent productive scientific career she has received numerous awards and scholarships. She was elected a Fellow of the Royal Society of Canada in 1993 and, in 2003, she received the prestigious Robert L. Noble Prize for Excellence in Cancer Research from the National Cancer Institute of Canada.
Her PhD studies provided the first evidence that two distinct cell populations contribute to the generation of antibody responses, heralding the discovery soon thereafter of B and T lymphocytes. This seminal work was published in Nature in 1967. As a postdoctoral fellow, Eaves’ studies contributed to the definition of the earliest stages of the red blood cell differentiation process. Her initial work as an independent investigator followed from this, laying the groundwork for the concept of a hierarchy of progenitor classes within different lineages in the blood-forming system, whose members can be distinguished by evolving biological properties and different regulatory mechanisms. She is widely recognized as a world authority on the stem cells of the blood-forming system and their regulation in both normal and perturbed states, with a particular emphasis on chronic myeloid leukemia (CML). Since the early 1990’s she has extended her contributions in understanding stem cell behaviour to normal and malignant breast cells.
Over the last 25 years Eaves has played a major role in the recruitment and education of many talented undergraduate and graduate students as well as post-doctoral fellows, particularly those with a clinical background, and has directly supervised more than 50 trainees at the post-graduate level. Many of these individuals have since become internationally recognized scientists in their own right in Canada, the U.S. and Europe. She remains particularly interested in the training of young investigators and continues to lead a dynamic research group at the Terry Fox Laboratory, with a publication record of more than 340 full papers including peer-reviewed articles, conference proceedings and book chapters.
Eaves has also devoted much energy to the successful development of collaborative research programs locally, nationally and internationally. She is currently involved in such activities within Genome BC, the Stem Cell Network (a Canadian NCE Program for which she served as the Associate Scientific Director for 4 years), a still active NCIC Program Project (started under her leadership in 1981) and an NIH-funded Program Project in Gene Therapy, now in its 10th year, that links investigators in Vancouver, New York, Boston and Chicago.
From 1996-99 she served an elected 3-year term as a Councillor of the American Society of Hematology and from 2000-2003 she was the elected Vice President, President-Elect and President of the International Society for Experimental Hematology. She continues to offer her services to grants panels, committees, NIH study sections and site review teams, reviews many papers each year for a variety of leading journals and has been an Associate Editor and/or member of the Editorial Board of most of the lead journals in hematology and stem cell biology including the recently started Cell Stem Cell.
Eaves is an active member of numerous national and international scientific societies and has held senior executive offices in the American Society of Hematology and the International Society for Experimental Hematology. She was one of the first Co-Chairs of the Canadian Breast Cancer Research Initiative and later served as President of the National Cancer Institute of Canada (1996-98). Dr. Eaves is a member of several editorial boards and the Associate Editor of Blood as well as the Biology of Blood and Marrow Transplantation.
# Personal life
Eaves is the mother of 4 children - all of whom are university graduates now developing successful careers in business, politics and academia. Besides her work and her family, her passions are music, art and gardening. | https://www.wikidoc.org/index.php/Connie_Eaves | |
f1002b8a210e29531f421ef2a6f862f3c4441016 | wikidoc | Contact lens | Contact lens
# Overview
A contact lens (also known simply as a "contact") is a corrective, cosmetic, or therapeutic lens usually placed on the cornea of the eye. Modern contact lenses were invented by the Czech chemist Otto Wichterle, who also invented the first gel used for their production.
Contact lenses usually serve the same corrective purpose as conventional glasses, but are lightweight and virtually invisible — many commercial lenses are tinted a faint blue to make them more visible when immersed in cleaning and storage solutions. Some cosmetic lenses are deliberately colored for altering the appearance of the eye.
It has been estimated that 125 million people use contact lenses worldwide (2%), including 28 to 38 million in the United Statesand 13 million in Japan. The types of lenses used and prescribed vary markedly between countries, with rigid lenses accounting for over 20% of currently-prescribed lenses in Japan, Netherlands and Germany but less than 5% in Scandinavia.
People choose to wear contact lenses for various reasons. Many consider their appearance to be more attractive with contact lenses than with glasses. Contact lenses are less affected by wet weather, do not steam up, and provide a wider field of vision. They are more suitable for a number of sporting activities. Additionally, ophthalmological conditions such as keratoconus and aniseikonia may not be accurately corrected with glasses.
# Historical Perspective
Leonardo da Vinci is frequently credited with introducing the general principle of contact lenses in his 1508 Codex of the eye, Manual D, where he described a method of directly altering corneal power by submerging the eye in a bowl of water. Leonardo, however, did not suggest his idea be used for correcting vision — he was more interested in learning about the mechanisms of accommodation of the eye.
René Descartes proposed another idea in 1636, in which a glass tube filled with liquid is placed in direct contact with the cornea. The protruding end was to be composed of clear glass, shaped to correct vision; however the idea was unworkable, since it would make blinking impossible.
In 1801, while conducting experiments concerning the mechanisms of accommodation, scientist Thomas Young constructed a liquid-filled "eyecup" which could be considered a predecessor to the contact lens. On the eyecup's base, Young fitted a microscope eyepiece. However, like da Vinci's, Young's device was not intended to correct refraction errors.
Sir John Herschel, in a footnote of the 1845 edition of the Encyclopedia Metropolitana, posed two ideas for the visual correction: the first "a spherical capsule of glass filled with animal jelly", and "a mould of the cornea" which could be impressed on "some sort of transparent medium". Though Herschel reportedly never tested these ideas, they were both later advanced by several independent inventors such as Hungarian Dr. Dallos (1929), who perfected a method of making molds from living eyes. This enabled the manufacture of lenses that, for the first time, conformed to the actual shape of the eye.
It was not until 1887 that a German glassblower, F.E. Muller, produced the first eye covering to be seen through and tolerated. In the next year, the German physiologist Adolf Eugen Fick constructed and fitted the first successful contact lens. While working in Zürich, he described fabricating afocal scleral contact shells, which rested on the less sensitive rim of tissue around the cornea, and experimentally fitting them: initially on rabbits, then on himself, and lastly on a small group of volunteers. These lenses were made from heavy brown glass and were 18–21mm in diameter. Fick filled the empty space between cornea/callosity and glass with a grape sugar solution. He published his work, "Contactbrille", in the journal Archiv für Augenheilkunde in March 1888.
Fick's lens was large, unwieldy, and could only be worn for a few hours at a time. August Müller in Kiel, Germany, corrected his own severe myopia with a more convenient glass-blown scleral contact lens of his own manufacture in 1888.
Also in 1887, Louis J. Girard invented a similar scleral form of contact lens.
Glass-blown scleral lenses remained the only form of contact lens until the 1930s when polymethyl methacrylate (PMMA or Perspex/Plexiglas) was developed, allowing plastic scleral lenses to be manufactured for the first time. In 1936, optometrist William Feinbloom introduced plastic lenses, making them lighter and more convenient. These lenses were a combination of glass and plastic.
In 1949, the first "corneal" lenses were developed. These were much smaller than the original scleral lenses, as they sat only on the cornea rather than across all of the visible ocular surface, and could be worn up to sixteen hours per day. PMMA corneal lenses became the first contact lenses to have mass appeal through the 1960s, as lens designs became more sophisticated with improving manufacturing (lathe) technology.
One important disadvantage of PMMA lenses is that no oxygen is transmitted through the lens to the cornea, which can cause a number of adverse clinical effects. By the end of the 1970s, and through the 1980s and 1990s, a range of oxygen-permeable but rigid materials were developed to overcome this problem. Collectively, these polymers are referred to as "rigid gas permeable" or "RGP" materials or lenses. Although all the above lens types — sclerals, PMMA lenses and RGPs — could be correctly referred to as being "hard" or "rigid," the term hard is now used to refer to the original PMMA lenses which are still occasionally fitted and worn, whereas rigid is a generic term which can be used for all these lens types. That is, hard lenses (PMMA lenses) are a sub-set of rigid lenses. Occasionally, the term "gas permeable" is used to describe RGP lenses, but this is potentially misleading, as soft lenses are also gas permeable in that they allow oxygen to move through the lens to the ocular surface.
The principal breakthrough in soft lenses was made by the Czech chemist Otto Wichterle who published his work "Hydrophilic gels for biological use" in the journal Nature in 1959. This led to the launch of the first soft (hydrogel) lenses in some countries in the 1960s and the first approval of the 'Soflens' material by the United States Food and Drug Administration (FDA) in 1971. These lenses were soon prescribed more often than rigid lenses, mainly due to the immediate comfort of soft lenses; by comparison, rigid lenses require a period of adaptation before full comfort is achieved. The polymers from which soft lenses are manufactured improved over the next 25 years, primarily in terms of increasing the oxygen permeability by varying the ingredients making up the polymers.
In 1999, an important development was the launch of the first silicone hydrogels onto the market. These new materials encapsulated the benefits of silicone — which has extremely high oxygen permeability — with the comfort and clinical performance of the conventional hydrogels which had been used for the previous 30 years. These lenses were initially advocated primarily for extended (overnight) wear although more recently, daily (no overnight) wear silicone hydrogels have been launched.
# Classification
## Types of Contact Lenses
Contact lenses are classified in many different manners.
### By Function
A corrective contact lens is a lens designed to improve vision. In many people, there is a mismatch between the refractive power of the eye and the length of the eye, leading to a refraction error. A contact lens neutralizes this mismatch and allows for correct focusing of light onto the retina. Conditions correctable with contact lenses include near (or short) sightedness (myopia), far (or long) sightedness (hypermetropia), astigmatism and presbyopia. Contact wearers must usually take their contacts out every night or every few days, depending on the brand and style of the contact. Recently there has been renewed interest in orthokeratology, the correction of myopia by deliberate overnight flattening of the cornea, leaving the eye without contact lens or eyeglasses correction during the day.
For those with certain color deficiencies, a red-tinted "X-Chrom" contact lens may be used. Although the lens does not restore normal color vision, it allows some colorblind individuals to distinguish colors better.
ChromaGen lenses have been used and these have been shown to have some limitations with vision at night although otherwise producing significant improvements in colour vision. An earlier study showed very significant improvements in colour vision and patient satisfaction
Later work that used these ChromaGen lenses with dyslexics in a randomised, double-blind, placebo controlled trial showed highly significant improvements in reading ability over reading without the lenses This system has been granted FDA approval in the United States, which is reassuring to patients, and so its scientific approach has been correctly validated.
A cosmetic contact lens is designed to change the appearance of the eye. These lenses may also correct the vision, but some blurring or obstruction of vision may occur as a result of the color or design. In the United States, the FDA frequently calls non-corrective cosmetic contact lenses decorative contact lenses.
Theatrical contact lenses are a type of cosmetic contact lens that are used primarily in the entertainment industry to make the eye appear pleasing, unusual or unnatural in appearance, most often in horror and zombie movies, where lenses can make one's eyes appear demonic, cloudy and lifeless, or even to make the pupils of the wearer appear dilated to simulate the natural appearance of the pupils under the influence of various illicit drugs.
Scleral lenses cover the white part of the eye (i.e. sclera) and are used in many theatrical lenses. Due to their size, these lenses are difficult to insert and do not move very well within the eye. They may also hamper the vision as the lens has a small area for the user to see through. As a result they generally cannot be worn for more than 3 hours as they can cause temporary vision disturbances.
Similar lenses have more direct medical applications. For example, some lenses can give the iris an enlarged appearance, or mask defects such as absence (aniridia) or damage (dyscoria) to the iris.
Although many brands of contact lenses are lightly tinted to make them easier to handle, cosmetic lenses worn to change the color of the eye are far less common, accounting for only 3% of contact lens fits in 2004.
Soft lenses are often used in the treatment and management of non-refractive disorders of the eye. A bandage contact lens protects an injured or diseased cornea from the constant rubbing of blinking eyelids thereby allowing it to heal. They are used in the treatment of conditions including bullous keratopathy, dry eyes, corneal ulcers and erosion, keratitis, corneal edema, descemetocele, corneal ectasis, Mooren's ulcer, anterior corneal dystrophy, and neurotrophic keratoconjunctivitis. Contact lenses that deliver drugs to the eye have also been developed.
### By Constructional Material
The first contact lenses were made of glass, which caused eye irritation, and were not wearable for extended periods of time. But when William Feinbloom introduced lenses made from polymethyl methacrylate (PMMA or Perspex/Plexiglas), contacts became much more convenient. These PMMA lenses are commonly referred to as "hard" lenses (this term is not used for other types of contacts).
However, PMMA lenses have their own side effects: no oxygen is transmitted through the lens to the cornea, which can cause a number of adverse clinical events. In the late 1970s, and through the 1980s and 1990s, improved rigid materials — which were also oxygen-permeable — were developed. Collectively, these polymers are referred to as rigid gas permeable or 'RGP' materials or lenses.
Rigid lenses offer a number of unique properties. In effect, the lens is able to replace the natural shape of the cornea with a new refracting surface. This means that a regular (spherical) rigid contact lens can provide good level of vision in people who have astigmatism or distorted corneal shapes as with keratoconus.
While rigid lenses have been around for about 120 years, soft lenses are a much more recent development. The principal breakthrough in soft lenses made by Otto Wichterle led to the launch of the first soft (hydrogel) lenses in some countries in the 1960s and the approval of the 'Soflens' material (polymacon) by the United States FDA in 1971. Soft lenses are immediately comfortable, while rigid lenses require a period of adaptation before full comfort is achieved. The polymers from which soft lenses are manufactured improved over the next 25 years, primarily in terms of increasing the oxygen permeability by varying the ingredients making up the polymers.
A small number of hybrid rigid/soft lenses exist. An alternative technique is piggybacking of contact lenses, a smaller, rigid lens being mounted atop a larger, soft lens. This is done for a variety of clinical situations where a single lens will not provide the optical power, fitting characteristics, or comfort required.
In 1999, 'silicone hydrogels' became available. Silicone hydrogels have both the extremely high oxygen permeability of silicone and the comfort and clinical performance of the conventional hydrogels. These lenses were initially advocated primarily for extended (overnight) wear, although more recently daily (no overnight) wear silicone hydrogels have been launched.
While it provides the oxygen permeability, the silicone also makes the lens surface highly hydrophobic and less "wettable." This frequently results in discomfort and dryness during lens wear. In order to compensate for the hydrophobicity, hydrogels are added (hence the name "silicone hydrogels") to make the lenses more hydrophilic. However the lens surface may still remain hydrophobic. Hence some of the lenses undergo surface modification processes which cover the hydrophobic sites of silicone. Some other lens types incorporate internal rewetting agents to make the lens surface hydrophilic.
### By Wear Time
A daily wear contact lens is designed to be removed prior to sleeping. An extended wear (EW) contact lens is designed for continuous overnight wear, typically for 6 or more consecutive nights. Newer materials, such as silicone hydrogels, allow for even longer wear periods of up to 30 consecutive nights; these longer-wear lenses are often referred to as continuous wear (CW). Generally, extended wear lenses are discarded after the specified length of time. These are increasing in popularity, due to their obvious convenience. Extended- and continuous-wear contact lenses can be worn for such long periods of time because of their high oxygen permeability (typically 5-6 times greater than conventional soft lenses), which allows the eye to remain remarkably healthy.
Extended lens wearers may have an increased risk for corneal infections and corneal ulcers, primarily due to poor care and cleaning of the lenses, tear film instability, and bacterial stagnation. Corneal neovascularization has historically also been a common complication of extended lens wear, though this does not appear to be a problem with silicone hydrogel extended wear. The most common complication of extended lens use is conjunctivitis, usually allergic or giant papillary conjunctivitis (GPC), sometimes associated with a poorly fitting contact lens.
### By Frequency of Replacement
The various soft contact lenses available are often categorized by their replacement schedule. The shortest replacement schedule is single use (daily disposable) lenses, which are disposed of each night. These may be best for patients with ocular allergies or other conditions, because it limits deposits of antigens and protein. Single use lenses are also useful for people who use contacts infrequently, or for purposes (e.g. swimming or other sporting activities) where losing a lens is likely. More commonly, contact lenses are prescribed to be disposed of on a two-week or monthly basis. Quarterly or annual lenses, which used to be very common, have lost favor because a more frequent disposal schedule allows for thinner lenses and limits deposits. Rigid gas permeable lenses are very durable and may last for several years without the need for replacement.
### By Design
A spherical contact lens is one in which both the inner and outer optical surfaces are portions of a sphere. A toric lens is one in which either or both of the optical surfaces have the effect of
a cylindrical lens, usually in combination with the effect of a spherical lens. Myopic (nearsighted) and hypermetropic (farsighted) people who also have astigmatism and who have been told they are not suitable for regular contact lenses may be able to use toric lenses. If one eye has astigmatism and the other does not, the patient may be told to use a spherical lens in one eye and a toric lens in the other. Toric lenses are made from the same materials as regular contact lenses but have a few extra characteristics:
- They correct for both spherical and cylindrical aberration.
- They may have a specific 'top' and 'bottom', as they are not symmetrical around their centre and must not be rotated. Lenses must be designed to maintain their orientation regardless of eye movement. Often lenses are thicker at the bottom and this thicker zone is pushed down by the upper eyelid during blinking to allow the lens to rotate into the correct position (with this thicker zone at the 6 'clock position on the eye). Toric lenses are usually marked with tiny striations to assist their fitting.
- They are usually more expensive to produce than non-toric lenses; therefore they are usually meant for extended wear. The first disposable toric lenses were introduced in 2000 by Vistakon.
Like eyeglasses, contact lenses can have one (single vision) or more (multifocal) focal points.
For correction of presbyopia or accommodative insufficiency multifocal contact lenses are almost always used; however, single vision lenses may also be used in a process known as monovision: single vision lenses are used to correct one eye's far vision and the other eye's near vision. Alternatively, a person may wear single vision contact lenses to improve distance vision and reading glasses to improve near vision.
Rigid gas permeable bifocal contact lenses most commonly have a small lens on the bottom for the near correction, when the eyes are lowered to read, this lens comes into the optical path. RGPs must translate (move vertically) to work properly, and thus the gaze of the eye can change from the near to the distant sections, much like bifocal eyeglasses.
Multifocal soft contact lenses are more complex to manufacture and require more skill to fit. All soft bifocal contact lenses are considered "simultaneous vision" because both far and near vision corrections are presented simultaneously to the retina, regardless of the position of the eye. Of course, only one correction is correct, the incorrect correction causes blur. Commonly these are designed with distance correction in the center of the lens and near correction in the periphery, or vice versa.
### Implantation
Intraocular lenses, also known as an implantable contact lenses, are special small corrective lenses surgically implanted in the eye's posterior chamber behind the iris and in front of the lens to correct higher degrees of myopia and hyperopia.
# Manufacturing of Contact Lenses
Most contact lenses are mass produced.
- Spin-cast lenses - A spin cast lens is a soft contact lens manufactured by whirling liquid plastic in a revolving mold at high speed.
- Lathe cut - A lathe cut contact lens is cut and ground on a lathe.
- Molded
- Hybrids
Although many companies make contact lenses, there are four major manufacturers: Vistakon/Johnson & Johnson, CIBA Vision, Bausch & Lomb, and CooperVision.
# Contact Lens Prescriptions
The prescribing of contact lenses is usually restricted to appropriately qualified eye care practitioners. In countries such as the United States (where all contact lenses are deemed to be medical devices by the Food and Drug Administration), the United Kingdom and Australia, optometrists are usually responsible. In France and eastern European countries, ophthalmologists play the major role. In other parts of the world, opticians usually prescribe contact lenses. Prescriptions for contact lenses and glasses may be similar, but are not interchangeable.
The practitioner or contact lens fitter typically determines an individual's suitability for contact lenses during an eye examination. Corneal health is verified; ocular allergies or dry eyes may affect a person's ability to successfully wear contact lenses. Especially above the age of 35 years dry eyes often makes wearing contact lenses too risky, especially soft lenses.
The parameters specified in a contact lenses prescription may include:
- Material (eg. Oxygen Permeability/Transmissibility (Dk/L, Dk/t), water content, modulus)
- Base curve radius (BC, BCR)
- Diameter (D, OAD)
- Power in dioptres - Spherical, Cylindrical and/or reading addition)
- Cylinder axis
- Center thickness (CT)
- Brand
Many people already wearing contact lenses order contact lenses over the internet at their own risk. It is also possible to convert the power of a glasses prescription to the power of contact lenses with the following formula:
where
- d is the distance of the glasses to the eye and
- F = 1/D are the focal length of the contact lens and the glass,
- D is the lens power in diopters.
The formula above is implemented in this online calculator.
In the US, The Fairness to Contact Lens Consumers Act, which became law in February, 2004, was intended to ensure the availability of contact lens prescriptions to patients . Under the law consumers have a right to obtain a copy of their contact lens prescription, allowing them to fill that prescription at the business of their choice.
# Complications
Complications due to contact lens wear affect roughly 4% of contact lens wearers each year. Excessive wear of contact lenses, particularly overnight wear, is associated with most of the safety concerns. Problems associated with contact lens wear may affect the eyelid, the conjunctiva, the various layers of the cornea, and even the tear film that covers the outer surface of the eye.
Eyelid:
- Ptosis
Conjunctiva:
- Contact dermatitis
- Giant papillary conjunctivitis
- Superior limbic keratoconjunctivitis
Cornea:
- Epithelium
- Corneal abrasion
- Corneal erosion
- Corneal ulcer
- Hypoxia
- Stroma
- Infection and keratitis
- Bacteria
- Protozoa: Acanthamoeba
- Fungal: Fusarium
- Contact lens acute red eye (CLARE)
- Keratoconus
- Endothelium
# Usage
Before touching the contact lens or one's eyes, it is important to thoroughly wash & rinse hands with a soap that does not contain moisturizers or allergens such as fragrances. The technique for removing or inserting a contact lens varies slightly depending upon whether the lens is soft or rigid.
## Insertion
Contact lenses are typically inserted into the eye by placing them on the index finger with the concave side upward and raising them to touch the cornea. The other hand may be employed to keep the eye open. Problems may arise particularly with disposable soft lenses; if the surface tension between the lens and the finger is too great the lens may turn itself inside out; alternatively it may fold itself in half. When the lens first contacts the eye, a brief period of irritation may ensue as the eye aclimatises to the lens and also (if a multi-use lens is not correctly cleansed) as dirt on the lens irritates the eye. Irrigation may help during this period, which generally should not exceed one minute.
## Removal
A soft lens may be removed by holding the eyelids open and grasping the lens with opposing digits. This method can cause irritation, could risk damage to the eye and may in many cases be difficult, in part due to the blink reflex. If the lens is pushed off the cornea it will buckle up (due to the difference in curvature), making it easier to grasp.
Rigid contact lenses may be removed by pulling with one finger on the outer or lateral canthus, then blinking to cause the lens to lose adhesion. The other hand is typically cupped underneath the eye to catch the lens. There also exist small tools specifically for removing lenses, which resemble small plungers made of flexible plastic; the concave end is raised to the eye and touched to the lens, forming a seal stronger than that of the lens with the cornea and allowing the lens to be removed from the eye.
## Care (Cleaning and Disinfection)
While daily disposable lenses require no cleaning, other types require regular cleaning and disinfecting in order to retain clear vision and prevent discomfort and infections by various microorganisms including bacteria, fungi, and Acanthamoeba, that form a biofilm on the lens surface. There are a number of products that can be used to perform these tasks:
- Multipurpose solution - The most popular cleaning solution for contact lenses. Used for rinsing, disinfecting, cleaning and storing the lenses. Using this product eliminates the need for protein removal enzyme tablets in most cases. Multipurpose solutions are not effective at disinfecting Acanthamoeba from the lens. In May 2007, one brand of multipurpose solution was recalled due to a cluster of Acanthamoeba infections.
- Saline solution - Used for rinsing the lens after cleaning and preparing it for insertion. Saline solutions do not disinfect the lenses.
- Daily cleaner - Used to clean lenses on a daily basis. A few drops of cleaner are applied to the lens while it rests in the palm of the hand, then the lens is rubbed for about 20 seconds with a fingertip (check the cleaner's directions) on each side. Long fingernails can damage the lens, so care should be taken.
- Hydrogen peroxide solution - Used for disinfecting the lenses, and available as 'two-step' or 'one-step' systems. If using a 'two-step' product, one must ensure that the lens taken out of the hydrogen peroxide is neutralized before it is worn, or else wear will be extremely painful. Saline must not be used to rinse away the peroxide. Some peroxide solutions, such as CIBA Vision's Clear Care, come with a special storage case that contains a catalyzing disk. If soaked in the solution with the disk for at least six hours, the hydrogen peroxide decomposes and the remaining solution is a saline that will not harm the eye. People with extremely sensitive, irritable eyes often use these types of cleaning solutions. Peroxide solutions are the only commonly used disinfectant effective against Acanthamoeba, although the two-step solutions are more effective than the one-step, which neutralize too quickly to kill the amoeba's cysts. If you get this solution in your eyes, it is highly recommended that you go to the Emergency Room and get your eye(s) irrigated.
- Enzymatic cleaner - Used for cleaning protein deposits off lenses, usually weekly, if the daily cleaner is not sufficient. Typically, this cleaner is in tablet form. Protein deposits make use of contact lenses uncomfortable, and may lead to various eye problems.
Some products must only be used with certain types of contact lenses: it is important to check the product label to make sure that it can be used for a given type of lens. It is also important to follow the product's directions carefully to reduce risk of eye infection or eye irritation.
It is important to ensure that the product does not become contaminated with microorganisms: the tips of the containers for these solutions should never touch any surface, and the container should be kept closed when not in use. To counteract minor contamination of the product and kill microorganisms on the contact lens, some products may contain preservatives such as thimerosal, benzalkonium chloride, benzyl alcohol, and other compounds. In 1989, thimerosal was responsible for about 10% of problems related to contact lenses: because of this, many products no longer contain thimerosal. Preservative-free products usually have shorter shelf life. For example, non-aerosol preservative-free saline solutions can typically be used for only two weeks once opened. The introduction of silicone-hydrogel soft contact lens materials in 1999 made selection of the proper disinfecting solution more important. One study has noted several incompatibilities between these new lens materials and some solutions resulting in corneal staining. | Contact lens
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A contact lens (also known simply as a "contact") is a corrective, cosmetic, or therapeutic lens usually placed on the cornea of the eye. Modern contact lenses were invented by the Czech chemist Otto Wichterle, who also invented the first gel used for their production.
Contact lenses usually serve the same corrective purpose as conventional glasses, but are lightweight and virtually invisible — many commercial lenses are tinted a faint blue to make them more visible when immersed in cleaning and storage solutions. Some cosmetic lenses are deliberately colored for altering the appearance of the eye.
It has been estimated that 125 million people use contact lenses worldwide (2%),[1] including 28 to 38 million in the United States[1][2]and 13 million in Japan.[3] The types of lenses used and prescribed vary markedly between countries, with rigid lenses accounting for over 20% of currently-prescribed lenses in Japan, Netherlands and Germany but less than 5% in Scandinavia.[1]
People choose to wear contact lenses for various reasons.[4] Many consider their appearance to be more attractive with contact lenses than with glasses. Contact lenses are less affected by wet weather, do not steam up, and provide a wider field of vision. They are more suitable for a number of sporting activities.[5] Additionally, ophthalmological conditions such as keratoconus and aniseikonia may not be accurately corrected with glasses.
# Historical Perspective
Leonardo da Vinci is frequently credited with introducing the general principle of contact lenses in his 1508 Codex of the eye, Manual D, where he described a method of directly altering corneal power by submerging the eye in a bowl of water. Leonardo, however, did not suggest his idea be used for correcting vision — he was more interested in learning about the mechanisms of accommodation of the eye.[6]
René Descartes proposed another idea in 1636, in which a glass tube filled with liquid is placed in direct contact with the cornea. The protruding end was to be composed of clear glass, shaped to correct vision; however the idea was unworkable, since it would make blinking impossible.
In 1801, while conducting experiments concerning the mechanisms of accommodation, scientist Thomas Young constructed a liquid-filled "eyecup" which could be considered a predecessor to the contact lens. On the eyecup's base, Young fitted a microscope eyepiece. However, like da Vinci's, Young's device was not intended to correct refraction errors.
Sir John Herschel, in a footnote of the 1845 edition of the Encyclopedia Metropolitana, posed two ideas for the visual correction: the first "a spherical capsule of glass filled with animal jelly", and "a mould of the cornea" which could be impressed on "some sort of transparent medium".[7] Though Herschel reportedly never tested these ideas, they were both later advanced by several independent inventors such as Hungarian Dr. Dallos (1929), who perfected a method of making molds from living eyes. This enabled the manufacture of lenses that, for the first time, conformed to the actual shape of the eye.
It was not until 1887 that a German glassblower, F.E. Muller, produced the first eye covering to be seen through and tolerated.[8] In the next year, the German physiologist Adolf Eugen Fick constructed and fitted the first successful contact lens. While working in Zürich, he described fabricating afocal scleral contact shells, which rested on the less sensitive rim of tissue around the cornea, and experimentally fitting them: initially on rabbits, then on himself, and lastly on a small group of volunteers. These lenses were made from heavy brown glass and were 18–21mm in diameter. Fick filled the empty space between cornea/callosity and glass with a grape sugar solution. He published his work, "Contactbrille", in the journal Archiv für Augenheilkunde in March 1888.
Fick's lens was large, unwieldy, and could only be worn for a few hours at a time. August Müller in Kiel, Germany, corrected his own severe myopia with a more convenient glass-blown scleral contact lens of his own manufacture in 1888.[9]
Also in 1887, Louis J. Girard invented a similar scleral form of contact lens.[10]
Glass-blown scleral lenses remained the only form of contact lens until the 1930s when polymethyl methacrylate (PMMA or Perspex/Plexiglas) was developed, allowing plastic scleral lenses to be manufactured for the first time. In 1936, optometrist William Feinbloom introduced plastic lenses, making them lighter and more convenient.[11] These lenses were a combination of glass and plastic.
In 1949, the first "corneal" lenses were developed.[12] These were much smaller than the original scleral lenses, as they sat only on the cornea rather than across all of the visible ocular surface, and could be worn up to sixteen hours per day. PMMA corneal lenses became the first contact lenses to have mass appeal through the 1960s, as lens designs became more sophisticated with improving manufacturing (lathe) technology.
One important disadvantage of PMMA lenses is that no oxygen is transmitted through the lens to the cornea, which can cause a number of adverse clinical effects. By the end of the 1970s, and through the 1980s and 1990s, a range of oxygen-permeable but rigid materials were developed to overcome this problem. Collectively, these polymers are referred to as "rigid gas permeable" or "RGP" materials or lenses. Although all the above lens types — sclerals, PMMA lenses and RGPs — could be correctly referred to as being "hard" or "rigid," the term hard is now used to refer to the original PMMA lenses which are still occasionally fitted and worn, whereas rigid is a generic term which can be used for all these lens types. That is, hard lenses (PMMA lenses) are a sub-set of rigid lenses. Occasionally, the term "gas permeable" is used to describe RGP lenses, but this is potentially misleading, as soft lenses are also gas permeable in that they allow oxygen to move through the lens to the ocular surface.
The principal breakthrough in soft lenses was made by the Czech chemist Otto Wichterle who published his work "Hydrophilic gels for biological use" in the journal Nature in 1959.[13] This led to the launch of the first soft (hydrogel) lenses in some countries in the 1960s and the first approval of the 'Soflens' material by the United States Food and Drug Administration (FDA) in 1971. These lenses were soon prescribed more often than rigid lenses, mainly due to the immediate comfort of soft lenses; by comparison, rigid lenses require a period of adaptation before full comfort is achieved. The polymers from which soft lenses are manufactured improved over the next 25 years, primarily in terms of increasing the oxygen permeability by varying the ingredients making up the polymers.
In 1999, an important development was the launch of the first silicone hydrogels onto the market. These new materials encapsulated the benefits of silicone — which has extremely high oxygen permeability — with the comfort and clinical performance of the conventional hydrogels which had been used for the previous 30 years. These lenses were initially advocated primarily for extended (overnight) wear although more recently, daily (no overnight) wear silicone hydrogels have been launched.
# Classification
## Types of Contact Lenses
Contact lenses are classified in many different manners.[14] [15]
### By Function
A corrective contact lens is a lens designed to improve vision. In many people, there is a mismatch between the refractive power of the eye and the length of the eye, leading to a refraction error. A contact lens neutralizes this mismatch and allows for correct focusing of light onto the retina. Conditions correctable with contact lenses include near (or short) sightedness (myopia), far (or long) sightedness (hypermetropia), astigmatism and presbyopia. Contact wearers must usually take their contacts out every night or every few days, depending on the brand and style of the contact. Recently there has been renewed interest in orthokeratology, the correction of myopia by deliberate overnight flattening of the cornea, leaving the eye without contact lens or eyeglasses correction during the day.
For those with certain color deficiencies, a red-tinted "X-Chrom" contact lens may be used. Although the lens does not restore normal color vision, it allows some colorblind individuals to distinguish colors better.[16][17]
ChromaGen lenses have been used and these have been shown to have some limitations with vision at night although otherwise producing significant improvements in colour vision.[18] An earlier study showed very significant improvements in colour vision and patient satisfaction[19]
Later work that used these ChromaGen lenses with dyslexics in a randomised, double-blind, placebo controlled trial showed highly significant improvements in reading ability over reading without the lenses [20] This system has been granted FDA approval in the United States, which is reassuring to patients, and so its scientific approach has been correctly validated.
A cosmetic contact lens is designed to change the appearance of the eye. These lenses may also correct the vision, but some blurring or obstruction of vision may occur as a result of the color or design. In the United States, the FDA frequently calls non-corrective cosmetic contact lenses decorative contact lenses.[21][22][23][24]
Theatrical contact lenses are a type of cosmetic contact lens that are used primarily in the entertainment industry to make the eye appear pleasing, unusual or unnatural in appearance[25], most often in horror and zombie movies, where lenses can make one's eyes appear demonic, cloudy and lifeless, or even to make the pupils of the wearer appear dilated to simulate the natural appearance of the pupils under the influence of various illicit drugs.
Scleral lenses cover the white part of the eye (i.e. sclera) and are used in many theatrical lenses. Due to their size, these lenses are difficult to insert and do not move very well within the eye. They may also hamper the vision as the lens has a small area for the user to see through. As a result they generally cannot be worn for more than 3 hours as they can cause temporary vision disturbances.[26]
Similar lenses have more direct medical applications. For example, some lenses can give the iris an enlarged appearance, or mask defects such as absence (aniridia) or damage (dyscoria) to the iris.
Although many brands of contact lenses are lightly tinted to make them easier to handle, cosmetic lenses worn to change the color of the eye are far less common, accounting for only 3% of contact lens fits in 2004.[27]
Soft lenses are often used in the treatment and management of non-refractive disorders of the eye. A bandage contact lens protects an injured or diseased cornea from the constant rubbing of blinking eyelids thereby allowing it to heal.[28] They are used in the treatment of conditions including bullous keratopathy, dry eyes, corneal ulcers and erosion, keratitis, corneal edema, descemetocele, corneal ectasis, Mooren's ulcer, anterior corneal dystrophy, and neurotrophic keratoconjunctivitis.[29] Contact lenses that deliver drugs to the eye have also been developed.[30]
### By Constructional Material
The first contact lenses were made of glass, which caused eye irritation, and were not wearable for extended periods of time. But when William Feinbloom introduced lenses made from polymethyl methacrylate (PMMA or Perspex/Plexiglas), contacts became much more convenient. These PMMA lenses are commonly referred to as "hard" lenses (this term is not used for other types of contacts).
However, PMMA lenses have their own side effects: no oxygen is transmitted through the lens to the cornea, which can cause a number of adverse clinical events. In the late 1970s, and through the 1980s and 1990s, improved rigid materials — which were also oxygen-permeable — were developed. Collectively, these polymers are referred to as rigid gas permeable or 'RGP' materials or lenses.
Rigid lenses offer a number of unique properties. In effect, the lens is able to replace the natural shape of the cornea with a new refracting surface. This means that a regular (spherical) rigid contact lens can provide good level of vision in people who have astigmatism or distorted corneal shapes as with keratoconus.
While rigid lenses have been around for about 120 years, soft lenses are a much more recent development. The principal breakthrough in soft lenses made by Otto Wichterle led to the launch of the first soft (hydrogel) lenses in some countries in the 1960s and the approval of the 'Soflens' material (polymacon) by the United States FDA in 1971. Soft lenses are immediately comfortable, while rigid lenses require a period of adaptation before full comfort is achieved. The polymers from which soft lenses are manufactured improved over the next 25 years, primarily in terms of increasing the oxygen permeability by varying the ingredients making up the polymers.
A small number of hybrid rigid/soft lenses exist. An alternative technique is piggybacking of contact lenses, a smaller, rigid lens being mounted atop a larger, soft lens. This is done for a variety of clinical situations where a single lens will not provide the optical power, fitting characteristics, or comfort required.
In 1999, 'silicone hydrogels' became available. Silicone hydrogels have both the extremely high oxygen permeability of silicone and the comfort and clinical performance of the conventional hydrogels. These lenses were initially advocated primarily for extended (overnight) wear, although more recently daily (no overnight) wear silicone hydrogels have been launched.
While it provides the oxygen permeability, the silicone also makes the lens surface highly hydrophobic and less "wettable." This frequently results in discomfort and dryness during lens wear. In order to compensate for the hydrophobicity, hydrogels are added (hence the name "silicone hydrogels") to make the lenses more hydrophilic. However the lens surface may still remain hydrophobic. Hence some of the lenses undergo surface modification processes which cover the hydrophobic sites of silicone. Some other lens types incorporate internal rewetting agents to make the lens surface hydrophilic.
### By Wear Time
A daily wear contact lens is designed to be removed prior to sleeping. An extended wear (EW) contact lens is designed for continuous overnight wear, typically for 6 or more consecutive nights. Newer materials, such as silicone hydrogels, allow for even longer wear periods of up to 30 consecutive nights; these longer-wear lenses are often referred to as continuous wear (CW). Generally, extended wear lenses are discarded after the specified length of time. These are increasing in popularity, due to their obvious convenience. Extended- and continuous-wear contact lenses can be worn for such long periods of time because of their high oxygen permeability (typically 5-6 times greater than conventional soft lenses), which allows the eye to remain remarkably healthy.
Extended lens wearers may have an increased risk for corneal infections and corneal ulcers, primarily due to poor care and cleaning of the lenses, tear film instability, and bacterial stagnation. Corneal neovascularization has historically also been a common complication of extended lens wear, though this does not appear to be a problem with silicone hydrogel extended wear. The most common complication of extended lens use is conjunctivitis, usually allergic or giant papillary conjunctivitis (GPC), sometimes associated with a poorly fitting contact lens.
### By Frequency of Replacement
The various soft contact lenses available are often categorized by their replacement schedule. The shortest replacement schedule is single use (daily disposable) lenses, which are disposed of each night. These may be best for patients with ocular allergies or other conditions, because it limits deposits of antigens and protein. Single use lenses are also useful for people who use contacts infrequently, or for purposes (e.g. swimming or other sporting activities) where losing a lens is likely. More commonly, contact lenses are prescribed to be disposed of on a two-week or monthly basis. Quarterly or annual lenses, which used to be very common, have lost favor because a more frequent disposal schedule allows for thinner lenses and limits deposits. Rigid gas permeable lenses are very durable and may last for several years without the need for replacement.
### By Design
A spherical contact lens is one in which both the inner and outer optical surfaces are portions of a sphere. A toric lens is one in which either or both of the optical surfaces have the effect of
a cylindrical lens, usually in combination with the effect of a spherical lens. Myopic (nearsighted) and hypermetropic (farsighted) people who also have astigmatism and who have been told they are not suitable for regular contact lenses may be able to use toric lenses. If one eye has astigmatism and the other does not, the patient may be told to use a spherical lens in one eye and a toric lens in the other. Toric lenses are made from the same materials as regular contact lenses but have a few extra characteristics:
- They correct for both spherical and cylindrical aberration.
- They may have a specific 'top' and 'bottom', as they are not symmetrical around their centre and must not be rotated. Lenses must be designed to maintain their orientation regardless of eye movement. Often lenses are thicker at the bottom and this thicker zone is pushed down by the upper eyelid during blinking to allow the lens to rotate into the correct position (with this thicker zone at the 6 'clock position on the eye). Toric lenses are usually marked with tiny striations to assist their fitting.
- They are usually more expensive to produce than non-toric lenses; therefore they are usually meant for extended wear. The first disposable toric lenses were introduced in 2000 by Vistakon.
Like eyeglasses, contact lenses can have one (single vision) or more (multifocal) focal points.
For correction of presbyopia or accommodative insufficiency multifocal contact lenses are almost always used; however, single vision lenses may also be used in a process known as monovision[31]: single vision lenses are used to correct one eye's far vision and the other eye's near vision. Alternatively, a person may wear single vision contact lenses to improve distance vision and reading glasses to improve near vision.
Rigid gas permeable bifocal contact lenses most commonly have a small lens on the bottom for the near correction, when the eyes are lowered to read, this lens comes into the optical path. RGPs must translate (move vertically) to work properly, and thus the gaze of the eye can change from the near to the distant sections, much like bifocal eyeglasses.
Multifocal soft contact lenses are more complex to manufacture and require more skill to fit. All soft bifocal contact lenses are considered "simultaneous vision" because both far and near vision corrections are presented simultaneously to the retina, regardless of the position of the eye. Of course, only one correction is correct, the incorrect correction causes blur. Commonly these are designed with distance correction in the center of the lens and near correction in the periphery, or vice versa.
### Implantation
Intraocular lenses, also known as an implantable contact lenses, are special small corrective lenses surgically implanted in the eye's posterior chamber behind the iris and in front of the lens to correct higher degrees of myopia and hyperopia.
# Manufacturing of Contact Lenses
Most contact lenses are mass produced.
- Spin-cast lenses - A spin cast lens is a soft contact lens manufactured by whirling liquid plastic in a revolving mold at high speed.[32]
- Lathe cut - A lathe cut contact lens is cut and ground on a lathe.[32]
- Molded
- Hybrids
Although many companies make contact lenses, there are four major manufacturers: Vistakon/Johnson & Johnson, CIBA Vision, Bausch & Lomb, and CooperVision.[33]
# Contact Lens Prescriptions
The prescribing of contact lenses is usually restricted to appropriately qualified eye care practitioners. In countries such as the United States (where all contact lenses are deemed to be medical devices by the Food and Drug Administration), the United Kingdom and Australia, optometrists are usually responsible. In France and eastern European countries, ophthalmologists play the major role. In other parts of the world, opticians usually prescribe contact lenses. Prescriptions for contact lenses and glasses may be similar, but are not interchangeable.
The practitioner or contact lens fitter typically determines an individual's suitability for contact lenses during an eye examination. Corneal health is verified; ocular allergies or dry eyes may affect a person's ability to successfully wear contact lenses. Especially above the age of 35 years dry eyes often makes wearing contact lenses too risky, especially soft lenses.
The parameters specified in a contact lenses prescription may include:
- Material (eg. Oxygen Permeability/Transmissibility (Dk/L, Dk/t), water content, modulus)
- Base curve radius (BC, BCR)
- Diameter (D, OAD)
- Power in dioptres - Spherical, Cylindrical and/or reading addition)
- Cylinder axis
- Center thickness (CT)
- Brand
Many people already wearing contact lenses order contact lenses over the internet at their own risk. It is also possible to convert the power of a glasses prescription to the power of contact lenses with the following formula:
where
- <math>d</math> is the distance of the glasses to the eye and
- <math>F = 1/D</math> are the focal length of the contact lens and the glass,
- <math>D</math> is the lens power in diopters.
The formula above is implemented in this online calculator.
In the US, The Fairness to Contact Lens Consumers Act, which became law in February, 2004, was intended to ensure the availability of contact lens prescriptions to patients [34]. Under the law consumers have a right to obtain a copy of their contact lens prescription, allowing them to fill that prescription at the business of their choice.
# Complications
Complications due to contact lens wear affect roughly 4% of contact lens wearers each year.[35] Excessive wear of contact lenses, particularly overnight wear, is associated with most of the safety concerns.[2] Problems associated with contact lens wear may affect the eyelid, the conjunctiva, the various layers of the cornea, and even the tear film that covers the outer surface of the eye.[35]
Eyelid:
- Ptosis
Conjunctiva:
- Contact dermatitis
- Giant papillary conjunctivitis
- Superior limbic keratoconjunctivitis
Cornea:
- Epithelium
- Corneal abrasion
- Corneal erosion
- Corneal ulcer
- Hypoxia
- Stroma
- Infection and keratitis
- Bacteria
- Protozoa: Acanthamoeba
- Fungal: Fusarium[36]
- Contact lens acute red eye (CLARE)
- Keratoconus
- Endothelium
# Usage
Before touching the contact lens or one's eyes, it is important to thoroughly wash & rinse hands with a soap that does not contain moisturizers or allergens such as fragrances. The technique for removing or inserting a contact lens varies slightly depending upon whether the lens is soft or rigid.
## Insertion
Contact lenses are typically inserted into the eye by placing them on the index finger with the concave side upward and raising them to touch the cornea. The other hand may be employed to keep the eye open. Problems may arise particularly with disposable soft lenses; if the surface tension between the lens and the finger is too great the lens may turn itself inside out; alternatively it may fold itself in half. When the lens first contacts the eye, a brief period of irritation may ensue as the eye aclimatises to the lens and also (if a multi-use lens is not correctly cleansed) as dirt on the lens irritates the eye. Irrigation may help during this period, which generally should not exceed one minute.
## Removal
A soft lens may be removed by holding the eyelids open and grasping the lens with opposing digits. This method can cause irritation, could risk damage to the eye and may in many cases be difficult, in part due to the blink reflex. If the lens is pushed off the cornea it will buckle up (due to the difference in curvature), making it easier to grasp.
Rigid contact lenses may be removed by pulling with one finger on the outer or lateral canthus, then blinking to cause the lens to lose adhesion. The other hand is typically cupped underneath the eye to catch the lens. There also exist small tools specifically for removing lenses, which resemble small plungers made of flexible plastic; the concave end is raised to the eye and touched to the lens, forming a seal stronger than that of the lens with the cornea and allowing the lens to be removed from the eye.
## Care (Cleaning and Disinfection)
While daily disposable lenses require no cleaning, other types require regular cleaning and disinfecting in order to retain clear vision and prevent discomfort and infections by various microorganisms including bacteria, fungi, and Acanthamoeba, that form a biofilm on the lens surface. There are a number of products that can be used to perform these tasks:
- Multipurpose solution - The most popular cleaning solution for contact lenses. Used for rinsing, disinfecting, cleaning and storing the lenses. Using this product eliminates the need for protein removal enzyme tablets in most cases. Multipurpose solutions are not effective at disinfecting Acanthamoeba from the lens.[37] In May 2007, one brand of multipurpose solution was recalled due to a cluster of Acanthamoeba infections.[38][39]
- Saline solution - Used for rinsing the lens after cleaning and preparing it for insertion. Saline solutions do not disinfect the lenses.
- Daily cleaner - Used to clean lenses on a daily basis. A few drops of cleaner are applied to the lens while it rests in the palm of the hand, then the lens is rubbed for about 20 seconds with a fingertip (check the cleaner's directions) on each side. Long fingernails can damage the lens, so care should be taken.
- Hydrogen peroxide solution - Used for disinfecting the lenses, and available as 'two-step' or 'one-step' systems. If using a 'two-step' product, one must ensure that the lens taken out of the hydrogen peroxide is neutralized before it is worn, or else wear will be extremely painful. Saline must not be used to rinse away the peroxide. Some peroxide solutions, such as CIBA Vision's Clear Care, come with a special storage case that contains a catalyzing disk. If soaked in the solution with the disk for at least six hours, the hydrogen peroxide decomposes and the remaining solution is a saline that will not harm the eye. People with extremely sensitive, irritable eyes often use these types of cleaning solutions. Peroxide solutions are the only commonly used disinfectant effective against Acanthamoeba, although the two-step solutions are more effective than the one-step, which neutralize too quickly to kill the amoeba's cysts. If you get this solution in your eyes, it is highly recommended that you go to the Emergency Room and get your eye(s) irrigated.[40]
- Enzymatic cleaner - Used for cleaning protein deposits off lenses, usually weekly, if the daily cleaner is not sufficient. Typically, this cleaner is in tablet form. Protein deposits make use of contact lenses uncomfortable, and may lead to various eye problems.
Some products must only be used with certain types of contact lenses: it is important to check the product label to make sure that it can be used for a given type of lens. It is also important to follow the product's directions carefully to reduce risk of eye infection or eye irritation.
It is important to ensure that the product does not become contaminated with microorganisms: the tips of the containers for these solutions should never touch any surface, and the container should be kept closed when not in use. To counteract minor contamination of the product and kill microorganisms on the contact lens, some products may contain preservatives such as thimerosal, benzalkonium chloride, benzyl alcohol, and other compounds. In 1989, thimerosal was responsible for about 10% of problems related to contact lenses[41]: because of this, many products no longer contain thimerosal. Preservative-free products usually have shorter shelf life. For example, non-aerosol preservative-free saline solutions can typically be used for only two weeks once opened. The introduction of silicone-hydrogel soft contact lens materials in 1999 made selection of the proper disinfecting solution more important. One study has noted several incompatibilities between these new lens materials and some solutions resulting in corneal staining.[42] | https://www.wikidoc.org/index.php/Contact_lens | |
efe2edd8e4ab8f5c012291b909a762d48ef6283f | wikidoc | Corojo Label | Corojo Label
Corojo Label is a brand of hand-made premium cigar owned by Cigar.com, Inc..
# History and Background
The development of this proprietary brand was begun in 2004 by the in-house blending team. In early 2006, the company sought out Pepin Garcia and with his aid and that of his son, Jaime, the desired final blend was obtained. It was introduced in late February of 2007. The cigars are manufactured in Estelí, Nicaragua, at Tabaclera Cubana (TACUBA). This brand is one in a series of brands, called House Blends, developed by Cigar.com and made for them by various manufacturers.
# Description
Full bodied, the wrapper is a Nicaraguan Corojo, the binder is Honduran and the filler is Nicaraguan. The cigars are packaged celloed in slide-top cabinet-style boxes of 20.
# Models/Vitolas
# Notes
- ↑ Jump up to: 1.0 1.1 1.2 Svenson, Alex, VP of Cigar.com, Inc. in litt. 2007
- ↑ House Blends (online catalogue) | Corojo Label
Corojo Label is a brand of hand-made premium cigar owned by Cigar.com, Inc..
# History and Background
The development of this proprietary brand was begun in 2004 by the in-house blending team. In early 2006, the company sought out Pepin Garcia and with his aid and that of his son, Jaime, the desired final blend was obtained. It was introduced in late February of 2007.[1] The cigars are manufactured in Estelí, Nicaragua, at Tabaclera Cubana (TACUBA).[1] This brand is one in a series of brands, called House Blends, developed by Cigar.com and made for them by various manufacturers.[2]
# Description
Full bodied, the wrapper is a Nicaraguan Corojo, the binder is Honduran and the filler is Nicaraguan.[1] The cigars are packaged celloed in slide-top cabinet-style boxes of 20.
# Models/Vitolas
# Notes
- ↑ Jump up to: 1.0 1.1 1.2 Svenson, Alex, VP of Cigar.com, Inc. in litt. 2007
- ↑ House Blends (online catalogue)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Corojo_Label | |
fb08ae994292d549d802341124c7cb7d3a3dd9d1 | wikidoc | Corticorelin | Corticorelin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Corticorelin is a diagnostic agent that is FDA approved for the diagnosis of differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing's syndrome. Common adverse reactions include flushing, tachycardia, hypotension, dyspnea, and chest compression or tightness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ACTHREL® is indicated for use in differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing's syndrome.
- There are two forms of Cushing's syndrome:
- ACTH-dependent (83%), in which hypercortisolism is due either to pituitary hypersecretion of ACTH (Cushing's disease) resulting from an adenoma (40%, usually microadenomas) or nonadenomatous hyperplasia, possibly of hypothalamic origin (28%), or to hypercortisolism that is secondary to ectopic secretion of ACTH (15%) and,
- ACTH- independent (17%), in which hypercortisolism is due to autonomous cortisol secretion by an adrenal tumor (9% adenomas, 8% carcinomas).
After the establishment of hypercortisolism consistent with the presence of Cushing's syndrome, and following the elimination of autonomous adrenal hyperfunction as its cause, the corticorelin test is used to aid in establishing the source of excessive ACTH secretion.
- The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism as follows:
- High basal plasma ACTH plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL ® injection (1 mcg/kg) results in:
- Increased plasma ACTH levels
- Increased plasma cortisol levels
- Diagnosis: Cushing's disease (ACTH of pituitary origin)
- High basal plasma ACTH (may be very high) plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL ® injection (1 mcg/kg) results in:
- Little or no response of plasma ACTH levels
- Little or no response of plasma cortisol levels
- Diagnosis: Ectopic ACTH syndrome
- Test Methodology
- To evaluate the status of the pituitary-adrenal axis in the differentiation of a pituitary source from an ectopic source of excessive ACTH secretion, a corticorelin test procedure requires a minimum of five blood samples.
- Venous blood samples should be drawn 15 minutes before and immediately prior to ACTHREL® administration. The ACTH baseline is obtained by averaging the values of the two samples.
- Administer ACTHREL® as an intravenous infusion over a 30 to 60- second interval at a dose of 1 mcg/kg body weight. Higher doses are not recommended.
- Draw venous blood samples at 15, 30, and 60 minutes after administration.
- Blood samples should be handled as recommended by the laboratory that will determine their ACTH content. It is extremely important to recognize that the reliability of the ACTHREL® test is directly related to the inter-assay and intra-assay variability of the laboratory performing the assay.
- Cortisol determinations may be performed on the same blood samples for the same time points as outlined above. The blood sample handling precautions noted for ACTH should be followed for cortisol.
- The interpretation of the ACTH and cortisol responses following ACTHREL® administration requires a knowledge of the clinical status of the individual patient, understanding of hypothalamic-pituitary-adrenal physiology, and familiarity with the normal hormonal ranges and the standards used by the laboratory that performs the ACTH and cortisol assays.
- The results of challenge with corticorelin injection have been reported in approximately 300 patients with Cushing's disease. Although the ACTH and cortisol responses were variable, a hyper-response to corticorelin was seen in a majority of patients, despite high basal cortisol levels. This response pattern indicates an impairment of the negative feedback of cortisol on the pituitary. Patients with pituitary-dependent Cushing's disease tested with corticorelin do not show the negative correlation between basal and stimulated levels of ACTH and cortisol that is found in normal subjects. A positive correlation between basal ACTH levels and maximum ACTH increments after corticorelin administration has been found in Cushing's disease patients.
- Patients with Cushing's syndrome due to ectopic ACTH secretion (N=32) were found to have very high basal levels of ACTH and cortisol, which were not further stimulated by corticorelin. However, there have been rare instances of patients with ectopic sources of ACTH that have responded to the corticorelin test.
- False negative responses to the corticorelin test in Cushing's disease patients occur approximately 5 to 10% of the time, which may lead the clinician to an incorrect diagnosis of ectopic production of ACTH at that frequency.
### Dosage
- A single intravenous dose of ACTHREL® at 1 mcg/kg is recommended for the testing of pituitary corticotrophin function. A dose of 1 mcg/kg is the lowest dose that produces maximal cortisol responses and significant (though apparently sub-maximal) ACTH responses. Doses above 1 mcg/kg are not recommended.
- At a dose of 1 mcg/kg, the ACTH and cortisol responses to ACTHREL® are prolonged and remain elevated for up to 2 hours. The maximum increment in plasma ACTH occurs between 15 and 60 minutes after ACTHREL® administration, whereas the maximum increment in plasma cortisol occurs between 30 and 120 minutes. In a clinical study of 30 normal healthy men, the peak plasma ACTH and cortisol responses to ACTHREL® administration in the early afternoon occurred at 42 ± 29 minutes and 65 ± 26 minutes (average ±SD), respectively. If a repeated evaluation using the corticorelin stimulation test with ACTHREL® is needed, it is recommended that the repeat test be carried out at the same time of day as the original test because there are differences in basal levels and peak response levels following a.m. or p.m. administration to normal humans.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Corticorelin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Corticorelin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Corticorelin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Corticorelin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Corticorelin in pediatric patients.
# Contraindications
There is limited information regarding Corticorelin Contraindications in the drug label.
# Warnings
### Precautions
- The severity of adverse effects to a corticorelin injection appear to be dose-dependent. Dosages above 1 mcg/kg are not recommended. While few adverse effects have been observed at the 1 mcg/kg or 100 mcg dose, higher doses have been associated with transient tachycardia, decreased blood pressure, loss of consciousness, and asystole. These symptoms can be substantially reduced by administering the drug as a 30-second intravenous infusion instead of a bolus injection. At a dose of 200 mcg corticorelin, 4 of 60 volunteers and patients with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis were reported to have had decreased blood pressures. One patient had a severe hypotensive reaction with asystole. Three other patients had an "absence-like" loss of consciousness lasting approximately 5 minutes. In subsequent investigations by the same researchers over a 3-year period using 100 mcg of corticorelin, one patient in approximately 150 to 200 experienced a severe drop in blood pressure and loss of sinus rhythm after receiving 55 mcg of corticorelin, which may have been due to interaction with heparin
# Adverse Reactions
## Clinical Trials Experience
- Adverse effects reported with 1 mcg/kg or 100 mcg/patient include flushing of the face, neck, and upper chest (16%; 45/276), beginning almost immediately and lasting 3 to 5 minutes. Recipients have also reported an urge to take a deep breath (6%; 3/49), which occurs with a timing similar to, but less frequently than, that of flushing. Higher doses (>3 mcg/kg) are associated with more prolonged flushing, tachycardia, hypotension, dyspnea, and "chest compression" or tightness. In addition, at doses of >5 mcg/kg, significant increases in heart rate and decreases in blood pressure were observed. The cardiovascular effects occurred 2-3 minutes after injection and lasted for 30-60 minutes. The facial flushing was more prolonged, lasting up to 4 hours in some subjects. All signs and symptoms could be reduced by administering the drug as a 30-second infusion instead of by bolus injection.
- Total doses of up to 200 mcg of corticorelin were administered as a bolus injection to 60 men and women, including both healthy normal subjects and patients with endocrine disorders. In most cases, only minor adverse effects, such as transient flushing and feelings of dyspnea, were noted. However, a few patients with disorders of the pituitary-adrenal axis had major symptoms. One patient had a precipitous fall in blood pressure and pulse rate and developed asystole, which required resuscitation. In two patients with Cushing's disease and in one with secondary adrenal insufficiency, an "absence-like" loss of consciousness occurred, which started within a few seconds after injection of corticorelin and lasted from 10 seconds to 5 minutes. This was accompanied by a slight fall in blood pressure. One patient with a well documented seizure diathesis experienced a grand mal epileptic seizure following ACTHREL® administration. The patient had discontinued anti-convulsant therapy the day of the procedure.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Corticorelin in the drug label.
# Drug Interactions
- The plasma ACTH response to corticorelin injection is inhibited or blunted in normal subjects pretreated with dexamethasone. The use of a heparin solution to maintain i.v. cannula patency during the corticorelin test is not recommended. A possible interaction between corticorelin and heparin may have been responsible for a major hypotensive reaction that occurred after corticorelin administration
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with corticorelin. It is also not known whether corticorelin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. ACTHREL® should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Corticorelin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Corticorelin during labor and delivery.
### Nursing Mothers
- It is not known whether corticorelin is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ACTHREL® is administered to a nursing woman.
### Pediatric Use
- Only a few tests have been performed on children. Dosages were 1 mcg/kg body weight. Patient studies have involved only children with multiple hypothalamic and/or pituitary hormone deficiencies, or tumors. Only two studies with normal pediatric subjects have been conducted. No differences in response to the corticorelin test have been reported in the children studied.
### Geriatic Use
There is no FDA guidance on the use of Corticorelin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Corticorelin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Corticorelin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Corticorelin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Corticorelin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Corticorelin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Corticorelin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- ACTHREL® is to be reconstituted aseptically with 2 mL of Sodium Chloride injection, USP (0.9% sodium chloride), at the time of use by injecting 2 mL of the saline diluent into the lyophilized drug product cake. To avoid bubble formation, DO NOT SHAKE the vial; instead, roll the vial to dissolve the product. The sterile solution containing 50 mcg corticorelin/mL is then ready for injection by the intravenous route. The dosage to be administered is determined by the patient's weight (1 mcg corticorelin/kg). Some of the adverse effects can be reduced by administering the drug as an infusion over 30 seconds instead of as a bolus injection.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
### Monitoring
There is limited information regarding Monitoring of Corticorelin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Corticorelin in the drug label.
# Overdosage
- Symptoms of overdose include severe facial flushing, cardiovascular changes, and dyspnea. In the event of toxic overdose, adverse effects should be treated symptomatically.
# Pharmacology
## Mechanism of Action
There is limited information regarding Corticorelin Mechanism of Action in the drug label.
## Structure
- ACTHREL® (corticorelin ovine triflutate for injection) is a sterile, nonpyrogenic, lyophilized white cake powder, containing corticorelin ovine triflutate, a trifluoroacetate salt of a synthetic peptide that is used for the determination of pituitary corticotroph responsiveness. Corticorelin ovine has an amino acid sequence identical to ovine corticotropin-releasing hormone (oCRH). Corticorelin ovine is an analogue of the naturally occurring human CRH (hCRH) peptide. Both peptides are potent stimulators of adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates cortisol production from the adrenal cortex. The structural formula for corticorelin ovine triflutate is described below:
- Ser-Gin-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gin-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH2∙xCF2COOH
- The empirical formula of corticorelin ovine is C205H339N59O63S with a molecular weight of 4670.35 Daltons.
- ACTHREL® for injection is available in vials containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The preparation is intended for intravenous administration.
## Pharmacodynamics
- In normal subjects, intravenous administration of corticorelin results in a rapid and sustained increase of plasma ACTH levels and a near parallel increase of plasma cortisol. In addition, intravenous administration of corticorelin to normal subjects causes a concomitant and prolonged release of the related proopiomelanocortin peptides β- and γ-lipotropins (β -and γ-LPH) and β-endorphin (β -END). A number of dose-response studies have been performed on normal subjects using a range of corticorelin doses. In one study, doses of corticorelin ranging from 0.001 to 30 mcg/kg body weight were administered to 29 healthy volunteers. Blood samples were taken over a 2-hour period for determination of plasma ACTH and cortisol concentrations. There was a direct dose-dependent relationship that was more pronounced for ACTH than for cortisol. The threshold dose was 0.03 mcg/kg, the half-maximal dose was 0.3-1.0 mcg/kg and the maximally effective dose was 3-10 mcg/kg.
- Plasma ACTH levels in normal subjects increased 2 minutes after injection of corticorelin doses of >0.3 mcg/kg and reached peak levels after 10-15 minutes. Plasma cortisol levels increased within 10 minutes and reached peak levels at 30 to 60 minutes. As the dose of corticorelin was increased, the rises in plasma ACTH and cortisol were more sustained, showing a biphasic response with a second lower peak at 2-3 hours after injection. Similar results were found in another study using 0.3, 3.0, and 30 mcg/kg doses. The duration of mean plasma ACTH increase after injection of 0.3, 3.0, and 30 mcg/kg was 4, 7, and 8 hours, respectively. The effect on plasma cortisol was similar, but more prolonged. Because there are differences in basal levels and peak response levels following a.m. or p.m. administration, it is recommended that subsequent evaluations in the same patient using the corticorelin stimulation test be carried out at the same time of day as the original evaluation.
- Baseline ACTH and cortisol levels are usually higher in the morning. Pooled ACTH values from normal unstressed subjects (n=119) were 25 ± 7 pg/mL in the a.m. and 10 ± 3 in the p.m.; similar pooled cortisol values (n=170) were 11 ± 3 mcg/dL in the a.m. and 4 ± 2 mcg/dL in the p.m. The normal unstressed person has about seven to ten secretory episodes of ACTH each day. Most of them occur in the early morning hours and are responsible for the morning plasma cortisol surge. The following figure shows the daily circadian rhythm of ACTH and cortisol secretions in a normal unstressed person. Insulin, plasma resin activity, prolactin, and growth hormone release are not affected by corticorelin administration in humans.
- Continuous 24-hour infusion of corticorelin (0.5, 1.0, and 3.0 mcg/kg/hr) increased plasma ACTH concentrations to a plateau of 15-20 pg/mL by the third hour and urinary-free cortisol reaches 173 ± 43 mcg/dL by 24 hours, comparable to those levels observed in patients with major depression, but less than levels noted in Cushing's disease. Continuous infusion did not abolish the circadian rhythm of plasma ACTH and cortisol, but did appear to desensitize the corticotroph. Intermittent doses of corticorelin (25 mcg every 4 hours for 72 hours), however, continued to elicit the expected ACTH and cortisol responses.
- Intravenous administration of 1 mcg/kg corticorelin in combination with 10 pressor units intramuscular vasopressin had a synergistic effect on ACTH and a less marked synergistic effect on cortisol secretion.
- The basal and peak response levels of ACTH and cortisol to a 1 mcg/kg or 100 mcg dose of corticorelin administered to normal volunteers in the morning and the evening are given below. These values were obtained by combining the results from 9 clinical trials conducted in the a.m. and 4 clinical trials conducted in the p.m.
- The following table is to be used only as a general guide.
## Pharmacokinetics
- Following a single intravenous injection of 1 mcg/kg of corticorelin to normal men, the disappearance of immunoreactive corticorelin (IR-corticorelin) from plasma follows a biexponential decay curve. Plasma half-lives for IR-corticorelin are 11.6 ± 1.5 minutes (mean ± SE) for the fast component and 73 ± 8 minutes for the slow component. The mean volume of distribution for IR-corticorelin is 6.2 ± 0.5 L with an approximate metabolic clearance rate of 95 ± 11 L/m2/day. Graded intravenous doses of corticorelin (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 mcg/kg) produced a linear increase in plasma IR-corticorelin. Corticorelin does not appear to be bound specifically by a circulating plasma protein.
## Nonclinical Toxicology
- Animal studies have not been conducted with corticorelin to evaluate carcinogenic potential, mutagenicity, or effect on fertility.
# Clinical Studies
There is limited information regarding Clinical Studies of Corticorelin in the drug label.
# How Supplied
- CTHREL® is supplied as a sterile, nonpyrogenic, lyophilized, white cake containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The package provides a single-dose, rubber-capped, 5 mL, brown-glass vial (NDC 55566-0302-1) containing 100 mcg corticorelin ovine (as the trifluoroacetate).
## Storage
- ACTHREL® is stable in the lyophilized form when stored refrigerated at 2°C to 8°C (36°F to 46°F) and protected from light. The reconstituted solution is stable up to 8 hours under refrigerated conditions. Discard unused reconstituted solution.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 100 MCG VIAL LABEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Corticorelin in the drug label.
# Precautions with Alcohol
- Alcohol-Corticorelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ACTHREL®
# Look-Alike Drug Names
There is limited information regarding Corticorelin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Corticorelin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Overview
Corticorelin is a diagnostic agent that is FDA approved for the diagnosis of differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing's syndrome. Common adverse reactions include flushing, tachycardia, hypotension, dyspnea, and chest compression or tightness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ACTHREL® is indicated for use in differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing's syndrome.
- There are two forms of Cushing's syndrome:
- ACTH-dependent (83%), in which hypercortisolism is due either to pituitary hypersecretion of ACTH (Cushing's disease) resulting from an adenoma (40%, usually microadenomas) or nonadenomatous hyperplasia, possibly of hypothalamic origin (28%), or to hypercortisolism that is secondary to ectopic secretion of ACTH (15%) and,
- ACTH- independent (17%), in which hypercortisolism is due to autonomous cortisol secretion by an adrenal tumor (9% adenomas, 8% carcinomas).
After the establishment of hypercortisolism consistent with the presence of Cushing's syndrome, and following the elimination of autonomous adrenal hyperfunction as its cause, the corticorelin test is used to aid in establishing the source of excessive ACTH secretion.
- The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism as follows:
- High basal plasma ACTH plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL ® injection (1 mcg/kg) results in:
- Increased plasma ACTH levels
- Increased plasma cortisol levels
- Diagnosis: Cushing's disease (ACTH of pituitary origin)
- High basal plasma ACTH (may be very high) plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL ® injection (1 mcg/kg) results in:
- Little or no response of plasma ACTH levels
- Little or no response of plasma cortisol levels
- Diagnosis: Ectopic ACTH syndrome
- Test Methodology
- To evaluate the status of the pituitary-adrenal axis in the differentiation of a pituitary source from an ectopic source of excessive ACTH secretion, a corticorelin test procedure requires a minimum of five blood samples.
- Venous blood samples should be drawn 15 minutes before and immediately prior to ACTHREL® administration. The ACTH baseline is obtained by averaging the values of the two samples.
- Administer ACTHREL® as an intravenous infusion over a 30 to 60- second interval at a dose of 1 mcg/kg body weight. Higher doses are not recommended.
- Draw venous blood samples at 15, 30, and 60 minutes after administration.
- Blood samples should be handled as recommended by the laboratory that will determine their ACTH content. It is extremely important to recognize that the reliability of the ACTHREL® test is directly related to the inter-assay and intra-assay variability of the laboratory performing the assay.
- Cortisol determinations may be performed on the same blood samples for the same time points as outlined above. The blood sample handling precautions noted for ACTH should be followed for cortisol.
- The interpretation of the ACTH and cortisol responses following ACTHREL® administration requires a knowledge of the clinical status of the individual patient, understanding of hypothalamic-pituitary-adrenal physiology, and familiarity with the normal hormonal ranges and the standards used by the laboratory that performs the ACTH and cortisol assays.
- The results of challenge with corticorelin injection have been reported in approximately 300 patients with Cushing's disease. Although the ACTH and cortisol responses were variable, a hyper-response to corticorelin was seen in a majority of patients, despite high basal cortisol levels. This response pattern indicates an impairment of the negative feedback of cortisol on the pituitary. Patients with pituitary-dependent Cushing's disease tested with corticorelin do not show the negative correlation between basal and stimulated levels of ACTH and cortisol that is found in normal subjects. A positive correlation between basal ACTH levels and maximum ACTH increments after corticorelin administration has been found in Cushing's disease patients.
- Patients with Cushing's syndrome due to ectopic ACTH secretion (N=32) were found to have very high basal levels of ACTH and cortisol, which were not further stimulated by corticorelin. However, there have been rare instances of patients with ectopic sources of ACTH that have responded to the corticorelin test.
- False negative responses to the corticorelin test in Cushing's disease patients occur approximately 5 to 10% of the time, which may lead the clinician to an incorrect diagnosis of ectopic production of ACTH at that frequency.
### Dosage
- A single intravenous dose of ACTHREL® at 1 mcg/kg is recommended for the testing of pituitary corticotrophin function. A dose of 1 mcg/kg is the lowest dose that produces maximal cortisol responses and significant (though apparently sub-maximal) ACTH responses. Doses above 1 mcg/kg are not recommended.
- At a dose of 1 mcg/kg, the ACTH and cortisol responses to ACTHREL® are prolonged and remain elevated for up to 2 hours. The maximum increment in plasma ACTH occurs between 15 and 60 minutes after ACTHREL® administration, whereas the maximum increment in plasma cortisol occurs between 30 and 120 minutes. In a clinical study of 30 normal healthy men, the peak plasma ACTH and cortisol responses to ACTHREL® administration in the early afternoon occurred at 42 ± 29 minutes and 65 ± 26 minutes (average ±SD), respectively. If a repeated evaluation using the corticorelin stimulation test with ACTHREL® is needed, it is recommended that the repeat test be carried out at the same time of day as the original test because there are differences in basal levels and peak response levels following a.m. or p.m. administration to normal humans.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Corticorelin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Corticorelin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Corticorelin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Corticorelin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Corticorelin in pediatric patients.
# Contraindications
There is limited information regarding Corticorelin Contraindications in the drug label.
# Warnings
### Precautions
- The severity of adverse effects to a corticorelin injection appear to be dose-dependent. Dosages above 1 mcg/kg are not recommended. While few adverse effects have been observed at the 1 mcg/kg or 100 mcg dose, higher doses have been associated with transient tachycardia, decreased blood pressure, loss of consciousness, and asystole. These symptoms can be substantially reduced by administering the drug as a 30-second intravenous infusion instead of a bolus injection. At a dose of 200 mcg corticorelin, 4 of 60 volunteers and patients with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis were reported to have had decreased blood pressures. One patient had a severe hypotensive reaction with asystole. Three other patients had an "absence-like" loss of consciousness lasting approximately 5 minutes. In subsequent investigations by the same researchers over a 3-year period using 100 mcg of corticorelin, one patient in approximately 150 to 200 experienced a severe drop in blood pressure and loss of sinus rhythm after receiving 55 mcg of corticorelin, which may have been due to interaction with heparin
# Adverse Reactions
## Clinical Trials Experience
- Adverse effects reported with 1 mcg/kg or 100 mcg/patient include flushing of the face, neck, and upper chest (16%; 45/276), beginning almost immediately and lasting 3 to 5 minutes. Recipients have also reported an urge to take a deep breath (6%; 3/49), which occurs with a timing similar to, but less frequently than, that of flushing. Higher doses (>3 mcg/kg) are associated with more prolonged flushing, tachycardia, hypotension, dyspnea, and "chest compression" or tightness. In addition, at doses of >5 mcg/kg, significant increases in heart rate and decreases in blood pressure were observed. The cardiovascular effects occurred 2-3 minutes after injection and lasted for 30-60 minutes. The facial flushing was more prolonged, lasting up to 4 hours in some subjects. All signs and symptoms could be reduced by administering the drug as a 30-second infusion instead of by bolus injection.
- Total doses of up to 200 mcg of corticorelin were administered as a bolus injection to 60 men and women, including both healthy normal subjects and patients with endocrine disorders. In most cases, only minor adverse effects, such as transient flushing and feelings of dyspnea, were noted. However, a few patients with disorders of the pituitary-adrenal axis had major symptoms. One patient had a precipitous fall in blood pressure and pulse rate and developed asystole, which required resuscitation. In two patients with Cushing's disease and in one with secondary adrenal insufficiency, an "absence-like" loss of consciousness occurred, which started within a few seconds after injection of corticorelin and lasted from 10 seconds to 5 minutes. This was accompanied by a slight fall in blood pressure. One patient with a well documented seizure diathesis experienced a grand mal epileptic seizure following ACTHREL® administration. The patient had discontinued anti-convulsant therapy the day of the procedure.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Corticorelin in the drug label.
# Drug Interactions
- The plasma ACTH response to corticorelin injection is inhibited or blunted in normal subjects pretreated with dexamethasone. The use of a heparin solution to maintain i.v. cannula patency during the corticorelin test is not recommended. A possible interaction between corticorelin and heparin may have been responsible for a major hypotensive reaction that occurred after corticorelin administration
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with corticorelin. It is also not known whether corticorelin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. ACTHREL® should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Corticorelin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Corticorelin during labor and delivery.
### Nursing Mothers
- It is not known whether corticorelin is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ACTHREL® is administered to a nursing woman.
### Pediatric Use
- Only a few tests have been performed on children. Dosages were 1 mcg/kg body weight. Patient studies have involved only children with multiple hypothalamic and/or pituitary hormone deficiencies, or tumors. Only two studies with normal pediatric subjects have been conducted. No differences in response to the corticorelin test have been reported in the children studied.
### Geriatic Use
There is no FDA guidance on the use of Corticorelin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Corticorelin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Corticorelin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Corticorelin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Corticorelin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Corticorelin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Corticorelin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- ACTHREL® is to be reconstituted aseptically with 2 mL of Sodium Chloride injection, USP (0.9% sodium chloride), at the time of use by injecting 2 mL of the saline diluent into the lyophilized drug product cake. To avoid bubble formation, DO NOT SHAKE the vial; instead, roll the vial to dissolve the product. The sterile solution containing 50 mcg corticorelin/mL is then ready for injection by the intravenous route. The dosage to be administered is determined by the patient's weight (1 mcg corticorelin/kg). Some of the adverse effects can be reduced by administering the drug as an infusion over 30 seconds instead of as a bolus injection.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
### Monitoring
There is limited information regarding Monitoring of Corticorelin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Corticorelin in the drug label.
# Overdosage
- Symptoms of overdose include severe facial flushing, cardiovascular changes, and dyspnea. In the event of toxic overdose, adverse effects should be treated symptomatically.
# Pharmacology
## Mechanism of Action
There is limited information regarding Corticorelin Mechanism of Action in the drug label.
## Structure
- ACTHREL® (corticorelin ovine triflutate for injection) is a sterile, nonpyrogenic, lyophilized white cake powder, containing corticorelin ovine triflutate, a trifluoroacetate salt of a synthetic peptide that is used for the determination of pituitary corticotroph responsiveness. Corticorelin ovine has an amino acid sequence identical to ovine corticotropin-releasing hormone (oCRH). Corticorelin ovine is an analogue of the naturally occurring human CRH (hCRH) peptide. Both peptides are potent stimulators of adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates cortisol production from the adrenal cortex. The structural formula for corticorelin ovine triflutate is described below:
- Ser-Gin-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gin-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH2∙xCF2COOH
- The empirical formula of corticorelin ovine is C205H339N59O63S with a molecular weight of 4670.35 Daltons.
- ACTHREL® for injection is available in vials containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The preparation is intended for intravenous administration.
## Pharmacodynamics
- In normal subjects, intravenous administration of corticorelin results in a rapid and sustained increase of plasma ACTH levels and a near parallel increase of plasma cortisol. In addition, intravenous administration of corticorelin to normal subjects causes a concomitant and prolonged release of the related proopiomelanocortin peptides β- and γ-lipotropins (β -and γ-LPH) and β-endorphin (β -END). A number of dose-response studies have been performed on normal subjects using a range of corticorelin doses. In one study, doses of corticorelin ranging from 0.001 to 30 mcg/kg body weight were administered to 29 healthy volunteers. Blood samples were taken over a 2-hour period for determination of plasma ACTH and cortisol concentrations. There was a direct dose-dependent relationship that was more pronounced for ACTH than for cortisol. The threshold dose was 0.03 mcg/kg, the half-maximal dose was 0.3-1.0 mcg/kg and the maximally effective dose was 3-10 mcg/kg.
- Plasma ACTH levels in normal subjects increased 2 minutes after injection of corticorelin doses of >0.3 mcg/kg and reached peak levels after 10-15 minutes. Plasma cortisol levels increased within 10 minutes and reached peak levels at 30 to 60 minutes. As the dose of corticorelin was increased, the rises in plasma ACTH and cortisol were more sustained, showing a biphasic response with a second lower peak at 2-3 hours after injection. Similar results were found in another study using 0.3, 3.0, and 30 mcg/kg doses. The duration of mean plasma ACTH increase after injection of 0.3, 3.0, and 30 mcg/kg was 4, 7, and 8 hours, respectively. The effect on plasma cortisol was similar, but more prolonged. Because there are differences in basal levels and peak response levels following a.m. or p.m. administration, it is recommended that subsequent evaluations in the same patient using the corticorelin stimulation test be carried out at the same time of day as the original evaluation.
- Baseline ACTH and cortisol levels are usually higher in the morning. Pooled ACTH values from normal unstressed subjects (n=119) were 25 ± 7 pg/mL in the a.m. and 10 ± 3 in the p.m.; similar pooled cortisol values (n=170) were 11 ± 3 mcg/dL in the a.m. and 4 ± 2 mcg/dL in the p.m. The normal unstressed person has about seven to ten secretory episodes of ACTH each day. Most of them occur in the early morning hours and are responsible for the morning plasma cortisol surge. The following figure shows the daily circadian rhythm of ACTH and cortisol secretions in a normal unstressed person. Insulin, plasma resin activity, prolactin, and growth hormone release are not affected by corticorelin administration in humans.
- Continuous 24-hour infusion of corticorelin (0.5, 1.0, and 3.0 mcg/kg/hr) increased plasma ACTH concentrations to a plateau of 15-20 pg/mL by the third hour and urinary-free cortisol reaches 173 ± 43 mcg/dL by 24 hours, comparable to those levels observed in patients with major depression, but less than levels noted in Cushing's disease. Continuous infusion did not abolish the circadian rhythm of plasma ACTH and cortisol, but did appear to desensitize the corticotroph. Intermittent doses of corticorelin (25 mcg every 4 hours for 72 hours), however, continued to elicit the expected ACTH and cortisol responses.
- Intravenous administration of 1 mcg/kg corticorelin in combination with 10 pressor units intramuscular vasopressin had a synergistic effect on ACTH and a less marked synergistic effect on cortisol secretion.
- The basal and peak response levels of ACTH and cortisol to a 1 mcg/kg or 100 mcg dose of corticorelin administered to normal volunteers in the morning and the evening are given below. These values were obtained by combining the results from 9 clinical trials conducted in the a.m. and 4 clinical trials conducted in the p.m.
- The following table is to be used only as a general guide.
## Pharmacokinetics
- Following a single intravenous injection of 1 mcg/kg of corticorelin to normal men, the disappearance of immunoreactive corticorelin (IR-corticorelin) from plasma follows a biexponential decay curve. Plasma half-lives for IR-corticorelin are 11.6 ± 1.5 minutes (mean ± SE) for the fast component and 73 ± 8 minutes for the slow component. The mean volume of distribution for IR-corticorelin is 6.2 ± 0.5 L with an approximate metabolic clearance rate of 95 ± 11 L/m2/day. Graded intravenous doses of corticorelin (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 mcg/kg) produced a linear increase in plasma IR-corticorelin. Corticorelin does not appear to be bound specifically by a circulating plasma protein.
## Nonclinical Toxicology
- Animal studies have not been conducted with corticorelin to evaluate carcinogenic potential, mutagenicity, or effect on fertility.
# Clinical Studies
There is limited information regarding Clinical Studies of Corticorelin in the drug label.
# How Supplied
- CTHREL® is supplied as a sterile, nonpyrogenic, lyophilized, white cake containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The package provides a single-dose, rubber-capped, 5 mL, brown-glass vial (NDC 55566-0302-1) containing 100 mcg corticorelin ovine (as the trifluoroacetate).
## Storage
- ACTHREL® is stable in the lyophilized form when stored refrigerated at 2°C to 8°C (36°F to 46°F) and protected from light. The reconstituted solution is stable up to 8 hours under refrigerated conditions. Discard unused reconstituted solution.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 100 MCG VIAL LABEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Corticorelin in the drug label.
# Precautions with Alcohol
- Alcohol-Corticorelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ACTHREL®[1]
# Look-Alike Drug Names
There is limited information regarding Corticorelin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Corticorelin | |
7b8446fd7c23d7e2c39f59b0f7e43d7cbfa69057 | wikidoc | Corticovirus | Corticovirus
The Corticovirus or Corticoviridae are a family of phages that consist of a round, icosahedral, non-enveloped capsid of a diameter of 60 nm and an internal lipid membrane located between outer and inner protein shell. The shells are composed of three layers which surfaces reveals a pattern with distinctive features, including bush-like spikes protruding from the twelve vertices.
# Genome
The genome is not segmented, constitutes 13% of the virus's weight and contains a single molecule of circular, supercoiled, double-stranded DNA of 9500-12000 nucleotides in length. The genome has a g + c content of 43%.
# Literature
- ↑ Kiveld, H.M., Kalkkinen, N. and Bamford, D.H. (2002). Bacteriophage PM2 has a protein capsid surrounding a spherical lipid-protein core. J. Virol., 76, 8169-8178.
- ↑ Kiveld, H.M., Männistö, R.H., Kalkkinen, N. and Bamford, D.H. (1999). Purification and protein composition of PM2, the first lipid-containing bacterial virus to be isolated. Virology, 262, 364-374.
- ↑ Harrison, S.C., Caspar, D.L., Camerini-Otero, R.D. and Franklin, R.M. (1971). Lipid and protein arrangement in bacteriophage PM2. Nat. New Biol., 229, 197-201.
- ↑ Männistö, R.H., Kivelä, H.M., Paulin, L., Bamford, D.H. and Bamford, J.K.H. (1999). The complete genome sequence of PM2, the first lipid-containing bacterial virus to be isolated. Virology, 262, 355-363. | Corticovirus
The Corticovirus or Corticoviridae are a family of phages that consist of a round, icosahedral, non-enveloped capsid of a diameter of 60 nm and an internal lipid membrane located between outer and inner protein shell[1]. The shells are composed of three layers which surfaces reveals a pattern with distinctive features[2], including bush-like spikes protruding from the twelve vertices[3].
# Genome
The genome is not segmented, constitutes 13% of the virus's weight and contains a single molecule of circular, supercoiled, double-stranded DNA of 9500-12000 nucleotides in length. The genome has a g + c content of 43%[4].
# Literature
- ↑ Kiveld, H.M., Kalkkinen, N. and Bamford, D.H. (2002). Bacteriophage PM2 has a protein capsid surrounding a spherical lipid-protein core. J. Virol., 76, 8169-8178.
- ↑ Kiveld, H.M., Männistö, R.H., Kalkkinen, N. and Bamford, D.H. (1999). Purification and protein composition of PM2, the first lipid-containing bacterial virus to be isolated. Virology, 262, 364-374.
- ↑ Harrison, S.C., Caspar, D.L., Camerini-Otero, R.D. and Franklin, R.M. (1971). Lipid and protein arrangement in bacteriophage PM2. Nat. New Biol., 229, 197-201.
- ↑ Männistö, R.H., Kivelä, H.M., Paulin, L., Bamford, D.H. and Bamford, J.K.H. (1999). The complete genome sequence of PM2, the first lipid-containing bacterial virus to be isolated. Virology, 262, 355-363.
Template:Virus-stub | https://www.wikidoc.org/index.php/Corticoviridae | |
672950160867dd4ee6ae858ddfc7ad3a851ac506 | wikidoc | Cremophor EL | Cremophor EL
Cremophor EL® is the registered trademark of BASF Corp. for its version of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. The resulting product is a mixture (CAS number 61791-12-6): the major component is the material in which the hydroxyl groups of the castor oil triglyceride have ethoxylated with ethylene oxide to form polyethylene glycol ethers. Minor components are the polyethyelene glycol esters of ricinoleic acid, polyethyelene glycols and polyethyelene glycol ethers of glycerol. . Cremophor EL is a synthetic, nonionic surfactant. Its utility comes from its ability to stabilize emulsions of nonpolar materials in aqueous systems.
Cremophor EL is an excipient or additive in drugs. Therapeutically, modern drugs are rarely given in a pure chemical state, so most active ingredients are combined with excipients or additives such as Cremophor EL
# Uses
- Miconazole, anti-fungal
- Paclitaxel, anti-cancer
- Aci-Jel (acetic acid / oxyquinoline / ricinoleic acid - vaginal)
- Sandimmune (cyclosporine injection, USP)
- Nelfinavir mesylate, HIV protese inhibitor
Cremophor EL is used in Taxol (paclitaxel) and has been called as a dose limiting agent because of its toxicities. (A formulation of paclitaxel that uses nanoparticle albumin instead of Cremophor EL is marketed as an alternative.) | Cremophor EL
Cremophor EL® is the registered trademark of BASF Corp. for its version of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. The resulting product is a mixture (CAS number 61791-12-6): the major component is the material in which the hydroxyl groups of the castor oil triglyceride have ethoxylated with ethylene oxide to form polyethylene glycol ethers. Minor components are the polyethyelene glycol esters of ricinoleic acid, polyethyelene glycols and polyethyelene glycol ethers of glycerol.[1] . Cremophor EL is a synthetic, nonionic surfactant. Its utility comes from its ability to stabilize emulsions of nonpolar materials in aqueous systems.
Cremophor EL is an excipient or additive in drugs. Therapeutically, modern drugs are rarely given in a pure chemical state, so most active ingredients are combined with excipients or additives such as Cremophor EL [2]
# Uses
- Miconazole, anti-fungal
- Paclitaxel, anti-cancer
- Aci-Jel (acetic acid / oxyquinoline / ricinoleic acid - vaginal)
- Sandimmune (cyclosporine injection, USP)
- Nelfinavir mesylate, HIV protese inhibitor
Cremophor EL is used in Taxol (paclitaxel) and has been called as a dose limiting agent because of its toxicities. (A formulation of paclitaxel that uses nanoparticle albumin instead of Cremophor EL is marketed as an alternative.[3][4]) | https://www.wikidoc.org/index.php/Cremophor | |
53878122bb7712393f9718ba6fbdb50e2f5488ed | wikidoc | Rosuvastatin | Rosuvastatin
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# Overview
Rosuvastatin is a HMG-CoA reductase inhibitor that is FDA approved for the treatment of hyperlipidemia and mixed dyslipidemia, hypertriglyceridemia, primary dysbetalipoproteinemia (Type III hyperlipoproteinemia), homozygous familial hypercholesterolemia, slowing of the progression of atherosclerosis, primary prevention of cardiovascular disease. Common adverse reactions include headache, myalgia, abdominal pain, asthenia, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 5 to 40 mg orally once daily.
### Homozygous Familial Hypercholesterolemia
- Dosing Information
- 20 mg once daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rosuvastatin in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 40 mg preprocedure
- Dosing Information
- 20 mg/day
- Dosing Information
- 10 mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- 5‑20 mg/day; the maximum recommended dose is 20 mg/day
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rosuvastatin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rosuvastatin in pediatric patients.
# Contraindications
- Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin.
- Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels.
- Women who are pregnant or may become pregnant. Because HMG‑CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin may cause fetal harm when administered to regnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
- Nursing mothers. Because another drug in this class passes into breast milk, and because HMG‑CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require rosuvastatin treatment should be advised not to nurse their infants.
# Warnings
### Skeletal Muscle Effects
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg).
Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment).
The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, lopinavir/ritonavir, or atazanavir/ritonavir. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin with colchicine.
Rosuvastatin therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin.
### Liver Enzyme Abnormalities
It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin, and if signs or symptoms of liver injury occur.
Increases in serum transaminases AST (SGOT) or ALT (SGPT) have been reported with HMG‑CoA reductase inhibitors, including rosuvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.
In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin.
Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of rosuvastatin.
### Concomitant Coumarin Anticoagulants
Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs.
### Proteinuria and Hematuria
In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator HMG‑CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.
### Endocrine Effects
Increases in HbA1c and fasting serum glucose levels have been reported with HMG‑CoA reductase inhibitors, including rosuvastatin. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus.
Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.
# Adverse Reactions
## Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Adverse reactions reported in ≥ 2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.
Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.
In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea.
Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 2.
In the JUPITER study, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.
In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients.
Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 3.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of rosuvastatin : arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares) and gynecomastia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
# Drug Interactions
### Cyclosporine
Cyclosporine increased rosuvastatin exposure (AUC) 7‑fold. Therefore, in patients taking cyclosporine, the dose of rosuvastatin should not exceed 5 mg once daily.
### Gemfibrozil
Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with rosuvastatin and gemfibrozil should be avoided. If used together, the dose of rosuvastatin should not exceed 10 mg once daily.
### Protease Inhibitors
Coadministration of rosuvastatin with certain protease inhibitors given in combination with ritonavir has differing effects on rosuvastatin exposure. The protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure (AUC) up to threefold. For these combinations the dose of rosuvastatin should not exceed 10 mg once daily. The combinations of tipranavir/ritonavir or fosamprenavir/ritonavir produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors given in combination with ritonavir.
### Coumarin Anticoagulants
Rosuvastatin significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with rosuvastatin. In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR] occurs.
### Niacin
The risk of skeletal muscle effects may be enhanced when rosuvastatin is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with rosuvastatin.
### Fenofibrate
When rosuvastatin was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with rosuvastatin.
### Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with HMG‑CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin with colchicine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Rosuvastatin is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy
There are no adequate and well-controlled studies of rosuvastatin in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-fourfold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Rosuvastatin crosses the placenta in rats and rabbits. In rats, rosuvastatin was not teratogenic at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10 12 times the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight among female pups, and delayed ossification. In rabbits, pup viability decreased and maternal mortality increased at doses equivalent to the human dose of 40 mg/day
Rosuvastatin may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking rosuvastatin, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rosuvastatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rosuvastatin during labor and delivery.
### Nursing Mothers
It is not known whether rosuvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of rosuvastatin are three times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG‑CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require rosuvastatin treatment should be advised not to nurse their infants.
### Pediatric Use
The safety and effectiveness of rosuvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial of 12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg, 10 mg, and 20 mg daily rosuvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. There was no detectable effect of rosuvastatin on growth, weight, BMI (body mass index), or sexual maturation in pediatric patients (10 to 17 years of age). Adolescent females should be counseled on appropriate contraceptive methods while on rosuvastatin therapy. Rosuvastatin has not been studied in controlled clinical trials involving prepubertal patients or patients younger than 10 years of age. Doses of rosuvastatin greater than 20 mg have not been studied in the pediatric population.
In children and adolescents with homozygous familial hypercholesterolemia experience is limited to eight patients (aged 8 years and above).
In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with heterozygous familial hypercholesterolemia received single and multiple oral doses of rosuvastatin . Both Cmax and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses.
### Geriatic Use
Of the 10,275 patients in clinical studies with rosuvastatin, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Elderly patients are at higher risk of myopathy and rosuvastatin should be prescribed with caution in the elderly
### Gender
There is no FDA guidance on the use of Rosuvastatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rosuvastatin with respect to specific racial populations.
### Renal Impairment
Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr ≥ 30 mL/min/1.73 m2); however, exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment who are not receiving hemodialysis. Rosuvastatin dosing should be adjusted in patients with severe renal impairment (CLcr < 30 mL/min/1.73 m2) not requiring hemodialysis.
### Hepatic Impairment
Rosuvastatin is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; Rosuvastatin should be used with caution in these patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rosuvastatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rosuvastatin in patients who are immunocompromised.
### Asian Patients
Pharmacokinetic studies have demonstrated an approximate 2‑fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. Rosuvastatin dosage should be adjusted in Asian patients
# Administration and Monitoring
### Administration
Oral
### Monitoring
In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs.
# IV Compatibility
There is limited information regarding the compatibility of Rosuvastatin and IV administrations.
# Overdosage
There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.
# Pharmacology
## Mechanism of Action
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3‑hydroxy‑3‑methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.
## Structure
The chemical name for rosuvastatin calcium is bis-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula:
The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca and the molecular weight is 1001.14. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0.
## Pharmacodynamics
There is limited information regarding Rosuvastatin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration.
- Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
- Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG‑CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG‑CoA reductase inhibitory activity is accounted for by the parent compound.
- Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t1/2) of rosuvastatin is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.
- Race: A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2‑fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group.
- Gender: There were no differences in plasma concentrations of rosuvastatin between men and women.
- Geriatric: There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).
- Renal Impairment: Mild to moderate renal impairment (CrCl ≥ 30 mL/min/1.73 m2) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3‑fold) in patients with severe renal impairment (CrCl 80 mL/min/1.73 m2).
- Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.
- Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased.
- In patients with Child‑Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function.
- In patients with Child‑Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.
In a 107-week carcinogenicity study in mice given 10, 60, 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.
Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.
In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6‑month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.
### Animal Toxicology and/or Pharmacology
Rosuvastatin crosses the placenta and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.
In female rats given oral gavage doses of 5, 15, 50 mg/kg/day rosuvastatin before mating and continuing through day 7 postcoitus results in decreased fetal body weight (female pups) and delayed ossification at the high dose (systemic exposures 10 times the human exposure at 40 mg/day based on AUC).
In pregnant rats given oral gavage doses of 2, 10, 50 mg/kg/day from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred in groups given 50 mg/kg/day, systemic exposures ≥ 12 times the human exposure at 40 mg/day based on body surface area.
In pregnant rabbits given oral gavage doses of 0.3, 1, 3 mg/kg/day from gestation day 6 to lactation day 18 (weaning), exposures equivalent to the human exposure at 40 mg/day based on body surface area, decreased fetal viability and maternal mortality was observed.
Rosuvastatin was not teratogenic in rats at ≤ 25 mg/kg/day or in rabbits ≤ 3 mg/kg/day (systemic exposures equivalent to the human exposure at 40 mg/day based on AUC or body surface area, respectively).
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year.
# Clinical Studies
### Hyperlipidemia and Mixed Dyslipidemia
Rosuvastatin reduces Total‑C, LDL‑C, ApoB, nonHDL‑C, and TG, and increases HDL‑C, in adult patients with ] and mixed dyslipidemia.
Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with ] rosuvastatin given as a single daily dose for 6 weeks significantly reduced Total‑C, LDL‑C, nonHDL‑C, and ApoB, across the dose range.
Active-Controlled Study: rosuvastatin was compared with the HMG‑CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin in a multicenter, open-label, dose-ranging study of 2240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either rosuvastatin, atorvastatin, simvastatin, or pravastatin (Figure 1 and Table 7).
Figure 1. Percent LDL‑ C Change by Dose of rosuvastatin, Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Patients with ] or Mixed Dyslipidemia
Box plots are a representation of the 25th, 50th, and 75th percentile values, with whiskers representing the 10th and 90th percentile values. Mean baseline LDL‑C: 189 mg/dL
### Heterozygous Familial Hypercholesterolemia
Active-Controlled Study: In a study of patients with heterozygous FH (baseline mean LDL of 291), patients were randomized to rosuvastatin 20 mg or atorvastatin 20 mg. The dose was increased by 6-week intervals. Significant LDL-C reductions from baseline were seen at each dose in both treatment groups (Table 8).
### Hypertriglyceridemia
Dose-Response Study: In a double-blind, placebo-controlled dose-response study in patients with baseline TG levels from 273 to 817 mg/dL, rosuvastatin given as a single daily dose (5 to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 9).
### Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
In a randomized, multicenter, double-blind crossover study, 32 patients (27 with є2/є2 and 4 with apo E mutation with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) entered a 6-week dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet. Following dietary lead-in, patients were randomized to a sequence of treatments in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg. rosuvastatin reduced nonHDL‑C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table below.
### Homozygous Familial Hypercholesterolemia
Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8‑63 years) were evaluated for their response to rosuvastatin 20 to 40 mg titrated at a 6‑week interval. In the overall population, the mean LDL‑C reduction from baseline was 22%. About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL‑C, the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL‑C reduction of <15%, 3 had no change or an increase in LDL‑C. Reductions in LDL‑C of 15% or greater were observed in 3 of 5 patients with known receptor negative status.
### Pediatric Patients with Heterozygous Familial Hypercholesterolemia
In a double blind, randomized, multicenter, placebo-controlled, 12 week study, 176 (97 male and 79 female) children and adolescents with heterozygous familial Hypercholesterolemia were randomized to rosuvastatin 5, 10 or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively. Females were at least 1 year postmenarche. Mean LDL C at baseline was 233 mg/dL (range of 129 to 399). The 12 week double blind phase was followed by a 40 week open label dose-titration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg rosuvastatin daily.
Rosuvastatin significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels at each dose compared to placebo. Results are shown in Table 11 below.
At the end of the 12 week, double blind treatment period, the percentage of patients achieving the LDL C goal of less than 110 mg/dL (2.8 mmol/L) was 0% for placebo, 12% for rosuvastatin 5 mg, 41% for rosuvastatin 10 mg and 41% for rosuvastatin 20 mg. For the 40 week, open label phase, 71% of the patients were titrated to the maximum dose of 20 mg and 41% of the patients achieved the LDL C goal of 110 mg/dL.
The long-term efficacy of rosuvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.
### Slowing of the Progression of Atherosclerosis
In the Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin 40 mg (METEOR) study, the effect of therapy with rosuvastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in patients with elevated LDL‑C, at low risk (Framingham risk <10% over ten years) for symptomatic coronary artery disease and with subclinical atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind, placebo-controlled clinical study 984 patients were randomized (of whom 876 were analyzed) in a 5:2 ratio to rosuvastatin 40 mg or placebo once daily. Ultrasonograms of the carotid walls were used to determine the annualized rate of change per patient from baseline to two years in mean maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the maximum cIMT analyzed over all 12 carotid artery sites between patients treated with rosuvastatin and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, –0.0093; p<0.0001).
The annualized rate of change from baseline for the placebo group was +0.0131 mm/year (p<0.0001). The annualized rate of change from baseline for the group treated with rosuvastatin was -0.0014 mm/year (p=0.32).
At an individual patient level in the group treated with rosuvastatin, 52.1% of patients demonstrated an absence of disease progression (defined as a negative annualized rate of change), compared to 37.7% of patients in the placebo group.
### Primary Prevention of Cardiovascular Disease
In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of rosuvastatin (rosuvastatin calcium) on the occurrence of major cardiovascular (CV) disease events was assessed in 17,802 men (≥50 years) and women (≥60 years) who had no clinically evident cardiovascular disease, LDL‑C levels <130 mg/dL (3.3 mmol/l) and hs‑CRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL‑C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%). Study participants had a median baseline LDL‑C of 108 mg/dL and hsCRP of 4.3 mg/L. Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects.
The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure.
Rosuvastatin significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0.001) relative risk reduction of 44% and absolute risk reduction of 1.2% (see Figure 2). The risk reduction for the primary end point was consistent across the following predefined subgroups: age, sex, race, smoking status, family history of premature CHD, body mass index, LDL‑C, HDL‑C, and hsCRP levels.
Figure 2. Time to first occurrence of major cardiovascular events in JUPITER
The individual components of the primary end point are presented in Figure 3. Rosuvastatin significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the rosuvastatin and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina.
Rosuvastatin significantly reduced the risk of myocardial infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in rosuvastatin-treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in rosuvastatin-treated subjects).
In a post-hoc subgroup analysis of JUPITER subjects (n=1405; rosuvastatin=725, placebo=680) with a hsCRP ≥2 mg/L and no other traditional risk factors (smoking, BP ≥140/90 or taking antihypertensives, low HDL‑C) other than age, after adjustment for high HDL‑C, there was no significant treatment benefit with rosuvastatin treatment.
At one year, rosuvastatin increased HDL‑C and reduced LDL‑C, hsCRP, total cholesterol and serum triglyceride levels (p<0.001 for all versus placebo).
# How Supplied
CRESTOR® (rosuvastatin calcium) Tablets are supplied as:
- NDC 0310-0755-90: 5 mg. Yellow, round, biconvex, coated tablets. Debossed “CRESTOR” and “5” on one side; bottle of 90 tablets
- NDC 0310-0751-90: 10 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side; bottle of 90 tablets
- NDC 0310-0751-39: 10 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side; unit dose packages of 100
- NDC 0310-0752-90: 20 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20” on one side; bottles of 90
- NDC 0310-0752-39: 20 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20”on one side; unit dose packages of 100
- NDC 0310-0754-30: 40 mg. Pink, oval, biconvex, coated tablets. Debossed “CRESTOR” on one side and “40” on the other side; bottles of 30
## Storage
Store at controlled room temperature, 20‑25ºC (68-77ºF). Protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Skeletal Muscle Effects
Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin.
### Concomitant Use of Antacids
When taking rosuvastatin with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin administration.
### Pregnancy
If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
### Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
# Precautions with Alcohol
Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.
# Brand Names
Crestor
# Look-Alike Drug Names
There is limited information regarding Rosuvastatin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Rosuvastatin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
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# Overview
Rosuvastatin is a HMG-CoA reductase inhibitor that is FDA approved for the treatment of hyperlipidemia and mixed dyslipidemia, hypertriglyceridemia, primary dysbetalipoproteinemia (Type III hyperlipoproteinemia), homozygous familial hypercholesterolemia, slowing of the progression of atherosclerosis, primary prevention of cardiovascular disease. Common adverse reactions include headache, myalgia, abdominal pain, asthenia, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 5 to 40 mg orally once daily.
### Homozygous Familial Hypercholesterolemia
- Dosing Information
- 20 mg once daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rosuvastatin in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 40 mg preprocedure
- Dosing Information
- 20 mg/day
- Dosing Information
- 10 mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- 5‑20 mg/day; the maximum recommended dose is 20 mg/day
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rosuvastatin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rosuvastatin in pediatric patients.
# Contraindications
- Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin.
- Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels.
- Women who are pregnant or may become pregnant. Because HMG‑CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin may cause fetal harm when administered to regnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
- Nursing mothers. Because another drug in this class passes into breast milk, and because HMG‑CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require rosuvastatin treatment should be advised not to nurse their infants.
# Warnings
### Skeletal Muscle Effects
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg).
Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment).
The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, lopinavir/ritonavir, or atazanavir/ritonavir. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin with colchicine.
Rosuvastatin therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin.
### Liver Enzyme Abnormalities
It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin, and if signs or symptoms of liver injury occur.
Increases in serum transaminases AST (SGOT) or ALT (SGPT) have been reported with HMG‑CoA reductase inhibitors, including rosuvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.
In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin.
Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of rosuvastatin.
### Concomitant Coumarin Anticoagulants
Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs.
### Proteinuria and Hematuria
In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator HMG‑CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.
### Endocrine Effects
Increases in HbA1c and fasting serum glucose levels have been reported with HMG‑CoA reductase inhibitors, including rosuvastatin. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus.
Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.
# Adverse Reactions
## Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Adverse reactions reported in ≥ 2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.
Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.
In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea.
Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 2.
In the JUPITER study, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.
In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients.
Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 3.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of rosuvastatin : arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares) and gynecomastia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
# Drug Interactions
### Cyclosporine
Cyclosporine increased rosuvastatin exposure (AUC) 7‑fold. Therefore, in patients taking cyclosporine, the dose of rosuvastatin should not exceed 5 mg once daily.
### Gemfibrozil
Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with rosuvastatin and gemfibrozil should be avoided. If used together, the dose of rosuvastatin should not exceed 10 mg once daily.
### Protease Inhibitors
Coadministration of rosuvastatin with certain protease inhibitors given in combination with ritonavir has differing effects on rosuvastatin exposure. The protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure (AUC) up to threefold. For these combinations the dose of rosuvastatin should not exceed 10 mg once daily. The combinations of tipranavir/ritonavir or fosamprenavir/ritonavir produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors given in combination with ritonavir.
### Coumarin Anticoagulants
Rosuvastatin significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with rosuvastatin. In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR] occurs.
### Niacin
The risk of skeletal muscle effects may be enhanced when rosuvastatin is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with rosuvastatin.
### Fenofibrate
When rosuvastatin was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with rosuvastatin.
### Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with HMG‑CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin with colchicine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Rosuvastatin is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy
There are no adequate and well-controlled studies of rosuvastatin in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-fourfold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Rosuvastatin crosses the placenta in rats and rabbits. In rats, rosuvastatin was not teratogenic at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10 12 times the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight among female pups, and delayed ossification. In rabbits, pup viability decreased and maternal mortality increased at doses equivalent to the human dose of 40 mg/day
Rosuvastatin may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking rosuvastatin, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rosuvastatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rosuvastatin during labor and delivery.
### Nursing Mothers
It is not known whether rosuvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of rosuvastatin are three times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG‑CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require rosuvastatin treatment should be advised not to nurse their infants.
### Pediatric Use
The safety and effectiveness of rosuvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial of 12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg, 10 mg, and 20 mg daily rosuvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. There was no detectable effect of rosuvastatin on growth, weight, BMI (body mass index), or sexual maturation in pediatric patients (10 to 17 years of age). Adolescent females should be counseled on appropriate contraceptive methods while on rosuvastatin therapy. Rosuvastatin has not been studied in controlled clinical trials involving prepubertal patients or patients younger than 10 years of age. Doses of rosuvastatin greater than 20 mg have not been studied in the pediatric population.
In children and adolescents with homozygous familial hypercholesterolemia experience is limited to eight patients (aged 8 years and above).
In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with heterozygous familial hypercholesterolemia received single and multiple oral doses of rosuvastatin . Both Cmax and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses.
### Geriatic Use
Of the 10,275 patients in clinical studies with rosuvastatin, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Elderly patients are at higher risk of myopathy and rosuvastatin should be prescribed with caution in the elderly
### Gender
There is no FDA guidance on the use of Rosuvastatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rosuvastatin with respect to specific racial populations.
### Renal Impairment
Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr ≥ 30 mL/min/1.73 m2); however, exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment who are not receiving hemodialysis. Rosuvastatin dosing should be adjusted in patients with severe renal impairment (CLcr < 30 mL/min/1.73 m2) not requiring hemodialysis.
### Hepatic Impairment
Rosuvastatin is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; Rosuvastatin should be used with caution in these patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rosuvastatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rosuvastatin in patients who are immunocompromised.
### Asian Patients
Pharmacokinetic studies have demonstrated an approximate 2‑fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. Rosuvastatin dosage should be adjusted in Asian patients
# Administration and Monitoring
### Administration
Oral
### Monitoring
In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs.
# IV Compatibility
There is limited information regarding the compatibility of Rosuvastatin and IV administrations.
# Overdosage
There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.
# Pharmacology
## Mechanism of Action
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3‑hydroxy‑3‑methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.
## Structure
The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula:
The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca and the molecular weight is 1001.14. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0.
## Pharmacodynamics
There is limited information regarding Rosuvastatin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration.
- Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
- Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG‑CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG‑CoA reductase inhibitory activity is accounted for by the parent compound.
- Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t1/2) of rosuvastatin is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.
- Race: A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2‑fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group.
- Gender: There were no differences in plasma concentrations of rosuvastatin between men and women.
- Geriatric: There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).
- Renal Impairment: Mild to moderate renal impairment (CrCl ≥ 30 mL/min/1.73 m2) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3‑fold) in patients with severe renal impairment (CrCl < 30 mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects (CrCl > 80 mL/min/1.73 m2).
- Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.
- Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased.
- In patients with Child‑Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function.
- In patients with Child‑Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.
In a 107-week carcinogenicity study in mice given 10, 60, 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.
Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.
In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6‑month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.
### Animal Toxicology and/or Pharmacology
Rosuvastatin crosses the placenta and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.
In female rats given oral gavage doses of 5, 15, 50 mg/kg/day rosuvastatin before mating and continuing through day 7 postcoitus results in decreased fetal body weight (female pups) and delayed ossification at the high dose (systemic exposures 10 times the human exposure at 40 mg/day based on AUC).
In pregnant rats given oral gavage doses of 2, 10, 50 mg/kg/day from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred in groups given 50 mg/kg/day, systemic exposures ≥ 12 times the human exposure at 40 mg/day based on body surface area.
In pregnant rabbits given oral gavage doses of 0.3, 1, 3 mg/kg/day from gestation day 6 to lactation day 18 (weaning), exposures equivalent to the human exposure at 40 mg/day based on body surface area, decreased fetal viability and maternal mortality was observed.
Rosuvastatin was not teratogenic in rats at ≤ 25 mg/kg/day or in rabbits ≤ 3 mg/kg/day (systemic exposures equivalent to the human exposure at 40 mg/day based on AUC or body surface area, respectively).
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year.
# Clinical Studies
### Hyperlipidemia and Mixed Dyslipidemia
Rosuvastatin reduces Total‑C, LDL‑C, ApoB, nonHDL‑C, and TG, and increases HDL‑C, in adult patients with [hyperlipidemia]] and mixed dyslipidemia.
Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with [hyperlipidemia]] rosuvastatin given as a single daily dose for 6 weeks significantly reduced Total‑C, LDL‑C, nonHDL‑C, and ApoB, across the dose range.
Active-Controlled Study: rosuvastatin was compared with the HMG‑CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin in a multicenter, open-label, dose-ranging study of 2240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either rosuvastatin, atorvastatin, simvastatin, or pravastatin (Figure 1 and Table 7).
Figure 1. Percent LDL‑ C Change by Dose of rosuvastatin, Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Patients with [hyperlipidemia]] or Mixed Dyslipidemia
Box plots are a representation of the 25th, 50th, and 75th percentile values, with whiskers representing the 10th and 90th percentile values. Mean baseline LDL‑C: 189 mg/dL
### Heterozygous Familial Hypercholesterolemia
Active-Controlled Study: In a study of patients with heterozygous FH (baseline mean LDL of 291), patients were randomized to rosuvastatin 20 mg or atorvastatin 20 mg. The dose was increased by 6-week intervals. Significant LDL-C reductions from baseline were seen at each dose in both treatment groups (Table 8).
### Hypertriglyceridemia
Dose-Response Study: In a double-blind, placebo-controlled dose-response study in patients with baseline TG levels from 273 to 817 mg/dL, rosuvastatin given as a single daily dose (5 to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 9).
### Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
In a randomized, multicenter, double-blind crossover study, 32 patients (27 with є2/є2 and 4 with apo E mutation [Arg145Cys] with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) entered a 6-week dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet. Following dietary lead-in, patients were randomized to a sequence of treatments in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg. rosuvastatin reduced nonHDL‑C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table below.
### Homozygous Familial Hypercholesterolemia
Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8‑63 years) were evaluated for their response to rosuvastatin 20 to 40 mg titrated at a 6‑week interval. In the overall population, the mean LDL‑C reduction from baseline was 22%. About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL‑C, the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL‑C reduction of <15%, 3 had no change or an increase in LDL‑C. Reductions in LDL‑C of 15% or greater were observed in 3 of 5 patients with known receptor negative status.
### Pediatric Patients with Heterozygous Familial Hypercholesterolemia
In a double blind, randomized, multicenter, placebo-controlled, 12 week study, 176 (97 male and 79 female) children and adolescents with heterozygous familial Hypercholesterolemia were randomized to rosuvastatin 5, 10 or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively. Females were at least 1 year postmenarche. Mean LDL C at baseline was 233 mg/dL (range of 129 to 399). The 12 week double blind phase was followed by a 40 week open label dose-titration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg rosuvastatin daily.
Rosuvastatin significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels at each dose compared to placebo. Results are shown in Table 11 below.
At the end of the 12 week, double blind treatment period, the percentage of patients achieving the LDL C goal of less than 110 mg/dL (2.8 mmol/L) was 0% for placebo, 12% for rosuvastatin 5 mg, 41% for rosuvastatin 10 mg and 41% for rosuvastatin 20 mg. For the 40 week, open label phase, 71% of the patients were titrated to the maximum dose of 20 mg and 41% of the patients achieved the LDL C goal of 110 mg/dL.
The long-term efficacy of rosuvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.
### Slowing of the Progression of Atherosclerosis
In the Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin 40 mg (METEOR) study, the effect of therapy with rosuvastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in patients with elevated LDL‑C, at low risk (Framingham risk <10% over ten years) for symptomatic coronary artery disease and with subclinical atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind, placebo-controlled clinical study 984 patients were randomized (of whom 876 were analyzed) in a 5:2 ratio to rosuvastatin 40 mg or placebo once daily. Ultrasonograms of the carotid walls were used to determine the annualized rate of change per patient from baseline to two years in mean maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the maximum cIMT analyzed over all 12 carotid artery sites between patients treated with rosuvastatin and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, –0.0093; p<0.0001).
The annualized rate of change from baseline for the placebo group was +0.0131 mm/year (p<0.0001). The annualized rate of change from baseline for the group treated with rosuvastatin was -0.0014 mm/year (p=0.32).
At an individual patient level in the group treated with rosuvastatin, 52.1% of patients demonstrated an absence of disease progression (defined as a negative annualized rate of change), compared to 37.7% of patients in the placebo group.
### Primary Prevention of Cardiovascular Disease
In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of rosuvastatin (rosuvastatin calcium) on the occurrence of major cardiovascular (CV) disease events was assessed in 17,802 men (≥50 years) and women (≥60 years) who had no clinically evident cardiovascular disease, LDL‑C levels <130 mg/dL (3.3 mmol/l) and hs‑CRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL‑C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%). Study participants had a median baseline LDL‑C of 108 mg/dL and hsCRP of 4.3 mg/L. Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects.
The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure.
Rosuvastatin significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0.001) relative risk reduction of 44% and absolute risk reduction of 1.2% (see Figure 2). The risk reduction for the primary end point was consistent across the following predefined subgroups: age, sex, race, smoking status, family history of premature CHD, body mass index, LDL‑C, HDL‑C, and hsCRP levels.
Figure 2. Time to first occurrence of major cardiovascular events in JUPITER
The individual components of the primary end point are presented in Figure 3. Rosuvastatin significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the rosuvastatin and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina.
Rosuvastatin significantly reduced the risk of myocardial infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in rosuvastatin-treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in rosuvastatin-treated subjects).
In a post-hoc subgroup analysis of JUPITER subjects (n=1405; rosuvastatin=725, placebo=680) with a hsCRP ≥2 mg/L and no other traditional risk factors (smoking, BP ≥140/90 or taking antihypertensives, low HDL‑C) other than age, after adjustment for high HDL‑C, there was no significant treatment benefit with rosuvastatin treatment.
At one year, rosuvastatin increased HDL‑C and reduced LDL‑C, hsCRP, total cholesterol and serum triglyceride levels (p<0.001 for all versus placebo).
# How Supplied
CRESTOR® (rosuvastatin calcium) Tablets are supplied as:
- NDC 0310-0755-90: 5 mg. Yellow, round, biconvex, coated tablets. Debossed “CRESTOR” and “5” on one side; bottle of 90 tablets
- NDC 0310-0751-90: 10 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side; bottle of 90 tablets
- NDC 0310-0751-39: 10 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side; unit dose packages of 100
- NDC 0310-0752-90: 20 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20” on one side; bottles of 90
- NDC 0310-0752-39: 20 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20”on one side; unit dose packages of 100
- NDC 0310-0754-30: 40 mg. Pink, oval, biconvex, coated tablets. Debossed “CRESTOR” on one side and “40” on the other side; bottles of 30
## Storage
Store at controlled room temperature, 20‑25ºC (68-77ºF). Protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Skeletal Muscle Effects
Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin.
### Concomitant Use of Antacids
When taking rosuvastatin with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin administration.
### Pregnancy
If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
### Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
# Precautions with Alcohol
Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.
# Brand Names
Crestor
# Look-Alike Drug Names
There is limited information regarding Rosuvastatin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Crestor | |
9f9197acc2a3eb14d2a9e6b063c8ff749d47fcc6 | wikidoc | Cryptobiosis | Cryptobiosis
Cryptobiosis is an ametabolic state of life entered by some lower organisms in response to adverse environmental conditions such as desiccation, freezing, and oxygen deficiency. In the cryptobiotic state, all metabolic procedures stop, preventing reproduction, development, and repair. An organism in a cryptobiotic state can essentially live indefinitely until environmental conditions return to being hospitable. When this occurs, the organism will return to its metabolic state of life as it was prior to the cryptobiosis.
# Forms of cryptobiosis
There are several forms of cryptobiosis. These are outlined below.
## Anhydrobiosis
Anhydrobiosis is the most studied form of cryptobiosis and occurs in situations of extreme desiccation. The term anhydrobiosis derives from the Greek for "life without water" and is most commonly used for the desiccation tolerance observed in certain invertebrate animals such as bdelloid rotifers, tardigrades, brine shrimp and nematodes. However, other life forms, including the resurrection plant Craterostigma plantagineum, the majority of plant seeds, and many micro-organisms such as bakers' yeast, also exhibit desiccation tolerance. Invertebrates undergoing anhydrobiosis often contract into a smaller shape and some proceed to form a sugar called trehalose. Desiccation tolerance in plants is associated with the production of another sugar, sucrose. These sugars are thought to protect the organism from desiccation damage, and studies have shown that anhydrobiotic organisms can survive for decades in the dry state. In some creatures, such as bdelloid rotifers, no trehalose has been found, which has led scientists to propose other mechanisms of anhydrobiosis.
As of 2004, a new application of anhydrobiosis is being applied to vaccines. The process allows some organisms to survive dried-up by replacing water with a sugar solution that keeps cells in a state of suspended animation until rehydration occurs. In vaccines, the process can produce a dry vaccine that reactivates once it is injected into the body. In theory, dry-vaccine technology could be used on any vaccine, including live vaccines such as the one for measles. It could also potentially be adapted to allow a vaccine's slow release, eliminating the need for boosters. This proposes to eliminate the need for refrigerating vaccines, thus making dry vaccines more widely available throughout the developing world where refrigeration, electricity, and proper storage are less accessible.(source BBC News: )
## Anoxybiosis
Anoxybiosis isn't considered a form of cryptobiosis by some. It takes place in situations lacking oxygen, and involves the organism intaking water and becoming turgid and immobile. Studies of the survival rates of organisms during anoxybiosis have given conflicting results.
## Chemobiosis
The cryptobiotic response to high levels of environmental toxins.
## Cryobiosis
Cryobiosis is a form of cryptobiosis that takes place in reaction to decreased temperature. To initiate cryobiosis, the organism freezes all of the water within its cells. This allows the organism to endure the freezing temperatures until more hospitable conditions return. Studies have shown that the longer an organism remains in cryobiosis, the longer it takes for the organism to come out of cryobiosis. This is because the organism must use its own energy to come out of cryobiosis, and the longer it stays in cryobiosis the less energy it has.
## Osmobiosis
Osmobiosis is the least studied of the four types of cryptobiosis. Osmobiosis occurs in response to increased solute concentration in the solution the organism lives in. Not much is known for sure, other than that osmobiosis appears to involve a cessation of metabolism.
# Examples
The most commonly-known organism that undergoes cryptobiosis is Artemia salina, commonly known for their brand name Sea-monkeys. The tardigrade, or water bear, is the most studied and most notable, partially because it can undergo all five types of cryptobiosis. While in this state, its metabolism lowers to less than 0.01% of what is normal, and its water content can drop to 1% of normal. It can withstand extreme temperature, radiation, and pressure while in a cryptobiotic state.
Some Nematodes and Rotifers can also undergo cryptobiosis. | Cryptobiosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cryptobiosis is an ametabolic state of life entered by some lower organisms in response to adverse environmental conditions such as desiccation, freezing, and oxygen deficiency. In the cryptobiotic state, all metabolic procedures stop, preventing reproduction, development, and repair. An organism in a cryptobiotic state can essentially live indefinitely until environmental conditions return to being hospitable. When this occurs, the organism will return to its metabolic state of life as it was prior to the cryptobiosis.
# Forms of cryptobiosis
There are several forms of cryptobiosis. These are outlined below.
## Anhydrobiosis
Anhydrobiosis is the most studied form of cryptobiosis and occurs in situations of extreme desiccation. The term anhydrobiosis derives from the Greek for "life without water" and is most commonly used for the desiccation tolerance observed in certain invertebrate animals such as bdelloid rotifers, tardigrades, brine shrimp and nematodes. However, other life forms, including the resurrection plant Craterostigma plantagineum, the majority of plant seeds, and many micro-organisms such as bakers' yeast, also exhibit desiccation tolerance. Invertebrates undergoing anhydrobiosis often contract into a smaller shape and some proceed to form a sugar called trehalose. Desiccation tolerance in plants is associated with the production of another sugar, sucrose. These sugars are thought to protect the organism from desiccation damage, and studies have shown that anhydrobiotic organisms can survive for decades in the dry state. In some creatures, such as bdelloid rotifers, no trehalose has been found, which has led scientists to propose other mechanisms of anhydrobiosis.
As of 2004, a new application of anhydrobiosis is being applied to vaccines. The process allows some organisms to survive dried-up by replacing water with a sugar solution that keeps cells in a state of suspended animation until rehydration occurs. In vaccines, the process can produce a dry vaccine that reactivates once it is injected into the body. In theory, dry-vaccine technology could be used on any vaccine, including live vaccines such as the one for measles. It could also potentially be adapted to allow a vaccine's slow release, eliminating the need for boosters. This proposes to eliminate the need for refrigerating vaccines, thus making dry vaccines more widely available throughout the developing world where refrigeration, electricity, and proper storage are less accessible.(source BBC News: [2] )
## Anoxybiosis
Anoxybiosis isn't considered a form of cryptobiosis by some. It takes place in situations lacking oxygen, and involves the organism intaking water and becoming turgid and immobile. Studies of the survival rates of organisms during anoxybiosis have given conflicting results.
## Chemobiosis
The cryptobiotic response to high levels of environmental toxins.
## Cryobiosis
Cryobiosis is a form of cryptobiosis that takes place in reaction to decreased temperature. To initiate cryobiosis, the organism freezes all of the water within its cells. This allows the organism to endure the freezing temperatures until more hospitable conditions return. Studies have shown that the longer an organism remains in cryobiosis, the longer it takes for the organism to come out of cryobiosis. This is because the organism must use its own energy to come out of cryobiosis, and the longer it stays in cryobiosis the less energy it has.
## Osmobiosis
Osmobiosis is the least studied of the four types of cryptobiosis. Osmobiosis occurs in response to increased solute concentration in the solution the organism lives in. Not much is known for sure, other than that osmobiosis appears to involve a cessation of metabolism.
# Examples
The most commonly-known organism that undergoes cryptobiosis is Artemia salina, commonly known for their brand name Sea-monkeys. The tardigrade, or water bear, is the most studied and most notable, partially because it can undergo all five types of cryptobiosis. While in this state, its metabolism lowers to less than 0.01% of what is normal, and its water content can drop to 1% of normal. It can withstand extreme temperature, radiation, and pressure while in a cryptobiotic state.
Some Nematodes and Rotifers can also undergo cryptobiosis. | https://www.wikidoc.org/index.php/Cryptobiosis | |
4063d5eb714652a75ffce5ccc39503a1dd1de42f | wikidoc | Cryptochrome | Cryptochrome
Cryptochromes (from the Greek κρυπτός χρώμα, "hidden colour") are a class of flavoproteins that are sensitive to blue light. They are found in plants and animals. Cryptochromes are involved in the circadian rhythms of plants and animals, and possibly also in the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the cryptic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.
The two genes Cry1 and Cry2 code for the two cryptochrome proteins CRY1 and CRY2. In insects and plants, CRY1 regulates the circadian clock in a light-dependent fashion, whereas, in mammals, CRY1 and CRY2 act as light-independent inhibitors of CLOCK-BMAL1 components of the circadian clock. In plants, blue-light photoreception can be used to cue developmental signals. Besides chlorophylls, cryptochromes are the only proteins known to form photoinduced radical-pairs in vivo.
# Discovery
Although Charles Darwin first documented plant responses to blue light in the 1880s, it was not until the 1980s that research began to identify the pigment responsible. In 1980, researchers discovered that the HY4 gene of the plant Arabidopsis thaliana was necessary for the plant's blue light sensitivity, and, when the gene was sequenced in 1993, it showed high sequence homology with photolyase, a DNA repair protein activated by blue light. By 1995, it became clear that the products of the HY4 gene and its two human homologs did not exhibit photolyase activity and were instead a new class of blue light photoreceptor hypothesized to be circadian photopigments. In 1996 and 1998, Cry homologs were identified in Drosophila and mice, respectively.
# Evolutionary history and structure
Cryptochromes (CRY1, CRY2) are evolutionarily old and highly conserved proteins that belong to the flavoproteins superfamily that exists in all kingdoms of life. All members of this superfamily have the characteristics of an N-terminal photolyase homology (PHR) domain. The PHR domain can bind to the flavin adenine dinucleotide (FAD) cofactor and a light-harvesting chromophore. Cryptochromes are derived from and closely related to photolyases, which are bacterial enzymes that are activated by light and involved in the repair of UV-induced DNA damage. In eukaryotes, cryptochromes no longer retain this original enzymatic activity.
The structure of cryptochrome involves a fold very similar to that of photolyase, with a single molecule of FAD noncovalently bound to the protein. These proteins have variable lengths and surfaces on the C-terminal end, due to the changes in genome and appearance that result from the lack of DNA repair enzymes. The Ramachandran plot shows that the secondary structure of the CRY1 protein is primarily a right-handed alpha helix with little to no steric overlap. The structure of CRY1 is almost entirely made up of alpha helices, with several loops and few beta sheets. The molecule is arranged as an orthogonal bundle.
# Function
## Phototropism
In plants, cryptochromes mediate phototropism, or directional growth toward a light source, in response to blue light. This response is now known to have its own set of photoreceptors, the phototropins.
Unlike phytochromes and phototropins, cryptochromes are not kinases. Their flavin chromophore is reduced by light and transported into the cell nucleus, where it affects the turgor pressure and causes subsequent stem elongation. To be specific, Cry2 is responsible for blue-light-mediated cotyledon and leaf expansion. Cry2 overexpression in transgenic plants increases blue-light-stimulated cotyledon expansion, which results in many broad leaves and no flowers rather than a few primary leaves with a flower. A double loss-of-function mutation in Arabidopsis thaliana Early Flowering 3 (elf3) and Cry2 genes delays flowering under continuous light and was shown to accelerate it during long and short days, which suggests that Arabidopsis CRY2 may play a role in accelerating flowering time during continuous light.
## Photomorphogenesis
Cryptochromes receptors cause plants to respond to blue light via photomorphogenesis. Cryptochromes help control seed and seedling development, as well as the switch from the vegetative to the flowering stage of development. In Arabidopsis, it is shown that cryptochromes controls plant growth during sub-optimal blue-light conditions.
## Light capture
Despite much research on the topic, cryptochrome photoreception and phototransduction in Drosophila and Arabidopsis thaliana is still poorly understood. Cryptochromes are known to possess two chromophores: pterin (in the form of 5,10-methenyltetrahydrofolic acid (MTHF)) and flavin (in the form of FAD). Both may absorb a photon, and in Arabidopsis, pterin appears to absorb at a wavelength of 380 nm and flavin at 450 nm. Past studies have supported a model by which energy captured by pterin is transferred to flavin. Under this model of phototransduction, FAD would then be reduced to FADH, which probably mediates the phosphorylation of a certain domain in cryptochrome. This could then trigger a signal transduction chain, possibly affecting gene regulation in the cell nucleus.
A new hypothesis proposes that in plant cryptochromes, the transduction of the light signal into a chemical signal that might be sensed by partner molecules could be triggered by a photo-induced negative charge within the protein - on the FAD cofactor or on the neighbouring aspartic acid. This negative charge would electrostatically repel the protein-bound ATP molecule and thereby also the protein C-terminal domain, which covers the ATP binding pocket prior to photon absorption. The resulting change in protein conformation could lead to phosphorylation of previously inaccessible phosphorylation sites on the C-terminus and the given phosphorylated segment could then liberate the transcription factor HY5 by competing for the same binding site at the negative regulator of photomorphogenesis COP1.
A different mechanism may function in Drosophila. The true ground state of the flavin cofactor in Drosophila CRY is still debated, with some models indicating that the FAD is in an oxidized form, while others support a model in which the flavin cofactor exists in anion radical form, FAD−. Recently, researchers have observed that oxidized FAD is readily reduced to FAD−- by light. Furthermore, mutations that blocked photoreduction had no effect on light-induced degradation of CRY, while mutations that altered the stability of FAD−- destroyed CRY photoreceptor function. These observations provide support for a ground state of FAD−. Researchers have also recently proposed a model in which FAD− is excited to its doublet or quartet state by absorption of a photon, which then leads to a conformational change in the CRY protein.
In sponge eyes, blue-light-receptive cryptochrome is also expressed. Most animal eyes utilize photo-sensitive opsin proteins expressed in neurons to communicate information of the light environment to the nervous system, whereas sponge larvae use pigment ring eyes to mediate phototactic swimming. However, despite possessing many other G-protein-coupled receptors (GPCRs), the fully sequenced genome of Amphimedon queenslandica, a demosponge larva, apparently lacks a gene for a light-sensitive opsin pigment, suggesting that the sponge's unique eyes might have evolved a novel light-detection mechanism. Research using RNA probes indicated that one of the two cryptochromes, Aq-Cry2, was produced near the sponge's simple eye cells. Aq-Cry2 lacks photolyase activity and contains a flavin-based co-factor that is responsive to wavelengths of light that also mediate larval photic behavior. Defined as an opsin-clade GPCR, it possesses a conserved Shiff base lysine that is central to opsin function. Like other sponges, A. queenslandica lacks a nervous system. This indicates that opsin-less sponge eyes utilize cryptochrome, along with other proteins, to direct or act in eye-mediated phototactic behavior.
## Circadian rhythm
Studies in animals and plants suggest that cryptochromes play a pivotal role in the generation and maintenance of circadian rhythms. Similarly, cryptochromes play an important role in the entrainment of circadian rhythms in plants. In Drosophila, cryptochrome (dCRY) acts as a blue-light photoreceptor that directly modulates light input into the circadian clock, while in mammals, cryptochromes (CRY1 and CRY2) act as transcription repressors within the circadian clockwork. Some insects, including the monarch butterfly, have both a mammal-like and a Drosophila-like version of cryptochrome, providing evidence for an ancestral clock mechanism involving both light-sensing and transcriptional-repression roles for cryptochrome.
Cry mutants have altered circadian rhythms, showing that Cry affects the circadian pacemaker. Drosophila with mutated Cry exhibit little to no mRNA cycling. A point mutation in cryb, which is required for flavin association in CRY protein, results in no PER or TIM protein cycling in either DD or LD. In addition, mice lacking Cry1 or Cry2 genes exhibit differentially altered free running periods, but are still capable of photoentrainment. However, mice that lack both Cry1 and Cry2 are arrhythmic in both LD and DD and always have high Per1 mRNA levels. These results suggest that cryptochromes play a photoreceptive role, as well as acting as negative regulators of Per gene expression in mice.
### In Drosophila
In Drosophila, cryptochrome functions as a blue light photoreceptor. Exposure to blue light induces a conformation similar to that of the always-active CRY mutant with a C-terminal deletion (CRYΔ). The half-life of this conformation is 15 minutes in the dark and facilitates the binding of CRY to other clock gene products, PER and TIM, in a light-dependent manner. Once bound by dCRY, dTIM is committed to degradation by the ubiquitin-proteasome system.
Although light pulses do not entrain, full photoperiod LD cycles can still drive cycling in the ventral-lateral neurons in the Drosophila brain. These data along with other results suggest that CRY is the cell-autonomous photoreceptor for body clocks in Drosophila and may play a role in nonparametric entrainment (entrainment by short discrete light pulses). However, the lateral neurons receive light information through both the blue light CRY pathway and the rhodopsin pathway. Therefore, CRY is involved in light perception and is an input to the circadian clock, however it is not the only input for light information, as a sustained rhythm has been shown in the absence of the CRY pathway, in which it is believed that the rhodopsin pathway is providing some light input. Recently, it has also been shown that there is a CRY-mediated light response that is independent of the classical circadian CRY-TIM interaction. This mechanism is believed to require a flavin redox-based mechanism that is dependent on potassium channel conductance. This CRY-mediated light response has been shown to increase action potential firing within seconds of a light response in opsin-knockout Drosophila.
Cryptochrome, like many genes involved in circadian rhythm, shows circadian cycling in mRNA and protein levels. In Drosophila, Cry mRNA concentrations cycle under a light-dark cycle (LD), with high levels in light and low levels in the dark. This cycling persists in constant darkness (DD), but with decreased amplitude. The transcription of the Cry gene also cycles with a similar trend. CRY protein levels, however, cycle in a different manner than Cry transcription and mRNA levels. In LD, CRY protein has low levels in light and high levels in dark, and, in DD, CRY levels increase continuously throughout the subjective day and night. Thus, CRY expression is regulated by the clock at the transcriptional level and by light at the translational and posttranslational level.
Overexpression of Cry also affects circadian light responses. In Drosophila, Cry overexpression increases flies' sensitivity to low-intensity light. This light regulation of CRY protein levels suggests that CRY has a circadian role upstream of other clock genes and components.
### In mammals
Cryptochrome is one of the four groups of mammalian clock genes/proteins that generate a transcription-translation negative-feedback loop (TTFL), along with Period (PER), CLOCK, and BMAL1. In this loop, CLOCK and BMAL1 proteins are transcriptional activators, which together bind to the promoters of the Cry and Per genes and activate their transcription. The CRY and PER proteins then bind to each other, enter the nucleus, and inhibit CLOCK-BMAL1-activated transcription.
In mice, Cry1 expression displays circadian rhythms in the suprachiasmatic nucleus, a brain region involved in the generation of circadian rhythms, with mRNA levels peaking during the light phase and reaching a minimum in the dark. These daily oscillations in expression are maintained in constant darkness.
While CRY has been well established as a TIM homolog in mammals, the role of CRY as a photoreceptor in mammals has been controversial. Early papers indicated that CRY has both light-independent and -dependent functions. A study in 2000 indicated that mice without rhodopsin but with cryptochrome still respond to light; however, in mice without either rhodopsin or cryptochrome, c-Fos transcription, a mediator of light sensitivity, significantly drops. In recent years, data have supported melanopsin as the main circadian photoreceptor, in particular melanopsin cells that mediate entrainment and communication between the eye and the suprachiasmatic nucleus (SCN). One of the main difficulties in confirming or denying CRY as a mammalian photoreceptor is that when the gene is knocked out the animal goes arrhythmic, so it is hard to measure its capacity as purely a photoreceptor. However, some recent studies indicate that human CRY may mediate light response in peripheral tissues.
Normal mammalian circadian rhythm relies critically on delayed expression of Cry1 following activation of the Cry1 promoter. Whereas rhythms in Per2 promoter activation and Per2 mRNA levels have almost the same phase, Cry1 mRNA production is delayed by approximately four hours relative to Cry1 promoter activation. This delay is independent of CRY1 or CRY2 levels and is mediated by a combination of E/E'-box and D-box elements in the promoter and RevErbA/ROR binding elements (RREs) in the gene's first intron. Transfection of arrhythmic Cry1−/− Cry2−/− double-knockout cells with only the Cry1 promoter (causing constitutive Cry1 expression) is not sufficient to rescue rhythmicity. Transfection of these cells with both the promoter and the first intron is required for restoration of circadian rhythms in these cells.
## Magnetoreception
Experimental data suggests that cryptochromes in the photoreceptor neurons of birds' eyes are involved in magnetic orientation during migration. Cryptochromes are also thought to be essential for the light-dependent ability of Drosophila to sense magnetic fields. Magnetic fields were once reported to affect cryptochromes also in Arabidopsis thaliana plants: growth behavior seemed to be affected by magnetic fields in the presence of blue (but not red) light. Nevertheless, these results have later turned out to be irreproducible under strictly controlled conditions in another laboratory, suggesting that plant cryptochromes do not respond to magnetic fields.
Cryptochrome forms a pair of radicals with correlated spins when exposed to blue light. Radical pairs can also be generated by the light-independent dark reoxidation of the flavin cofactor by molecular oxygen through the formation of a spin-correlated FADH-superoxide radical pairs. Magnetoreception is hypothesized to function through the surrounding magnetic field's effect on the correlation (parallel or anti-parallel) of these radicals, which affects the lifetime of the activated form of cryptochrome. Activation of cryptochrome may affect the light-sensitivity of retinal neurons, with the overall result that the animal can sense the magnetic field. Animal cryptochromes and closely related animal (6-4) photolyases contain a longer chain of electron-transferring tryptophans than other proteins of the cryptochrome-photolyase superfamily (a tryptophan tetrad instead of a triad). The longer chain leads to a better separation and over 1000× longer lifetimes of the photoinduced flavin-tryptophan radical pairs than in proteins with a mere triad of tryptophans. The absence of spin-selective recombination of these radical pairs on the nanosecond to microsecond timescales seems to be incompatible with the suggestion that magnetoreception by cryptochromes is based on the forward light reaction. | Cryptochrome
Cryptochromes (from the Greek κρυπτός χρώμα, "hidden colour") are a class of flavoproteins that are sensitive to blue light. They are found in plants and animals. Cryptochromes are involved in the circadian rhythms of plants and animals, and possibly also in the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the cryptic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.[1]
The two genes Cry1 and Cry2 code for the two cryptochrome proteins CRY1 and CRY2.[2] In insects and plants, CRY1 regulates the circadian clock in a light-dependent fashion, whereas, in mammals, CRY1 and CRY2 act as light-independent inhibitors of CLOCK-BMAL1 components of the circadian clock.[3] In plants, blue-light photoreception can be used to cue developmental signals.[4] Besides chlorophylls, cryptochromes are the only proteins known to form photoinduced radical-pairs in vivo.[5]
# Discovery
Although Charles Darwin first documented plant responses to blue light in the 1880s, it was not until the 1980s that research began to identify the pigment responsible.[6] In 1980, researchers discovered that the HY4 gene of the plant Arabidopsis thaliana was necessary for the plant's blue light sensitivity, and, when the gene was sequenced in 1993, it showed high sequence homology with photolyase, a DNA repair protein activated by blue light.[7] By 1995, it became clear that the products of the HY4 gene and its two human homologs did not exhibit photolyase activity and were instead a new class of blue light photoreceptor hypothesized to be circadian photopigments.[8] In 1996 and 1998, Cry homologs were identified in Drosophila and mice, respectively.[9][10]
# Evolutionary history and structure
Cryptochromes (CRY1, CRY2) are evolutionarily old and highly conserved proteins that belong to the flavoproteins superfamily that exists in all kingdoms of life.[4] All members of this superfamily have the characteristics of an N-terminal photolyase homology (PHR) domain. The PHR domain can bind to the flavin adenine dinucleotide (FAD) cofactor and a light-harvesting chromophore.[4] Cryptochromes are derived from and closely related to photolyases, which are bacterial enzymes that are activated by light and involved in the repair of UV-induced DNA damage. In eukaryotes, cryptochromes no longer retain this original enzymatic activity.[11]
The structure of cryptochrome involves a fold very similar to that of photolyase, with a single molecule of FAD noncovalently bound to the protein.[4] These proteins have variable lengths and surfaces on the C-terminal end, due to the changes in genome and appearance that result from the lack of DNA repair enzymes. The Ramachandran plot[12] shows that the secondary structure of the CRY1 protein is primarily a right-handed alpha helix with little to no steric overlap.[13] The structure of CRY1 is almost entirely made up of alpha helices, with several loops and few beta sheets. The molecule is arranged as an orthogonal bundle.[4]
# Function
## Phototropism
In plants, cryptochromes mediate phototropism, or directional growth toward a light source, in response to blue light. This response is now known to have its own set of photoreceptors, the phototropins.
Unlike phytochromes and phototropins, cryptochromes are not kinases. Their flavin chromophore is reduced by light and transported into the cell nucleus, where it affects the turgor pressure and causes subsequent stem elongation. To be specific, Cry2 is responsible for blue-light-mediated cotyledon and leaf expansion. Cry2 overexpression in transgenic plants increases blue-light-stimulated cotyledon expansion, which results in many broad leaves and no flowers rather than a few primary leaves with a flower.[14] A double loss-of-function mutation in Arabidopsis thaliana Early Flowering 3 (elf3) and Cry2 genes delays flowering under continuous light and was shown to accelerate it during long and short days, which suggests that Arabidopsis CRY2 may play a role in accelerating flowering time during continuous light.[15]
## Photomorphogenesis
Cryptochromes receptors cause plants to respond to blue light via photomorphogenesis. Cryptochromes help control seed and seedling development, as well as the switch from the vegetative to the flowering stage of development. In Arabidopsis, it is shown that cryptochromes controls plant growth during sub-optimal blue-light conditions.[16]
## Light capture
Despite much research on the topic, cryptochrome photoreception and phototransduction in Drosophila and Arabidopsis thaliana is still poorly understood. Cryptochromes are known to possess two chromophores: pterin (in the form of 5,10-methenyltetrahydrofolic acid (MTHF)) and flavin (in the form of FAD).[17] Both may absorb a photon, and in Arabidopsis, pterin appears to absorb at a wavelength of 380 nm and flavin at 450 nm. Past studies have supported a model by which energy captured by pterin is transferred to flavin.[18] Under this model of phototransduction, FAD would then be reduced to FADH, which probably mediates the phosphorylation of a certain domain in cryptochrome. This could then trigger a signal transduction chain, possibly affecting gene regulation in the cell nucleus.
A new hypothesis[19] proposes that in plant cryptochromes, the transduction of the light signal into a chemical signal that might be sensed by partner molecules could be triggered by a photo-induced negative charge within the protein - on the FAD cofactor or on the neighbouring aspartic acid.[20][21] This negative charge would electrostatically repel the protein-bound ATP molecule and thereby also the protein C-terminal domain, which covers the ATP binding pocket prior to photon absorption. The resulting change in protein conformation could lead to phosphorylation of previously inaccessible phosphorylation sites on the C-terminus and the given phosphorylated segment could then liberate the transcription factor HY5 by competing for the same binding site at the negative regulator of photomorphogenesis COP1.
A different mechanism may function in Drosophila. The true ground state of the flavin cofactor in Drosophila CRY is still debated, with some models indicating that the FAD is in an oxidized form,[22] while others support a model in which the flavin cofactor exists in anion radical form, FAD−•. Recently, researchers have observed that oxidized FAD is readily reduced to FAD−• by light. Furthermore, mutations that blocked photoreduction had no effect on light-induced degradation of CRY, while mutations that altered the stability of FAD−• destroyed CRY photoreceptor function.[23][24] These observations provide support for a ground state of FAD−•. Researchers have also recently proposed a model in which FAD− is excited to its doublet or quartet state by absorption of a photon, which then leads to a conformational change in the CRY protein.[25]
In sponge eyes, blue-light-receptive cryptochrome is also expressed. Most animal eyes utilize photo-sensitive opsin proteins expressed in neurons to communicate information of the light environment to the nervous system, whereas sponge larvae use pigment ring eyes to mediate phototactic swimming. However, despite possessing many other G-protein-coupled receptors (GPCRs), the fully sequenced genome of Amphimedon queenslandica, a demosponge larva, apparently lacks a gene for a light-sensitive opsin pigment, suggesting that the sponge's unique eyes might have evolved a novel light-detection mechanism. Research using RNA probes indicated that one of the two cryptochromes, Aq-Cry2, was produced near the sponge's simple eye cells. Aq-Cry2 lacks photolyase activity and contains a flavin-based co-factor that is responsive to wavelengths of light that also mediate larval photic behavior. Defined as an opsin-clade GPCR, it possesses a conserved Shiff base lysine that is central to opsin function. Like other sponges, A. queenslandica lacks a nervous system. This indicates that opsin-less sponge eyes utilize cryptochrome, along with other proteins, to direct or act in eye-mediated phototactic behavior.[26]
## Circadian rhythm
Studies in animals and plants suggest that cryptochromes play a pivotal role in the generation and maintenance of circadian rhythms.[27] Similarly, cryptochromes play an important role in the entrainment of circadian rhythms in plants.[28] In Drosophila, cryptochrome (dCRY) acts as a blue-light photoreceptor that directly modulates light input into the circadian clock,[29] while in mammals, cryptochromes (CRY1 and CRY2) act as transcription repressors within the circadian clockwork.[30] Some insects, including the monarch butterfly, have both a mammal-like and a Drosophila-like version of cryptochrome, providing evidence for an ancestral clock mechanism involving both light-sensing and transcriptional-repression roles for cryptochrome.[31][32]
Cry mutants have altered circadian rhythms, showing that Cry affects the circadian pacemaker. Drosophila with mutated Cry exhibit little to no mRNA cycling.[33] A point mutation in cryb, which is required for flavin association in CRY protein, results in no PER or TIM protein cycling in either DD or LD.[34] In addition, mice lacking Cry1 or Cry2 genes exhibit differentially altered free running periods, but are still capable of photoentrainment. However, mice that lack both Cry1 and Cry2 are arrhythmic in both LD and DD and always have high Per1 mRNA levels. These results suggest that cryptochromes play a photoreceptive role, as well as acting as negative regulators of Per gene expression in mice.[35]
### In Drosophila
In Drosophila, cryptochrome functions as a blue light photoreceptor. Exposure to blue light induces a conformation similar to that of the always-active CRY mutant with a C-terminal deletion (CRYΔ).[25] The half-life of this conformation is 15 minutes in the dark and facilitates the binding of CRY to other clock gene products, PER and TIM, in a light-dependent manner.[3][25][29][36] Once bound by dCRY, dTIM is committed to degradation by the ubiquitin-proteasome system.[25][36]
Although light pulses do not entrain, full photoperiod LD cycles can still drive cycling in the ventral-lateral neurons in the Drosophila brain. These data along with other results suggest that CRY is the cell-autonomous photoreceptor for body clocks in Drosophila and may play a role in nonparametric entrainment (entrainment by short discrete light pulses). However, the lateral neurons receive light information through both the blue light CRY pathway and the rhodopsin pathway. Therefore, CRY is involved in light perception and is an input to the circadian clock, however it is not the only input for light information, as a sustained rhythm has been shown in the absence of the CRY pathway, in which it is believed that the rhodopsin pathway is providing some light input.[37] Recently, it has also been shown that there is a CRY-mediated light response that is independent of the classical circadian CRY-TIM interaction. This mechanism is believed to require a flavin redox-based mechanism that is dependent on potassium channel conductance. This CRY-mediated light response has been shown to increase action potential firing within seconds of a light response in opsin-knockout Drosophila.[38]
Cryptochrome, like many genes involved in circadian rhythm, shows circadian cycling in mRNA and protein levels. In Drosophila, Cry mRNA concentrations cycle under a light-dark cycle (LD), with high levels in light and low levels in the dark.[33] This cycling persists in constant darkness (DD), but with decreased amplitude.[33] The transcription of the Cry gene also cycles with a similar trend.[33] CRY protein levels, however, cycle in a different manner than Cry transcription and mRNA levels. In LD, CRY protein has low levels in light and high levels in dark, and, in DD, CRY levels increase continuously throughout the subjective day and night.[33] Thus, CRY expression is regulated by the clock at the transcriptional level and by light at the translational and posttranslational level.[33]
Overexpression of Cry also affects circadian light responses. In Drosophila, Cry overexpression increases flies' sensitivity to low-intensity light.[33] This light regulation of CRY protein levels suggests that CRY has a circadian role upstream of other clock genes and components.[33]
### In mammals
Cryptochrome is one of the four groups of mammalian clock genes/proteins that generate a transcription-translation negative-feedback loop (TTFL), along with Period (PER), CLOCK, and BMAL1.[39] In this loop, CLOCK and BMAL1 proteins are transcriptional activators, which together bind to the promoters of the Cry and Per genes and activate their transcription.[39] The CRY and PER proteins then bind to each other, enter the nucleus, and inhibit CLOCK-BMAL1-activated transcription.[39]
In mice, Cry1 expression displays circadian rhythms in the suprachiasmatic nucleus, a brain region involved in the generation of circadian rhythms, with mRNA levels peaking during the light phase and reaching a minimum in the dark.[40] These daily oscillations in expression are maintained in constant darkness.[40]
While CRY has been well established as a TIM homolog in mammals, the role of CRY as a photoreceptor in mammals has been controversial. Early papers indicated that CRY has both light-independent and -dependent functions. A study in 2000 indicated that mice without rhodopsin but with cryptochrome still respond to light; however, in mice without either rhodopsin or cryptochrome, c-Fos transcription, a mediator of light sensitivity, significantly drops.[41] In recent years, data have supported melanopsin as the main circadian photoreceptor, in particular melanopsin cells that mediate entrainment and communication between the eye and the suprachiasmatic nucleus (SCN).[42] One of the main difficulties in confirming or denying CRY as a mammalian photoreceptor is that when the gene is knocked out the animal goes arrhythmic, so it is hard to measure its capacity as purely a photoreceptor. However, some recent studies indicate that human CRY may mediate light response in peripheral tissues.[43]
Normal mammalian circadian rhythm relies critically on delayed expression of Cry1 following activation of the Cry1 promoter. Whereas rhythms in Per2 promoter activation and Per2 mRNA levels have almost the same phase, Cry1 mRNA production is delayed by approximately four hours relative to Cry1 promoter activation.[44] This delay is independent of CRY1 or CRY2 levels and is mediated by a combination of E/E'-box and D-box elements in the promoter and RevErbA/ROR binding elements (RREs) in the gene's first intron.[45] Transfection of arrhythmic Cry1−/− Cry2−/− double-knockout cells with only the Cry1 promoter (causing constitutive Cry1 expression) is not sufficient to rescue rhythmicity. Transfection of these cells with both the promoter and the first intron is required for restoration of circadian rhythms in these cells.[45]
## Magnetoreception
Experimental data suggests that cryptochromes in the photoreceptor neurons of birds' eyes are involved in magnetic orientation during migration.[46] Cryptochromes are also thought to be essential for the light-dependent ability of Drosophila to sense magnetic fields.[47] Magnetic fields were once reported to affect cryptochromes also in Arabidopsis thaliana plants: growth behavior seemed to be affected by magnetic fields in the presence of blue (but not red) light.[48] Nevertheless, these results have later turned out to be irreproducible under strictly controlled conditions in another laboratory,[49] suggesting that plant cryptochromes do not respond to magnetic fields.
Cryptochrome forms a pair of radicals with correlated spins when exposed to blue light.[50][51] Radical pairs can also be generated by the light-independent dark reoxidation of the flavin cofactor by molecular oxygen through the formation of a spin-correlated FADH-superoxide radical pairs.[52] Magnetoreception is hypothesized to function through the surrounding magnetic field's effect on the correlation (parallel or anti-parallel) of these radicals, which affects the lifetime of the activated form of cryptochrome. Activation of cryptochrome may affect the light-sensitivity of retinal neurons, with the overall result that the animal can sense the magnetic field.[53][54] Animal cryptochromes and closely related animal (6-4) photolyases contain a longer chain of electron-transferring tryptophans than other proteins of the cryptochrome-photolyase superfamily (a tryptophan tetrad instead of a triad).[55][56] The longer chain leads to a better separation and over 1000× longer lifetimes of the photoinduced flavin-tryptophan radical pairs than in proteins with a mere triad of tryptophans.[55][56] The absence of spin-selective recombination of these radical pairs on the nanosecond to microsecond timescales seems to be incompatible with the suggestion that magnetoreception by cryptochromes is based on the forward light reaction. | https://www.wikidoc.org/index.php/Cryptochrome | |
95f4f329ae264167357d274e9ae8ea4bf33fccb4 | wikidoc | Cryptomnesia | Cryptomnesia
Cryptomnesia, or "concealed recollection," is the name for a theoretical phenomenon involving suppressed or 'forgotten' memories. It refers to cases where (apparently) a person believes that he or she is creating or inventing something new, such as a story, poem, artwork, or joke, but is actually recalling a similar or identical work which he or she has previously encountered. According to the theory of cryptomnesia, the person is not engaging in plagiarism, but is rather experiencing a memory as if it were inspiration. Proponents of the cryptomnesia phenomenon believe it is possibly a means of recalling to mind certain experiences that one otherwise would not remember.
# Cryptomnesia in writing
As explained by Carl Jung, in Man and His Symbols,
"An author may be writing steadily to a preconceived plan, working out an argument or developing the line of a story, when he suddenly runs off at a tangent. Perhaps a fresh idea has occurred to him, or a different image, or a whole new sub-plot. If you ask him what prompted the digression, he will not be able to tell you. He may not even have noticed the change, though he has now produced material that is entirely fresh and apparently unknown to him before. Yet it can sometimes be shown convincingly that what he has written bears a striking similarity to the work of another author--a work that he believes he has never seen."
Jung goes on to list more specific examples. Friedrich Nietzsche's book Thus Spoke Zarathustra includes an almost word for word account of an incident also included in a book published about 1835, half a century before Nietzsche wrote. This is neither considered to be purposeful plagiarism nor pure coincidence. Nietzsche's sister confirmed that he had indeed read the original account when he was 11 years old.
Helen Keller seriously compromised her and her teacher's credibility with an incident of cryptomnesia which was misapprehended as plagiarism. The Frost King, which Keller wrote out of buried memories of a fairytale read to her four years previously, left Keller a nervous wreck, and unable to write fiction for the rest of her life.
Cryptomnesia may be the result of some memories becoming forcibly unconscious ones, due to lack of reinforcement through use. There may be enough of the memory left to recall it but not to recall its origin. Therefore it does not always take the shape of plagiarism, as it would in writing, as well as musical compositions, and other art forms, but can also be the basis of philosophy.
"The ability to reach a rich vein of such material and to translate it effectively into philosophy, literature, music or scientific discovery is one of the hallmarks of what is commonly called genius." ---Carl Jung, Man and His Symbols.
"We can find clear proof of this fact in the history of science itself. For example, the French mathematician Poincaré and the chemist Kekulé owed important scientific discoveries (as they themselves admit) to sudden pictorial 'revelations' from the unconscious. The so-called 'mystical' experience of the French philosopher Descartes involved a similar sudden revelation in which he saw in a flash the 'order of all sciences.' The British author Robert Louis Stevenson had spent years looking for a story that would fit his 'strong sense of man's double being,' when the plot of Dr. Jekyll and Mr. Hyde was suddenly revealed to him in a dream." ---Carl Jung Man and His Symbols
The mention of Kekulé is most interesting. While researching benzene, the German chemist dreamed of a snake with its tail in its mouth. Kekulé interpreted the snake as a representation of the closed-carbon ring of benzene, but the symbol of the snake with its tail in its mouth is an ancient one known as the Ouroboros. It can be found in Greek manuscripts from as long ago as the third century BC. This snake can also symbolize reversible chemical reactions.
Robert Louis Stevenson refers to an incident of cryptomnesia that took place during the writing of Treasure Island, and that he discovered to his embarrassment several years afterward:
I am now upon a painful chapter. No doubt the parrot once belonged to Robinson Crusoe. No doubt the skeleton is conveyed from Poe. I think little of these, they are trifles and details; and no man can hope to have a monopoly of skeletons or make a corner in talking birds. The stockade, I am told, is from Masterman Ready. It may be, I care not a jot. These useful writers had fulfilled the poet’s saying: departing, they had left behind them Footprints on the sands of time, Footprints which perhaps another - and I was the other! It is my debt to Washington Irving that exercises my conscience, and justly so, for I believe plagiarism was rarely carried farther. I chanced to pick up the Tales of a Traveller some years ago with a view to an anthology of prose narrative, and the book flew up and struck me: Billy Bones, his chest, the company in the parlour, the whole inner spirit, and a good deal of the material detail of my first chapters - all were there, all were the property of Washington Irving. But I had no guess of it then as I sat writing by the fireside, in what seemed the spring-tides of a somewhat pedestrian inspiration; nor yet day by day, after lunch, as I read aloud my morning’s work to the family. It seemed to me original as sin; it seemed to belong to me like my right eye.
# Validity
Critics of the cryptomnesia explanation point out that there has never been any scientific proof of its validity. Every supposed incident of cryptomnesia may also be explained by deliberate plagiarism—the testimony of those involved cannot be held to be scientifically reliable. For the same reason, though, cryptomnesia as a valid phenomenon cannot be ruled out solely based on testimonial evidence. As a result, the validity of cryptomnesia remains a matter of opinion. However, the human, unpracticed reactions and the later testimony of the accused "plagiarists", as shown in their initial honest surprise at the information of their "borrowing" and their undisguised embarrassment when they realize the true source of their unconscious "inspiration", tends to provide reasonable evidence that "conscious" copying was not the case.
Nevertheless, precedent in United States copyright law as of 2006 is to treat alleged cryptomnesia no differently from deliberate plagiarism. The seminal case is Bright Tunes Music v. Harrisongs Music, where the publisher of "He's So Fine", written by Ronald Mack, demonstrated to the court that George Harrison borrowed substantial portions of his song "My Sweet Lord" from "He's So Fine". The Court imposed damages despite a claim that the copying was subconscious. The ruling was upheld by the Second Circuit in ABKCO Music v. Harrisongs Music, and the case Three Boys Music v. Michael Bolton , upheld by the Ninth Circuit, affirmed the principle. | Cryptomnesia
Cryptomnesia, or "concealed recollection," is the name for a theoretical phenomenon involving suppressed or 'forgotten' memories. It refers to cases where (apparently) a person believes that he or she is creating or inventing something new, such as a story, poem, artwork, or joke, but is actually recalling a similar or identical work which he or she has previously encountered. According to the theory of cryptomnesia, the person is not engaging in plagiarism, but is rather experiencing a memory as if it were inspiration. Proponents of the cryptomnesia phenomenon believe it is possibly a means of recalling to mind certain experiences that one otherwise would not remember.
# Cryptomnesia in writing
As explained by Carl Jung, in Man and His Symbols,
"An author may be writing steadily to a preconceived plan, working out an argument or developing the line of a story, when he suddenly runs off at a tangent. Perhaps a fresh idea has occurred to him, or a different image, or a whole new sub-plot. If you ask him what prompted the digression, he will not be able to tell you. He may not even have noticed the change, though he has now produced material that is entirely fresh and apparently unknown to him before. Yet it can sometimes be shown convincingly that what he has written bears a striking similarity to the work of another author--a work that he believes he has never seen."
Jung goes on to list more specific examples. Friedrich Nietzsche's book Thus Spoke Zarathustra includes an almost word for word account of an incident also included in a book published about 1835, half a century before Nietzsche wrote. This is neither considered to be purposeful plagiarism nor pure coincidence. Nietzsche's sister confirmed that he had indeed read the original account when he was 11 years old.
Helen Keller seriously compromised her and her teacher's credibility with an incident of cryptomnesia which was misapprehended as plagiarism. The Frost King, which Keller wrote out of buried memories of a fairytale read to her four years previously, left Keller a nervous wreck, and unable to write fiction for the rest of her life.
Cryptomnesia may be the result of some memories becoming forcibly unconscious ones, due to lack of reinforcement through use. There may be enough of the memory left to recall it but not to recall its origin.[citation needed] Therefore it does not always take the shape of plagiarism, as it would in writing, as well as musical compositions, and other art forms, but can also be the basis of philosophy.
"The ability to reach a rich vein of such material [of the unconscious] and to translate it effectively into philosophy, literature, music or scientific discovery is one of the hallmarks of what is commonly called genius." ---Carl Jung, Man and His Symbols.
"We can find clear proof of this fact in the history of science itself. For example, the French mathematician Poincaré and the chemist Kekulé owed important scientific discoveries (as they themselves admit) to sudden pictorial 'revelations' from the unconscious. The so-called 'mystical' experience of the French philosopher Descartes involved a similar sudden revelation in which he saw in a flash the 'order of all sciences.' The British author Robert Louis Stevenson had spent years looking for a story that would fit his 'strong sense of man's double being,' when the plot of Dr. Jekyll and Mr. Hyde was suddenly revealed to him in a dream." ---Carl Jung Man and His Symbols
The mention of Kekulé is most interesting. While researching benzene, the German chemist dreamed of a snake with its tail in its mouth. Kekulé interpreted the snake as a representation of the closed-carbon ring of benzene, but the symbol of the snake with its tail in its mouth is an ancient one known as the Ouroboros. It can be found in Greek manuscripts from as long ago as the third century BC. This snake can also symbolize reversible chemical reactions.
Robert Louis Stevenson refers to an incident of cryptomnesia that took place during the writing of Treasure Island, and that he discovered to his embarrassment several years afterward:
I am now upon a painful chapter. No doubt the parrot once belonged to Robinson Crusoe. No doubt the skeleton is conveyed from Poe. I think little of these, they are trifles and details; and no man can hope to have a monopoly of skeletons or make a corner in talking birds. The stockade, I am told, is from Masterman Ready. It may be, I care not a jot. These useful writers had fulfilled the poet’s saying: departing, they had left behind them Footprints on the sands of time, Footprints which perhaps another - and I was the other! It is my debt to Washington Irving that exercises my conscience, and justly so, for I believe plagiarism was rarely carried farther. I chanced to pick up the Tales of a Traveller some years ago with a view to an anthology of prose narrative, and the book flew up and struck me: Billy Bones, his chest, the company in the parlour, the whole inner spirit, and a good deal of the material detail of my first chapters - all were there, all were the property of Washington Irving. But I had no guess of it then as I sat writing by the fireside, in what seemed the spring-tides of a somewhat pedestrian inspiration; nor yet day by day, after lunch, as I read aloud my morning’s work to the family. It seemed to me original as sin; it seemed to belong to me like my right eye.[1]
# Validity
Critics of the cryptomnesia explanation point out that there has never been any scientific proof of its validity. Every supposed incident of cryptomnesia may also be explained by deliberate plagiarism—the testimony of those involved cannot be held to be scientifically reliable. For the same reason, though, cryptomnesia as a valid phenomenon cannot be ruled out solely based on testimonial evidence. As a result, the validity of cryptomnesia remains a matter of opinion. However, the human, unpracticed reactions and the later testimony of the accused "plagiarists", as shown in their initial honest surprise at the information of their "borrowing" and their undisguised embarrassment when they realize the true source of their unconscious "inspiration", tends to provide reasonable evidence that "conscious" copying was not the case.
Nevertheless, precedent in United States copyright law as of 2006 is to treat alleged cryptomnesia no differently from deliberate plagiarism. The seminal case is Bright Tunes Music v. Harrisongs Music,[1] where the publisher of "He's So Fine", written by Ronald Mack, demonstrated to the court that George Harrison borrowed substantial portions of his song "My Sweet Lord" from "He's So Fine". The Court imposed damages despite a claim that the copying was subconscious. The ruling was upheld by the Second Circuit in ABKCO Music v. Harrisongs Music,[2] and the case Three Boys Music v. Michael Bolton [3], upheld by the Ninth Circuit, affirmed the principle. | https://www.wikidoc.org/index.php/Cryptomnesia | |
c62cc521a55fe75ab359f2339213dcef52c0ec81 | wikidoc | Cryptotaenia | Cryptotaenia
Cryptotaenia is a genus of two species of herbaceous perennial plants, native to North America and eastern Asia, growing wild in moist, shady places.
- Cryptotaenia canadensis
- Cryptotaenia japonica (syn. C. canadensis subsp. japonica)
Some other species previously included in this genus (as C. africana, C. calycina and C. elegans) have been shown by molecular evidence not to belong in Cryptotaenia (Hardway et al., 2004).
# Uses
C. japonica is raised as a seasoning (similar to angelica) and a strengthening tonic, and the sprouts are used in salads. English names for the plant include mitsuba, Japanese wild parsley, honeywort, san ip, and san ye qin (from Template:Zh-cp). Like parsley, the flavor is clean and refreshing with a slightly bitter taste. | Cryptotaenia
Cryptotaenia is a genus of two species of herbaceous perennial plants, native to North America and eastern Asia, growing wild in moist, shady places.
- Cryptotaenia canadensis
- Cryptotaenia japonica (syn. C. canadensis subsp. japonica)
Some other species previously included in this genus (as C. africana, C. calycina and C. elegans) have been shown by molecular evidence not to belong in Cryptotaenia (Hardway et al., 2004).
# Uses
C. japonica is raised as a seasoning (similar to angelica) and a strengthening tonic, and the sprouts are used in salads. English names for the plant include mitsuba, Japanese wild parsley, honeywort, san ip, and san ye qin (from Template:Zh-cp). Like parsley, the flavor is clean and refreshing with a slightly bitter taste.
# External links
- Hardway, T. M. et al. (2004). Circumscription of Apiaceae tribe Oenantheae. South African Journal of Botany 70: 393-406. Available online (pdf file)
- Technical description of Cryptotaenia japonica
- Plants for a Future database on Cryptotaenia japonica
Template:Herbs & spices
Template:Apiaceae-stub
de:Mitsuba | https://www.wikidoc.org/index.php/Cryptotaenia | |
26d9e6a958ea87ae98ae8c51b7ef7b556d9b2acc | wikidoc | Cult suicide | Cult suicide
# Overview
A cult suicide is a mass suicide by the members of a cult.
In some cases all, or nearly all members have committed suicide at the same time and place. Groups which have committed such mass suicides include Heaven's Gate, Order of the Solar Temple, Peoples Temple (in the Jonestown incident) and the Movement for the Restoration of the Ten Commandments of God. In other cases, such as Filippians and the Taiping, a group has apparently supported mass suicide but without necessarily encouraging all members to participate.
# Known cult suicides
## Peoples Temple
On November 18, 1978, 918 Americans died in Peoples Temple-related incidents, including 909 members of the Temple, led by Jim Jones, in Jonestown, Guyana. The dead included 274 children. A tape of the Temple's final meeting in a Jonestown pavilion contains repeated discussions of the group committing "revolutionary suicide," including reference to people taking the poison and the vats to be used. On that tape, Jones tells Temple members that Russia, with whom the Temple had been negotiating a potential exodus for months, would not take them after the Temple had murdered Congressman Leo Ryan, NBC reporter Don Harris and three others at a nearby airstrip. When members apparently cried, Jones counseled "Stop this hysterics. This is not the way for people who are Socialists or Communists to die. No way for us to die. We must die with some dignity." At the end of the tape, Jones concludes: "We didn't commit suicide, we committed an act of revolutionary suicide protesting the conditions of an inhumane world." The people in Jonsetown died of an apparent cyanide poisoning, except for Jones (injury consistent with self-inflicted gunshot wound) and his personal nurse. The Temple had spoken of committing "revolutionary suicide" in prior instances, and members had previously drunk what Jones told them was poison at least once before, but the "Flavor Aid" drink they ingested contained no poison. Concurrently, four other members died in the Temple's headquarters in Georgetown.
## Movement for the Restoration of the Ten Commandments of God
On March 17 2000, 778 members of the Movement for the Restoration of the Ten Commandments of God died in Uganda. The theory that all of the members died in a mass suicide was changed to mass murder when decomposing bodies were discovered in pits with signs of strangulation while others had stab wounds. The group had diverged from the Roman Catholic Church in order to emphasize apocalypticism and alleged Marian apparitions. The group had been called inward-looking movement that wore matching uniforms and restricted their speech to avoid saying anything dishonest or sinful. On the suicide itself locals said they held a party at which 70 crates of soft drinks and three bulls were consumed.
This version of events has been criticized, most notably Irving Hexham, and a Ugandan source states that even today "no one can really explain the whys, hows, whats, where, when, etc."
## Solar Temple
From 1994 to 1997, the Order of the Solar Temple's members began a series of mass suicides, which led to roughly 74 deaths. Farewell letters were left by members, stating that they believed their deaths would be an escape from the "hypocrisies and oppression of this world." Added to this they felt they were "moving on to Sirius." Records seized by the Quebec police showed that some members had personally donated over $1 million to the cult's leader, Joseph Di Mambro.
There was also another attempted mass suicide of the remaining members, which was thwarted in the late 1990s. All the suicide/murders and attempts occurred around the dates of the equinoxes and solstices, which likely held some relation to the beliefs of the group.
## Heaven's Gate
On March 26 1997, 39 followers of Heaven's Gate died in a mass suicide in Rancho Santa Fe, California, which borders San Diego to the north. These people believed, according to the teachings of their cult, that through their suicides they were "exiting their human vehicles" so that their souls could go on a journey aboard a spaceship they believed to be following comet Hale-Bopp. Some male members of the cult underwent voluntary castration in preparation for the genderless life they believed awaited them after the suicide.
On March 30 199, Robert Leon Nichols, a former roadie for the Grateful Dead, was discovered dead in his California trailer, with a note nearby that read in part "I'm going to the spaceship with Hale-Bopp to be with those who have gone before me." Using propane gas rather than vodka and phenobarbital to end his life, Nichols, like the members of Heaven's Gate, had his head covered by a plastic bag and his upper torso covered with a purple shroud. Nichols' connection with the cult is unknown.
In May 1997, two Heaven's Gate members who had not been present for the mass suicide attempted suicide, one succeeding in the attempt, the other going into coma for two days and then recovering. In February 1998 the survivor, Chuck Humphrey, committed suicide.
# Suspected cult suicides
## Branch Davidians
On April 19, 1993, the Bureau of Alcohol, Tobacco and Firearms siege of the Branch Davidians near Waco, Texas ended with an assault and subsequent firestorm that destroyed the compound and killed most of the inhabitants. During the siege, highly concentrated C.S. gas and pyrotechnic "flash-bang" grenades were fired.
Some believe these devices ignited the gasoline stockpiled inside the building.
Richard L. Sherrow, a fire and explosion investigator hired by plaintiffs in a civil lawsuit to investigate the cause of the fire stated in his conclusion that "the fire originated in the southeast corner tower from the tipping of a lit Coleman-type lantern which fell onto combustible materials, most likely bedding materials, as the room was utilized as sleeping quarters, and was most likely caused by violent contact or mechanical shock associated with the CEV removing the corner of the southeast tower directly under the point of origin."
The mainstream media reported immediately after the fire that the Branch Davidians, when being overrun, started fires, and therefore this incident was a "cult suicide" or even a murder-suicide perpetrated by the leaders. However, some independent journalists, academics, and other experts contend that the fires could have been an accident or result of a panic. Others accuse the ATF of inadvertently causing or even intentionally starting fires during the assault.
# Disputed cult suicides
## The Family International
At the beginning of 2005, the cult gained renewed media attention due to the premeditated murder-suicide of former member Ricky Rodriguez, biological son of current leader Karen Zerby and informally adopted son of the group's founder, David Berg. It revived allegations that the group is abusive and inciting of suicidal ideation. Thus his death was widely called a "suicide of a cult member", or "cult suicide", though this view was far from universal. The event made it to popular culture in oblique references in NBC shows Third Watch and Law & Order
Defenders of the group contend that Rodriguez's behavior was not typical of the group, and that there is no evidence their members are more suicidal than those in mainstream society.
## Las Cañadas suicide sect scare
Heidi Fittkau-Garthe, a German psychologist, and a previously high-profile Brahma Kumaris, was charged in the Canary Islands with a plot of murder-suicide in which 31 group members, including five children, were to ingest poison. After the suicides, they were told they would be picked up by a spaceship and taken to an unspecified destination. However a more recent article in Tenerife News casts doubt that there was any intention on the part of the group to commit suicide.
## Tiananmen Square self-immolation incident
On January 23, 2001, six people set themselves on fire in Tiananmen Square, Beijing. The state-media claimed them to be Falun Gong practitioners. Time magazine said that it was possible for misguided practitioners to have taken it upon themselves to demonstrate in this manner, sparking a "propaganda bonanza" for the Chinese authorities. Falun Gong in New York denies that these people could have been practitioners on grounds that the teachings explicitly forbid suicide and killing. Falun Gong and some third-party commentators point to apparent inconsistencies in the government's version of events, and claim that the incident was staged in order to turn public opinion against the practice and build support for its crackdown against the movement.
# Martyrdom
Some argue that martyrdom, as found in religions such as Christianity or Islam, is tantamount to suicide. This argument states that by accepting -- or even inviting-- their own death, the martyr is committing something like assisted suicide. This theory is not in itself new. Richard Marius's unflattering biography of Thomas More indicated More felt hesitant about accepting martyrdom too easily, for fear that would be too similar to suicide. This idea has gained more currency in modern times.
Most mainstream religions traditionally forbid members to take their own lives. Martyrdom generally involves losing one's life (usually passively) due to one's religious beliefs or practices. The Roman Catholic Church considers life to be a gift whose sole "owner" is "God", who is consequently the only individual who may legitimately decide when to interrupt it. Special cases exist, such as the giving of one's own life to save that of another, but most cultures do not consider such acts to be true suicides.
Islam arguably has the harshest view of suicide of any major religion. Therefore some of the lowest suicide rates are found in Muslim nations like Jordan or Egypt.
Mass suicide can also occur as a means of escape when a religious group perceives itself to be hopelessly besieged by its enemies or other adverse external pressure. These external foes may be real or imagined (see Masada). The legend of Masada, and similar examples, are sometimes explicitly used by cult-suicides as a justification. They may say that like those at Masada they are in danger from an evil empire, even if that evil empire is imaginary. They therefore prefer death to surrender, hence criticisms have arisen over the occasional glorification of Masada.
# Related Chapters
- Destructive cult
- Mass suicide | Cult suicide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A cult suicide is a mass suicide by the members of a cult.
[1] In some cases all, or nearly all members have committed suicide at the same time and place. Groups which have committed such mass suicides include Heaven's Gate, Order of the Solar Temple, Peoples Temple (in the Jonestown incident) and the Movement for the Restoration of the Ten Commandments of God. In other cases, such as Filippians and the Taiping, a group has apparently supported mass suicide but without necessarily encouraging all members to participate.
# Known cult suicides
## Peoples Temple
On November 18, 1978, 918 Americans died in Peoples Temple-related incidents, including 909 members of the Temple, led by Jim Jones, in Jonestown, Guyana.[2] The dead included 274 children. A tape of the Temple's final meeting in a Jonestown pavilion contains repeated discussions of the group committing "revolutionary suicide," including reference to people taking the poison and the vats to be used.[3] On that tape, Jones tells Temple members that Russia, with whom the Temple had been negotiating a potential exodus for months, would not take them after the Temple had murdered Congressman Leo Ryan, NBC reporter Don Harris and three others at a nearby airstrip.[3] When members apparently cried, Jones counseled "Stop this hysterics. This is not the way for people who are Socialists or Communists to die. No way for us to die. We must die with some dignity."[3] At the end of the tape, Jones concludes: "We didn't commit suicide, we committed an act of revolutionary suicide protesting the conditions of an inhumane world."[3] The people in Jonsetown died of an apparent cyanide poisoning, except for Jones (injury consistent with self-inflicted gunshot wound) and his personal nurse.[4] The Temple had spoken of committing "revolutionary suicide" in prior instances, and members had previously drunk what Jones told them was poison at least once before, but the "Flavor Aid" drink they ingested contained no poison.[5] Concurrently, four other members died in the Temple's headquarters in Georgetown.
## Movement for the Restoration of the Ten Commandments of God
On March 17 2000, 778 members of the Movement for the Restoration of the Ten Commandments of God died in Uganda.[6] The theory that all of the members died in a mass suicide was changed to mass murder when decomposing bodies were discovered in pits with signs of strangulation while others had stab wounds.[7] The group had diverged from the Roman Catholic Church in order to emphasize apocalypticism and alleged Marian apparitions.[8] The group had been called inward-looking movement that wore matching uniforms and restricted their speech to avoid saying anything dishonest or sinful.[9][10] On the suicide itself locals said they held a party at which 70 crates of soft drinks and three bulls were consumed.[11]
This version of events has been criticized, most notably Irving Hexham,[12] and a Ugandan source states that even today "no one can really explain the whys, hows, whats, where, when, etc."[13]
## Solar Temple
From 1994 to 1997, the Order of the Solar Temple's members began a series of mass suicides, which led to roughly 74 deaths. Farewell letters were left by members, stating that they believed their deaths would be an escape from the "hypocrisies and oppression of this world." Added to this they felt they were "moving on to Sirius." Records seized by the Quebec police showed that some members had personally donated over $1 million to the cult's leader, Joseph Di Mambro.
There was also another attempted mass suicide of the remaining members, which was thwarted in the late 1990s. All the suicide/murders and attempts occurred around the dates of the equinoxes and solstices, which likely held some relation to the beliefs of the group.[14][15][16][17][18]
## Heaven's Gate
On March 26 1997, 39 followers of Heaven's Gate died in a mass suicide in Rancho Santa Fe, California, which borders San Diego to the north. These people believed, according to the teachings of their cult, that through their suicides they were "exiting their human vehicles" so that their souls could go on a journey aboard a spaceship they believed to be following comet Hale-Bopp.[19] Some male members of the cult underwent voluntary castration in preparation for the genderless life they believed awaited them after the suicide.[20]
On March 30 199, Robert Leon Nichols, a former roadie for the Grateful Dead, was discovered dead in his California trailer, with a note nearby that read in part "I'm going to the spaceship with Hale-Bopp to be with those who have gone before me." Using propane gas rather than vodka and phenobarbital to end his life, Nichols, like the members of Heaven's Gate, had his head covered by a plastic bag and his upper torso covered with a purple shroud. Nichols' connection with the cult is unknown.
In May 1997, two Heaven's Gate members who had not been present for the mass suicide attempted suicide, one succeeding in the attempt, the other going into coma for two days and then recovering.[21] In February 1998 the survivor, Chuck Humphrey, committed suicide.[22]
# Suspected cult suicides
## Branch Davidians
On April 19, 1993, the Bureau of Alcohol, Tobacco and Firearms siege of the Branch Davidians near Waco, Texas ended with an assault and subsequent firestorm that destroyed the compound and killed most of the inhabitants. During the siege, highly concentrated C.S. gas and pyrotechnic "flash-bang" grenades[23] were fired.[24]
Some believe these devices ignited the gasoline stockpiled inside the building.
Richard L. Sherrow, a fire and explosion investigator hired by plaintiffs in a civil lawsuit to investigate the cause of the fire stated in his conclusion that "the fire originated in the southeast corner tower from the tipping of a lit Coleman-type lantern which fell onto combustible materials, most likely bedding materials, as the room was utilized as sleeping quarters, and was most likely caused by violent contact or mechanical shock associated with the CEV removing the corner of the southeast tower directly under the point of origin."[25]
The mainstream media reported immediately after the fire that the Branch Davidians, when being overrun, started fires, and therefore this incident was a "cult suicide" or even a murder-suicide perpetrated by the leaders. However, some independent journalists, academics, and other experts contend that the fires could have been an accident or result of a panic. Others accuse the ATF of inadvertently causing or even intentionally starting fires during the assault.
# Disputed cult suicides
## The Family International
At the beginning of 2005, the cult gained renewed media attention due to the premeditated[26] murder-suicide of former member Ricky Rodriguez, biological son of current leader Karen Zerby and informally adopted son of the group's founder, David Berg. It revived allegations that the group is abusive and inciting of suicidal ideation. Thus his death was widely called a "suicide of a cult member", or "cult suicide", though this view was far from universal. The event made it to popular culture in oblique references in NBC shows Third Watch and Law & Order [27]
Defenders of the group contend that Rodriguez's behavior was not typical of the group, and that there is no evidence their members are more suicidal than those in mainstream society. [28]
## Las Cañadas suicide sect scare
Heidi Fittkau-Garthe, a German psychologist, and a previously high-profile Brahma Kumaris, was charged in the Canary Islands with a plot of murder-suicide in which 31 group members, including five children, were to ingest poison. After the suicides, they were told they would be picked up by a spaceship and taken to an unspecified destination.[29] However a more recent article in Tenerife News casts doubt that there was any intention on the part of the group to commit suicide.[30]
## Tiananmen Square self-immolation incident
On January 23, 2001, six people set themselves on fire in Tiananmen Square, Beijing. The state-media claimed them to be Falun Gong practitioners. Time magazine said that it was possible for misguided practitioners to have taken it upon themselves to demonstrate in this manner, sparking a "propaganda bonanza" for the Chinese authorities. Falun Gong in New York denies that these people could have been practitioners on grounds that the teachings explicitly forbid suicide and killing.[31] Falun Gong and some third-party commentators point to apparent inconsistencies in the government's version of events, and claim that the incident was staged in order to turn public opinion against the practice and build support for its crackdown against the movement.
# Martyrdom
Some argue that martyrdom, as found in religions such as Christianity or Islam, is tantamount to suicide. This argument states that by accepting -- or even inviting-- their own death, the martyr is committing something like assisted suicide. This theory is not in itself new. Richard Marius's unflattering biography of Thomas More indicated More felt hesitant about accepting martyrdom too easily, for fear that would be too similar to suicide. This idea has gained more currency in modern times.
Most mainstream religions traditionally forbid members to take their own lives. Martyrdom generally involves losing one's life (usually passively) due to one's religious beliefs or practices. The Roman Catholic Church considers life to be a gift whose sole "owner" is "God", who is consequently the only individual who may legitimately decide when to interrupt it. Special cases exist, such as the giving of one's own life to save that of another, but most cultures do not consider such acts to be true suicides.
Islam arguably has the harshest view of suicide of any major religion. Therefore some of the lowest suicide rates are found in Muslim nations like Jordan or Egypt.
[32]
Mass suicide can also occur as a means of escape when a religious group perceives itself to be hopelessly besieged by its enemies or other adverse external pressure. These external foes may be real or imagined (see Masada). The legend of Masada, and similar examples, are sometimes explicitly used by cult-suicides as a justification. They may say that like those at Masada they are in danger from an evil empire, even if that evil empire is imaginary. They therefore prefer death to surrender, hence criticisms have arisen over the occasional glorification of Masada.
# Related Chapters
- Destructive cult
- Mass suicide | https://www.wikidoc.org/index.php/Cult_suicide | |
c6b035661b3aebc00cae469d1dbc94891c11f4d8 | wikidoc | Fire cupping | Fire cupping
Fire cupping is a method of applying acupressure by creating a vacuum next to the patient's skin. In traditional Chinese medicine (TCM) it involves placing glass, plastic, or bamboo cups on the skin with a vacuum. The therapy is used to relieve what is called "stagnation" in TCM terms, and is used in the treatment of respiratory diseases such as the common cold, pneumonia, and bronchitis. Cupping is also used to treat back, neck, shoulder, and other musculoskeletal pain. Its advocates claim it has other applications as well. This technique, in varying forms, has also been found in the folk medicine of Vietnam, the Balkans, modern Greece, Mexico, and Russia, among other places, including Iran where it is called 'bod-kesh' meaning literally 'pull with air'.
# Method
Instead of using a vacuum pump, a vacuum is created by air (heated by fire) in a glass cup placed flush against the patient's skin. As the air cools in the cup, a vacuum forms that pulls up on the skin, stimulating the acupressure effect.
The cups are usually roughly bell shaped with a capacity of about 4 fluid ounces. Most commonly, a total of from 8 to 12 cups are applied to the subject's back in two parallel 'vertical' columns, midway between the spine and each edge of the body, spaced about 4 inches on center within each column. An interesting animation of the process may be found here (requires Shockwave Flash).
There are several ways of heating the air in the cup with fire:
1. One can swab rubbing alcohol (minimum 90%) into the bottom of a cup, then light it and place the cup immediately against the skin. By creating the seal the immediate loss of oxygen puts the fire out, preventing the person from being burned. The smaller the amount of alcohol, and the quicker the flame is extinguished by application of the cup, the better, so long as there is no risk of the cups falling off due to lack of a proper seal.
2. One can hold the cup inverted over a flame (e.g. a lit candle), heating the air, then place the cup immediately against the skin. Care must be taken not to heat the glass itself. Even so, the person to whom the cup is applied will feel distinctly more heat than in the previous method.
3. One can ignite a flame with a small alcohol-soaked cotton wad resting on a small pad of leather or other insulating material that rests directly on the patient's skin, then place the cup immediately over the flame, putting out the fire. The quickness with which the flame is extinguished depends on the size and shape of the cup.
Methods 1 and 2 heat the glass to some extent and have a risk of burning the patient if not carefully executed. Method 3 risks the cotton falling off the insulating pad onto the patient's skin, and leaves the pad and cotton wadding inside the adhering cup which could be considered cumbersome.
Baby oil massaged onto the skin first causes a better seal to form, making it possible to use this therapy with less heating of the cup. It is often possible to slide the adhered cup around on the skin, preserving the suction seal as it glides. Care must be taken not to move the cup over protruding moles, skin tags, scabs, etc.
The longer a cup is left on, the more of a circular mark is created. The skin pores are more open, and the patient may have a feeling like sunburn. An application of about 20 minutes is average, for the back; however this varies with the individual. In no case should the cups be left in place if the subject reports noticeable discomfort.
According to the American Cancer Society, "vailable scientific evidence does not support cupping as a cure for cancer or any other disease". It can leave temporary unsightly marks on the skin and there is also a small risk of burns. Persons who claim this therapy to be beneficial report that its effect is a long lasting feeling of relaxation and invigoration. It is possible that whatever relief is obtained by this procedure is derived from the same principles that are employed in shiatsu massage, where instead of the outward sucking of the cups, strong inward pressure is directed at the muscles of the dorsal ribcage and abdomen.
Cupping was commonly used as a Eastern European Jewish folk remedy, with the Yiddish name באנקעס (bankes).
The proverb 'עס וועט העלפן ווי א טויטען באנקס’ (Es vet helfn vi a toyten bankes, literally "It would help like cupping a corpse") is used to opine that a course of action would be futile.
# Wet cupping
In this variant, a form of bloodletting also called blood cupping, a small scratch or incision is made with a lancet prior to the cupping, and the pressure difference extracts blood from the skin.
Islamic traditional medicine uses this technique - called in Arabic hijamah or hijama - with a number of hadith supporting its recommendation and use by Muhammad (although Muhammad is said to have explicitly stated, roughly put, to have as much knowledge in things that need skill as any average person). | Fire cupping
Template:Chinese
Fire cupping is a method of applying acupressure by creating a vacuum next to the patient's skin. In traditional Chinese medicine (TCM) it involves placing glass, plastic, or bamboo cups on the skin with a vacuum. The therapy is used to relieve what is called "stagnation" in TCM terms, and is used in the treatment of respiratory diseases such as the common cold, pneumonia, and bronchitis. Cupping is also used to treat back, neck, shoulder, and other musculoskeletal pain. Its advocates claim it has other applications as well. This technique, in varying forms, has also been found in the folk medicine of Vietnam, the Balkans, modern Greece, Mexico, and Russia, among other places, including Iran where it is called 'bod-kesh' meaning literally 'pull with air'.
# Method
Instead of using a vacuum pump, a vacuum is created by air (heated by fire) in a glass cup placed flush against the patient's skin. As the air cools in the cup, a vacuum forms that pulls up on the skin, stimulating the acupressure effect.
The cups are usually roughly bell shaped with a capacity of about 4 fluid ounces. Most commonly, a total of from 8 to 12 cups are applied to the subject's back in two parallel 'vertical' columns, midway between the spine and each edge of the body, spaced about 4 inches on center within each column. An interesting animation of the process may be found here [1] (requires Shockwave Flash).
There are several ways of heating the air in the cup with fire:
1. One can swab rubbing alcohol (minimum 90%) into the bottom of a cup, then light it and place the cup immediately against the skin. By creating the seal the immediate loss of oxygen puts the fire out, preventing the person from being burned. The smaller the amount of alcohol, and the quicker the flame is extinguished by application of the cup, the better, so long as there is no risk of the cups falling off due to lack of a proper seal.
2. One can hold the cup inverted over a flame (e.g. a lit candle), heating the air, then place the cup immediately against the skin. Care must be taken not to heat the glass itself. Even so, the person to whom the cup is applied will feel distinctly more heat than in the previous method.
3. One can ignite a flame with a small alcohol-soaked cotton wad resting on a small pad of leather or other insulating material that rests directly on the patient's skin, then place the cup immediately over the flame, putting out the fire. The quickness with which the flame is extinguished depends on the size and shape of the cup.
Methods 1 and 2 heat the glass to some extent and have a risk of burning the patient if not carefully executed. Method 3 risks the cotton falling off the insulating pad onto the patient's skin, and leaves the pad and cotton wadding inside the adhering cup which could be considered cumbersome.
Baby oil massaged onto the skin first causes a better seal to form, making it possible to use this therapy with less heating of the cup. It is often possible to slide the adhered cup around on the skin, preserving the suction seal as it glides. Care must be taken not to move the cup over protruding moles, skin tags, scabs, etc.
The longer a cup is left on, the more of a circular mark is created. The skin pores are more open, and the patient may have a feeling like sunburn. An application of about 20 minutes is average, for the back; however this varies with the individual. In no case should the cups be left in place if the subject reports noticeable discomfort.
According to the American Cancer Society, "[a]vailable scientific evidence does not support cupping as a cure for cancer or any other disease"[1]. It can leave temporary unsightly marks on the skin and there is also a small risk of burns. Persons who claim this therapy to be beneficial report that its effect is a long lasting feeling of relaxation and invigoration. It is possible that whatever relief is obtained by this procedure is derived from the same principles that are employed in shiatsu massage, where instead of the outward sucking of the cups, strong inward pressure is directed at the muscles of the dorsal ribcage and abdomen.
Cupping was commonly used as a Eastern European Jewish folk remedy, with the Yiddish name באנקעס (bankes).
[2]
[3]
The proverb 'עס וועט העלפן ווי א טויטען באנקס’ (Es vet helfn vi a toyten bankes, literally "It would help like cupping a corpse") is used to opine that a course of action would be futile.
[4]
[3]
# Wet cupping
In this variant, a form of bloodletting also called blood cupping, a small scratch or incision is made with a lancet prior to the cupping, and the pressure difference extracts blood from the skin.
Islamic traditional medicine uses this technique - called in Arabic hijamah or hijama - with a number of hadith supporting its recommendation and use by Muhammad (although Muhammad is said to have explicitly stated, roughly put, to have as much knowledge in things that need skill as any average person). | https://www.wikidoc.org/index.php/Cupping | |
0bf85df438498f55d2db8cb7244b905989115b32 | wikidoc | Cycle (gene) | Cycle (gene)
Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc . Orthologs performing the same function in other species include ARNTL and ARNTL2.
# Function
Cycle is primarily known for its role in the genetic transcription-translation feedback loop that generates circadian rhythms in Drosophila. In the cell nucleus, the CYCLE protein (CYC) forms a heterodimer with a second bHLH-PAS protein, CLOCK (CLK). This CYC-CLK protein complex binds to E-box elements in promoter regions of the genes period and timeless, functioning as a transcription factor in the translation of the proteins PER and TIM. After the PER and TIM proteins accumulate in the cytoplasm and bind together, the PER-TIM complex translocates to the nucleus. The TIM protein in these complexes mediate the accumulation of the dimeric PER-TIM protein complex and their subsequent importation into the nucleus, where the PER protein in these complexes then mediates the release of CYC-CLK from the chromatin, repressing CYC-CLK dependent transcription. Thus, CLK and CYC act as positive factors and PER and TIM as negative factors. CYC also plays a role in the post-translational regulation of CLK in the cytoplasm. These four proteins of the feedback loop are later degraded by a casein kinase-mediated phosphorylation cycle, allowing fluctuations in gene expression according to environmental cues. This cycle is called the transcription-translation feedback loop as demonstrated in this video by the Howard Hughes Medical Institution. Though cyc is a clock gene and plays a role in setting and keeping rhythms, cyc is expressed constitutively (continuously) in Drosophila cells and is present in native Drosophila tissue culture cells, unlike clk, per, or tim. Regulation thus occurs primarily through the negative feedback by the PER-TIM protein complex in the transcription-translation feedback loop described above.
The CYC-CLK also interacts with the Clockwork Orange (CWO) protein in such a way that increases the robustness in the generation of high amplitude oscillations. CWO is a transcriptional repressor and antagonistic competition between CYC-CLK and CWO lead to control of E-box mediated transcription. Some findings suggest that CWO preferentially aids in the termination of CYC-CLK mediated transcription during late night.
Cyc is involved with the genetic basis of other behaviors that relate to circadian processes, such as sleep, which is important for survival, as sleep deprivation can cause death in Drosophila. There is significant correlation between having functioning cyc and longevity. Though the exact mechanism of this correlation is not known, it is suspected that it is due primarily to cyc playing a role in regulating expression of heat-shock genes, which in turn play a role in regulating duration and quality of sleep. Without proper regulation of sleep, Drosophila may become sleep deprived and die. In male Drosophila, three strains were bred, one containing no copies of functioning cyc, one containing one copy of functioning cyc, and one containing two copies of functioning cyc (wild-type). On average, Drosophila with no copies died after 48 days, Drosophila with one copy died after 52 days, and Drosophila with two copies died after 60 days.The premature deaths are accounted for by poor sleep in the absence of two functioning cyc. This effect, however, did display gender dimorphism, as female Drosophila showed no significant shortening in life span even when their cyc was knocked out. This suggests female Drosophila may have other mechanisms to compensate for a lack of cyc that male Drosophila do not possess. However, to fully understand these processes, work must be done to identify downstream interactions of CYCLE proteins. In addition, similar findings have been found in mice deficient in BMAL1, the mammalian ortholog of CYC, but without the sexual dimorphism exhibited by drosophila.
Cyc is also involved in Drosophila’s responses to starvation, which also directly affect life span. Starvation in Drosophila potently suppresses sleep, suggesting that the homeostatically regulated behaviors of feeding and sleep are integrated in flies. Clk and cyc act during starvation to modulate the conflict of whether flies sleep or search for food, thus playing a critical role for proper sleep suppression during starvation.
# Discovery
The identification, characterization, and cloning of cyc was reported in May 1998 in Cell by Jeffrey Hall and Michael Rosbash’s labs at Brandeis University along with first author Joan E. Rutila at the Howard Hughes Medical Institute. Prior to its discovery, the mechanism by which PER and TIM transcription was regulated rhythmically was not fully understood. They published the papers reporting the discovery of CYCLE and CLOCK in the same issue of Cell. They found both genes as a result of a technique of forward genetics, chemically mutagenzing flies and screening for altered locomotor activity rhythms. From the screen, cycle was identified as a recessive arrhythmic mutant in one fly line because it shows arrhythmic locomotor activity patterns when a fly has 2 mutant chromosomes number 3. These mutant flies were also found to display arrhythmic eclosion. Because the mutants displayed no circadian rhythms and the heterozygote flies displayed long circadian periods, they determined that cycle has a dominant phenotype. These data also suggest that the Cycle gene is part of the biological clock because of the similarity between the cycle mutant phenotype and that of the clock mutant. This suggests that Cycle is part of the biological clock with its phenotype similar to that of the clock mutant. Assaying PER and TIM transcription levels in the cyc mutant showed reduced mRNA levels of both proteins. Cloning of the cyc gene revealed that it encodes a novel bHLH-PAS protein related to mammalian bmal1, and that it likely binds to Clock to activate transcription of circadian rhythm genes.
Cycle gene expression has been discovered in a variety of cell types and tissues including the adult head, adult eye, larval/adult central nervous system, adult crop, adult midgut, adult hindgut, larval/adult Malpighian tubules, larval/adult fat body, adult salivary gland, adult female reproductive system, adult male accessory gland, and adult carcass.
Recent research on cycle has largely focused on the role of circadian rhythmicity in other processes. In 2012, it was reported that aging reduces transcriptional oscillations of core clock genes in the fly head including cycle. Wild type Drosophila show low activity of the CLOCK/CYCLE protein dimer in the morning, and it was recently found that lowering levels of these proteins can affect neuronal signaling. Research from 2012 on sleep architecture and nutrition found that circadian clock mutants, including cyc01 still maintained a normal diet response without circadian rhythmicity. Future work focusing on understanding the role of circadian rhythms in Drosophila will continue to investigate cycle's role in maintaining rhythmicity.
# Species distribution
The cycle gene found in Drosophila melanogaster has many orthologs among eukaryotes including other members of the genus Drosophila, mosquitoes, various non-dipteran insects, non insect arthropods, humans, and other mammals. In other members of Drosophila, functional orthologs of the D. melanogaster cycle gene can either be found in chromosome 3 or in scaffold/matrix attachment regions. In each case, the orthologs retain functional PAS domains, signal transduction function, and transcription factor activity. Other non-arthropods containing the functional ortholog of the Drosophila cycle ARNTL and ARNTL2 include humans, house mice, domestic chicken and zebrafish. Most vertebrate creatures retain a functionally and structurally similar protein. Unlike dipterans, however, these animals have two different orthologs of the cycle gene most likely caused by a gene duplication event. Much like CYCLE, the ARNTL proteins have a basic helix-loop-helix and a PAS domain containing transcription factors responsible for the autoregulatory transcription translation negative feedback loops (above), which are responsible for generating molecular circadian rhythms. For a more complete list of ARNTL homologs visit the ARNTL species distribution article.
The cyc gene found in the moth Sesamia nonagrioides, or commonly known as the Mediterranean corn borer, has been cloned in a recent study; this SnCYC was found to have 667 amino acids. Further structural analysis showed that it also contains a BCTR domain in its C-terminal in addition to the common domains found in Drosophila CYC. Researchers found that the mRNAs of Sncyc expression was rhythmic in long day (16L:8D), constant darkness, and short day (10L:14D) cycles after investigating its expression patterns in larvae brains. Furthermore, it was found that photoperiodic conditions affect the expression patterns and/or amplitudes of this gene. In Sesamia nonagrioides, this Sncyc gene is associated with diapause. This is due to the fact that under short day (diapause conditions) the photoperiodic signal alters the accumulation of mRNA. However, in Drosophila, this gene does not oscillate or change in expression patterns in response to photoperiod, therefore suggesting that this species may be useful in further studying the molecular control of circadian and photoperiodic clocks in insects.
# Mutations
There are currently 19 known alleles of cyc found in Drosophila melanogaster, and most of these have been mutagenized and engineered by researchers in the laboratory.
## Cyc01
Cyc01 also known as cyc0 is a recessive null mutant allele. This means that a Drosophila with two copies of the cyc01 mutant does not produce a functional CYCLE protein. The resulting Drosophila exhibits arrhythmic activity and cannot entrain to any light-dark cycle. Cyc01 mutants showed a disproportionately large sleep rebound and died after 10 hours of sleep deprivation, although they were more resistant than other clock mutants to various stressors. Unlike other clock mutants, cyc01 flies showed a reduced expression of heat-shock genes after sleep loss. However, activating heat-shock genes before sleep deprivation rescued cyc01 flies from its lethal effects.
## Cyc02
Cyc02 is a recessive mutant, characterized by a severe reduction in levels of PER protein. In each case, the mutation was the result of a nonsense mutation in the PAS-encoding region found in 1999 following a forward screen of ethyl methanesulfonatemutants. Under both light-dark and continuous dark conditions, the cyc02 mutant was arrhythmic and nearly continuously active. Both the cyc01 and the cyc02 mutants were identified by the same team.
## CycΔ
CycΔ mutation is a dominant-negative mutation which blocks the ability of CYCLE-CLOCK complexes from activating E-box dependent transcription of timeless. The mutation is the result of a 15 to 17 base pair deletion from the cyc gene.
## CycG4677
A cycG4677 mutant strain is available from Bloomington Drosophila Stock Center at Indiana University. The cycG4677 mutant strain is the result of a p-transposable element insertion. No information about the phenotype is publicly available.
Fifteen other mutant alleles are known, but are less commonly researched. | Cycle (gene)
Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain.[1] The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc .[2][3] Orthologs performing the same function in other species include ARNTL and ARNTL2.
# Function
Cycle is primarily known for its role in the genetic transcription-translation feedback loop that generates circadian rhythms in Drosophila. In the cell nucleus, the CYCLE protein (CYC) forms a heterodimer with a second bHLH-PAS protein, CLOCK (CLK). This CYC-CLK protein complex binds to E-box elements in promoter regions of the genes period and timeless, functioning as a transcription factor in the translation of the proteins PER and TIM.[4] After the PER and TIM proteins accumulate in the cytoplasm and bind together, the PER-TIM complex translocates to the nucleus. The TIM protein in these complexes mediate the accumulation of the dimeric PER-TIM protein complex and their subsequent importation into the nucleus, where the PER protein in these complexes then mediates the release of CYC-CLK from the chromatin, repressing CYC-CLK dependent transcription. Thus, CLK and CYC act as positive factors and PER and TIM as negative factors. CYC also plays a role in the post-translational regulation of CLK in the cytoplasm.[5] These four proteins of the feedback loop are later degraded by a casein kinase-mediated phosphorylation cycle, allowing fluctuations in gene expression according to environmental cues. This cycle is called the transcription-translation feedback loop as demonstrated in this video by the Howard Hughes Medical Institution. Though cyc is a clock gene and plays a role in setting and keeping rhythms, cyc is expressed constitutively (continuously) in Drosophila cells[4] and is present in native Drosophila tissue culture cells, unlike clk, per, or tim.[6] Regulation thus occurs primarily through the negative feedback by the PER-TIM protein complex in the transcription-translation feedback loop described above.
The CYC-CLK also interacts with the Clockwork Orange (CWO) protein in such a way that increases the robustness in the generation of high amplitude oscillations. CWO is a transcriptional repressor and antagonistic competition between CYC-CLK and CWO lead to control of E-box mediated transcription.[7] Some findings suggest that CWO preferentially aids in the termination of CYC-CLK mediated transcription during late night.[8]
Cyc is involved with the genetic basis of other behaviors that relate to circadian processes, such as sleep, which is important for survival, as sleep deprivation can cause death in Drosophila. There is significant correlation between having functioning cyc and longevity.[9] Though the exact mechanism of this correlation is not known, it is suspected that it is due primarily to cyc playing a role in regulating expression of heat-shock genes, which in turn play a role in regulating duration and quality of sleep.[10] Without proper regulation of sleep, Drosophila may become sleep deprived and die. In male Drosophila, three strains were bred, one containing no copies of functioning cyc, one containing one copy of functioning cyc, and one containing two copies of functioning cyc (wild-type). On average, Drosophila with no copies died after 48 days, Drosophila with one copy died after 52 days, and Drosophila with two copies died after 60 days.The premature deaths are accounted for by poor sleep in the absence of two functioning cyc.[9] This effect, however, did display gender dimorphism, as female Drosophila showed no significant shortening in life span even when their cyc was knocked out. This suggests female Drosophila may have other mechanisms to compensate for a lack of cyc that male Drosophila do not possess.[9] However, to fully understand these processes, work must be done to identify downstream interactions of CYCLE proteins. In addition, similar findings have been found in mice deficient in BMAL1, the mammalian ortholog of CYC, but without the sexual dimorphism exhibited by drosophila.[11]
Cyc is also involved in Drosophila’s responses to starvation, which also directly affect life span. Starvation in Drosophila potently suppresses sleep, suggesting that the homeostatically regulated behaviors of feeding and sleep are integrated in flies. Clk and cyc act during starvation to modulate the conflict of whether flies sleep or search for food, thus playing a critical role for proper sleep suppression during starvation.[12]
# Discovery
The identification, characterization, and cloning of cyc was reported in May 1998 in Cell by Jeffrey Hall and Michael Rosbash’s labs at Brandeis University along with first author Joan E. Rutila at the Howard Hughes Medical Institute.[4] Prior to its discovery, the mechanism by which PER and TIM transcription was regulated rhythmically was not fully understood. They published the papers reporting the discovery of CYCLE and CLOCK in the same issue of Cell. They found both genes as a result of a technique of forward genetics, chemically mutagenzing flies and screening for altered locomotor activity rhythms.[13] From the screen, cycle was identified as a recessive arrhythmic mutant in one fly line because it shows arrhythmic locomotor activity patterns when a fly has 2 mutant chromosomes number 3.[4] These mutant flies were also found to display arrhythmic eclosion.[4] Because the mutants displayed no circadian rhythms and the heterozygote flies displayed long circadian periods, they determined that cycle has a dominant phenotype. These data also suggest that the Cycle gene is part of the biological clock because of the similarity between the cycle mutant phenotype and that of the clock mutant.[4] This suggests that Cycle is part of the biological clock with its phenotype similar to that of the clock mutant. Assaying PER and TIM transcription levels in the cyc mutant showed reduced mRNA levels of both proteins. Cloning of the cyc gene revealed that it encodes a novel bHLH-PAS protein related to mammalian bmal1, and that it likely binds to Clock to activate transcription of circadian rhythm genes.[4]
Cycle gene expression has been discovered in a variety of cell types and tissues including the adult head, adult eye, larval/adult central nervous system, adult crop, adult midgut, adult hindgut, larval/adult Malpighian tubules, larval/adult fat body, adult salivary gland, adult female reproductive system, adult male accessory gland, and adult carcass.[3]
Recent research on cycle has largely focused on the role of circadian rhythmicity in other processes. In 2012, it was reported that aging reduces transcriptional oscillations of core clock genes in the fly head including cycle.[14] Wild type Drosophila show low activity of the CLOCK/CYCLE protein dimer in the morning, and it was recently found that lowering levels of these proteins can affect neuronal signaling.[15] Research from 2012 on sleep architecture and nutrition found that circadian clock mutants, including cyc01 still maintained a normal diet response without circadian rhythmicity.[16] Future work focusing on understanding the role of circadian rhythms in Drosophila will continue to investigate cycle's role in maintaining rhythmicity.
# Species distribution
The cycle gene found in Drosophila melanogaster has many orthologs among eukaryotes including other members of the genus Drosophila, mosquitoes, various non-dipteran insects, non insect arthropods, humans, and other mammals. In other members of Drosophila, functional orthologs of the D. melanogaster cycle gene can either be found in chromosome 3 or in scaffold/matrix attachment regions. In each case, the orthologs retain functional PAS domains, signal transduction function, and transcription factor activity. Other non-arthropods containing the functional ortholog of the Drosophila cycle ARNTL and ARNTL2 include humans, house mice, domestic chicken and zebrafish. Most vertebrate creatures retain a functionally and structurally similar protein. Unlike dipterans, however, these animals have two different orthologs of the cycle gene most likely caused by a gene duplication event.[17] Much like CYCLE, the ARNTL proteins have a basic helix-loop-helix and a PAS domain containing transcription factors responsible for the autoregulatory transcription translation negative feedback loops (above), which are responsible for generating molecular circadian rhythms.[18] For a more complete list of ARNTL homologs visit the ARNTL species distribution article.
The cyc gene found in the moth Sesamia nonagrioides, or commonly known as the Mediterranean corn borer, has been cloned in a recent study; this SnCYC was found to have 667 amino acids. Further structural analysis showed that it also contains a BCTR domain in its C-terminal in addition to the common domains found in Drosophila CYC. Researchers found that the mRNAs of Sncyc expression was rhythmic in long day (16L:8D), constant darkness, and short day (10L:14D) cycles after investigating its expression patterns in larvae brains. Furthermore, it was found that photoperiodic conditions affect the expression patterns and/or amplitudes of this gene. In Sesamia nonagrioides, this Sncyc gene is associated with diapause. This is due to the fact that under short day (diapause conditions) the photoperiodic signal alters the accumulation of mRNA. However, in Drosophila, this gene does not oscillate or change in expression patterns in response to photoperiod, therefore suggesting that this species may be useful in further studying the molecular control of circadian and photoperiodic clocks in insects.[19]
# Mutations
There are currently 19 known alleles of cyc found in Drosophila melanogaster, and most of these have been mutagenized and engineered by researchers in the laboratory.
## Cyc01
Cyc01 also known as cyc0 is a recessive null mutant allele. This means that a Drosophila with two copies of the cyc01 mutant does not produce a functional CYCLE protein. The resulting Drosophila exhibits arrhythmic activity and cannot entrain to any light-dark cycle. Cyc01 mutants showed a disproportionately large sleep rebound and died after 10 hours of sleep deprivation, although they were more resistant than other clock mutants to various stressors. Unlike other clock mutants, cyc01 flies showed a reduced expression of heat-shock genes after sleep loss. However, activating heat-shock genes before sleep deprivation rescued cyc01 flies from its lethal effects.[20]
## Cyc02
Cyc02 is a recessive mutant, characterized by a severe reduction in levels of PER protein. In each case, the mutation was the result of a nonsense mutation in the PAS-encoding region found in 1999 following a forward screen of ethyl methanesulfonatemutants. Under both light-dark and continuous dark conditions, the cyc02 mutant was arrhythmic and nearly continuously active.[21] Both the cyc01 and the cyc02 mutants were identified by the same team.[22]
## CycΔ
CycΔ mutation is a dominant-negative mutation which blocks the ability of CYCLE-CLOCK complexes from activating E-box dependent transcription of timeless. The mutation is the result of a 15 to 17 base pair deletion from the cyc gene.[23]
## CycG4677
A cycG4677 mutant strain is available from Bloomington Drosophila Stock Center at Indiana University. The cycG4677 mutant strain is the result of a p-transposable element insertion. No information about the phenotype is publicly available.
Fifteen other mutant alleles are known, but are less commonly researched. | https://www.wikidoc.org/index.php/Cycle_(gene) | |
58ede6544755f295a63cd3eb71f127b0cda6391b | wikidoc | Cyclodextrin | Cyclodextrin
File:Beta-cyclodextrin3D.png
Cyclodextrins (sometimes called cycloamyloses) make up a family of cyclic oligosaccharides, composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, even at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape. thus denoting:
- α-cyclodextrin: six sugar ring molecule
- β-cyclodextrin: seven sugar ring molecule
- γ-cyclodextrin: eight sugar ring molecule
Cyclodextrins are produced from starch by means of enzymatic conversion. Over the last few years they have found a wide range of applications in food, pharmaceutical and chemical industries as well as agriculture and environmental engineering. It is also the chief active compound found in Procter and Gamble's deodorizing product "Febreze".
File:Cyclodextrin.svg
# History of cyclodextrins
Cyclodextrins, as they are known today, were called "cellulosine" when first described by A. Villiers in 1891. Soon after, F. Schardinger identified the three naturally occurring cyclodextrins -α, -β, and -γ. These compounds were therefore referred to as "Schardinger sugars". For 25 years, between 1911 and 1935, Pringsheim in Germany was the leading researcher in this area, demonstrating that cyclodextrins formed stable aqueous complexes with many other chemicals. By the mid 1970's, each of the natural cyclodextrins had been structurally and chemically characterized and many more complexes had been studied. Since the 1970s, extensive work has been conducted by Szejtli and others exploring encapsulation by cyclodextrins and their derivatives for industrial and pharmacologic applications.
# Structure
Typical cyclodextrins are constituted by 6-8 glucopyranoside units, can be topologically represented as toroids with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively. Because of this arrangement, the interior of the toroids is not hydrophobic, but considerably less hydrophilic than the aqueous environment and thus able to host other hydrophobic molecules. On the contrary the exterior is sufficiently hydrophilic to impart cyclodextrins (or their complexes) water solubility.
The formation of the inclusion compounds greatly modifies the physical and chemical properties of the guest molecule, mostly in terms of water solubility. This is the reason why cyclodextrins have attracted much interest in many fields, especially pharmaceutical applications: because inclusion compounds of cyclodextrins with hydrophobic molecules are able to penetrate body tissues, these can be used to release biologically active compounds under specific conditions. In most cases the mechanism of controlled degradation of such complexes is based on pH change of water solutions, leading to the cleavage of hydrogen or ionic bonds between the host and the guest molecules. Alternative means for the disruption of the complexes take advantage of heating or action of enzymes able to cleave α-1,4 linkages between glucose monomers.
# Synthesis
The production of cyclodextrins is relatively simple and involves treatment of ordinary starch with a set of easily available enzymes. Commonly cyclodextrin glycosyltransferase (CGTase) is employed along with α-amylase. First starch is liquified either by heat treatment or using α-amylase, then CGTase is added for the enzymatic conversion. CGTases can synthesize all forms of cyclodextrins, thus the product of the conversion results in a mixture of the three main types of cyclic molecules, in ratios that are strictly dependent on the enzyme used: each CGTase has its own characteristic α:β:γ synthesis ratio. Purification of the three types of cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is very poorly water soluble (18.5 g/l or 16.3mM) (at 25C???) can be easily retrieved through crystallization while the more soluble α- and γ-CDs (145 and 232 g/l respectively) are usually purified by means of expensive and time consuming chromatography techniques.
As an alternative a "complexing agent" can be added during the enzymatic conversion step: such agents (usually organic solvents like toluene, acetone or ethanol) form a complex with the desired cyclodextrin which subsequently precipitates. The complex formation drives the conversion of starch towards the synthesis of the precipitated cyclodextrin, thus enriching its content in the final mixture of products. The precipitated cyclodextrin is easily retrieved by centrifugation and is later separated from the complexing agent.
# Uses
Cyclodextrins are able to form host-guest complexes with hydrophobic molecules given the unique nature imparted by their structure. As a result these molecules have found a number of applications in a wide range of fields.
Other than the above mentioned pharmaceutical applications for drug release, cyclodextrins can be employed in environmental protection: these molecules can effectively immobilise inside their rings toxic compounds, like trichloroethane or heavy metals, or can form complexes with stable substances, like trichlorfon (an organophosphorus insecticide) or sewage sludge, enhancing their decomposition.
In the food industry cyclodextrins are employed for the preparation of cholesterol free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed, leaving behind a "low fat" food.
Other food applications further include the ability to stabilize volatile or unstable compounds and the reduction of unwanted tastes and odour.
Reportedly cyclodextrins are used in alcohol powder, a powder for mixing alcoholic drinks.
The strong ability of complexing fragrances can also be used for another purpose: first dry, solid cyclodextrin microparticles are exposed to a controlled contact with fumes of active compounds, then they are added to fabric or paper products. Such devices are capable of releasing fragrances during ironing or when heated by human body. Such a device commonly used is a typical 'dryer sheet'. The heat from a clothes dryer releases the fragrance into the clothing.
The ability of cyclodextrins to form complexes with hydrophobic molecules has led to their usage in supramolecular chemistry. In particular they have been used to synthesize certain mechanically-interlocked molecular architectures, such as rotaxanes and catenanes, by reacting the ends of the threaded guest.
# Derivatives
Both β-cyclodextrin and MβCD remove cholesterol from cultured cells. The methylated form MβCD was found to be more efficient than β-cyclodextrin. The water-soluble MβCD is known to form soluble inclusion complexes with cholesterol, thereby enhancing its solubility in aqueous solution. Methyl-β-cyclodextrin are employed for the preparation of cholesterol-free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. It is also employed to disrupt lipid rafts by removing the cholesterol from the membrane in research. | Cyclodextrin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
File:Beta-cyclodextrin3D.png
Cyclodextrins (sometimes called cycloamyloses) make up a family of cyclic oligosaccharides, composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, even at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape. thus denoting:
- α-cyclodextrin: six sugar ring molecule
- β-cyclodextrin: seven sugar ring molecule
- γ-cyclodextrin: eight sugar ring molecule
Cyclodextrins are produced from starch by means of enzymatic conversion. Over the last few years they have found a wide range of applications in food, pharmaceutical and chemical industries as well as agriculture and environmental engineering. It is also the chief active compound found in Procter and Gamble's deodorizing product "Febreze".
File:Cyclodextrin.svg
# History of cyclodextrins
Cyclodextrins, as they are known today, were called "cellulosine" when first described by A. Villiers in 1891. Soon after, F. Schardinger identified the three naturally occurring cyclodextrins -α, -β, and -γ. These compounds were therefore referred to as "Schardinger sugars". For 25 years, between 1911 and 1935, Pringsheim in Germany was the leading researcher in this area, demonstrating that cyclodextrins formed stable aqueous complexes with many other chemicals. By the mid 1970's, each of the natural cyclodextrins had been structurally and chemically characterized and many more complexes had been studied. Since the 1970s, extensive work has been conducted by Szejtli and others exploring encapsulation by cyclodextrins and their derivatives for industrial and pharmacologic applications. [1]
# Structure
Typical cyclodextrins are constituted by 6-8 glucopyranoside units, can be topologically represented as toroids with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively. Because of this arrangement, the interior of the toroids is not hydrophobic, but considerably less hydrophilic than the aqueous environment and thus able to host other hydrophobic molecules. On the contrary the exterior is sufficiently hydrophilic to impart cyclodextrins (or their complexes) water solubility.
The formation of the inclusion compounds greatly modifies the physical and chemical properties of the guest molecule, mostly in terms of water solubility. This is the reason why cyclodextrins have attracted much interest in many fields, especially pharmaceutical applications: because inclusion compounds of cyclodextrins with hydrophobic molecules are able to penetrate body tissues, these can be used to release biologically active compounds under specific conditions. In most cases the mechanism of controlled degradation of such complexes is based on pH change of water solutions, leading to the cleavage of hydrogen or ionic bonds between the host and the guest molecules. Alternative means for the disruption of the complexes take advantage of heating or action of enzymes able to cleave α-1,4 linkages between glucose monomers.
# Synthesis
The production of cyclodextrins is relatively simple and involves treatment of ordinary starch with a set of easily available enzymes. Commonly cyclodextrin glycosyltransferase (CGTase) is employed along with α-amylase. First starch is liquified either by heat treatment or using α-amylase, then CGTase is added for the enzymatic conversion. CGTases can synthesize all forms of cyclodextrins, thus the product of the conversion results in a mixture of the three main types of cyclic molecules, in ratios that are strictly dependent on the enzyme used: each CGTase has its own characteristic α:β:γ synthesis ratio. Purification of the three types of cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is very poorly water soluble (18.5 g/l or 16.3mM) (at 25C???) can be easily retrieved through crystallization while the more soluble α- and γ-CDs (145 and 232 g/l respectively) are usually purified by means of expensive and time consuming chromatography techniques.
As an alternative a "complexing agent" can be added during the enzymatic conversion step: such agents (usually organic solvents like toluene, acetone or ethanol) form a complex with the desired cyclodextrin which subsequently precipitates. The complex formation drives the conversion of starch towards the synthesis of the precipitated cyclodextrin, thus enriching its content in the final mixture of products. The precipitated cyclodextrin is easily retrieved by centrifugation and is later separated from the complexing agent.
# Uses
Cyclodextrins are able to form host-guest complexes with hydrophobic molecules given the unique nature imparted by their structure. As a result these molecules have found a number of applications in a wide range of fields.
Other than the above mentioned pharmaceutical applications for drug release, cyclodextrins can be employed in environmental protection: these molecules can effectively immobilise inside their rings toxic compounds, like trichloroethane or heavy metals, or can form complexes with stable substances, like trichlorfon (an organophosphorus insecticide) or sewage sludge, enhancing their decomposition.
In the food industry cyclodextrins are employed for the preparation of cholesterol free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed, leaving behind a "low fat" food.
Other food applications further include the ability to stabilize volatile or unstable compounds and the reduction of unwanted tastes and odour.
Reportedly cyclodextrins are used in alcohol powder, a powder for mixing alcoholic drinks.
The strong ability of complexing fragrances can also be used for another purpose: first dry, solid cyclodextrin microparticles are exposed to a controlled contact with fumes of active compounds, then they are added to fabric or paper products. Such devices are capable of releasing fragrances during ironing or when heated by human body. Such a device commonly used is a typical 'dryer sheet'. The heat from a clothes dryer releases the fragrance into the clothing.
The ability of cyclodextrins to form complexes with hydrophobic molecules has led to their usage in supramolecular chemistry. In particular they have been used to synthesize certain mechanically-interlocked molecular architectures, such as rotaxanes and catenanes, by reacting the ends of the threaded guest.
# Derivatives
Both β-cyclodextrin and MβCD remove cholesterol from cultured cells. The methylated form MβCD was found to be more efficient than β-cyclodextrin. The water-soluble MβCD is known to form soluble inclusion complexes with cholesterol, thereby enhancing its solubility in aqueous solution. Methyl-β-cyclodextrin are employed for the preparation of cholesterol-free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. It is also employed to disrupt lipid rafts by removing the cholesterol from the membrane in research. | https://www.wikidoc.org/index.php/Cyclodextrin | |
7ff3c43e79d0b66a6c42d6f8bfcb43b0d9c72d5b | wikidoc | Cyclopropane | Cyclopropane
Cyclopropane is a cycloalkane molecule with the molecular formula C3H6, consisting of three carbon atoms linked to each other to form a ring, with each carbon atom bearing two hydrogen atoms. The bonds between the carbon atoms are a great deal weaker than in a typical carbon-carbon bond. This is the result of the 60° angle between the carbon atoms, which is far less than the normal angle of 109.5°. For bonds between atoms with sp3 hybridised orbitals. This angle strain has to be subtracted from the normal C-C bond energy, making the resultant compound more reactive than acyclic alkanes and other cycloalkanes such as cyclohexane and cyclopentane. This is the banana bond description of cycloalkanes.
There is also torsional strain because the hydrogen atoms are held in the eclipsed conformation.
However, cyclopropanes are more stable than a simple angle strain analysis would suggest. Cyclopropane can also be modeled as a three-center-bonded orbital combination of methylene carbenes. This results in the Walsh orbital description of cyclopropane, where the C-C bonds have mostly pi character. This is also why cyclopropanes often have reactivity similar to alkenes. This is also why carbenes can easily add into alkenes to produce cyclopropanes. Cyclopropanes taken to the extreme are tetrahedranes and propellanes.
Cyclopropane is an anaesthetic when inhaled, but has been superseded by other agents in modern anaesthetic practice. This is due to its extreme reactivity under normal conditions: when the gas is mixed with oxygen there is a significant risk of explosion.
# Safety
Because of the strain in the carbon-carbon bonds of cyclopropane, the molecule has an enormous amount of potential energy. In pure form, it will break down to form linear hydrocarbons, including "normal", non-cyclic propene. This decomposition is potentially explosive, especially if the cyclopropane is liquified, pressurized, or contained within tanks. Explosions of cyclopropane and oxygen are even more powerful, because the energy released by the formation of normal propane is compounded by the energy released via the oxidation of the carbon and hydrogen present. At room temperature, sufficient volumes of liquified cyclopropane will self-detonate. To guard against this, the liquid is shipped in cylinders filled with tungsten wool, which prevents high-speed collisions between molecules and vastly improves stability. Pipes to carry cyclopropane must likewise be of small diameter, or else filled with unreactive metal or glass wool, to prevent explosions. Even if these precautions are followed, cyclopropane is dangerous to handle and manufacture, and is no longer used for anaesthesia.
# Cyclopropanes
Cyclopropanes are a class of organic compounds sharing the common cyclopropane ring, in which one or more hydrogens may be substituted. These compounds are found in biomolecules; for instance, the pyrethrum insecticides (found in certain Chrysanthemum species) contain a cyclopropane ring.
## Organic synthesis
Cyclopropanes can be prepared in the laboratory by organic synthesis in various ways and many methods are simply called cyclopropanation:
- addition of zinc to 1,3-dichloropropane in the Freund reaction (1882)
- addition to an alkene of a zinc carbenoid in the Simmons-Smith reaction (1958) for example to cinnamyl alcohol. In one adaptation an amide is reacted with two equivalents of dichloromethane aided by titanium tetrachloride and magnesium:
- addition to an alkene of a carbene such as dibromocarbene in the synthesis of propellane or methyl diazoacetate
- nucleophilic displacement of a leaving group by a carbon nucleophile in a 1,3 relationship, for example the synthesis of cyclopropylacetylene from 5-chloro-1-pentyne. Another example can be found in the Bingel reaction. An asymmetric reaction creating three stereocenters is demonstrated in a reaction of cyclohexenone with bromonitromethane assisted by trans-2,5-dimethylpiperazine as a base and a pyrrolidine based tetrazole organocatalyst:
- an intramolecular Wurtz coupling for example in the synthesis of bicyclobutane
- Rearrangement reaction of certain cyclobutane compounds for instance the conversion of 1,2-cyclobutanediol to cyclopropanecarboxaldehyde
- photochemical rearrangement reaction of 1,4-dienes to vinylcyclopropanes in the di-pi-methane rearrangement
## Organic reactions
Although cyclopropanes are formally cycloalkanes, they are very reactive due to considerable strain energy and due to double bond character.
- Cyclopropyl groups participate in cycloaddition reaction such as the formal cycloaddition shown below:
- Cyclopropyl groups also engage in many rearrangement reactions. An extreme example is found in the compound bullvalene. A cyclopropane ring is an intermediate in the Favorskii rearrangement. Certain methylenecyclopropanes are found to convert to cyclobutenes: | Cyclopropane
Template:Chembox new
Cyclopropane is a cycloalkane molecule with the molecular formula C3H6, consisting of three carbon atoms linked to each other to form a ring, with each carbon atom bearing two hydrogen atoms. The bonds between the carbon atoms are a great deal weaker than in a typical carbon-carbon bond. This is the result of the 60° angle between the carbon atoms, which is far less than the normal angle of 109.5°. For bonds between atoms with sp3 hybridised orbitals. This angle strain has to be subtracted from the normal C-C bond energy, making the resultant compound more reactive than acyclic alkanes and other cycloalkanes such as cyclohexane and cyclopentane. This is the banana bond description of cycloalkanes.
There is also torsional strain because the hydrogen atoms are held in the eclipsed conformation.
However, cyclopropanes are more stable than a simple angle strain analysis would suggest. Cyclopropane can also be modeled as a three-center-bonded orbital combination of methylene carbenes. This results in the Walsh orbital description of cyclopropane, where the C-C bonds have mostly pi character. This is also why cyclopropanes often have reactivity similar to alkenes. This is also why carbenes can easily add into alkenes to produce cyclopropanes. Cyclopropanes taken to the extreme are tetrahedranes and propellanes.
Cyclopropane is an anaesthetic when inhaled, but has been superseded by other agents in modern anaesthetic practice. This is due to its extreme reactivity under normal conditions: when the gas is mixed with oxygen there is a significant risk of explosion.
# Safety
Because of the strain in the carbon-carbon bonds of cyclopropane, the molecule has an enormous amount of potential energy. In pure form, it will break down to form linear hydrocarbons, including "normal", non-cyclic propene. This decomposition is potentially explosive, especially if the cyclopropane is liquified, pressurized, or contained within tanks. Explosions of cyclopropane and oxygen are even more powerful, because the energy released by the formation of normal propane is compounded by the energy released via the oxidation of the carbon and hydrogen present. At room temperature, sufficient volumes of liquified cyclopropane will self-detonate. To guard against this, the liquid is shipped in cylinders filled with tungsten wool, which prevents high-speed collisions between molecules and vastly improves stability. Pipes to carry cyclopropane must likewise be of small diameter, or else filled with unreactive metal or glass wool, to prevent explosions. Even if these precautions are followed, cyclopropane is dangerous to handle and manufacture, and is no longer used for anaesthesia.
# Cyclopropanes
Cyclopropanes are a class of organic compounds sharing the common cyclopropane ring, in which one or more hydrogens may be substituted. These compounds are found in biomolecules; for instance, the pyrethrum insecticides (found in certain Chrysanthemum species) contain a cyclopropane ring.
## Organic synthesis
Cyclopropanes can be prepared in the laboratory by organic synthesis in various ways and many methods are simply called cyclopropanation:
- addition of zinc to 1,3-dichloropropane in the Freund reaction (1882)[1]
- addition to an alkene of a zinc carbenoid in the Simmons-Smith reaction (1958) for example to cinnamyl alcohol.[2] In one adaptation[3] an amide is reacted with two equivalents of dichloromethane aided by titanium tetrachloride and magnesium:
- addition to an alkene of a carbene such as dibromocarbene in the synthesis of propellane[5] or methyl diazoacetate[6]
- nucleophilic displacement of a leaving group by a carbon nucleophile in a 1,3 relationship, for example the synthesis of cyclopropylacetylene from 5-chloro-1-pentyne.[7] Another example can be found in the Bingel reaction. An asymmetric reaction creating three stereocenters is demonstrated in a reaction of cyclohexenone with bromonitromethane assisted by trans-2,5-dimethylpiperazine as a base and a pyrrolidine based tetrazole organocatalyst[8][9]:
- an intramolecular Wurtz coupling for example in the synthesis of bicyclo[1.1.0]butane[10]
- Rearrangement reaction of certain cyclobutane compounds for instance the conversion of 1,2-cyclobutanediol to cyclopropanecarboxaldehyde[11]
- photochemical rearrangement reaction of 1,4-dienes to vinylcyclopropanes in the di-pi-methane rearrangement[12]
## Organic reactions
Although cyclopropanes are formally cycloalkanes, they are very reactive due to considerable strain energy and due to double bond character.
- Cyclopropyl groups participate in cycloaddition reaction such as the formal [5+2]cycloaddition shown below:
- Cyclopropyl groups also engage in many rearrangement reactions. An extreme example is found in the compound bullvalene. A cyclopropane ring is an intermediate in the Favorskii rearrangement. Certain methylenecyclopropanes are found to convert to cyclobutenes[14]: | https://www.wikidoc.org/index.php/Cyclopropane | |
1b8278959adac0db2625be91436a796237537a58 | wikidoc | Cypermethrin | Cypermethrin
Cypermethrin is a synthetic pyrethroid used as an insecticide in large-scale commercial agricultural applications as well as in consumer products for domestic purposes. It behaves as a fast-acting neurotoxin in insects. It is easily degraded on soil and plants but can be effective for weeks when applied to indoor inert surfaces. Exposure to sunlight, water and oxygen will accelerate its decomposition. Cypermethrin is highly toxic to fish, bees and aquatic insects, according to the National Pesticides Telecommunications Network (NPTN). It is found in many household ant and cockroach killers, including Raid and ant chalk.
# Human exposure
Excessive exposure can cause nausea, headache, muscle weakness, salivation, shortness of breath and seizures. In humans, cypermethrin is deactivated by enzymatic hydrolysis to several carboxylic acid metabolites, which are eliminated in the urine. Worker exposure to the chemical can be monitored by measurement of the urinary metabolites, while severe overdosage may be confirmed by quantitation of cypermethrin in blood or plasma.
# Study in animals
A recent study at Xuzhou Medical College in China showed that, in male rats, cypermethrin can exhibit a toxic effect on the reproductive system. After 15 days of continual dosing, both androgen receptor levels and serum testosterone levels were significantly reduced. These data suggested that cypermethrin can induce impairments of the structure of seminiferous tubules and spermatogenesis in male rats at high doses.
Long-term exposure to cypermethrin during adulthood is found to induce dopaminergic neurodegeneration in rats, and postnatal exposure enhances the susceptibility of animals to dopaminergic neurodegeneration if rechallenged during adulthood.
If exposed to cypermethrin during pregnancy, rats give birth to offspring with developmental delays. In male rats exposed to cypermethrin, the proportion of abnormal sperm increases. It causes genetic damage: chromosomal abnormalities increased in bone marrow and spleen cells when mice were exposed to cypermethrin. Cypermethrin is classified as a possible human carcinogen, because it causes an increase in the frequency of lung tumors in female mice. Cypermethrin has been linked to an increase in bone marrow micronuclei in both mice and humans.
One study showed that cypermethrin inhibits “gap junctional intercellular communication”, which plays an important role in cell growth and is inhibited by carcinogenic agents. Studies have shown that residue from cypermethrin can last for 84 days in the air, on walls, the floor and on furniture.
# Environmental effects
Cypermethrin is a broad-spectrum insecticide, which means it kills beneficial insects and animals as well as the targeted insects. Fish are particularly susceptible to cypermethrin. Resistance to cypermethrin has developed quickly in insects exposed frequently and can render it ineffective. | Cypermethrin
Cypermethrin is a synthetic pyrethroid used as an insecticide in large-scale commercial agricultural applications as well as in consumer products for domestic purposes. It behaves as a fast-acting neurotoxin in insects. It is easily degraded on soil and plants but can be effective for weeks when applied to indoor inert surfaces. Exposure to sunlight, water and oxygen will accelerate its decomposition. Cypermethrin is highly toxic to fish, bees and aquatic insects, according to the National Pesticides Telecommunications Network (NPTN). It is found in many household ant and cockroach killers, including Raid and ant chalk.
# Human exposure
Excessive exposure can cause nausea, headache, muscle weakness, salivation, shortness of breath and seizures. In humans, cypermethrin is deactivated by enzymatic hydrolysis to several carboxylic acid metabolites, which are eliminated in the urine. Worker exposure to the chemical can be monitored by measurement of the urinary metabolites, while severe overdosage may be confirmed by quantitation of cypermethrin in blood or plasma.[1]
# Study in animals
A recent study at Xuzhou Medical College in China showed that, in male rats, cypermethrin can exhibit a toxic effect on the reproductive system. After 15 days of continual dosing, both androgen receptor levels and serum testosterone levels were significantly reduced. These data suggested that cypermethrin can induce impairments of the structure of seminiferous tubules and spermatogenesis in male rats at high doses.[2]
Long-term exposure to cypermethrin during adulthood is found to induce dopaminergic neurodegeneration in rats, and postnatal exposure enhances the susceptibility of animals to dopaminergic neurodegeneration if rechallenged during adulthood.[3]
If exposed to cypermethrin during pregnancy, rats give birth to offspring with developmental delays. In male rats exposed to cypermethrin, the proportion of abnormal sperm increases. It causes genetic damage: chromosomal abnormalities increased in bone marrow and spleen cells when mice were exposed to cypermethrin.[4] Cypermethrin is classified as a possible human carcinogen, because it causes an increase in the frequency of lung tumors in female mice. Cypermethrin has been linked to an increase in bone marrow micronuclei in both mice and humans.[5]
One study showed that cypermethrin inhibits “gap junctional intercellular communication”, which plays an important role in cell growth and is inhibited by carcinogenic agents.[6] Studies have shown that residue from cypermethrin can last for 84 days in the air, on walls, the floor and on furniture.[7]
# Environmental effects
Cypermethrin is a broad-spectrum insecticide, which means it kills beneficial insects and animals as well as the targeted insects.[8] Fish are particularly susceptible to cypermethrin.[9] Resistance to cypermethrin has developed quickly in insects exposed frequently and can render it ineffective.[10] | https://www.wikidoc.org/index.php/Cypermethrin | |
3ab3f4166909a3c0db13d8d03747e3d85d70b0d5 | wikidoc | Cytochrome c | Cytochrome c
The cytochrome complex, or cyt c is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is highly water-soluble, unlike other cytochromes, and is an essential component of the electron transport chain, where it carries one electron. It is capable of undergoing oxidation and reduction, but does not bind oxygen. It transfers electrons between Complexes III (Coenzyme Q – Cyt C reductase) and IV (Cyt C oxidase). In humans, cytochrome c is encoded by the CYCS gene.
# Species distribution
Cytochrome c is a highly conserved protein across the spectrum of species, found in plants, animals, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 daltons), makes it useful in studies of cladistics. The cytochrome c molecule has been studied for the glimpse it gives into evolutionary biology.
Cytochrome c has a primary structure consisting of a chain of about 100 amino acids. Many higher-order organisms possess a chain of 104 amino acids. The sequences of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs more from that of horses.
Cytochrome c has an amino acid sequence that is highly conserved in eukaryotes, differing by only a few residues. In more than thirty species tested in one study, 34 of the 104 amino acids were conserved; identical at their characteristic position. For example, human cytochrome oxidase reacts with wheat cytochrome c, in vitro; which held true for all pairs of species tested. In addition, the redox potential of +0.25 volts is the same in all cytochrome c molecules studied.
# Structure
Cytochrome c belongs to class I of the c-type cytochrome family and contains a characteristic CXXCH (cysteine-any-any-cysteine-histidine) amino acid motif that binds heme. This motif is located towards the N-terminus of the peptide chain and it contains a histidine as the fifth ligand of the heme iron. The sixth ligand is provided by a methionine residue found towards the C-terminus. The protein backbone is folded into five α-helices that are numbered α1-α5 from N-terminus to C-terminus. Helices α3, α4 and α5 are referred to as 50s, 60s and 70s helix respectively when referring to mitochondrial cytochrome c.
## Heme c
While most heme proteins are attached to the prosthetic group through iron ion ligation and tertiary interactions, the heme group of cytochrome c makes thioether bonds with two cysteine side chains of the protein. One of the main properties of heme c, which allows cytochrome c to have variety of functions, is its ability to have different reduction potentials in nature. This property determines the kinetics and thermodynamics of an electron transfer reaction.
## Dipole moment
The dipole moment has an important role in orienting proteins to the proper directions and enhancing their abilities to bind to other molecules. The dipole moment of cytochrome c is a result from a cluster of negatively charged amino acid side chains at the "back" of the enzyme. Despite variations in the number of bound heme groups and variations in sequence, the dipole moment of vertebrate cytochromes c is remarkably conserved. For examples, vertebrate cytochromes c all have dipole moment of approximately 320 debye while cytochromes c of plants and insects have dipole moment of approximately 340 debye.
# Function
Cytochrome c is a component of the electron transport chain in mitochondria. The heme group of cytochrome c accepts electrons from the bc1 complex and transfers electrons to the complex IV. Cytochrome c is also involved in initiation of apoptosis. Upon release of cytochrome c to the cytoplasm, the protein binds apoptotic protease activating factor-1 (Apaf-1).
Cytochrome c can also catalyze several redox reactions such as hydroxylation and aromatic oxidation, and shows peroxidase activity by oxidation of various electron donors such as 2,2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.
A bacterial cytochrome c functions as a nitrite reductase.
## Role in apoptosis
Cytochrome c also has an intermediate role in apoptosis, a controlled form of cell death used to kill cells in the process of development or in response to infection or DNA damage.
Cytochrome c binds to cardiolipin in the inner mitochondrial membrane, thus anchoring its presence and keeping it from releasing out of the mitochondria and initiating apoptosis. While the initial attraction between cardiolipin and cytochrome c is electrostatic due to the extreme positive charge on cytochrome c, the final interaction is hydrophobic, where a hydrophobic tail from cardiolipin inserts itself into the hydrophobic portion of cytochrome c.
During the early phase of apoptosis, mitochondrial ROS production is stimulated, and cardiolipin is oxidized by a peroxidase function of the cardiolipin–cytochrome c complex. The hemoprotein is then detached from the mitochondrial inner membrane and can be extruded into the soluble cytoplasm through pores in the outer membrane.
The sustained elevation in calcium levels precedes cyt c release from the mitochondria. The release of small amounts of cyt c leads to an interaction with the IP3 receptor (IP3R) on the endoplasmic reticulum (ER), causing ER calcium release. The overall increase in calcium triggers a massive release of cyt c, which then acts in the positive feedback loop to maintain ER calcium release through the IP3Rs. This explains how the ER calcium release can reach cytotoxic levels. This release of cytochrome c in turn activates caspase 9, a cysteine protease. Caspase 9 can then go on to activate caspase 3 and caspase 7, which are responsible for destroying the cell from within.
## Inhibition of apoptosis
One of the ways cell apoptosis is activated is by release of cytochrome c from the mitochondria into cytosol. A study has shown that cells are able to protect themselves from apoptosis by blocking the release of cytochrome c using Bcl-xL. Another way that cells can control apoptosis is by phosphorylation of Tyr48 which would turn cytochrome c into an anti-apoptotic switch.
## As an antioxidative enzyme
Cytochrome c is known to play a role in the electron transport chain and cell apoptosis. However, a recent study has shown that it can also act as an antioxidative enzyme in the mitochondria; and it does so by removing superoxide (O2–) and hydrogen peroxide (H2O2) from mitochondria. Therefore, not only is cytochrome c required in the mitochondria for cell respiration, but it is also needed in the mitochondria to limit the production of O2– and H2O2.
# Extramitochondrial localization
Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions. The release of cytochrome-c from mitochondria to the cytosol, where it activates the caspase family of proteases is believed to be primary trigger leading to the onset of apoptosis. Measuring the amount of cytochrome c leaking from mitochondria to cytosol, and out of the cell to culture medium, is a sensitive method to monitor the degree of apoptosis. However, detailed immunoelectron microscopic studies with rat tissues sections employing cytochrome c-specific antibodies provide compelling evidence that cytochrome-c under normal cellular conditions is also present at extramitochondrial locations. In pancreatic acinar cells and the anterior pituitary, strong and specific presence of cytochrome-c was detected in zymogen granules and in growth hormone granules respectively. In the pancreas, cytochrome-c was also found in condensing vacuoles and in the acinar lumen. The extramitochondrial localization of cytochrome c was shown to be specific as it was completely abolished upon adsorption of the primary antibody with the purified cytochrome c. The presence of cytochrome-c outside of mitochondria at specific location under normal physiological conditions raises important questions concerning its cellular function and translocation mechanism. Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA. This raises the possibility about existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.
# Applications
## Superoxide detection
Cytochrome c has been used to detect peroxide production in biological systems. As superoxide is produced, the number of oxidized cytochrome c3+ increases, and reduced cytochrome c2+ decreases. However, superoxide is often produced with nitric oxide. In the presence of nitric oxide, the reduction of cytochrome c3+ is inhibited. This leads to the oxidization of cytochrome c2+ to cytochrome c3+ by peroxynitrous acid, an intermediate made through the reaction of nitric oxide and superoxide. Presence of peroxynitrite or H2O2 and nitrogen dioxide NO2 in the mitochondria can be lethal since they nitrate tyrosine residues of cytochrome c which leads to disruption of cytochrome c’s function as an electron carrier in the electron transfer chain. | Cytochrome c
The cytochrome complex, or cyt c is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is highly water-soluble, unlike other cytochromes, and is an essential component of the electron transport chain, where it carries one electron. It is capable of undergoing oxidation and reduction, but does not bind oxygen. It transfers electrons between Complexes III (Coenzyme Q – Cyt C reductase) and IV (Cyt C oxidase). In humans, cytochrome c is encoded by the CYCS gene.[1][2]
# Species distribution
Cytochrome c is a highly conserved protein across the spectrum of species, found in plants, animals, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 daltons),[3] makes it useful in studies of cladistics.[4] The cytochrome c molecule has been studied for the glimpse it gives into evolutionary biology.
Cytochrome c has a primary structure consisting of a chain of about 100 amino acids. Many higher-order organisms possess a chain of 104 amino acids.[5] The sequences of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs more from that of horses.[6]
Cytochrome c has an amino acid sequence that is highly conserved in eukaryotes, differing by only a few residues. In more than thirty species tested in one study, 34 of the 104 amino acids were conserved; identical at their characteristic position.[7] For example, human cytochrome oxidase reacts with wheat cytochrome c, in vitro; which held true for all pairs of species tested.[7] In addition, the redox potential of +0.25 volts is the same in all cytochrome c molecules studied.[7]
# Structure
Cytochrome c belongs to class I of the c-type cytochrome family[9] and contains a characteristic CXXCH (cysteine-any-any-cysteine-histidine) amino acid motif that binds heme.[10] This motif is located towards the N-terminus of the peptide chain and it contains a histidine as the fifth ligand of the heme iron. The sixth ligand is provided by a methionine residue found towards the C-terminus. The protein backbone is folded into five α-helices that are numbered α1-α5 from N-terminus to C-terminus. Helices α3, α4 and α5 are referred to as 50s, 60s and 70s helix respectively when referring to mitochondrial cytochrome c.[11]
## Heme c
While most heme proteins are attached to the prosthetic group through iron ion ligation and tertiary interactions, the heme group of cytochrome c makes thioether bonds with two cysteine side chains of the protein.[12] One of the main properties of heme c, which allows cytochrome c to have variety of functions, is its ability to have different reduction potentials in nature. This property determines the kinetics and thermodynamics of an electron transfer reaction.[13]
## Dipole moment
The dipole moment has an important role in orienting proteins to the proper directions and enhancing their abilities to bind to other molecules.[14][15] The dipole moment of cytochrome c is a result from a cluster of negatively charged amino acid side chains at the "back" of the enzyme.[15] Despite variations in the number of bound heme groups and variations in sequence, the dipole moment of vertebrate cytochromes c is remarkably conserved. For examples, vertebrate cytochromes c all have dipole moment of approximately 320 debye while cytochromes c of plants and insects have dipole moment of approximately 340 debye.[15]
# Function
Cytochrome c is a component of the electron transport chain in mitochondria. The heme group of cytochrome c accepts electrons from the bc1 complex and transfers electrons to the complex IV. Cytochrome c is also involved in initiation of apoptosis. Upon release of cytochrome c to the cytoplasm, the protein binds apoptotic protease activating factor-1 (Apaf-1).[1]
Cytochrome c can also catalyze several redox reactions such as hydroxylation and aromatic oxidation, and shows peroxidase activity by oxidation of various electron donors such as 2,2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.
A bacterial cytochrome c functions as a nitrite reductase.[16]
## Role in apoptosis
Cytochrome c also has an intermediate role in apoptosis, a controlled form of cell death used to kill cells in the process of development or in response to infection or DNA damage.[17]
Cytochrome c binds to cardiolipin in the inner mitochondrial membrane, thus anchoring its presence and keeping it from releasing out of the mitochondria and initiating apoptosis. While the initial attraction between cardiolipin and cytochrome c is electrostatic due to the extreme positive charge on cytochrome c, the final interaction is hydrophobic, where a hydrophobic tail from cardiolipin inserts itself into the hydrophobic portion of cytochrome c.
During the early phase of apoptosis, mitochondrial ROS production is stimulated, and cardiolipin is oxidized by a peroxidase function of the cardiolipin–cytochrome c complex. The hemoprotein is then detached from the mitochondrial inner membrane and can be extruded into the soluble cytoplasm through pores in the outer membrane.[18]
The sustained elevation in calcium levels precedes cyt c release from the mitochondria. The release of small amounts of cyt c leads to an interaction with the IP3 receptor (IP3R) on the endoplasmic reticulum (ER), causing ER calcium release. The overall increase in calcium triggers a massive release of cyt c, which then acts in the positive feedback loop to maintain ER calcium release through the IP3Rs.[19] This explains how the ER calcium release can reach cytotoxic levels. This release of cytochrome c in turn activates caspase 9, a cysteine protease. Caspase 9 can then go on to activate caspase 3 and caspase 7, which are responsible for destroying the cell from within.
## Inhibition of apoptosis
One of the ways cell apoptosis is activated is by release of cytochrome c from the mitochondria into cytosol. A study has shown that cells are able to protect themselves from apoptosis by blocking the release of cytochrome c using Bcl-xL.[20] Another way that cells can control apoptosis is by phosphorylation of Tyr48 which would turn cytochrome c into an anti-apoptotic switch.[21]
## As an antioxidative enzyme
Cytochrome c is known to play a role in the electron transport chain and cell apoptosis. However, a recent study has shown that it can also act as an antioxidative enzyme in the mitochondria; and it does so by removing superoxide (O2–) and hydrogen peroxide (H2O2) from mitochondria.[22] Therefore, not only is cytochrome c required in the mitochondria for cell respiration, but it is also needed in the mitochondria to limit the production of O2– and H2O2.[22]
# Extramitochondrial localization
Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions.[23] The release of cytochrome-c from mitochondria to the cytosol, where it activates the caspase family of proteases is believed to be primary trigger leading to the onset of apoptosis.[24] Measuring the amount of cytochrome c leaking from mitochondria to cytosol, and out of the cell to culture medium, is a sensitive method to monitor the degree of apoptosis.[25][26] However, detailed immunoelectron microscopic studies with rat tissues sections employing cytochrome c-specific antibodies provide compelling evidence that cytochrome-c under normal cellular conditions is also present at extramitochondrial locations.[27] In pancreatic acinar cells and the anterior pituitary, strong and specific presence of cytochrome-c was detected in zymogen granules and in growth hormone granules respectively. In the pancreas, cytochrome-c was also found in condensing vacuoles and in the acinar lumen. The extramitochondrial localization of cytochrome c was shown to be specific as it was completely abolished upon adsorption of the primary antibody with the purified cytochrome c.[27] The presence of cytochrome-c outside of mitochondria at specific location under normal physiological conditions raises important questions concerning its cellular function and translocation mechanism.[27] Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.[28][29][30] This raises the possibility about existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.[30][31]
# Applications
## Superoxide detection
Cytochrome c has been used to detect peroxide production in biological systems. As superoxide is produced, the number of oxidized cytochrome c3+ increases, and reduced cytochrome c2+ decreases.[32] However, superoxide is often produced with nitric oxide. In the presence of nitric oxide, the reduction of cytochrome c3+ is inhibited.[33] This leads to the oxidization of cytochrome c2+ to cytochrome c3+ by peroxynitrous acid, an intermediate made through the reaction of nitric oxide and superoxide.[33] Presence of peroxynitrite or H2O2 and nitrogen dioxide NO2 in the mitochondria can be lethal since they nitrate tyrosine residues of cytochrome c which leads to disruption of cytochrome c’s function as an electron carrier in the electron transfer chain.[34] | https://www.wikidoc.org/index.php/Cytochrome_C | |
60c942816852b25b3c6275f40d0bcc070fff60a9 | wikidoc | Cytogenetics | Cytogenetics
# Overview
Cytogenetics is the study of the structure of chromosome material. It includes routine analysis of G-Banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH).
# History
## Early years
Barbara McClintock began her career as a maize cytogeneticist. In 1931 McClintock and Harriet Creighton demonstrated that cytological recombination of marked chromosomes correlated with recombination of genetic traits (genes). McClintock continued her career in cytogenetics studying the mechanics and inheritance of broken and ring (circular) chromosomes of maize. During her cytogenetic work, McClintock discovered transposons, a find which eventually led to her Nobel Prize in 1983.
Modern cytogenetics is generally said to have begun in 1956 with the discovery that normal human cells contain 46 chromosomes by Tjio and Levan. This discovery was aided by a new technique of slide preparation utilizing a hypotonic solution discovered by TC Hsu in 1952. A hypotonic solution is a salt solution less concentrated than that inside human cells, when added to a cell solution this causes the cells to swell. When the cells are added to the slide after treatment with hypotonic solution the chromosomes spread out more allowing for much easier enumeration. Previously humans were thought to have 48 chromosomes.
It is notable that while Flemming and Arnold first observed human chromosomes in the 1880s, the number of human chromosomes remained unknown for over 70 years. The causes for this are numerous.
For many valid scientific reasons, many geneticists at the time relied heavily on animal models for their research, and thus research in human genetics did not keep up with species like the fruit fly Drosophila. This was also the period of the eugenics movement and many geneticists wanted to distance themselves from human genetics.
## Progress in numerical abnormalities
With the advent of harvest procedures which allowed easy enumeration of chromosomes, discoveries were quickly made in abnormalities arising from nondysjunction events which cause cells with aneuploidy (additions or deletions of entire chromosomes). In 1959 Lejeune discovered patients with Down syndrome had an extra copy of chromosome 21. Down syndrome is also referred to as trisomy 21. In 1960 Nowell discovered a small chromosome, dubbed the Philadelphia chromosome, which was shown to be the cause of Chronic myelogenous leukemia. 13 years later this was shown by Janet Rowley to be a translocation of chromosomes 9 and 22.
Other numerical abnormalities discovered include sex chromosome abnormalities. An individual with only one sex chromosome (the X) has Turner syndrome, an additional X chromosome in a male, resulting in 47 total chromosomes, has Klinefelter's Syndrome. Many other sex chromosome combinations are compatible with live birth including XXX, XYY, and XXXX. The ability for mammals to tolerate aneuploidies in the sex chromosomes arises from the ability to inactivate them, which is required in normal females to compensate for having two copies of the chromosome. Not all genes on the X Chromosome are inactivated, which is why there is a phenotypic effect seen in individuals with an extra or missing X.
Trisomy 13 was associated with Patau's Syndrome and trisomy 18 with Edward's Syndrome.
## Advent of banding techniques
In the late 1960's Caspersson developed banding techniques which differentially stain chromosomes. This allows chromosomes of otherwise equal size to be differentiated as well as to elucidate the breakpoints and constituent chromosomes involved in chromosome translocations. Deletions within one chromosome could also now be more specifically named and understood. Deletion syndromes such as DiGeorge syndrome, Prader-Willi syndrome and others were discovered to be caused by deletions in chromosome material.
Diagrams identifying the chromosomes based on the banding patterns are known as cytogenetic maps. These maps became the basis for both prenatal and oncological fields to quickly move cytogenetics into the clinical lab where karyotyping allowed scientists to look for chromosomal alterations. Techniques were expanded to allow for culture of free amniocytes recovered from amniotic fluid, and elongation techniques for all culture types that allow for higher resolution banding.
## Beginnings of molecular cytogenetics
In the 1980s advances were made in molecular cytogenetics. While radioisotope-labeled probes had been hybridized with DNA since 1969, movement was now made in using fluorescently labeled probes. Hybridizing them to chromosomes preparations made using existing techniques came to be known as fluorescent in situ hybridization (FISH). This change significantly increased the usage of probing techniques as fluorescently labeled probes are safer and can be used almost indefinitely. Further advances in micromanipulation and examination of chromosomes led to the technique of chromosome microdissection whereby aberrations in chromosomal structure could be isolated, cloned and studied in ever greater detail.
# Uses
In some forms of cancer, especially hematological malignancies, cytogenetics can determine which chromosomal translocations are present in the malignant cells, facilitating diagnosis and susceptibility to treatment (e.g. imatinib mesylate in the presence of the Philadelphia chromosome).
In congenital disorders, such as Down's syndrome, cytogenetics can determine the nature of the chromosomal defect - a "simple" trisomy, a mosaic, "balanced" translocation, a deletion, or an insertion in one - or both - of the parents, or in the fetus.
With the advent of harvest procedures which allowed easy enumeration of chromosomes, discoveries were quickly made in abnormalities arising from nondysjunction events which cause cells with aneusomy (additions or deletions of entire chromosomes). In 1959 Lejeune discovered patients with Down syndrome had an extra copy of chromosome 21. Down syndrome is also referred to as trisomy 21. In 1960 Nowell discovered a small chromosome, dubbed the Philadelphia chromosome, which was shown to be the cause of Chronic myelogenous leukemia. 13 years later this was shown by Janet Rowley to be a translocation of chromosomes 9 and 22.
Other numerical abnormalities discovered include sex chromosome abnormalities. An individual with only one sex chromosome (the X) has Turner syndrome, an additional X chromosome in a male, resulting in 47 total chromosomes, has Klinefelter's Syndrome. Many other sex chromosome combinations are compatible with live birth including XXX, XYY, and XXXX. The ability for mammals to tolerate aneusomies in the sex chromosomes arises from the ability to inactivate them, which is required in normal females to compensate for having two copies of the chromosome.
Trisomy 13 was associated with Patau's Syndrome and trisomy 18 with Edward's Syndrome.
# Techniques
## Routine analysis
Routine chromosome analysis refers to analysis of metaphase chromosomes which have been banded using trypsin followed by Giemsa, Leishmanns, or a mixture of the two. This creates unique banding patterns on the chromosomes. The molecular mechanism and reason for these patterns is unknown, although it likely related to replication timing and chromatin packing.
Several chromosome-banding techniques are used in cytogenetics laboratories. Quinacrine banding (Q-banding) was the first staining method used to produce specific banding patterns. This method requires a fluorescence microscope and is no longer as widely used as Giemsa banding (G-banding). Reverse banding (R-banding) requires heat treatment and reverses the usual white and black pattern that is seen in G-bands and Q-bands. This method is particularly helpful for staining the distal ends of chromosomes. Other staining techniques include C-banding and nucleolar organizing region stains (NOR stains). These latter methods specifically stain certain portions of the chromosome. C-banding stains the constitutive heterochromatin, which usually lies near the centromere, and NOR staining highlights the satellites and stalks of acrocentric chromosomes.
High-resolution banding involves the staining of chromosomes during prophase or early metaphase (prometaphase), before they reach maximal condensation. Because prophase and prometaphase chromosomes are more extended than metaphase chromosomes, the number of bands observable for all chromosomes increases from about 300 to 450 to as many as 800. This allows the detection of less obvious abnormalities usually not seen with conventional banding.
### Slide preparation
Cells from bone marrow, blood, amniotic fluid, cord blood, tumor, and tissues (including skin, umbilical cord, liver, and many other organs) can be cultured using standard cell culture techniques in order to increase their number. A mitotic inhibitor (colchicine, colcemid) is then added to the culture. This stops cell division at mitosis which allows an increased yield of mitotic cells for analysis. The cells are then centrifuged and media and mitotic inhibitor is removed, and replaced with a hypotonic solution. This causes the cells to swell so that the chromosomes will spread when added to a slide. After the cells have been allowed to sit in hypotonic, Carnoy's fixative (3:1 methanol to glacial acetic acid) is added. This kills the cells, lyses the red blood cells, and hardens the nuclei of the remaining white blood cells. The cells are generally fixed repeatedly to remove any debris or remaining red blood cells. The cell suspension is then dropped onto specimen slides. After aging the slides in an oven or waiting a few days they are ready for banding and analysis.
### Analysis
Analysis of banded chromosomes is done at a microscope by a clinical laboratory specialist in cytogenetics (CLSp(CG)). Generally 20 cells are analyzed which is enough to rule out mosaicism to an acceptable level. The results are summarized and given to a board-certified medical geneticist and a pathologist for review, and to write an interpretation taking into account the patients previous history and other clinical findings. The results are then given out reported in an International System for Human Cytogenetic Nomenclature 2005 (ISCN2005).
## Fluorescent in situ hybridization
Fluorescent in situ hybridization refers to using fluorescently labeled probe to hybridize to cytogenetic cell preparations.
In addition to standard preparations FISH can also be performed on:
- bone marrow smears
- blood smears
- paraffin embedded tissue preparations
- enzymatically dissociated tissue samples
- uncultured bone marrow
- uncultured amniocytes
- cytospin preparations
### Slide preparation
This section refers to preparation of standard cytogenetic preparations
The slide is aged using a salt solution usually consisting of 2X SSC (salt, sodium citrate). The slides are then dehydrated in ethanol, and the probe mixture is added. The sample DNA and the probe DNA are then co-denatured using a heated plate and allowed to re-anneal for at least 4 hours. The slides are then washed to remove excess unbound probe, and counterstained with 4',6-Diamidino-2-phenylindole (DAPI) or propidium iodide.
### Analysis
Analysis of FISH specimens is done by fluorescence microscopy by a clinical laboratory specialist in cytogenetics (CLSp(CG)). For oncology generally a large number of interphase cells are scored in order to rule out low level residual disease, generally between 200 and 1000 cells are counted and scored. For congenital problems usually 20 metaphase cells are scored.
# Future of cytogenetics
Advances now focus on molecular cytogenetics including techniques such as comparative genomic hybridization arrays, CGH, SNP-array based karyotyping and automated systems for counting the results of standard FISH preparations. | Cytogenetics
# Overview
Cytogenetics is the study of the structure of chromosome material. It includes routine analysis of G-Banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH).
# History
## Early years
Barbara McClintock began her career as a maize cytogeneticist. In 1931 McClintock and Harriet Creighton demonstrated that cytological recombination of marked chromosomes correlated with recombination of genetic traits (genes). McClintock continued her career in cytogenetics studying the mechanics and inheritance of broken and ring (circular) chromosomes of maize. During her cytogenetic work, McClintock discovered transposons, a find which eventually led to her Nobel Prize in 1983.
Modern cytogenetics is generally said to have begun in 1956 with the discovery that normal human cells contain 46 chromosomes by Tjio and Levan[1]. This discovery was aided by a new technique of slide preparation utilizing a hypotonic solution discovered by TC Hsu in 1952. A hypotonic solution is a salt solution less concentrated than that inside human cells, when added to a cell solution this causes the cells to swell. When the cells are added to the slide after treatment with hypotonic solution the chromosomes spread out more allowing for much easier enumeration. Previously humans were thought to have 48 chromosomes.
It is notable that while Flemming and Arnold first observed human chromosomes in the 1880s, the number of human chromosomes remained unknown for over 70 years. The causes for this are numerous.
For many valid scientific reasons, many geneticists at the time relied heavily on animal models for their research, and thus research in human genetics did not keep up with species like the fruit fly Drosophila. This was also the period of the eugenics movement and many geneticists wanted to distance themselves from human genetics.
## Progress in numerical abnormalities
With the advent of harvest procedures which allowed easy enumeration of chromosomes, discoveries were quickly made in abnormalities arising from nondysjunction events which cause cells with aneuploidy (additions or deletions of entire chromosomes). In 1959 Lejeune[2] discovered patients with Down syndrome had an extra copy of chromosome 21. Down syndrome is also referred to as trisomy 21. In 1960 Nowell[3] discovered a small chromosome, dubbed the Philadelphia chromosome, which was shown to be the cause of Chronic myelogenous leukemia. 13 years later this was shown by Janet Rowley to be a translocation of chromosomes 9 and 22.
Other numerical abnormalities discovered include sex chromosome abnormalities. An individual with only one sex chromosome (the X) has Turner syndrome, an additional X chromosome in a male, resulting in 47 total chromosomes, has Klinefelter's Syndrome. Many other sex chromosome combinations are compatible with live birth including XXX, XYY, and XXXX. The ability for mammals to tolerate aneuploidies in the sex chromosomes arises from the ability to inactivate them, which is required in normal females to compensate for having two copies of the chromosome. Not all genes on the X Chromosome are inactivated, which is why there is a phenotypic effect seen in individuals with an extra or missing X.
Trisomy 13 was associated with Patau's Syndrome and trisomy 18 with Edward's Syndrome.
## Advent of banding techniques
In the late 1960's Caspersson developed banding techniques which differentially stain chromosomes. This allows chromosomes of otherwise equal size to be differentiated as well as to elucidate the breakpoints and constituent chromosomes involved in chromosome translocations. Deletions within one chromosome could also now be more specifically named and understood. Deletion syndromes such as DiGeorge syndrome, Prader-Willi syndrome and others were discovered to be caused by deletions in chromosome material.
Diagrams identifying the chromosomes based on the banding patterns are known as cytogenetic maps. These maps became the basis for both prenatal and oncological fields to quickly move cytogenetics into the clinical lab where karyotyping allowed scientists to look for chromosomal alterations. Techniques were expanded to allow for culture of free amniocytes recovered from amniotic fluid, and elongation techniques for all culture types that allow for higher resolution banding.
## Beginnings of molecular cytogenetics
In the 1980s advances were made in molecular cytogenetics. While radioisotope-labeled probes had been hybridized with DNA since 1969, movement was now made in using fluorescently labeled probes. Hybridizing them to chromosomes preparations made using existing techniques came to be known as fluorescent in situ hybridization (FISH). This change significantly increased the usage of probing techniques as fluorescently labeled probes are safer and can be used almost indefinitely. Further advances in micromanipulation and examination of chromosomes led to the technique of chromosome microdissection whereby aberrations in chromosomal structure could be isolated, cloned and studied in ever greater detail.
# Uses
In some forms of cancer, especially hematological malignancies, cytogenetics can determine which chromosomal translocations are present in the malignant cells, facilitating diagnosis and susceptibility to treatment (e.g. imatinib mesylate in the presence of the Philadelphia chromosome).
In congenital disorders, such as Down's syndrome, cytogenetics can determine the nature of the chromosomal defect - a "simple" trisomy, a mosaic, "balanced" translocation, a deletion, or an insertion in one - or both - of the parents, or in the fetus.
With the advent of harvest procedures which allowed easy enumeration of chromosomes, discoveries were quickly made in abnormalities arising from nondysjunction events which cause cells with aneusomy (additions or deletions of entire chromosomes). In 1959 Lejeune[2] discovered patients with Down syndrome had an extra copy of chromosome 21. Down syndrome is also referred to as trisomy 21. In 1960 Nowell[3] discovered a small chromosome, dubbed the Philadelphia chromosome, which was shown to be the cause of Chronic myelogenous leukemia. 13 years later this was shown by Janet Rowley to be a translocation of chromosomes 9 and 22.
Other numerical abnormalities discovered include sex chromosome abnormalities. An individual with only one sex chromosome (the X) has Turner syndrome, an additional X chromosome in a male, resulting in 47 total chromosomes, has Klinefelter's Syndrome. Many other sex chromosome combinations are compatible with live birth including XXX, XYY, and XXXX. The ability for mammals to tolerate aneusomies in the sex chromosomes arises from the ability to inactivate them, which is required in normal females to compensate for having two copies of the chromosome.
Trisomy 13 was associated with Patau's Syndrome and trisomy 18 with Edward's Syndrome.
# Techniques
## Routine analysis
Routine chromosome analysis refers to analysis of metaphase chromosomes which have been banded using trypsin followed by Giemsa, Leishmanns, or a mixture of the two. This creates unique banding patterns on the chromosomes. The molecular mechanism and reason for these patterns is unknown, although it likely related to replication timing and chromatin packing.
Several chromosome-banding techniques are used in cytogenetics laboratories. Quinacrine banding (Q-banding) was the first staining method used to produce specific banding patterns. This method requires a fluorescence microscope and is no longer as widely used as Giemsa banding (G-banding). Reverse banding (R-banding) requires heat treatment and reverses the usual white and black pattern that is seen in G-bands and Q-bands. This method is particularly helpful for staining the distal ends of chromosomes. Other staining techniques include C-banding and nucleolar organizing region stains (NOR stains). These latter methods specifically stain certain portions of the chromosome. C-banding stains the constitutive heterochromatin, which usually lies near the centromere, and NOR staining highlights the satellites and stalks of acrocentric chromosomes.
High-resolution banding involves the staining of chromosomes during prophase or early metaphase (prometaphase), before they reach maximal condensation. Because prophase and prometaphase chromosomes are more extended than metaphase chromosomes, the number of bands observable for all chromosomes increases from about 300 to 450 to as many as 800. This allows the detection of less obvious abnormalities usually not seen with conventional banding.
### Slide preparation
Cells from bone marrow, blood, amniotic fluid, cord blood, tumor, and tissues (including skin, umbilical cord, liver, and many other organs) can be cultured using standard cell culture techniques in order to increase their number. A mitotic inhibitor (colchicine, colcemid) is then added to the culture. This stops cell division at mitosis which allows an increased yield of mitotic cells for analysis. The cells are then centrifuged and media and mitotic inhibitor is removed, and replaced with a hypotonic solution. This causes the cells to swell so that the chromosomes will spread when added to a slide. After the cells have been allowed to sit in hypotonic, Carnoy's fixative (3:1 methanol to glacial acetic acid) is added. This kills the cells, lyses the red blood cells, and hardens the nuclei of the remaining white blood cells. The cells are generally fixed repeatedly to remove any debris or remaining red blood cells. The cell suspension is then dropped onto specimen slides. After aging the slides in an oven or waiting a few days they are ready for banding and analysis.
### Analysis
Analysis of banded chromosomes is done at a microscope by a clinical laboratory specialist in cytogenetics (CLSp(CG)). Generally 20 cells are analyzed which is enough to rule out mosaicism to an acceptable level. The results are summarized and given to a board-certified medical geneticist and a pathologist for review, and to write an interpretation taking into account the patients previous history and other clinical findings. The results are then given out reported in an International System for Human Cytogenetic Nomenclature 2005 (ISCN2005).
## Fluorescent in situ hybridization
Fluorescent in situ hybridization refers to using fluorescently labeled probe to hybridize to cytogenetic cell preparations.
In addition to standard preparations FISH can also be performed on:
- bone marrow smears
- blood smears
- paraffin embedded tissue preparations
- enzymatically dissociated tissue samples
- uncultured bone marrow
- uncultured amniocytes
- cytospin preparations
### Slide preparation
This section refers to preparation of standard cytogenetic preparations
The slide is aged using a salt solution usually consisting of 2X SSC (salt, sodium citrate). The slides are then dehydrated in ethanol, and the probe mixture is added. The sample DNA and the probe DNA are then co-denatured using a heated plate and allowed to re-anneal for at least 4 hours. The slides are then washed to remove excess unbound probe, and counterstained with 4',6-Diamidino-2-phenylindole (DAPI) or propidium iodide.
### Analysis
Analysis of FISH specimens is done by fluorescence microscopy by a clinical laboratory specialist in cytogenetics (CLSp(CG)). For oncology generally a large number of interphase cells are scored in order to rule out low level residual disease, generally between 200 and 1000 cells are counted and scored. For congenital problems usually 20 metaphase cells are scored.
# Future of cytogenetics
Advances now focus on molecular cytogenetics including techniques such as comparative genomic hybridization arrays, CGH, SNP-array based karyotyping and automated systems for counting the results of standard FISH preparations. | https://www.wikidoc.org/index.php/Cytogenetic | |
a09c412953f020d872a88941897c7e883c3c5738 | wikidoc | Cytoskeleton | Cytoskeleton
# Overview
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained, as all other organelles, within the cytoplasm. It is contained in all eukaryotic cells and recent research has shown it can be present in prokaryotic cells too. It is a dynamic structure that maintains cell shape, and also has been known to protect the cell, enables some cell motion (using structures such as flagella and cilia), and plays important roles in both intra-cellular transport (the movement of vesicles and organelles, for example) and cellular division. It is a bone-like structure floating around within the cytoplasm.
# The prokaryotic cytoskeleton
The cytoskeleton was previously thought to be a feature only of eukaryotic cells, but homologues to all the major proteins of the eukaryotic cytoskeleton have recently been found in prokaryotes. Although the evolutionary relationships are so distant that they are not obvious from protein sequence comparisons alone, the similarity of their three-dimensional structures provides strong evidence that the eukaryotic and prokaryotic cytoskeletons are truly homologous. However, some structures in the bacterial cytoskeleton may have yet to be identified.
## FtsZ
FtsZ was the first protein of the prokaryotic cytoskeleton to be identified. Like tubulin, FtsZ forms filaments in the presence of GTP, but these filaments do not group into tubules. During cell division, FtsZ is the first protein to move to the division site, and is essential for recruiting other proteins that synthesize the new cell wall between the dividing cells.
## MreB and ParM
Prokaryotic actin-like proteins, such as MreB, are involved in the maintenance of cell shape. All non-spherical bacteria have genes encoding actin-like proteins, and these proteins form a helical network beneath the cell membrane that guides the proteins involved in cell wall biosynthesis.
Some plasmids encode a partitioning system that involves an actin-like protein ParM. Filaments of ParM exhibit dynamic instability, and may partition plasmid DNA into the dividing daughter cells by a mechanism analogous to that used by microtubules during eukaryotic mitosis.
## Crescentin
The bacterium Caulobacter crescentus contains a third protein, crescentin, that is related to the intermediate filaments of eukaryotic cells. Crescentin is also involved in maintaining cell shape, but the mechanism by which it does this is currently unclear.
# The eukaryotic cytoskeleton
The cytoskeleton provides the cell with structure and shape, and by excluded volume macromolecules from some of the cytosol add to the level of macromolecular crowding in this compartment. Cytoskeletal elements (the membrane skeleton) interact extensively and intimately with cellular membranes.
Intimately connected to the cytoskeleton across the nuclear envelope (NE) is the nucleoskeleton (NS), which provides shape and support for the NE and the important activities of the nucleus.
Eukaryotic cells contain three main kinds of cytoskeletal filaments, which are microfilaments, intermediate filaments, and microtubules.
## Actin microfilaments
Around 6 nm in diameter, this filament type is composed of two intertwined actin chains. Microfilaments are most concentrated just beneath the cell membrane, and are responsible for resisting tension and maintaining cellular shape, forming cytoplasmatic protuberances (like pseudopodia and microvilli- although these by different mechanisms), and participation in some cell-to-cell or cell-to-matrix junctions. In association with these latter roles, microfilaments are essential to transduction. They are also important for cytokinesis (specifically, formation of the cleavage furrow) and, along with myosin, muscular contraction. Actin/Myosin interactions also help produce cytoplasmic streaming in most cells.
## Intermediate filaments
These filaments, around 10 nanometers in diameter, are more stable (strongly bound) than actin filaments, and heterogeneous constituents of the cytoskeleton. Although little work has been done on intermediate filaments in plants, there is some evidence that cytosolic intermediate filaments might be present, and plant nuclear filaments have been detected. Like actin filaments, they function in the maintenance of cell-shape by bearing tension (microtubules, by contrast, resist compression. Intermediate filaments organize the internal tridimensional structure of the cell, anchoring organelles and serving as structural components of the nuclear lamina and sarcomeres. They also participate in some cell-cell and cell-matrix junctions.
Different intermediate filaments are:
- made of vimentins, being the common structural support of many cells.
- made of keratin, found in skin cells, hair and nails.
- neurofilaments of neural cells.
- made of lamin, giving structural support to the nuclear envelope.
## Microtubules
Microtubules are hollow cylinders about 23 nm in diameter (lumen = approximately 15nm in diameter), most commonly comprised of 13 protofilaments which, in turn, are polymers of alpha and beta tubulin. They have a very dynamic behaviour, binding GTP for polymerization. They are commonly organized by the centrosome.
In nine triplet sets (star-shaped), they form the centrioles, and in nine doublets oriented about two additional microtubules (wheel-shaped) they form cilia and flagella. The latter formation is commonly referred to as a "9+2" arrangement, wherein each doublet is connected to another by the protein dynein. As both flagella and cilia are structural components of the cell, and are maintained by microtubules, they can be considered part of the cytoskeleton.
They play key roles in:
- intracellular transport (associated with dyneins and kinesins, they transport organelles like mitochondria or vesicles).
- the axoneme of cilia and flagella.
- the mitotic spindle.
- synthesis of the cell wall in plants.
## Comparison
# History of cytoskeleton
The concept and the term (cytosquelette, in French) was first introduced by French embryologist Paul Wintrebert in 1931. | Cytoskeleton
Editor In-Chief: Henry A. Hoff
# Overview
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained, as all other organelles, within the cytoplasm. It is contained in all eukaryotic cells and recent research has shown it can be present in prokaryotic cells too.[1] It is a dynamic structure that maintains cell shape, and also has been known to protect the cell, enables some cell motion (using structures such as flagella and cilia), and plays important roles in both intra-cellular transport (the movement of vesicles and organelles, for example) and cellular division. It is a bone-like structure floating around within the cytoplasm.
# The prokaryotic cytoskeleton
The cytoskeleton was previously thought to be a feature only of eukaryotic cells, but homologues to all the major proteins of the eukaryotic cytoskeleton have recently been found in prokaryotes.[1] Although the evolutionary relationships are so distant that they are not obvious from protein sequence comparisons alone, the similarity of their three-dimensional structures provides strong evidence that the eukaryotic and prokaryotic cytoskeletons are truly homologous.[2] However, some structures in the bacterial cytoskeleton may have yet to be identified.[3]
## FtsZ
FtsZ was the first protein of the prokaryotic cytoskeleton to be identified. Like tubulin, FtsZ forms filaments in the presence of GTP, but these filaments do not group into tubules. During cell division, FtsZ is the first protein to move to the division site, and is essential for recruiting other proteins that synthesize the new cell wall between the dividing cells.
## MreB and ParM
Prokaryotic actin-like proteins, such as MreB, are involved in the maintenance of cell shape. All non-spherical bacteria have genes encoding actin-like proteins, and these proteins form a helical network beneath the cell membrane that guides the proteins involved in cell wall biosynthesis.
Some plasmids encode a partitioning system that involves an actin-like protein ParM. Filaments of ParM exhibit dynamic instability, and may partition plasmid DNA into the dividing daughter cells by a mechanism analogous to that used by microtubules during eukaryotic mitosis.
## Crescentin
The bacterium Caulobacter crescentus contains a third protein, crescentin, that is related to the intermediate filaments of eukaryotic cells. Crescentin is also involved in maintaining cell shape, but the mechanism by which it does this is currently unclear.[4]
# The eukaryotic cytoskeleton
The cytoskeleton provides the cell with structure and shape, and by excluded volume macromolecules from some of the cytosol add to the level of macromolecular crowding in this compartment.[5] Cytoskeletal elements (the membrane skeleton) interact extensively and intimately with cellular membranes.[6]
Intimately connected to the cytoskeleton across the nuclear envelope (NE) is the nucleoskeleton (NS), which provides shape and support for the NE and the important activities of the nucleus.
Eukaryotic cells contain three main kinds of cytoskeletal filaments, which are microfilaments, intermediate filaments, and microtubules.
## Actin microfilaments
Around 6 nm in diameter, this filament type is composed of two intertwined actin chains. Microfilaments are most concentrated just beneath the cell membrane, and are responsible for resisting tension and maintaining cellular shape, forming cytoplasmatic protuberances (like pseudopodia and microvilli- although these by different mechanisms), and participation in some cell-to-cell or cell-to-matrix junctions. In association with these latter roles, microfilaments are essential to transduction. They are also important for cytokinesis (specifically, formation of the cleavage furrow) and, along with myosin, muscular contraction. Actin/Myosin interactions also help produce cytoplasmic streaming in most cells.
## Intermediate filaments
These filaments, around 10 nanometers in diameter, are more stable (strongly bound) than actin filaments, and heterogeneous constituents of the cytoskeleton. Although little work has been done on intermediate filaments in plants, there is some evidence that cytosolic intermediate filaments might be present,[7] and plant nuclear filaments have been detected.[8] Like actin filaments, they function in the maintenance of cell-shape by bearing tension (microtubules, by contrast, resist compression. Intermediate filaments organize the internal tridimensional structure of the cell, anchoring organelles and serving as structural components of the nuclear lamina and sarcomeres. They also participate in some cell-cell and cell-matrix junctions.
Different intermediate filaments are:
- made of vimentins, being the common structural support of many cells.
- made of keratin, found in skin cells, hair and nails.
- neurofilaments of neural cells.
- made of lamin, giving structural support to the nuclear envelope.
## Microtubules
Microtubules are hollow cylinders about 23 nm in diameter (lumen = approximately 15nm in diameter), most commonly comprised of 13 protofilaments which, in turn, are polymers of alpha and beta tubulin. They have a very dynamic behaviour, binding GTP for polymerization. They are commonly organized by the centrosome.
In nine triplet sets (star-shaped), they form the centrioles, and in nine doublets oriented about two additional microtubules (wheel-shaped) they form cilia and flagella. The latter formation is commonly referred to as a "9+2" arrangement, wherein each doublet is connected to another by the protein dynein. As both flagella and cilia are structural components of the cell, and are maintained by microtubules, they can be considered part of the cytoskeleton.
They play key roles in:
- intracellular transport (associated with dyneins and kinesins, they transport organelles like mitochondria or vesicles).
- the axoneme of cilia and flagella.
- the mitotic spindle.
- synthesis of the cell wall in plants.
## Comparison
# History of cytoskeleton
The concept and the term (cytosquelette, in French) was first introduced by French embryologist Paul Wintrebert in 1931.[11] | https://www.wikidoc.org/index.php/Cytoskeletal | |
4385318c27dd296653d51a00d38a616f5588dce1 | wikidoc | Cytotoxicity | Cytotoxicity
# Definition
Cytotoxicity is the quality of being toxic to cells.
# Toxic agents
Examples of toxic agents are a chemical substance or an immune cell.
# Ways to measure cytotoxicity
Cytotoxicity can be measured by the MTT assay, Trypan blue (TB) assay, Sulforhodamine B (SRB) assay, WST assay and clonogenic assay.
# Antibody-dependent cell-mediated cytotoxicity
Antibody-dependent cell-mediated cytotoxicity (ADCC) describes the cell-killing ability of certain lymphocytes, which requires the target cell being marked by an antibody.
# Lymphocyte-mediated cytotoxicity and Complement-dependent cytotoxicity
Lymphocyte-mediated cytotoxicity, on the other hand, does not have to be mediated by antibodies; nor does complement-dependent cytotoxicity (CDC), which is mediated by the complement system.
# Cytotoxic lymphocytes
Three groups of cytotoxic lymphocytes are distinguished:
- Cytotoxic T cells
- Natural killer cells
- Natural Killer T cells | Cytotoxicity
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Definition
Cytotoxicity is the quality of being toxic to cells.
# Toxic agents
Examples of toxic agents are a chemical substance or an immune cell.
# Ways to measure cytotoxicity
Cytotoxicity can be measured by the MTT assay, Trypan blue (TB) assay, Sulforhodamine B (SRB) assay, WST assay and clonogenic assay.
# Antibody-dependent cell-mediated cytotoxicity
Antibody-dependent cell-mediated cytotoxicity (ADCC) describes the cell-killing ability of certain lymphocytes, which requires the target cell being marked by an antibody.
# Lymphocyte-mediated cytotoxicity and Complement-dependent cytotoxicity
Lymphocyte-mediated cytotoxicity, on the other hand, does not have to be mediated by antibodies; nor does complement-dependent cytotoxicity (CDC), which is mediated by the complement system.
# Cytotoxic lymphocytes
Three groups of cytotoxic lymphocytes are distinguished:
- Cytotoxic T cells
- Natural killer cells
- Natural Killer T cells
# External links
- Cytotoxins at the US National Library of Medicine Medical Subject Headings (MeSH)
de:Zytotoxizität
no:Cellegift
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cytotoxic | |
ee189270f8fcb7b23c5c9b202537ee65779aa0cf | wikidoc | DD:backpain1 | DD:backpain1
the differential diagnosis of acute onset lower back pain, with bowel and bladder dysfunction, sensory and motor deficits,
- ↑ Ozateş M, Kemaloglu S, Gürkan F, Ozkan U, Hoşoglu S, Simşek MM (January 2000). "CT of the brain in tuberculous meningitis. A review of 289 patients". Acta Radiol. 41 (1): 13–7. PMID 10665863..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 Bach F, Larsen BH, Rohde K, Børgesen SE, Gjerris F, Bøge-Rasmussen T, Agerlin N, Rasmusson B, Stjernholm P, Sørensen PS (1990). "Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression". Acta Neurochir (Wien). 107 (1–2): 37–43. PMID 2096606.
- ↑ Jump up to: 3.0 3.1 Helweg-Larsen S, Sørensen PS (1994). "Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients". Eur. J. Cancer. 30A (3): 396–8. PMID 8204366.
- ↑ Nathoo N, Nadvi SS, van Dellen JR (April 1999). "Cranial extradural empyema in the era of computed tomography: a review of 82 cases". Neurosurgery. 44 (4): 748–53, discussion 753–4. PMID 10201299.
- ↑ Heran NS, Steinbok P, Cochrane DD (October 2003). "Conservative neurosurgical management of intracranial epidural abscesses in children". Neurosurgery. 53 (4): 893–7, discussion 897–8. PMID 14519222.
- ↑ Bischoff RJ, Rodriguez RP, Gupta K, Righi A, Dalton JE, Whitecloud TS (August 1993). "A comparison of computed tomography-myelography, magnetic resonance imaging, and myelography in the diagnosis of herniated nucleus pulposus and spinal stenosis". J Spinal Disord. 6 (4): 289–95. PMID 8219542.
- ↑ Tarulli AW, Raynor EM (May 2007). "Lumbosacral radiculopathy". Neurol Clin. 25 (2): 387–405. doi:10.1016/j.ncl.2007.01.008.
- ↑ Hay MC (June 1976). "Anatomy of the lumbar spine". Med. J. Aust. 1 (23): 874–6. PMID 967084.
- ↑ Jump up to: 9.0 9.1 Vroomen PC, de Krom MC, Wilmink JT, Kester AD, Knottnerus JA (February 1999). "Lack of effectiveness of bed rest for sciatica". N. Engl. J. Med. 340 (6): 418–23. doi:10.1056/NEJM199902113400602. PMID 9971865. | DD:backpain1
Template:Backpain1
the differential diagnosis of acute onset lower back pain, with bowel and bladder dysfunction, sensory and motor deficits,
- ↑ Ozateş M, Kemaloglu S, Gürkan F, Ozkan U, Hoşoglu S, Simşek MM (January 2000). "CT of the brain in tuberculous meningitis. A review of 289 patients". Acta Radiol. 41 (1): 13–7. PMID 10665863..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 Bach F, Larsen BH, Rohde K, Børgesen SE, Gjerris F, Bøge-Rasmussen T, Agerlin N, Rasmusson B, Stjernholm P, Sørensen PS (1990). "Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression". Acta Neurochir (Wien). 107 (1–2): 37–43. PMID 2096606.
- ↑ Jump up to: 3.0 3.1 Helweg-Larsen S, Sørensen PS (1994). "Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients". Eur. J. Cancer. 30A (3): 396–8. PMID 8204366.
- ↑ Nathoo N, Nadvi SS, van Dellen JR (April 1999). "Cranial extradural empyema in the era of computed tomography: a review of 82 cases". Neurosurgery. 44 (4): 748–53, discussion 753–4. PMID 10201299.
- ↑ Heran NS, Steinbok P, Cochrane DD (October 2003). "Conservative neurosurgical management of intracranial epidural abscesses in children". Neurosurgery. 53 (4): 893–7, discussion 897–8. PMID 14519222.
- ↑ Bischoff RJ, Rodriguez RP, Gupta K, Righi A, Dalton JE, Whitecloud TS (August 1993). "A comparison of computed tomography-myelography, magnetic resonance imaging, and myelography in the diagnosis of herniated nucleus pulposus and spinal stenosis". J Spinal Disord. 6 (4): 289–95. PMID 8219542.
- ↑ Tarulli AW, Raynor EM (May 2007). "Lumbosacral radiculopathy". Neurol Clin. 25 (2): 387–405. doi:10.1016/j.ncl.2007.01.008.
- ↑ Hay MC (June 1976). "Anatomy of the lumbar spine". Med. J. Aust. 1 (23): 874–6. PMID 967084.
- ↑ Jump up to: 9.0 9.1 Vroomen PC, de Krom MC, Wilmink JT, Kester AD, Knottnerus JA (February 1999). "Lack of effectiveness of bed rest for sciatica". N. Engl. J. Med. 340 (6): 418–23. doi:10.1056/NEJM199902113400602. PMID 9971865. | https://www.wikidoc.org/index.php/DD:backpain1 | |
d61a9e1f717661c5f562c59271c339a7e237dd28 | wikidoc | DEFINE Trial | DEFINE Trial
# Official Title
A 76-Week, Worldwide, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Tolerability and Efficacy of Anacetrapib When Added to Ongoing Therapy With a Statin in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease
# Objective
The objective of this trial is to study the therapeutic and adverse effect of anacetrapib, a CETP inhibitor, alone and with statin.
# Sponsor
Merck
# Timeline
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00685776.
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00685776.
# Eligibility Criteria
## Inclusion Criteria
- Base Study:
Patient has Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease and is treated with a statin, with well controlled LDL-C
- Patient has Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease and is treated with a statin, with well controlled LDL-C
- Extension Study:
Patient has completed the base study including the reversibility period (i.e. 12 or to up to 24 weeks)
Patient is on statin therapy ± lipid-modifying therapy since the end of the base study and planning to continue taking a statin throughout the study
- Patient has completed the base study including the reversibility period (i.e. 12 or to up to 24 weeks)
- Patient is on statin therapy ± lipid-modifying therapy since the end of the base study and planning to continue taking a statin throughout the study
## Exclusion Criteria
- History of heart failure, arrhythmias, heart attack, unstable angina, or stroke within 3 months prior to screening, uncontrolled blood pressure, uncontrolled *High cholesterol or liver disease.
- History of mental instability, drug/alcohol abuse within the past 5 years
- Pregnant or breast-feeding
- History of cancer within the last 5 years
- HIV positive
- Donated blood products within 8 weeks
- Currently participating or have participated in a study with an investigational compound within the last 30 days
# Outcomes
## Primary Outcomes
Reduction in LDL-C compared to placebo
## Secondary Outcomes
Increase in HDL-C, safety (adverse events, vital signs, ECG, physical exam, and laboratory tests)
# Publications
## Results
- 17.6% of patients on anacetrapib vs. only 0.1% of placebo were discontinued due to LDL < 25 mg/dL at 2 consecutive visits.
- With respect to LDL reduction and HDL elevation, anacetrapib showed significant changes: 39.8% and 138.1% change, respectively at 24 weeks. LDL was approximately halved from 81 to 45 mg/dL and HDL increased from 41 to 101 mg/dL. Change in HDL was further accentuated in patients with baseline low HDL < 40 mg/dL, with an increase of 152% in this sub-population.
- Similarly, a significant decrease in apoB, non-HDL-C, lipoprotein, and triglycerides, and an increase in ApoA-I were all seen with anacetrapib at 24 and 76 weeks.
- In the reversal phage, 1398 patients were enrolled. Significant reduction in LDL, non-HDL, apo-B and an increase in HDL and apo A-I persisted during that period for patients on anacetrapib, who continued to have trace concentrations of the medication. These alterations reached 50-60% of values observed during on-medication trial period.
- Anacetrapib had no effect on adverse events during the trial or the reversal phase, but had a significantly lower number of patients with liver function test disturbances by the end of the trial (p=0.02).
- In comparison to placebo, Post-hoc analysis revealed that patients on anacetrapib had significantly less revascularization procedures (p=0.001) and cardiovascular end points (p=0.048).
After balancing proportions, the percentage of patients who discontinued the study due to 2 consecutive LDL-C levels < 25 mg/dL was 14.6% in patients receiving anacetrapib and 17.4% in patients receiving placebo.
The decrease in LDL-C levels after 24 weeks of treatment was significant in patients receiving anacetrapib compared to those on placebo. The LDL-C in the former group was reduced from 81 mg/dL to 45 mg/dL, where was it was only reduced from 82 mg/dL to 77 mg/dL in the latter (p<0.001). The percent change of LDL-C in anacetrapib group was a 39.8% reduction. Similarly, HDL-C increased 138.1%, from 41 mg/dL to 101 mg/dL in anacetrapib group, also significantly different from placebo that only raised HDL-C from 40 mg/dL to 46 mg/dL after 24 weeks (p<0.001).
There was a 44.7% increase in apo A-1 and a 21% decrease in apo B among patients receiving anacetrapib (p<0.001).
Changes associated with anacetrapib were maintained throughout 76 weeks of follow-up.
No adverse event was significantly associated with anacetrapib alone when compared to placebo. Common adverse events in both groups included: elevation in systolic and diastolic blood pressures, electrolyte disturbances, elevation in creatinine kinase, and myalgias. Significantly, there was a 0.96mmol/L decrease in serum sodium levels in patients on anacetrapib vs. a 1.2 mmol/L in patients on placebo (p=0.02). The rates of liver function tests increase to three times above upper normal limit was in fact significantly less in patients on anacetrapib (p=0.02).
## Conclusion
Anacetrapib is associated with a significant increase in HDL and decrease in LDL with a tolerable side effect probile. Further clinical trials are required to prove the beneficial effects of increasing HDL levels in preventing adverse cardiovascular events in high risk patients. | DEFINE Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]
Click here to download slides for DEFINE Trial.
# Official Title
A 76-Week, Worldwide, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Tolerability and Efficacy of Anacetrapib When Added to Ongoing Therapy With a Statin in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease
# Objective
The objective of this trial is to study the therapeutic and adverse effect of anacetrapib, a CETP inhibitor, alone and with statin.[1]
# Sponsor
Merck
# Timeline
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00685776.
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00685776.
# Eligibility Criteria
## Inclusion Criteria
- Base Study:
Patient has Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease and is treated with a statin, with well controlled LDL-C
- Patient has Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease and is treated with a statin, with well controlled LDL-C
- Extension Study:
Patient has completed the base study including the reversibility period (i.e. 12 or to up to 24 weeks)
Patient is on statin therapy ± lipid-modifying therapy since the end of the base study and planning to continue taking a statin throughout the study
- Patient has completed the base study including the reversibility period (i.e. 12 or to up to 24 weeks)
- Patient is on statin therapy ± lipid-modifying therapy since the end of the base study and planning to continue taking a statin throughout the study
## Exclusion Criteria
- History of heart failure, arrhythmias, heart attack, unstable angina, or stroke within 3 months prior to screening, uncontrolled blood pressure, uncontrolled *High cholesterol or liver disease.
- History of mental instability, drug/alcohol abuse within the past 5 years
- Pregnant or breast-feeding
- History of cancer within the last 5 years
- HIV positive
- Donated blood products within 8 weeks
- Currently participating or have participated in a study with an investigational compound within the last 30 days
# Outcomes
## Primary Outcomes
Reduction in LDL-C compared to placebo [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
## Secondary Outcomes
Increase in HDL-C, safety (adverse events, vital signs, ECG, physical exam, and laboratory tests) [ Time Frame: 76 weeks ] [ Designated as safety issue: No ]
# Publications
## Results
- 17.6% of patients on anacetrapib vs. only 0.1% of placebo were discontinued due to LDL < 25 mg/dL at 2 consecutive visits.
- With respect to LDL reduction and HDL elevation, anacetrapib showed significant changes: 39.8% and 138.1% change, respectively at 24 weeks. LDL was approximately halved from 81 to 45 mg/dL and HDL increased from 41 to 101 mg/dL. Change in HDL was further accentuated in patients with baseline low HDL < 40 mg/dL, with an increase of 152% in this sub-population.
- Similarly, a significant decrease in apoB, non-HDL-C, lipoprotein, and triglycerides, and an increase in ApoA-I were all seen with anacetrapib at 24 and 76 weeks.
- In the reversal phage, 1398 patients were enrolled. Significant reduction in LDL, non-HDL, apo-B and an increase in HDL and apo A-I persisted during that period for patients on anacetrapib, who continued to have trace concentrations of the medication. These alterations reached 50-60% of values observed during on-medication trial period.
- Anacetrapib had no effect on adverse events during the trial or the reversal phase, but had a significantly lower number of patients with liver function test disturbances by the end of the trial (p=0.02).
- In comparison to placebo, Post-hoc analysis revealed that patients on anacetrapib had significantly less revascularization procedures (p=0.001) and cardiovascular end points (p=0.048).[2]
After balancing proportions, the percentage of patients who discontinued the study due to 2 consecutive LDL-C levels < 25 mg/dL was 14.6% in patients receiving anacetrapib and 17.4% in patients receiving placebo.
The decrease in LDL-C levels after 24 weeks of treatment was significant in patients receiving anacetrapib compared to those on placebo. The LDL-C in the former group was reduced from 81 mg/dL to 45 mg/dL, where was it was only reduced from 82 mg/dL to 77 mg/dL in the latter (p<0.001). The percent change of LDL-C in anacetrapib group was a 39.8% reduction. Similarly, HDL-C increased 138.1%, from 41 mg/dL to 101 mg/dL in anacetrapib group, also significantly different from placebo that only raised HDL-C from 40 mg/dL to 46 mg/dL after 24 weeks (p<0.001).
There was a 44.7% increase in apo A-1 and a 21% decrease in apo B among patients receiving anacetrapib (p<0.001).
Changes associated with anacetrapib were maintained throughout 76 weeks of follow-up.
No adverse event was significantly associated with anacetrapib alone when compared to placebo. Common adverse events in both groups included: elevation in systolic and diastolic blood pressures, electrolyte disturbances, elevation in creatinine kinase, and myalgias. Significantly, there was a 0.96mmol/L decrease in serum sodium levels in patients on anacetrapib vs. a 1.2 mmol/L in patients on placebo (p=0.02). The rates of liver function tests increase to three times above upper normal limit was in fact significantly less in patients on anacetrapib (p=0.02).
## Conclusion
Anacetrapib is associated with a significant increase in HDL and decrease in LDL with a tolerable side effect probile. Further clinical trials are required to prove the beneficial effects of increasing HDL levels in preventing adverse cardiovascular events in high risk patients. | https://www.wikidoc.org/index.php/DEFINE_Trial | |
342579d1108dc575e265a1e41e4b6743246c2174 | wikidoc | Dengue virus | Dengue virus
Synonyms and keywords: DENV
# Overview
The dengue virus (DENV) in one of five serotypes is the cause of dengue fever. It is a mosquito-borne single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. All five serotypes can cause the full spectrum of disease.
Its genome is about 11000 bases that codes for three structural proteins, capsid protein C, membrane protein M, envelope protein E; seven nonstructural proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5; and short non-coding regions on both the 5' and 3' ends. Further classification of each serotype into genotypes often relates to the region where particular strains are commonly found or were first found.
# Evolution
The dengue type 1 virus appears to have evolved in the early 19th century. Based on the analysis of the envelope protein there are at least four genotypes (1 to 4). The rate of nucleotide substitution for this virus has been estimated to be 6.5Template:E per nucleotide per year, a rate similar to other RNA viruses. The American African genotype has been estimated to have evolved between 1907 to 1949. This period includes World War I and II which were associated with considerable movement of populations and environmental disturbance, factors known to promote the evolution of new vector borne viral species.
# Life Cycle
Until a few hundred years ago dengue virus was transmitted in sylvatic cycles in Africa and Asia between mosquitoes of the genus Aedes and non-human primates with rare emergences into human populations. The global spread of dengue virus, however, has followed its emergence from sylvatic cycles and the primary life cycle now exclusively involves transmission between humans and Aedes mosquitoes. Vertical transmission from mosquito to mosquito has also been observed in some vector species.
# Structure
## E Protein
The DENV E (envelope) protein, found on the viral surface, is important in the initial attachment of the viral particle to the host cell. Dengue virus is transmitted by a mosquito known as Aedes some time called enfluenga. Several molecules which interact with the viral E protein (ICAM3-grabbing non-integrin), CD209, Rab 5, GRP 78, and The Mannose Receptor )have been shown to be important factors mediating attachment and viral entry.
## prM/M Protein
The DENV prM (membrane) protein, which is important in the formation and maturation of the viral particle, consists of seven antiparallel β-strands stabilized by three disulfide bonds.
The glycoprotein shell of the mature DENV virion consists of 180 copies each of the E protein and M protein. The immature virion starts out with the E and prM proteins forming 90 heterodimers that give a spiky exterior to the viral particle. This immature viral particle buds into the endoplasmic reticulum and eventually travels via the secretory pathway to the Golgi apparatus. As the virion passes through the trans-Golgi Network (TGN) it is exposed to low pH. This acidic environment causes a conformational change in the E protein which disassociates it from the prM protein and causes it to form E homodimers. These homodimers lie flat against the viral surface giving the maturing virion a smooth appearance. During this maturation pr peptide is cleaved from the M peptide by the host protease, furin. The M protein then acts as a transmembrane protein under the E-protein shell of the mature virion. The pr peptide stays associated with the E protein until the viral particle is released into the extracellular environment. This pr peptide acts like a cap, covering the hydrophobic fusion loop of the E protein until the viral particle has exited the cell.
## NS3 Protein
The DENV NS3 is a serine protease, as well as an RNA helicase and RTPase/NTPase. The protease domain consists of six β-strands arranged into two β-barrels formed by residues 1–180 of the protein. The catalytic triad (His-51, Asp-75 and Ser-135), is found between these two β-barrels, and its activity is dependent on the presence of the NS2B cofactor. This cofactor wraps around the NS3 protease domain and becomes part of the active site. The remaining NS3 residues (180–618), form the three subdomains of the DENV helicase. A six-stranded parallel β-sheet surrounded by four α-helices make up subdomains I and II, and subdomain III is composed of 4 α-helices surrounded by three shorter α-helices and two antiparallel β-strands.
## NS5 Protein
The DENV NS5 protein is a 900 residue peptide with a methyltransferase domain at its N-terminal end (residues 1–296) and a RNA-dependent RNA polymerase (RdRp) at its C-terminal end (residues 320–900). The methyltransferase domain consists of an α/β/β sandwich flanked by N-and C-terminal subdomains. The DENV RdRp is similar to other RdRps containing palm, finger, and thumb subdomains and a GDD motif for incorporating nucleotides.
## Severe Disease
The reason that some people suffer from more severe forms of dengue, such as dengue hemorrhagic fever, is multifactorial. Different strains of viruses interacting with people with different immune backgrounds lead to a complex interaction. Among the possible causes are cross-serotypic immune response, through a mechanism known as antibody-dependent enhancement, which happens when a person who has been previously infected with dengue gets infected for the second, third or fourth time. The previous antibodies to the old strain of dengue virus now interfere with the immune response to the current strain, leading paradoxically to more virus entry and uptake.
# Immune System Interaction
In recent years, many studies have shown that flaviviruses, especially dengue virus has the ability to inhibit the innate immune response during the infection.
Indeed, the dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. These proteins act on two levels :
## Inhibition of Interferon Signaling by Blocking Signal Transducer
NS4B it is a small hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha, beta. In fact, the activity of Tyk2 kinase decreases with the dengue virus, so STAT 1 phosphorylation decreases too. Therefore, the innate immune system response may be blocked. Thus there is no production of ISG. NS2A and NS4A cofactor may also take part in the STAT 1 inhibition.
NS5 : the presence of this 105 kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone.
When NS5 is cleaved with NS4B by a protease (NS2B3) it can degrade STAT2. In fact, after the cleavage of NS5 by the protease, there is an E3 ligase association with STAT2, and the E3 ligase targets STAT2 for the degradation.
## Inhibition of the Type I Interferon Response
NS2B3 protease complex is a proteolytic core consisting of the last 40 amino acids of NS2B and the first 180 amino acids of NS3.
Cleavage of the NS2B3 precursor activates the protease complex.
This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter: studies have shown that NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3.
A recent study shows that the NS2B3 protease complex inhibits (by cleaving) protein MITA which allows the IRF3 activation.
## Vaccine Research
There currently is no human vaccine available. Several vaccines are under development by private and public researchers. Developing a vaccine against the disease is challenging. With five different serotypes of the dengue virus that can cause the disease, the vaccine must immunize against all five types to be effective. Vaccination against only one serotype could possibly lead to severe dengue hemorrhagic shock (DHS) when infected with another serotype due to antibody-dependent enhancement. One vaccine was in phase III trials in 2012 and planning for vaccine usage and effectiveness surveillance had started.
In September 2012, it was announced that one of the vaccines had not done well in clinical trials.
As researchers continue their work, governments should also make efforts in protecting their citizens by providing clean environments to live in, which can be done through developing cleaning teams to keep the cities clean.
# Gallery
- (TEM) depicts a number of round, Dengue virus particles that were revealed in this tissue specimen. From Public Health Image Library (PHIL).
- Aedes mediovittatus mosquito is a vector in the transmission of Dengue Fever. From Public Health Image Library (PHIL).
- Illustration identifying the pecten on the terminal abdominal segment of an Aedes mosquito larva, vector of Dengue transmission. From Public Health Image Library (PHIL).
- Red blood meal visible through her now transparent abdomen of female Aedes aegypti mosquito after leaving host’s skin surface. From Public Health Image Library (PHIL).
- Aedes aegypti female was from a strain of mosquitoes named LVP-IB12. From Public Health Image Library (PHIL). | Dengue virus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: DENV
# Overview
The dengue virus (DENV) in one of five[1] serotypes is the cause of dengue fever. It is a mosquito-borne single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus.[2][3] All five serotypes can cause the full spectrum of disease.[2]
Its genome is about 11000 bases that codes for three structural proteins, capsid protein C, membrane protein M, envelope protein E; seven nonstructural proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5; and short non-coding regions on both the 5' and 3' ends.[2][4] Further classification of each serotype into genotypes often relates to the region where particular strains are commonly found or were first found.
# Evolution
The dengue type 1 virus appears to have evolved in the early 19th century.[5] Based on the analysis of the envelope protein there are at least four genotypes (1 to 4). The rate of nucleotide substitution for this virus has been estimated to be 6.5Template:E per nucleotide per year, a rate similar to other RNA viruses. The American African genotype has been estimated to have evolved between 1907 to 1949. This period includes World War I and II which were associated with considerable movement of populations and environmental disturbance, factors known to promote the evolution of new vector borne viral species.
# Life Cycle
Until a few hundred years ago dengue virus was transmitted in sylvatic cycles in Africa and Asia between mosquitoes of the genus Aedes and non-human primates with rare emergences into human populations.[6][7] The global spread of dengue virus, however, has followed its emergence from sylvatic cycles and the primary life cycle now exclusively involves transmission between humans and Aedes mosquitoes.[8] Vertical transmission from mosquito to mosquito has also been observed in some vector species.[9]
# Structure
## E Protein
The DENV E (envelope) protein, found on the viral surface, is important in the initial attachment of the viral particle to the host cell. Dengue virus is transmitted by a mosquito known as Aedes some time called enfluenga. Several molecules which interact with the viral E protein (ICAM3-grabbing non-integrin),[10] CD209,[11] Rab 5,[12] GRP 78,[13] and The Mannose Receptor [14])have been shown to be important factors mediating attachment and viral entry.[15]
## prM/M Protein
The DENV prM (membrane) protein, which is important in the formation and maturation of the viral particle, consists of seven antiparallel β-strands stabilized by three disulfide bonds.[15]
The glycoprotein shell of the mature DENV virion consists of 180 copies each of the E protein and M protein. The immature virion starts out with the E and prM proteins forming 90 heterodimers that give a spiky exterior to the viral particle. This immature viral particle buds into the endoplasmic reticulum and eventually travels via the secretory pathway to the Golgi apparatus. As the virion passes through the trans-Golgi Network (TGN) it is exposed to low pH. This acidic environment causes a conformational change in the E protein which disassociates it from the prM protein and causes it to form E homodimers. These homodimers lie flat against the viral surface giving the maturing virion a smooth appearance. During this maturation pr peptide is cleaved from the M peptide by the host protease, furin. The M protein then acts as a transmembrane protein under the E-protein shell of the mature virion. The pr peptide stays associated with the E protein until the viral particle is released into the extracellular environment. This pr peptide acts like a cap, covering the hydrophobic fusion loop of the E protein until the viral particle has exited the cell.[15]
## NS3 Protein
The DENV NS3 is a serine protease, as well as an RNA helicase and RTPase/NTPase. The protease domain consists of six β-strands arranged into two β-barrels formed by residues 1–180 of the protein. The catalytic triad (His-51, Asp-75 and Ser-135), is found between these two β-barrels, and its activity is dependent on the presence of the NS2B cofactor. This cofactor wraps around the NS3 protease domain and becomes part of the active site. The remaining NS3 residues (180–618), form the three subdomains of the DENV helicase. A six-stranded parallel β-sheet surrounded by four α-helices make up subdomains I and II, and subdomain III is composed of 4 α-helices surrounded by three shorter α-helices and two antiparallel β-strands.[15]
## NS5 Protein
The DENV NS5 protein is a 900 residue peptide with a methyltransferase domain at its N-terminal end (residues 1–296) and a RNA-dependent RNA polymerase (RdRp) at its C-terminal end (residues 320–900). The methyltransferase domain consists of an α/β/β sandwich flanked by N-and C-terminal subdomains. The DENV RdRp is similar to other RdRps containing palm, finger, and thumb subdomains and a GDD motif for incorporating nucleotides.[15]
## Severe Disease
The reason that some people suffer from more severe forms of dengue, such as dengue hemorrhagic fever, is multifactorial. Different strains of viruses interacting with people with different immune backgrounds lead to a complex interaction. Among the possible causes are cross-serotypic immune response, through a mechanism known as antibody-dependent enhancement, which happens when a person who has been previously infected with dengue gets infected for the second, third or fourth time. The previous antibodies to the old strain of dengue virus now interfere with the immune response to the current strain, leading paradoxically to more virus entry and uptake.[16]
# Immune System Interaction
In recent years, many studies have shown that flaviviruses, especially dengue virus has the ability to inhibit the innate immune response during the infection.[17][18]
Indeed, the dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. These proteins act on two levels :
## Inhibition of Interferon Signaling by Blocking Signal Transducer
NS4B it is a small hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha, beta. In fact, the activity of Tyk2 kinase decreases with the dengue virus, so STAT 1 phosphorylation decreases too.[19] Therefore, the innate immune system response may be blocked. Thus there is no production of ISG. NS2A and NS4A cofactor may also take part in the STAT 1 inhibition.[20]
NS5 : the presence of this 105 kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone.[21]
When NS5 is cleaved with NS4B by a protease (NS2B3) it can degrade STAT2. In fact, after the cleavage of NS5 by the protease, there is an E3 ligase association with STAT2, and the E3 ligase targets STAT2 for the degradation.[22][23]
## Inhibition of the Type I Interferon Response
NS2B3 protease complex is a proteolytic core consisting of the last 40 amino acids of NS2B and the first 180 amino acids of NS3.
Cleavage of the NS2B3 precursor activates the protease complex.[24]
This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter: studies have shown that NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3.[25]
A recent study shows that the NS2B3 protease complex inhibits (by cleaving) protein MITA which allows the IRF3 activation.[26]
## Vaccine Research
There currently is no human vaccine available. Several vaccines are under development by private and public researchers.[27] Developing a vaccine against the disease is challenging. With five different serotypes of the dengue virus that can cause the disease, the vaccine must immunize against all five types to be effective.[1] Vaccination against only one serotype could possibly lead to severe dengue hemorrhagic shock (DHS) when infected with another serotype due to antibody-dependent enhancement. One vaccine was in phase III trials in 2012 and planning for vaccine usage and effectiveness surveillance had started.[28]
In September 2012, it was announced that one of the vaccines had not done well in clinical trials.[1]
As researchers continue their work, governments should also make efforts in protecting their citizens by providing clean environments to live in, which can be done through developing cleaning teams to keep the cities clean.
# Gallery
- (TEM) depicts a number of round, Dengue virus particles that were revealed in this tissue specimen. From Public Health Image Library (PHIL). [29]
- Aedes mediovittatus mosquito is a vector in the transmission of Dengue Fever. From Public Health Image Library (PHIL). [29]
- Illustration identifying the pecten on the terminal abdominal segment of an Aedes mosquito larva, vector of Dengue transmission. From Public Health Image Library (PHIL). [29]
- Red blood meal visible through her now transparent abdomen of female Aedes aegypti mosquito after leaving host’s skin surface. From Public Health Image Library (PHIL). [29]
- Aedes aegypti female was from a strain of mosquitoes named LVP-IB12. From Public Health Image Library (PHIL). [29] | https://www.wikidoc.org/index.php/DENV | |
de4574f05d0eba4d9464e626cc8cc231d6db7ff1 | wikidoc | DNA sequence | DNA sequence
# Overview
A DNA sequence or genetic sequence is a succession of letters representing the primary structure of a real or hypothetical DNA molecule or strand, with the capacity to carry information.
The possible letters are A, C, G, and T, representing the four nucleotide subunits of a DNA strand - adenine, cytosine, guanine, thymine bases covalently linked to phospho-backbone. In the typical case, the sequences are printed abutting one another without gaps, as in the sequence AAAGTCTGAC, going from 5' to 3' from left to right. A succession of any number of nucleotides greater than four is liable to be called a sequence. With regard to its biological function, which may depend on context, a sequence may be sense or anti-sense, and either coding or noncoding. DNA sequences can also contain "junk DNA."
Sequences can be derived from the biological raw material through a process called DNA sequencing.
In some special cases, letters besides A, T, C, and G are present in a sequence. These letters represent ambiguity. Of all the molecules sampled, there is more than one kind of nucleotide at that position. The rules of the International Union of Pure and Applied Chemistry (IUPAC) are as follows: | DNA sequence
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A DNA sequence or genetic sequence is a succession of letters representing the primary structure of a real or hypothetical DNA molecule or strand, with the capacity to carry information.
The possible letters are A, C, G, and T, representing the four nucleotide subunits of a DNA strand - adenine, cytosine, guanine, thymine bases covalently linked to phospho-backbone. In the typical case, the sequences are printed abutting one another without gaps, as in the sequence AAAGTCTGAC, going from 5' to 3' from left to right. A succession of any number of nucleotides greater than four is liable to be called a sequence. With regard to its biological function, which may depend on context, a sequence may be sense or anti-sense, and either coding or noncoding. DNA sequences can also contain "junk DNA."
Sequences can be derived from the biological raw material through a process called DNA sequencing.
In some special cases, letters besides A, T, C, and G are present in a sequence. These letters represent ambiguity. Of all the molecules sampled, there is more than one kind of nucleotide at that position. The rules of the International Union of Pure and Applied Chemistry (IUPAC) are as follows: | https://www.wikidoc.org/index.php/DNA_sequence | |
a301bf46fb45868dd97f97cd684ba1954760ab9b | wikidoc | DSM-IV Codes | DSM-IV Codes
# Overview
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, also known as DSM-IV-TR, is a manual published by the American Psychiatric Association (APA) that includes all currently recognized mental health disorders. The coding system utilized by the DSM-IV is designed to correspond with codes from the International Classification of Diseases, commonly referred to as the ICD. Since early versions of the DSM did not correspond with ICD codes and updates of the publications for the ICD and the DSM are not simultaneous, some distinctions in the coding systems may still be present. For this reason, it is recommended that users of these manuals consult the appropriate reference when accessing diagnostic codes.
To see these codes listed alphabetically, rather than by category, click here.
- NOS = Not Otherwise Specified.
DSM cautionary statement
# Disorders usually first diagnosed in infancy, childhood, or adolescence
## Mental retardation
- 317 Mild Mental Retardation
- 318.0 Moderate Mental Retardation
- 318.1 Severe Mental Retardation
- 318.2 Profound Mental Retardation
- 319 Mental Retardation, Severity Unspecified
## Learning Disorders
- 315.00 Reading Disorder
- 315.1 Mathematics Disorder
- 315.2 Disorder of Written Expression
- 315.9 Learning Disorder NOS
## Motor Skills Disorders
- 315.4 Developmental Coordination Disorder
## Communication Disorders
- 315.31 Expressive Language Disorder
- 315.32 Mixed Receptive-Expressive Language Disorder
- 315.39 Phonological Disorder
- 307.0 Stuttering
- 307.9 Communication Disorder NOS
## Pervasive Developmental Disorders
- 299.00 Autistic Disorder
- 299.80 Rett's Disorder
- 299.10 Childhood Disintegrative Disorder
- 299.80 Asperger’s Disorder
- 299.80 Pervasive Developmental Disorder NOS
## Attention-Deficit and Disruptive Behavior Disorders
- Attention-Deficit Hyperactivity Disorder
314.01 Combined Subtype
314.01 Predominantly Hyperactive-Impulsive Subtype
314.00 Predominantly Inattentive Subtype
314.9 Attention-Deficit Hyperactivity Disorder NOS
- 314.01 Combined Subtype
- 314.01 Predominantly Hyperactive-Impulsive Subtype
- 314.00 Predominantly Inattentive Subtype
- 314.9 Attention-Deficit Hyperactivity Disorder NOS
- Conduct Disorder
312.81 Childhood Onset
312.82 Adolescent Onset
312.89 Unspecified Onset
- 312.81 Childhood Onset
- 312.82 Adolescent Onset
- 312.89 Unspecified Onset
- 313.81 Oppositional Defiant Disorder
- 312.9 Disruptive Behavior Disorder NOS
## Feeding and Eating Disorders of Infancy or Early Childhood
- 307.52 Pica
- 307.53 Rumination Disorder
- 307.59 Feeding Disorder of Infancy or Early Childhood
## Tic Disorders
- 307.23 Tourette’s Disorder
- 307.22 Chronic Motor or Vocal Tic Disorder
- 307.21 Transient Tic Disorder
- 307.20 Tic Disorder NOS
## Elimination Disorders
- Encopresis
787.6 Encopresis, With Constipation and Overflow Incontinence
307.7 Encopresis, Without Constipation and Overflow Incontinence
- 787.6 Encopresis, With Constipation and Overflow Incontinence
- 307.7 Encopresis, Without Constipation and Overflow Incontinence
- 307.6 Enuresis (Not Due to a General Medical Condition)
## Other Disorders of Infancy, Childhood, or Adolescenece
- 309.21 Separation Anxiety Disorder
- 313.23 Selective Mutism
- 313.89 Reactive Attachment Disorder of Infancy or Early Childhood
- 307.3 Stereotypic Movement Disorder
- 313.9 Disorder of Infancy, Childhood, or Adolescence NOS
Top
# Delirium, Dementia, and Amnestic and Other Cognitive Disorders
## Delirium
- 293.0 Delirium Due to...
- 780.09 Delirium NOS
## Dementia
- 290.10 Dementia Due to Creutzfeldt-Jakob Disease
- 294.1 Dementia Due to Head Trauma
- 294.9 Dementia Due to HIV Disease
- 294.1 Dementia Due to Huntington's disease
- 294.1 Dementia Due to Parkinson's disease
- 290.10 Dementia Due to Pick’s disease
- 294.1 Dementia Due to...
- 294.8 Dementia NOS
- Dementia of the Alzheimer’s Type, With Early Onset
290.10 Uncomplicated
290.11 With Delirium
290.12 With Delusions
290.13 With Depressed Mood
- 290.10 Uncomplicated
- 290.11 With Delirium
- 290.12 With Delusions
- 290.13 With Depressed Mood
- Dementia of the Alzheimer’s Type, With Late Onset
290.0 Uncomplicated
290.3 With Delirium
290.20 With Delusions
290.21 With Depressed Mood
- 290.0 Uncomplicated
- 290.3 With Delirium
- 290.20 With Delusions
- 290.21 With Depressed Mood
- Vascular Dementia
290.41 With Delirium
290.42 With Delusions
290.43 With Depressed Mood
- 290.41 With Delirium
- 290.42 With Delusions
- 290.43 With Depressed Mood
## Amnestic Disorders
- 294.0 Amnestic Disorder Due to...
- 294.8 Amnestic Disorder NOS
## Other Cognitive Disorders
- 294.9 Cognitive Disorder NOS
Top
# Mental Disorders Due to a General Medical Condition Not Elsewhere Classified
- 293.89 Catatonic Disorder Due to...
- 310.1 Personality Change Due to...
- 293.9 Mental Disorder NOS Due to...
Top
# Substance-Related Disorders
## Alcohol-Related Disorders
- Alcohol
305.00 Abuse
303.90 Dependence
291.8 -Induced Anxiety Disorder
291.8 -Induced Mood Disorder
291.1 -Induced Persisting Amnestic Disorder
291.2 -Induced Persisting Dementia
291.5 -Induced Psychotic Disorder, With Delusions
291.3 -Induced Psychotic Disorder, With Hallucinations
291.8 -Induced Sexual Dysfunction
291.8 -Induced Sleep Disorder
303.00 Intoxication
291.0 Intoxication Delirium
291.9 -Related Disorder NOS
291.8 Withdrawal
291.0 Withdrawal Delirium
- 305.00 Abuse
- 303.90 Dependence
- 291.8 -Induced Anxiety Disorder
- 291.8 -Induced Mood Disorder
- 291.1 -Induced Persisting Amnestic Disorder
- 291.2 -Induced Persisting Dementia
- 291.5 -Induced Psychotic Disorder, With Delusions
- 291.3 -Induced Psychotic Disorder, With Hallucinations
- 291.8 -Induced Sexual Dysfunction
- 291.8 -Induced Sleep Disorder
- 303.00 Intoxication
- 291.0 Intoxication Delirium
- 291.9 -Related Disorder NOS
- 291.8 Withdrawal
- 291.0 Withdrawal Delirium
## Amphetamine (Or Amphetamine-Like) Related Disorders
- Amphetamine (or Amphetamine-Like)
305.70 Abuse
304.40 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep disorder
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.70 Abuse
- 304.40 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep disorder
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
## Caffeine-Related Disorders
- Caffeine
292.89 -Induced Anxiety Disorder
292.89 -Induced Sleep Disorder
305.90 Intoxication
292.9 -Related Disorder NOS
- 292.89 -Induced Anxiety Disorder
- 292.89 -Induced Sleep Disorder
- 305.90 Intoxication
- 292.9 -Related Disorder NOS
## Cannabis-Related Disorders
- Cannabis
305.20 Abuse
304.30 Dependence
292.89 -Induced Anxiety Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
- 305.20 Abuse
- 304.30 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
## Cocaine-Related Disorders
- Cocaine
305.60 Abuse
304.20 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep Disorder
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.60 Abuse
- 304.20 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep Disorder
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
## Hallucinogen-Related Disorders
- Hallucinogen
305.30 Abuse
304.50 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 Intoxication
292.81 Intoxication Delirium
292.89 Persisting Perception Disorder
292.9 -Related Disorder NOS
- 305.30 Abuse
- 304.50 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.89 Persisting Perception Disorder
- 292.9 -Related Disorder NOS
## Inhalant-Related Disorders
- Inhalant
305.90 Abuse
304.60 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.82 -Induced Persisting Dementia
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
- 305.90 Abuse
- 304.60 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.82 -Induced Persisting Dementia
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
## Nicotine-Related Disorders
- Nicotine
305.10 Dependence
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.10 Dependence
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
## Opioid-Related Disorders
- Opioid
305.50 Abuse
304.00 Dependence
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep Disorder
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.50 Abuse
- 304.00 Dependence
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep Disorder
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
## Phencyclidine (Or Phencyclidine-Like)-Related Disorders
- Phencyclidine (or Phencyclidine-Like)
305.90 Abuse
304.90 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
- 305.90 Abuse
- 304.90 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
## Sedative-, Hypnotic-, or Anxiolytic-Related Disorders
- Sedative, Hypnotic, or Anxiolytic
305.40 Abuse
304.10 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.83 -Induced Persisting Amnestic Disorder
292.82 -Induced Persisting Dementia
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep Disorder
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
292.0 Withdrawal
292.81 Withdrawal Delirium
- 305.40 Abuse
- 304.10 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.83 -Induced Persisting Amnestic Disorder
- 292.82 -Induced Persisting Dementia
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep Disorder
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
- 292.81 Withdrawal Delirium
## Polysubstance-Related Disorder
- 304.80 Polysubstance Dependence
## Other (or Unknown) Substance-Related Disorder
- Other (or Unknown) Substance
305.90 Abuse
304.90 Dependence
292.89 -Induced Anxiety Disorder
292.81 -Induced Delirium
292.84 -Induced Mood Disorder
292.83 -Induced Persisting Amnestic Disorder
292.82 -Induced Persisting Dementia
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep Disorder
292.89 Intoxication
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.90 Abuse
- 304.90 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.81 -Induced Delirium
- 292.84 -Induced Mood Disorder
- 292.83 -Induced Persisting Amnestic Disorder
- 292.82 -Induced Persisting Dementia
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep Disorder
- 292.89 Intoxication
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
Top
# Schizophrenia and Other Psychotic Disorders
- Schizophrenia
295.2 Catatonic Type
295.1 Disorganized Type
295.3 Paranoid Type
295.6 Residual Type
295.9 Undifferentiated Type
- 295.2 Catatonic Type
- 295.1 Disorganized Type
- 295.3 Paranoid Type
- 295.6 Residual Type
- 295.9 Undifferentiated Type
- 295.4 Schizophreniform Disorder
- 295.7 Schizoaffective Disorder
- 297.1 Delusional Disorder
- 298.8 Brief Psychotic Disorder
- 297.3 Shared Psychotic Disorder
- Psychotic Disorder Due to...
293.81 With Delusions
293.82 With Hallucinations
- 293.81 With Delusions
- 293.82 With Hallucinations
- 298.9 Psychotic disorder NOS
Top
# Mood Disorders
## Depressive Disorders
- 300.4 Dysthymic Disorder
- Major Depressive Disorder
Major Depressive Disorder, Recurrent
296.36 In Full Remission
296.35 In Partial Remission
296.31 Mild
296.32 Moderate
296.33 Severe Without Psychotic Features
296.34 Severe With Psychotic Features
296.30 Unspecified
Major Depressive Disorder, Single Episode
296.26 In Full Remission
296.25 In Partial Remission
296 21 Mild
296.22 Moderate
296.23 Severe Without Psychotic Features
296.24 Severe With Psychotic Features
296.20 Unspecified
- Major Depressive Disorder, Recurrent
296.36 In Full Remission
296.35 In Partial Remission
296.31 Mild
296.32 Moderate
296.33 Severe Without Psychotic Features
296.34 Severe With Psychotic Features
296.30 Unspecified
- 296.36 In Full Remission
- 296.35 In Partial Remission
- 296.31 Mild
- 296.32 Moderate
- 296.33 Severe Without Psychotic Features
- 296.34 Severe With Psychotic Features
- 296.30 Unspecified
- Major Depressive Disorder, Single Episode
296.26 In Full Remission
296.25 In Partial Remission
296 21 Mild
296.22 Moderate
296.23 Severe Without Psychotic Features
296.24 Severe With Psychotic Features
296.20 Unspecified
- 296.26 In Full Remission
- 296.25 In Partial Remission
- 296 21 Mild
- 296.22 Moderate
- 296.23 Severe Without Psychotic Features
- 296.24 Severe With Psychotic Features
- 296.20 Unspecified
- 311 Depressive Disorder NOS
## Bipolar Disorders
- Bipolar Disorders
296.80 Bipolar Disorder NOS
Bipolar I Disorder, Most Recent Episode Depressed
296.56 In Full Remission
296.55 In Partial Remission
296.51 Mild
296.52 Moderate
296.53 Severe Without Psychotic Features
296.54 Severe With Psychotic Features
296.50 Unspecified
296.40 Bipolar Disorder I, Most Recent Episode Hypomanic
Bipolar Disorder I, Most Recent Episode Manic
296.46 In Full Remission
296.45 In Partial Remission
296.41 Mild
296.42 Moderate
296.43 Severe Without Psychotic Features
296.44 Severe With Psychotic Features
296.40 Unspecified
Bipolar Disorder I, Most Recent Episode Mixed
296.66 In Full Remission
296.65 In Partial Remission
296.61 Mild
296.62 Moderate
296.63 Severe Without Psychotic Features
296.64 Severe With Psychotic Features
296.60 Unspecified
296.7 Bipolar I Disorder, Most Recent Episode Unspecified
Bipolar I Disorder, Single Manic Episode
296.06 In Full Remission
296.05 In Partial Remission
296.01 Mild
296.02 Moderate
296.03 Severe Without Psychotic Features
296.04 Severe With Psychotic Features
296.00 Unspecified
296.89 Bipolar II Disorder
- 296.80 Bipolar Disorder NOS
- Bipolar I Disorder, Most Recent Episode Depressed
296.56 In Full Remission
296.55 In Partial Remission
296.51 Mild
296.52 Moderate
296.53 Severe Without Psychotic Features
296.54 Severe With Psychotic Features
296.50 Unspecified
- 296.56 In Full Remission
- 296.55 In Partial Remission
- 296.51 Mild
- 296.52 Moderate
- 296.53 Severe Without Psychotic Features
- 296.54 Severe With Psychotic Features
- 296.50 Unspecified
- 296.40 Bipolar Disorder I, Most Recent Episode Hypomanic
- Bipolar Disorder I, Most Recent Episode Manic
296.46 In Full Remission
296.45 In Partial Remission
296.41 Mild
296.42 Moderate
296.43 Severe Without Psychotic Features
296.44 Severe With Psychotic Features
296.40 Unspecified
- 296.46 In Full Remission
- 296.45 In Partial Remission
- 296.41 Mild
- 296.42 Moderate
- 296.43 Severe Without Psychotic Features
- 296.44 Severe With Psychotic Features
- 296.40 Unspecified
- Bipolar Disorder I, Most Recent Episode Mixed
296.66 In Full Remission
296.65 In Partial Remission
296.61 Mild
296.62 Moderate
296.63 Severe Without Psychotic Features
296.64 Severe With Psychotic Features
296.60 Unspecified
- 296.66 In Full Remission
- 296.65 In Partial Remission
- 296.61 Mild
- 296.62 Moderate
- 296.63 Severe Without Psychotic Features
- 296.64 Severe With Psychotic Features
- 296.60 Unspecified
- 296.7 Bipolar I Disorder, Most Recent Episode Unspecified
- Bipolar I Disorder, Single Manic Episode
296.06 In Full Remission
296.05 In Partial Remission
296.01 Mild
296.02 Moderate
296.03 Severe Without Psychotic Features
296.04 Severe With Psychotic Features
296.00 Unspecified
- 296.06 In Full Remission
- 296.05 In Partial Remission
- 296.01 Mild
- 296.02 Moderate
- 296.03 Severe Without Psychotic Features
- 296.04 Severe With Psychotic Features
- 296.00 Unspecified
- 296.89 Bipolar II Disorder
- 301.13 Cyclothymic Disorder
- Mood Disorder
293.83 Mood Disorder Due to...
296.90 Mood Disorder NOS
- 293.83 Mood Disorder Due to...
- 296.90 Mood Disorder NOS
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# Anxiety Disorders
- 300.02 Generalized Anxiety Disorder
- Panic Disorder
300.21 With Agoraphobia
300.01 Without Agoraphobia
- 300.21 With Agoraphobia
- 300.01 Without Agoraphobia
- 300.22 Agoraphobia Without History of Panic Disorder
- 300.29 Specific Phobia
- 300.23 Social Phobia
- 300.3 Obsessive-Compulsive Disorder
- 309.81 Posttraumatic Stress Disorder
- 308.3 Acute Stress Disorder
- Anxiety Disorder
293.89 Anxiety Disorder Due to...
300.00 Anxiety Disorder NOS
- 293.89 Anxiety Disorder Due to...
- 300.00 Anxiety Disorder NOS
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# Somatoform Disorders
- 300.81 Somatization Disorder
- 300.81 Undifferentiated Somatoform disorder
- 300.11 Conversion Disorder
- Pain Disorder
307.89 Associated With Both Psychological Factors and a General Medical Condition
307.80 Associated With Psychological Factors
- 307.89 Associated With Both Psychological Factors and a General Medical Condition
- 307.80 Associated With Psychological Factors
- 300.7 Hypochondriasis
- 300.7 Body Dysmorphic Disorder
- 300.81 Somatoform disorder NOS
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# Factitious Disorders
- Factitious Disorder
300.19 With Combined Psychological and Physical Signs and Symptoms
300.19 With Predominantly Physical Signs and Symptoms
300.16 With Predominantly Psychological Signs and Symptoms
300.19 Factitious Disorder NOS
- 300.19 With Combined Psychological and Physical Signs and Symptoms
- 300.19 With Predominantly Physical Signs and Symptoms
- 300.16 With Predominantly Psychological Signs and Symptoms
- 300.19 Factitious Disorder NOS
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# Dissociative Disorders
- 300.6 Depersonalization disorder
- 300.12 Dissociative Amnesia
- 300.13 Dissociative Fugue
- 300.14 Dissociative Identity Disorder
- 300.15 Dissociative Disorder NOS
Top
# Sexual and Gender Identity Disorder
## Sexual Dysfunctions
- 625.8 Female Hypoactive Sexual Desire Disorder Due to...
- 608.89 Male Hypoactive Sexual Desire Disorder Due to...
- 302.71 Hypoactive Sexual Desire Disorder
- 302.79 Sexual Aversion Disorder
- 302.72 Female Sexual Arousal Disorder
- 302.72 Male Erectile Disorder
- 607.84 Male Erectile Disorder Due to...
- 302.73 Female Orgasmic Disorder
- 302.74 Male Orgasmic Disorder
- 302.75 Premature Ejaculation
- 302.76 Dyspareunia (Not Due to a General Medical Condition)
- 625.0 Female Dyspareunia Due to...
- 608.89 Male Dyspareunia Due to...
- 306.51 Vaginismus (Not Due to a General Medical Condition)
- 625.8 Other Female Sexual Dysfunction Due to...
- 608.89 Other Male Sexual Dysfunction Due to...
- Sexual Abuse
V61.1 Sexual Abuse of Adult
995.81 Sexual Abuse of Adult (if focus of attention is on victim)
V61.21 Sexual Abuse of Child
995.5 Sexual Abuse of Child (if focus of attention is on victim)
- V61.1 Sexual Abuse of Adult
- 995.81 Sexual Abuse of Adult (if focus of attention is on victim)
- V61.21 Sexual Abuse of Child
- 995.5 Sexual Abuse of Child (if focus of attention is on victim)
- 302.9 Sexual Disorder NOS
- 302.70 Sexual Dysfunction NOS
## Paraphilias
- 302.4 Exhibitionism
- 302.81 Fetishism
- 302.89 Frotteurism
- 302.2 Pedophilia
- 302.83 Sexual Masochism
- 302.84 Sexual Sadism
- 302.3 Transvestic Fetishism
- 302.82 Voyeurism
- 302.9 Paraphilia NOS
## Gender Identity Disorders
- Gender Identity Disorder
302.85 in Adolescents or Adults
302.6 in Children
302.6 Gender Identity Disorder NOS
- 302.85 in Adolescents or Adults
- 302.6 in Children
- 302.6 Gender Identity Disorder NOS
# Eating Disorders
- 307.1 Anorexia Nervosa
- 307.51 Bulimia Nervosa
- 307.50 Eating disorder not otherwise specified (EDNOS)
Top
# Sleep Disorders
## Primary Sleep Disorders
- 307.44 Primary Hypersomnia
- 307.42 Primary Insomnia
- 347 Narcolepsy
- 780.59 Breathing-Related Sleep Disorder
- 307.45 Circadian Rhythm Sleep Disorder
- 307.47 Dyssomnia NOS
## Parasomnias
- 307.47 Nightmare Disorder
- 307.46 Sleep Terror Disorder
- 307.46 Sleepwalking Disorder
- 307.47 Parasomnia NOS
## Other Sleep Disorders
- Sleep Disorder
Sleep Disorder Due to...
780.54 Hypersomnia Type
780.52 Insomnia Type
780.59 Mixed Type
780.59 Parasomnia Type
- Sleep Disorder Due to...
- 780.54 Hypersomnia Type
- 780.52 Insomnia Type
- 780.59 Mixed Type
- 780.59 Parasomnia Type
- 307.42 Insomnia Related to...
- 307.44 Hypersomnia related to...
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# Impulse-Control Disorders Not Elsewhere Classified
- 312.34 Intermittent Explosive Disorder
- 312.32 Kleptomania
- 312.33 Pyromania
- 312.31 Pathological Gambling
- 312.39 Trichotillomania
- 312.30 Impulse-Control Disorder NOS
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# Adjustment Disorders
- Adjustment Disorders
309.9 Unspecified
309.24 With Anxiety
309.0 With Depressed Mood
309.3 With Disturbance of Conduct
309.28 With Mixed Anxiety and Depressed Mood
309.4 With Mixed Disturbance of Emotions and Conduct
- 309.9 Unspecified
- 309.24 With Anxiety
- 309.0 With Depressed Mood
- 309.3 With Disturbance of Conduct
- 309.28 With Mixed Anxiety and Depressed Mood
- 309.4 With Mixed Disturbance of Emotions and Conduct
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# Personality Disorders
- 301.0 Paranoid Personality Disorder
- 301.20 Schizoid Personality Disorder
- 301.22 Schizotypal Personality Disorder
- 301.7 Antisocial Personality Disorder
- 301.83 Borderline Personality Disorder
- 301.50 Histrionic Personality Disorder
- 301.81 Narcissistic Personality Disorder
- 301.82 Avoidant Personality Disorder
- 301.6 Dependent Personality Disorder
- 301.4 Obsessive-Compulsive Personality Disorder
- 301.9 Personality Disorder NOS
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# Additional codes
- V62.3 Academic Problem
- V62.4 Acculturation Problem
- 995.2 Adverse Effects of Medication NOS
- 780.9 Age-Related Cognitive Decline
- Antisocial Behavior
V71.01 Adult Antisocial Behavior
V71.02 Child or Adolescent Antisocial Behavior
- V71.01 Adult Antisocial Behavior
- V71.02 Child or Adolescent Antisocial Behavior
- V62.82 Bereavement
- V62.89 Borderline Intellectual Functioning
- 313.82 Identity Problem
- Medication-Induced
- Movement Disorder
333.90 Movement Disorder NOS
333.1 Postural Tremor
- 333.90 Movement Disorder NOS
- 333.1 Postural Tremor
- Neglect of Child
V61.21 Neglect of Child
995.5 Neglect of Child (if focus of attention is on victim)
- V61.21 Neglect of Child
- 995.5 Neglect of Child (if focus of attention is on victim)
- Neuroleptic-Induced
333.99 Acute Akathisia
333.7 Acute Dystonia
332.1 Parkinsonism
333.82 Tardive Dyskinesia
333.92 Neuroleptic Malignant Syndrome
- 333.99 Acute Akathisia
- 333.7 Acute Dystonia
- 332.1 Parkinsonism
- 333.82 Tardive Dyskinesia
- 333.92 Neuroleptic Malignant Syndrome
- V71.09 No Diagnosis on Axis II
- V71.09 No Diagnosis or Condition on Axis I
- V15.81 Noncompliance With Treatment
- V62.2 Occupational Problem
- V61.20 Parent-Child Relational Problem
- V61.1 Partner Relational Problem
- V62.89 Phase of Life Problem
- Physical Abuse
V61.1 Physical Abuse of Adult
995.81 Physical Abuse of Adult (if focus of attention is on victim)
V61.21 Physical Abuse of Child
995.5 Physical Abuse of Child (if focus of attention is on victim)
- V61.1 Physical Abuse of Adult
- 995.81 Physical Abuse of Adult (if focus of attention is on victim)
- V61.21 Physical Abuse of Child
- 995.5 Physical Abuse of Child (if focus of attention is on victim)
- 316 Psychological Factors Affecting Medical Condition
- Relational Problem
V62.81 Relational Problem NOS
V61.9 Relational Problem Related to a Mental Disorder or General Medical Condition
- V62.81 Relational Problem NOS
- V61.9 Relational Problem Related to a Mental Disorder or General Medical Condition
- V62.89 Religious or Spiritual Problem
- V61.8 Sibling Relational Problem
- 300.9 Unspecified Mental Disorder (nonpsychotic)
- 799.9 Diagnosis Deferred on Axis II
- 799.9 Diagnosis or Condition Deferred on Axis I
- V65.2 Malingering | DSM-IV Codes
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, also known as DSM-IV-TR, is a manual published by the American Psychiatric Association (APA) that includes all currently recognized mental health disorders. The coding system utilized by the DSM-IV is designed to correspond with codes from the International Classification of Diseases, commonly referred to as the ICD. Since early versions of the DSM did not correspond with ICD codes and updates of the publications for the ICD and the DSM are not simultaneous, some distinctions in the coding systems may still be present. For this reason, it is recommended that users of these manuals consult the appropriate reference when accessing diagnostic codes.
To see these codes listed alphabetically, rather than by category, click here.
- NOS = Not Otherwise Specified.
DSM cautionary statement
# Disorders usually first diagnosed in infancy, childhood, or adolescence
## Mental retardation
- 317 Mild Mental Retardation
- 318.0 Moderate Mental Retardation
- 318.1 Severe Mental Retardation
- 318.2 Profound Mental Retardation
- 319 Mental Retardation, Severity Unspecified
## Learning Disorders
- 315.00 Reading Disorder
- 315.1 Mathematics Disorder
- 315.2 Disorder of Written Expression
- 315.9 Learning Disorder NOS
## Motor Skills Disorders
- 315.4 Developmental Coordination Disorder
## Communication Disorders
- 315.31 Expressive Language Disorder
- 315.32 Mixed Receptive-Expressive Language Disorder
- 315.39 Phonological Disorder
- 307.0 Stuttering
- 307.9 Communication Disorder NOS
## Pervasive Developmental Disorders
- 299.00 Autistic Disorder
- 299.80 Rett's Disorder
- 299.10 Childhood Disintegrative Disorder
- 299.80 Asperger’s Disorder
- 299.80 Pervasive Developmental Disorder NOS
## Attention-Deficit and Disruptive Behavior Disorders
- Attention-Deficit Hyperactivity Disorder
314.01 Combined Subtype
314.01 Predominantly Hyperactive-Impulsive Subtype
314.00 Predominantly Inattentive Subtype
314.9 Attention-Deficit Hyperactivity Disorder NOS
- 314.01 Combined Subtype
- 314.01 Predominantly Hyperactive-Impulsive Subtype
- 314.00 Predominantly Inattentive Subtype
- 314.9 Attention-Deficit Hyperactivity Disorder NOS
- Conduct Disorder
312.81 Childhood Onset
312.82 Adolescent Onset
312.89 Unspecified Onset
- 312.81 Childhood Onset
- 312.82 Adolescent Onset
- 312.89 Unspecified Onset
- 313.81 Oppositional Defiant Disorder
- 312.9 Disruptive Behavior Disorder NOS
## Feeding and Eating Disorders of Infancy or Early Childhood
- 307.52 Pica
- 307.53 Rumination Disorder
- 307.59 Feeding Disorder of Infancy or Early Childhood
## Tic Disorders
- 307.23 Tourette’s Disorder
- 307.22 Chronic Motor or Vocal Tic Disorder
- 307.21 Transient Tic Disorder
- 307.20 Tic Disorder NOS
## Elimination Disorders
- Encopresis
787.6 Encopresis, With Constipation and Overflow Incontinence
307.7 Encopresis, Without Constipation and Overflow Incontinence
- 787.6 Encopresis, With Constipation and Overflow Incontinence
- 307.7 Encopresis, Without Constipation and Overflow Incontinence
- 307.6 Enuresis (Not Due to a General Medical Condition)
## Other Disorders of Infancy, Childhood, or Adolescenece
- 309.21 Separation Anxiety Disorder
- 313.23 Selective Mutism
- 313.89 Reactive Attachment Disorder of Infancy or Early Childhood
- 307.3 Stereotypic Movement Disorder
- 313.9 Disorder of Infancy, Childhood, or Adolescence NOS
Top
# Delirium, Dementia, and Amnestic and Other Cognitive Disorders
## Delirium
- 293.0 Delirium Due to...[Indicate the General Medical Condition]
- 780.09 Delirium NOS
## Dementia
- 290.10 Dementia Due to Creutzfeldt-Jakob Disease
- 294.1 Dementia Due to Head Trauma
- 294.9 Dementia Due to HIV Disease
- 294.1 Dementia Due to Huntington's disease
- 294.1 Dementia Due to Parkinson's disease
- 290.10 Dementia Due to Pick’s disease
- 294.1 Dementia Due to...[Indicate Other General Medical Condition]
- 294.8 Dementia NOS
- Dementia of the Alzheimer’s Type, With Early Onset
290.10 Uncomplicated
290.11 With Delirium
290.12 With Delusions
290.13 With Depressed Mood
- 290.10 Uncomplicated
- 290.11 With Delirium
- 290.12 With Delusions
- 290.13 With Depressed Mood
- Dementia of the Alzheimer’s Type, With Late Onset
290.0 Uncomplicated
290.3 With Delirium
290.20 With Delusions
290.21 With Depressed Mood
- 290.0 Uncomplicated
- 290.3 With Delirium
- 290.20 With Delusions
- 290.21 With Depressed Mood
- Vascular Dementia
290.41 With Delirium
290.42 With Delusions
290.43 With Depressed Mood
- 290.41 With Delirium
- 290.42 With Delusions
- 290.43 With Depressed Mood
## Amnestic Disorders
- 294.0 Amnestic Disorder Due to...[Indicate the General Medical Condition]
- 294.8 Amnestic Disorder NOS
## Other Cognitive Disorders
- 294.9 Cognitive Disorder NOS
Top
# Mental Disorders Due to a General Medical Condition Not Elsewhere Classified
- 293.89 Catatonic Disorder Due to...[Indicate the General Medical Condition]
- 310.1 Personality Change Due to...[Indicate the General Medical Condition]
- 293.9 Mental Disorder NOS Due to...[Indicate the General Medical Condition]
Top
# Substance-Related Disorders
## Alcohol-Related Disorders
- Alcohol
305.00 Abuse
303.90 Dependence
291.8 -Induced Anxiety Disorder
291.8 -Induced Mood Disorder
291.1 -Induced Persisting Amnestic Disorder
291.2 -Induced Persisting Dementia
291.5 -Induced Psychotic Disorder, With Delusions
291.3 -Induced Psychotic Disorder, With Hallucinations
291.8 -Induced Sexual Dysfunction
291.8 -Induced Sleep Disorder
303.00 Intoxication
291.0 Intoxication Delirium
291.9 -Related Disorder NOS
291.8 Withdrawal
291.0 Withdrawal Delirium
- 305.00 Abuse
- 303.90 Dependence
- 291.8 -Induced Anxiety Disorder
- 291.8 -Induced Mood Disorder
- 291.1 -Induced Persisting Amnestic Disorder
- 291.2 -Induced Persisting Dementia
- 291.5 -Induced Psychotic Disorder, With Delusions
- 291.3 -Induced Psychotic Disorder, With Hallucinations
- 291.8 -Induced Sexual Dysfunction
- 291.8 -Induced Sleep Disorder
- 303.00 Intoxication
- 291.0 Intoxication Delirium
- 291.9 -Related Disorder NOS
- 291.8 Withdrawal
- 291.0 Withdrawal Delirium
## Amphetamine (Or Amphetamine-Like) Related Disorders
- Amphetamine (or Amphetamine-Like)
305.70 Abuse
304.40 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep disorder
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.70 Abuse
- 304.40 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep disorder
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
## Caffeine-Related Disorders
- Caffeine
292.89 -Induced Anxiety Disorder
292.89 -Induced Sleep Disorder
305.90 Intoxication
292.9 -Related Disorder NOS
- 292.89 -Induced Anxiety Disorder
- 292.89 -Induced Sleep Disorder
- 305.90 Intoxication
- 292.9 -Related Disorder NOS
## Cannabis-Related Disorders
- Cannabis
305.20 Abuse
304.30 Dependence
292.89 -Induced Anxiety Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
- 305.20 Abuse
- 304.30 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
## Cocaine-Related Disorders
- Cocaine
305.60 Abuse
304.20 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep Disorder
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.60 Abuse
- 304.20 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep Disorder
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
## Hallucinogen-Related Disorders
- Hallucinogen
305.30 Abuse
304.50 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 Intoxication
292.81 Intoxication Delirium
292.89 Persisting Perception Disorder
292.9 -Related Disorder NOS
- 305.30 Abuse
- 304.50 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.89 Persisting Perception Disorder
- 292.9 -Related Disorder NOS
## Inhalant-Related Disorders
- Inhalant
305.90 Abuse
304.60 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.82 -Induced Persisting Dementia
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
- 305.90 Abuse
- 304.60 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.82 -Induced Persisting Dementia
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
## Nicotine-Related Disorders
- Nicotine
305.10 Dependence
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.10 Dependence
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
## Opioid-Related Disorders
- Opioid
305.50 Abuse
304.00 Dependence
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep Disorder
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.50 Abuse
- 304.00 Dependence
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep Disorder
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
## Phencyclidine (Or Phencyclidine-Like)-Related Disorders
- Phencyclidine (or Phencyclidine-Like)
305.90 Abuse
304.90 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
- 305.90 Abuse
- 304.90 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
## Sedative-, Hypnotic-, or Anxiolytic-Related Disorders
- Sedative, Hypnotic, or Anxiolytic
305.40 Abuse
304.10 Dependence
292.89 -Induced Anxiety Disorder
292.84 -Induced Mood Disorder
292.83 -Induced Persisting Amnestic Disorder
292.82 -Induced Persisting Dementia
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep Disorder
292.89 Intoxication
292.81 Intoxication Delirium
292.9 -Related Disorder NOS
292.0 Withdrawal
292.81 Withdrawal Delirium
- 305.40 Abuse
- 304.10 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.84 -Induced Mood Disorder
- 292.83 -Induced Persisting Amnestic Disorder
- 292.82 -Induced Persisting Dementia
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep Disorder
- 292.89 Intoxication
- 292.81 Intoxication Delirium
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
- 292.81 Withdrawal Delirium
## Polysubstance-Related Disorder
- 304.80 Polysubstance Dependence
## Other (or Unknown) Substance-Related Disorder
- Other (or Unknown) Substance
305.90 Abuse
304.90 Dependence
292.89 -Induced Anxiety Disorder
292.81 -Induced Delirium
292.84 -Induced Mood Disorder
292.83 -Induced Persisting Amnestic Disorder
292.82 -Induced Persisting Dementia
292.11 -Induced Psychotic Disorder, With Delusions
292.12 -Induced Psychotic Disorder, With Hallucinations
292.89 -Induced Sexual Dysfunction
292.89 -Induced Sleep Disorder
292.89 Intoxication
292.9 -Related Disorder NOS
292.0 Withdrawal
- 305.90 Abuse
- 304.90 Dependence
- 292.89 -Induced Anxiety Disorder
- 292.81 -Induced Delirium
- 292.84 -Induced Mood Disorder
- 292.83 -Induced Persisting Amnestic Disorder
- 292.82 -Induced Persisting Dementia
- 292.11 -Induced Psychotic Disorder, With Delusions
- 292.12 -Induced Psychotic Disorder, With Hallucinations
- 292.89 -Induced Sexual Dysfunction
- 292.89 -Induced Sleep Disorder
- 292.89 Intoxication
- 292.9 -Related Disorder NOS
- 292.0 Withdrawal
Top
# Schizophrenia and Other Psychotic Disorders
- Schizophrenia
295.2 Catatonic Type
295.1 Disorganized Type
295.3 Paranoid Type
295.6 Residual Type
295.9 Undifferentiated Type
- 295.2 Catatonic Type
- 295.1 Disorganized Type
- 295.3 Paranoid Type
- 295.6 Residual Type
- 295.9 Undifferentiated Type
- 295.4 Schizophreniform Disorder
- 295.7 Schizoaffective Disorder
- 297.1 Delusional Disorder
- 298.8 Brief Psychotic Disorder
- 297.3 Shared Psychotic Disorder
- Psychotic Disorder Due to...[Indicate the General Medical Condition]
293.81 With Delusions
293.82 With Hallucinations
- 293.81 With Delusions
- 293.82 With Hallucinations
- 298.9 Psychotic disorder NOS
Top
# Mood Disorders
## Depressive Disorders
- 300.4 Dysthymic Disorder
- Major Depressive Disorder
Major Depressive Disorder, Recurrent
296.36 In Full Remission
296.35 In Partial Remission
296.31 Mild
296.32 Moderate
296.33 Severe Without Psychotic Features
296.34 Severe With Psychotic Features
296.30 Unspecified
Major Depressive Disorder, Single Episode
296.26 In Full Remission
296.25 In Partial Remission
296 21 Mild
296.22 Moderate
296.23 Severe Without Psychotic Features
296.24 Severe With Psychotic Features
296.20 Unspecified
- Major Depressive Disorder, Recurrent
296.36 In Full Remission
296.35 In Partial Remission
296.31 Mild
296.32 Moderate
296.33 Severe Without Psychotic Features
296.34 Severe With Psychotic Features
296.30 Unspecified
- 296.36 In Full Remission
- 296.35 In Partial Remission
- 296.31 Mild
- 296.32 Moderate
- 296.33 Severe Without Psychotic Features
- 296.34 Severe With Psychotic Features
- 296.30 Unspecified
- Major Depressive Disorder, Single Episode
296.26 In Full Remission
296.25 In Partial Remission
296 21 Mild
296.22 Moderate
296.23 Severe Without Psychotic Features
296.24 Severe With Psychotic Features
296.20 Unspecified
- 296.26 In Full Remission
- 296.25 In Partial Remission
- 296 21 Mild
- 296.22 Moderate
- 296.23 Severe Without Psychotic Features
- 296.24 Severe With Psychotic Features
- 296.20 Unspecified
- 311 Depressive Disorder NOS
## Bipolar Disorders
- Bipolar Disorders
296.80 Bipolar Disorder NOS
Bipolar I Disorder, Most Recent Episode Depressed
296.56 In Full Remission
296.55 In Partial Remission
296.51 Mild
296.52 Moderate
296.53 Severe Without Psychotic Features
296.54 Severe With Psychotic Features
296.50 Unspecified
296.40 Bipolar Disorder I, Most Recent Episode Hypomanic
Bipolar Disorder I, Most Recent Episode Manic
296.46 In Full Remission
296.45 In Partial Remission
296.41 Mild
296.42 Moderate
296.43 Severe Without Psychotic Features
296.44 Severe With Psychotic Features
296.40 Unspecified
Bipolar Disorder I, Most Recent Episode Mixed
296.66 In Full Remission
296.65 In Partial Remission
296.61 Mild
296.62 Moderate
296.63 Severe Without Psychotic Features
296.64 Severe With Psychotic Features
296.60 Unspecified
296.7 Bipolar I Disorder, Most Recent Episode Unspecified
Bipolar I Disorder, Single Manic Episode
296.06 In Full Remission
296.05 In Partial Remission
296.01 Mild
296.02 Moderate
296.03 Severe Without Psychotic Features
296.04 Severe With Psychotic Features
296.00 Unspecified
296.89 Bipolar II Disorder
- 296.80 Bipolar Disorder NOS
- Bipolar I Disorder, Most Recent Episode Depressed
296.56 In Full Remission
296.55 In Partial Remission
296.51 Mild
296.52 Moderate
296.53 Severe Without Psychotic Features
296.54 Severe With Psychotic Features
296.50 Unspecified
- 296.56 In Full Remission
- 296.55 In Partial Remission
- 296.51 Mild
- 296.52 Moderate
- 296.53 Severe Without Psychotic Features
- 296.54 Severe With Psychotic Features
- 296.50 Unspecified
- 296.40 Bipolar Disorder I, Most Recent Episode Hypomanic
- Bipolar Disorder I, Most Recent Episode Manic
296.46 In Full Remission
296.45 In Partial Remission
296.41 Mild
296.42 Moderate
296.43 Severe Without Psychotic Features
296.44 Severe With Psychotic Features
296.40 Unspecified
- 296.46 In Full Remission
- 296.45 In Partial Remission
- 296.41 Mild
- 296.42 Moderate
- 296.43 Severe Without Psychotic Features
- 296.44 Severe With Psychotic Features
- 296.40 Unspecified
- Bipolar Disorder I, Most Recent Episode Mixed
296.66 In Full Remission
296.65 In Partial Remission
296.61 Mild
296.62 Moderate
296.63 Severe Without Psychotic Features
296.64 Severe With Psychotic Features
296.60 Unspecified
- 296.66 In Full Remission
- 296.65 In Partial Remission
- 296.61 Mild
- 296.62 Moderate
- 296.63 Severe Without Psychotic Features
- 296.64 Severe With Psychotic Features
- 296.60 Unspecified
- 296.7 Bipolar I Disorder, Most Recent Episode Unspecified
- Bipolar I Disorder, Single Manic Episode
296.06 In Full Remission
296.05 In Partial Remission
296.01 Mild
296.02 Moderate
296.03 Severe Without Psychotic Features
296.04 Severe With Psychotic Features
296.00 Unspecified
- 296.06 In Full Remission
- 296.05 In Partial Remission
- 296.01 Mild
- 296.02 Moderate
- 296.03 Severe Without Psychotic Features
- 296.04 Severe With Psychotic Features
- 296.00 Unspecified
- 296.89 Bipolar II Disorder
- 301.13 Cyclothymic Disorder
- Mood Disorder
293.83 Mood Disorder Due to...[Indicate the General Medical Condition]
296.90 Mood Disorder NOS
- 293.83 Mood Disorder Due to...[Indicate the General Medical Condition]
- 296.90 Mood Disorder NOS
Top
# Anxiety Disorders
- 300.02 Generalized Anxiety Disorder
- Panic Disorder
300.21 With Agoraphobia
300.01 Without Agoraphobia
- 300.21 With Agoraphobia
- 300.01 Without Agoraphobia
- 300.22 Agoraphobia Without History of Panic Disorder
- 300.29 Specific Phobia
- 300.23 Social Phobia
- 300.3 Obsessive-Compulsive Disorder
- 309.81 Posttraumatic Stress Disorder
- 308.3 Acute Stress Disorder
- Anxiety Disorder
293.89 Anxiety Disorder Due to...[Indicate the General Medical Condition]
300.00 Anxiety Disorder NOS
- 293.89 Anxiety Disorder Due to...[Indicate the General Medical Condition]
- 300.00 Anxiety Disorder NOS
Top
# Somatoform Disorders
- 300.81 Somatization Disorder
- 300.81 Undifferentiated Somatoform disorder
- 300.11 Conversion Disorder
- Pain Disorder
307.89 Associated With Both Psychological Factors and a General Medical Condition
307.80 Associated With Psychological Factors
- 307.89 Associated With Both Psychological Factors and a General Medical Condition
- 307.80 Associated With Psychological Factors
- 300.7 Hypochondriasis
- 300.7 Body Dysmorphic Disorder
- 300.81 Somatoform disorder NOS
Top
# Factitious Disorders
- Factitious Disorder
300.19 With Combined Psychological and Physical Signs and Symptoms
300.19 With Predominantly Physical Signs and Symptoms
300.16 With Predominantly Psychological Signs and Symptoms
300.19 Factitious Disorder NOS
- 300.19 With Combined Psychological and Physical Signs and Symptoms
- 300.19 With Predominantly Physical Signs and Symptoms
- 300.16 With Predominantly Psychological Signs and Symptoms
- 300.19 Factitious Disorder NOS
Top
# Dissociative Disorders
- 300.6 Depersonalization disorder
- 300.12 Dissociative Amnesia
- 300.13 Dissociative Fugue
- 300.14 Dissociative Identity Disorder
- 300.15 Dissociative Disorder NOS
Top
# Sexual and Gender Identity Disorder
## Sexual Dysfunctions
- 625.8 Female Hypoactive Sexual Desire Disorder Due to...[Indicate the General Medical Condition]
- 608.89 Male Hypoactive Sexual Desire Disorder Due to...[Indicate the General Medical Condition]
- 302.71 Hypoactive Sexual Desire Disorder
- 302.79 Sexual Aversion Disorder
- 302.72 Female Sexual Arousal Disorder
- 302.72 Male Erectile Disorder
- 607.84 Male Erectile Disorder Due to...[Indicate the General Medical Condition]
- 302.73 Female Orgasmic Disorder
- 302.74 Male Orgasmic Disorder
- 302.75 Premature Ejaculation
- 302.76 Dyspareunia (Not Due to a General Medical Condition)
- 625.0 Female Dyspareunia Due to...[Indicate the General Medical Condition]
- 608.89 Male Dyspareunia Due to...[Indicate the General Medical Condition]
- 306.51 Vaginismus (Not Due to a General Medical Condition)
- 625.8 Other Female Sexual Dysfunction Due to...[Indicate the General Medical Condition]
- 608.89 Other Male Sexual Dysfunction Due to...[Indicate the General Medical Condition]
- Sexual Abuse
V61.1 Sexual Abuse of Adult
995.81 Sexual Abuse of Adult (if focus of attention is on victim)
V61.21 Sexual Abuse of Child
995.5 Sexual Abuse of Child (if focus of attention is on victim)
- V61.1 Sexual Abuse of Adult
- 995.81 Sexual Abuse of Adult (if focus of attention is on victim)
- V61.21 Sexual Abuse of Child
- 995.5 Sexual Abuse of Child (if focus of attention is on victim)
- 302.9 Sexual Disorder NOS
- 302.70 Sexual Dysfunction NOS
## Paraphilias
- 302.4 Exhibitionism
- 302.81 Fetishism
- 302.89 Frotteurism
- 302.2 Pedophilia
- 302.83 Sexual Masochism
- 302.84 Sexual Sadism
- 302.3 Transvestic Fetishism
- 302.82 Voyeurism
- 302.9 Paraphilia NOS
## Gender Identity Disorders
- Gender Identity Disorder
302.85 in Adolescents or Adults
302.6 in Children
302.6 Gender Identity Disorder NOS
- 302.85 in Adolescents or Adults
- 302.6 in Children
- 302.6 Gender Identity Disorder NOS
# Eating Disorders
- 307.1 Anorexia Nervosa
- 307.51 Bulimia Nervosa
- 307.50 Eating disorder not otherwise specified (EDNOS)
Top
# Sleep Disorders
## Primary Sleep Disorders
- 307.44 Primary Hypersomnia
- 307.42 Primary Insomnia
- 347 Narcolepsy
- 780.59 Breathing-Related Sleep Disorder
- 307.45 Circadian Rhythm Sleep Disorder
- 307.47 Dyssomnia NOS
## Parasomnias
- 307.47 Nightmare Disorder
- 307.46 Sleep Terror Disorder
- 307.46 Sleepwalking Disorder
- 307.47 Parasomnia NOS
## Other Sleep Disorders
- Sleep Disorder
Sleep Disorder Due to...[Indicate the General Medical Condition]
780.54 Hypersomnia Type
780.52 Insomnia Type
780.59 Mixed Type
780.59 Parasomnia Type
- Sleep Disorder Due to...[Indicate the General Medical Condition]
- 780.54 Hypersomnia Type
- 780.52 Insomnia Type
- 780.59 Mixed Type
- 780.59 Parasomnia Type
- 307.42 Insomnia Related to...[Indicate the Axis I or Axis II Disorder]
- 307.44 Hypersomnia related to...[Indicate the Axis I or Axis II Disorder]
Top
# Impulse-Control Disorders Not Elsewhere Classified
- 312.34 Intermittent Explosive Disorder
- 312.32 Kleptomania
- 312.33 Pyromania
- 312.31 Pathological Gambling
- 312.39 Trichotillomania
- 312.30 Impulse-Control Disorder NOS
Top
# Adjustment Disorders
- Adjustment Disorders
309.9 Unspecified
309.24 With Anxiety
309.0 With Depressed Mood
309.3 With Disturbance of Conduct
309.28 With Mixed Anxiety and Depressed Mood
309.4 With Mixed Disturbance of Emotions and Conduct
- 309.9 Unspecified
- 309.24 With Anxiety
- 309.0 With Depressed Mood
- 309.3 With Disturbance of Conduct
- 309.28 With Mixed Anxiety and Depressed Mood
- 309.4 With Mixed Disturbance of Emotions and Conduct
Top
# Personality Disorders
- 301.0 Paranoid Personality Disorder
- 301.20 Schizoid Personality Disorder
- 301.22 Schizotypal Personality Disorder
- 301.7 Antisocial Personality Disorder
- 301.83 Borderline Personality Disorder
- 301.50 Histrionic Personality Disorder
- 301.81 Narcissistic Personality Disorder
- 301.82 Avoidant Personality Disorder
- 301.6 Dependent Personality Disorder
- 301.4 Obsessive-Compulsive Personality Disorder
- 301.9 Personality Disorder NOS
Top
# Additional codes
- V62.3 Academic Problem
- V62.4 Acculturation Problem
- 995.2 Adverse Effects of Medication NOS
- 780.9 Age-Related Cognitive Decline
- Antisocial Behavior
V71.01 Adult Antisocial Behavior
V71.02 Child or Adolescent Antisocial Behavior
- V71.01 Adult Antisocial Behavior
- V71.02 Child or Adolescent Antisocial Behavior
- V62.82 Bereavement
- V62.89 Borderline Intellectual Functioning
- 313.82 Identity Problem
- Medication-Induced
- Movement Disorder
333.90 Movement Disorder NOS
333.1 Postural Tremor
- 333.90 Movement Disorder NOS
- 333.1 Postural Tremor
- Neglect of Child
V61.21 Neglect of Child
995.5 Neglect of Child (if focus of attention is on victim)
- V61.21 Neglect of Child
- 995.5 Neglect of Child (if focus of attention is on victim)
- Neuroleptic-Induced
333.99 Acute Akathisia
333.7 Acute Dystonia
332.1 Parkinsonism
333.82 Tardive Dyskinesia
333.92 Neuroleptic Malignant Syndrome
- 333.99 Acute Akathisia
- 333.7 Acute Dystonia
- 332.1 Parkinsonism
- 333.82 Tardive Dyskinesia
- 333.92 Neuroleptic Malignant Syndrome
- V71.09 No Diagnosis on Axis II
- V71.09 No Diagnosis or Condition on Axis I
- V15.81 Noncompliance With Treatment
- V62.2 Occupational Problem
- V61.20 Parent-Child Relational Problem
- V61.1 Partner Relational Problem
- V62.89 Phase of Life Problem
- Physical Abuse
V61.1 Physical Abuse of Adult
995.81 Physical Abuse of Adult (if focus of attention is on victim)
V61.21 Physical Abuse of Child
995.5 Physical Abuse of Child (if focus of attention is on victim)
- V61.1 Physical Abuse of Adult
- 995.81 Physical Abuse of Adult (if focus of attention is on victim)
- V61.21 Physical Abuse of Child
- 995.5 Physical Abuse of Child (if focus of attention is on victim)
- 316 Psychological Factors Affecting Medical Condition
- Relational Problem
V62.81 Relational Problem NOS
V61.9 Relational Problem Related to a Mental Disorder or General Medical Condition
- V62.81 Relational Problem NOS
- V61.9 Relational Problem Related to a Mental Disorder or General Medical Condition
- V62.89 Religious or Spiritual Problem
- V61.8 Sibling Relational Problem
- 300.9 Unspecified Mental Disorder (nonpsychotic)
- 799.9 Diagnosis Deferred on Axis II
- 799.9 Diagnosis or Condition Deferred on Axis I
- V65.2 Malingering | https://www.wikidoc.org/index.php/DSM-IV_Codes | |
c06a7f9a2ede7a1bacc57f2be3c47bc224d15933 | wikidoc | Dactinomycin | Dactinomycin
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# Black Box Warning
# Overview
Dactinomycin is a Antibiotic and a antineoplastic Agent that is FDA approved for the treatment of Wilm's tumor, childhood rhabdomyosarcoma, Ewing’s sarcoma and metastatic, nonseminomatous testicular cancer, gestational trophoblastic neoplasia, and adjunctive treatment of locally recurrent or locoregional solid malignancies.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Diarrhea, Nausea and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- COSMEGEN, as part of a combination chemotherapy and/or multi-modality treatment regimen, is indicated for the treatment of Wilms’ tumor, childhood rhabdomyosarcoma, Ewing’s sarcoma and metastatic, nonseminomatous testicular cancer.
- COSMEGEN is indicated as a single agent, or as part of a combination chemotherapy regimen, for the treatment of gestational trophoblastic neoplasia.
- COSMEGEN, as a component of regional perfusion, is indicated for the palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies.
### Dosage
- Not for oral administration: Toxic reactions due to COSMEGEN are frequent and may be severe, thus limiting in many instances the amount that may be administered. However, the severity of toxicity varies markedly and is only partly dependent on the dose employed.
- Careful calculation of the dosage should be performed prior to administration of each dose.
- The dosage of COSMEGEN varies depending on the tolerance of the patient, the size and location of the neoplasm, and the use of other forms of therapy. It may be necessary to decrease the usual dosages suggested below when additional chemotherapy or radiation therapy is used concomitantly or has been used previously.
- The dosage for COSMEGEN is calculated in micrograms (mcg). The dose intensity per 2-week cycle for adults or children should not exceed 15 mcg/kg/day or 400-600 mcg/m2/day intravenously for five days. Calculation of the dosage for obese or edematous patients should be performed on the basis of surface area in an effort to more closely relate dosage to lean body mass.
- A wide variety of single agent and combination chemotherapy regimens with COSMEGEN may be employed. Because chemotherapeutic regimens are constantly changing, dosing and administration should be performed under the direct supervision of physicians familiar with current oncologic practices and new advances in therapy. The following suggested regimens are based upon a review of current literature concerning therapy with COSMEGEN and are on a per cycle basis.
- Regimens of 15 mcg/kg intravenously daily for five days administered in various combinations and schedules with other chemotherapeutic agents have been utilized in the treatment of Wilms’ tumor, rhabdomyosarcoma and Ewing’s sarcoma.
- 1000 mcg/m2 intravenously on Day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin.
- 12 mcg/kg intravenously daily for five days as a single agent.
- 500 mcg intravenously on Days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin.
- The dosage schedules and the technique itself vary from one investigator to another; the published literature, therefore, should be consulted for details. - In general, the following doses are suggested:
- 50 mcg (0.05 mg) per kilogram of body weight for lower extremity or pelvis.
- 35 mcg (0.035 mg) per kilogram of body weight for upper extremity.
- It may be advisable to use lower doses in obese patients, or when previous chemotherapy or radiation therapy has been employed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dactinomycin in adult patients.
### Non–Guideline-Supported Use
- Kaposi's sarcoma
- Sarcoma
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The greater frequency of toxic effects of COSMEGEN in infants suggest that this drug should be administered to infants only over the age of 6 to 12 months.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dactinomycin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dactinomycin in pediatric patients.
# Contraindications
- Hypersensitivity to any component of this product.
- COSMEGEN should not be given at or about the time of infection with chickenpox or herpes zoster because of the risk of severe generalized disease which may result in death.
# Warnings
- Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as COSMEGEN. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.
### Precautions
- This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Since COSMEGEN is extremely corrosive to soft tissues, it is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling COSMEGEN. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse .
- As with all antineoplastic agents, COSMEGEN is a toxic drug and very careful and frequent observation of the patient for adverse reactions is necessary. These reactions may involve any tissue of the body, most commonly the hematopoietic system resulting in myelosuppression. As such, live virus vaccines should not be administered during therapy with COSMEGEN. The possibility of an anaphylactoid reaction should be borne in mind.
- It is extremely important to observe the patient daily for toxic side effects when combination chemotherapy is employed, since a full course of therapy occasionally is not tolerated. If stomatitis, diarrhea, or severe hematopoietic depression appear during therapy, these drugs should be discontinued until the patient has recovered.
- Veno-occlusive disease (primarily hepatic) may result in fatality, particularly in children younger than 48 months.
- An increased incidence of gastrointestinal toxicity and marrow suppression has been reported with combined therapy incorporating COSMEGEN and radiation. Moreover, the normal skin, as well as the buccal and pharyngeal mucosa, may show early erythema. A smaller than usual radiation dose administered in combination with COSMEGEN causes erythema and vesiculation, which progress more rapidly through the stages of tanning and desquamation. Healing may occur in four to six weeks rather than two to three months. Erythema from previous radiation therapy may be reactivated by COSMEGEN alone, even when radiotherapy was administered many months earlier, and especially when the interval between the two forms of therapy is brief. This potentiation of radiation effect represents a special problem when the radiotherapy involves the mucous membrane. When irradiation is directed toward the nasopharynx, the combination may produce severe oropharyngeal mucositis. Severe reactions may ensue if high doses of both COSMEGEN and radiation therapy are used or if the patient is particularly sensitive to such combined therapy.
- Particular caution is necessary when administering COSMEGEN within two months of irradiation for the treatment of right-sided Wilms’ tumor, since hepatomegaly and elevated AST levels have been noted. In general, COSMEGEN should not be concomitantly administered with radiotherapy in the treatment of Wilms’ tumor unless the benefit outweighs the risk.
- Complications of the perfusion technique are related mainly to the amount of drug that escapes into the systemic circulation and may consist of hematopoietic depression, absorption of toxic products from massive destruction of neoplastic tissue, increased susceptibility to infection, impaired wound healing, and superficial ulceration of the gastric mucosa. Other side effects may include edema of the extremity involved, damage to soft tissues of the perfused area, and (potentially) venous thrombosis.
- Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic diseases receiving COSMEGEN. Renal, hepatic, and bone marrow functions should be assessed frequently.
# Adverse Reactions
## Clinical Trials Experience
- Toxic effects (excepting nausea and vomiting) usually do not become apparent until two to four days after a course of therapy is stopped, and may not peak until one to two weeks have elapsed. Deaths have been reported. However, adverse reactions are usually reversible on discontinuance of therapy. They include the following:
- Sepsis (including neutropenic sepsis) with fatal outcome, infection, malaise, fatigue, lethargy, fever, myalgia, proctitis, hypocalcemia and growth retardation.
- cheilitis, dysphagia, esophagitis, ulcerative stomatitis, pharyngitis.
- pneumonitis.
- anorexia, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal ulceration. Nausea and vomiting, which occur early during the first few hours after administration, may be alleviated by the administration of anti-emetics.
- liver toxicity including liver function test abnormalities, ascites, hepatomegaly, hepatitis, hepatic failure with reports of death, hepatic veno-occlusive disease which may be associated with intravascular clotting disorder and multi-organ failure .
- anemia, even to the point of aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia. Platelet and white cell counts should be performed frequently to detect severe hematopoietic depression. If either count markedly decreases, the drug should be withheld to allow marrow recovery. This often takes up to three weeks.
- alopecia, skin eruptions, acne, erythema multiforme, flare-up of erythema or increased pigmentation of previously irradiated skin. Toxic Epidermal Necrolysis (TEN) and Stevens Johnson Syndrome (SJS) have been observed from postmarketing experience.
- Dactinomycin is extremely corrosive. If extravasation occurs during intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms. Epidermolysis, erythema, and edema, at times severe, have been reported with regional limb perfusion.
- Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic diseases receiving COSMEGEN. Renal, hepatic, and bone marrow functions should be assessed frequently.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Dactinomycin in the drug label.
# Drug Interactions
- Dactinomycin may interfere with bioassay procedures for the determination of antibacterial drug levels.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- COSMEGEN may cause fetal harm when administered to a pregnant woman. COSMEGEN has been shown to cause malformations and embryotoxicity in rat, rabbit, and hamster when given in doses of 50-100 mcg/kg (approximately 0.5-2 times the maximum recommended daily human dose on a body surface area basis). If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential must be warned to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dactinomycin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dactinomycin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COSMEGEN, a decision should be made as to discontinuation of nursing and/or drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The greater frequency of toxic effects of COSMEGEN in infants suggest that this drug should be administered to infants only over the age of 6 to 12 months.
### Geriatic Use
- Clinical studies of COSMEGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, a published meta-analysis of all studies performed by the Eastern Cooperative Oncology Group (ECOG) over a 13-year period suggests that administration of COSMEGEN to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Dactinomycin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dactinomycin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dactinomycin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dactinomycin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dactinomycin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dactinomycin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see BOXED WARNING and HOW SUPPLIED, SPECIAL HANDLING). Since COSMEGEN is extremely corrosive to soft tissues, it is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling COSMEGEN. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse. (See HOW SUPPLIED, SPECIAL HANDLING.)
- Reconstitute COSMEGEN by adding 1.1 mL of Sterile Water for Injection (without preservative) using aseptic precautions. The resulting solution of COSMEGEN will contain approximately 500 mcg (0.5 mg) per mL.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstituted, COSMEGEN is a clear, gold-colored solution.
- Once reconstituted, the solution of COSMEGEN can be added to infusion solutions of Dextrose Injection 5 percent or Sodium Chloride Injection either directly or to the tubing of a running intravenous infusion.
- Although reconstituted COSMEGEN is chemically stable, the product does not contain a preservative and accidental microbial contamination might result. Any unused portion should be discarded. Use of water containing preservatives (benzyl alcohol or parabens) to reconstitute COSMEGEN for Injection, results in the formation of a precipitate.
- Studies conducted on dactinomycin lyophilized powder for injection demonstrate that drug product diluted at concentrations of 10 mcg/mL or higher in WFI, 0.9% saline and 5% dextrose in glass or PVC infusion containers are chemically stable for up to 10 hours when stored at ambient room temperature. Drug product diluted to concentrations lower than 10 mcg/mL and stored at ambient room temperature showed significantly lower recoveries. Therefore, only drug product diluted at concentrations greater than 10 mcg/mL are recommended for administration. Since the product contains no preservatives, the final prepared product (which has undergone reconstitution and dilution) must be used within 4 hours of initial reconstitution when stored at ambient room temperature.
- Partial removal of COSMEGEN from intravenous solutions by cellulose ester membrane filters used in some intravenous in-line filters has been reported.
- Since dactinomycin is extremely corrosive to soft tissue, precautions for materials of this nature should be observed.
- If the drug is given directly into the vein without the use of an infusion, the “two-needle technique” should be used. Reconstitute and withdraw the calculated dose from the vial with one sterile needle. Use another sterile needle for direct injection into the vein.
- Discard any unused portion of the COSMEGEN solution.
- Care in the administration of COSMEGEN will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of COSMEGEN, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 minutes 4 times daily for 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.
### Monitoring
- Renal, hepatic, and bone marrow functions should be assessed frequently.
# IV Compatibility
There is limited information regarding IV Compatibility of Dactinomycin in the drug label.
# Overdosage
- Dactinomycin was lethal to mice and rats at intravenous doses of 700 and 500 mcg/kg, respectively (approximately 3.8 and 5.4 times the maximum recommended daily human dose on a body surface area basis, respectively). The oral LD50 of dactinomycin is 7.8 mg/kg and 7.2 mg/kg in the mouse and rat, respectively.
- Manifestations of overdose in patients have included nausea, vomiting, diarrhea, mucositis including stomatitis, gastrointestinal ulceration, severe skin disorders including skin exfoliation, exanthema, desquamation and epidermolysis, severe hematopoietic depression, veno-occlusive disease, acute renal failure, sepsis (including neutropenic sepsis) with fatal outcome and death. No specific information is available on the treatment of overdosage with COSMEGEN. Treatment is symptomatic and supportive. It is advisable to check skin and mucous membrane integrity as well as renal, hepatic, and bone marrow functions frequently.
# Pharmacology
## Mechanism of Action
- Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases.
- Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implants. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.
## Structure
- Dactinomycin is one of the actinomycins, a group of antibiotics produced by various species of Streptomyces. Dactinomycin is the principal component of the mixture of actinomycins produced by Streptomyces parvullus. Unlike other species of Streptomyces, this organism yields an essentially pure substance that contains only traces of similar compounds differing in the amino acid content of the peptide side chains. The empirical formula is C62H86N12O16 and the structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dactinomycin in the drug label.
## Pharmacokinetics
- Results of a study in patients with malignant melanoma indicate that dactinomycin (3H actinomycin D) is minimally metabolized, is concentrated in nucleated cells, and does not penetrate the blood-brain barrier. Approximately 30% of the dose was recovered in urine and feces in one week. The terminal plasma half-life for radioactivity was approximately 36 hours.
## Nonclinical Toxicology
- Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as COSMEGEN. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.
- The International Agency on Research on Cancer has judged that dactinomycin is a positive carcinogen in animals. Local sarcomas were produced in mice and rats after repeated subcutaneous or intraperitoneal injection. Mesenchymal tumors occurred in male F344 rats given intraperitoneal injections of 50 mcg/kg, 2 to 5 times per week for 18 weeks. The first tumor appeared at 23 weeks.
- Dactinomycin has been shown to be mutagenic in a number of test systems in vitro and in vivo including human fibroblasts and leukocytes, and HeLa cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat.
- Adequate fertility studies have not been reported, although, reports suggest an increased incidence of infertility following treatment with other antineoplastic agents.
# Clinical Studies
- A wide variety of single agent and combination chemotherapy regimens with COSMEGEN have been studied. Because chemotherapeutic regimens are constantly changing, the decision to employ COSMEGEN should be directly supervised by physicians familiar with current oncologic practices and new advances in therapy.
- The neoplasm responding most frequently to COSMEGEN is Wilms’ tumor. Data from the National Wilms’ Tumor Studies (NWTS-1, NWTS-2, NWTS-3 and NWTS-4) support the use of COSMEGEN in Wilms’ tumor. The NWTS-3 evaluated results in 1,439 patients randomized to various regimens incorporating COSMEGEN (see table below).
- It should be noted that the complete results from NWTS-4 have not yet been published. Changes in NWTS-4 and NWTS-5 have consisted of alterations in duration as well as dose intensity of COSMEGEN. As a consequence, appropriate consultation with physicians experienced in the management of Wilms’ tumor should be sought.
- The Third Intergroup Rhabdomyosarcoma Study (IRS-III) studied 1,062 previously untreated pediatric patients and young adults (≤21 years of age) and compared outcomes amongst a number of treatment regimens.
- COSMEGEN was included in all arms as a standard component of the treatment regimen; thus, comparative data are not available from this study. Nevertheless, it does provide information on treatment outcomes in a large group of closely studied patients. For treatment purposes, patients were stratified according to clinical group, histologic subtype, and site of disease. Patients in most strata were randomized, but clinical group I patients with favorable histology were not randomized and treated according to a single regimen.
- Combinations of vinblastine, cyclophosphamide, COSMEGEN, bleomycin and cisplatin (VAB-6 regimen) have been employed in the treatment of metastatic nonseminomatous testicular cancer. In a retrospective analysis of 142 evaluable patients with primary advanced stage II or clinical stage III testicular cancer 112 (79%) achieved a complete response (CR) after treatment with VAB-6 alone or in combination with surgery. Relapses were uncommon (12%) and 117 of 166 patients (71%) were categorized as alive without evidence of disease during the four years covered by the study.
- COSMEGEN in conjunction with vincristine, doxorubicin, cyclophosphamide and radiotherapy has been used in the management of both metastatic and non-metastatic Ewing’s sarcoma. Of 120 previously untreated patients with non-metastatic disease treated with COSMEGEN as part of maintenance therapy in the United Kingdom Children’s Cancer Study Group Ewing’s Tumor Study (ET-1), 49 (41%) were free of disease at 5 years and 53 (44%) were alive at 5 years. Outcomes in regional and metastatic disease for previously untreated patients administered COSMEGEN resulted in 31 of 44 patients (70%) achieving a CR after a median time on study of 83 weeks. Eight of 44 (18%) patients achieved a partial response (PR) and the remaining 5 (11%) demonstrated no response to the regimen.
- Single agent COSMEGEN has been used in the management of nonmetastatic gestational trophoblastic neoplasia. In a series of 31 patients with nonmetastatic disease, complete and sustained remissions were achieved with COSMEGEN alone in 94% of treated patients. Alternating combination regimens incorporating COSMEGEN in conjunction with etoposide, methotrexate, vincristine and cyclophosphamide (EMA-CO regimen) have also been used in the treatment of poor prognosis gestational trophoblastic neoplasia. Administration of EMA-CO to 148 women with poor prognosis gestational trophoblastic neoplasia resulted in 110 (80%) complete and 25 (18%) partial responses after a mean follow-up of 50.4 months. Overall survival during the study period was 85% and relapses were uncommon (5.4%). Meticulous monitoring of beta-hCG (human chorionic gonadotropin) must be incorporated into the treatment regimen.
- COSMEGEN, as a component of regional perfusion, has been administered as palliative treatment and as an adjunct to tumor resection in the management of locally recurrent and locoregional sarcomas, carcinomas and adenocarcinomas.
# How Supplied
- COSMEGEN for Injection is a lyophilized powder. In the dry form the compound is an amorphous yellow to orange powder. The solution is clear, gold-colored and essentially free from visible particles. COSMEGEN for Injection is supplied in vials containing 0.5 mg (500 micrograms) of dactinomycin and 20.0 mg of mannitol.
NDC 55292-811-55
## Storage
- Store at 20-25ºC (68-77ºF). See USP controlled room temperature. Protect from light and humidity.
- Animal studies have shown dactinomycin to be corrosive to skin, irritating to the eyes and mucous membranes of the respiratory tract and highly toxic by the oral route. It has also been shown to be carcinogenic, mutagenic, embryotoxic and teratogenic. Due to the drug’s toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of COSMEGEN for parenteral administration. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. The National Institutes of Health presently recommends that the preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers. Additional body garments should be used based upon the task being performed (e.g., sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapors and dust. Appropriate techniques should be used to remove potentially contaminated clothing.
- Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered.-
- Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 55292-811-55 12 Single Dose Vials
Cosmegen® for Injection
(dactinomycin for injection)
500 mcg (0.5 mg)
Store at 20-25ºC (68-77ºF).
See USP controlled room temperature.
Protect from light and humidity.
RECORDATI RARE DISEASES GROUP
Rx only
Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany
For: Recordati Rare Diseases Inc., Lebanon, NJ 08833, U.S.A.
® Trademark of Recordati Rare Diseases Inc.
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Dactinomycin in the drug label.
# Precautions with Alcohol
- Alcohol-Dactinomycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cosmegen®
# Look-Alike Drug Names
There is limited information regarding Dactinomycin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Dactinomycin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Dactinomycin is a Antibiotic and a antineoplastic Agent that is FDA approved for the treatment of Wilm's tumor, childhood rhabdomyosarcoma, Ewing’s sarcoma and metastatic, nonseminomatous testicular cancer, gestational trophoblastic neoplasia, and adjunctive treatment of locally recurrent or locoregional solid malignancies.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Diarrhea, Nausea and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- COSMEGEN, as part of a combination chemotherapy and/or multi-modality treatment regimen, is indicated for the treatment of Wilms’ tumor, childhood rhabdomyosarcoma, Ewing’s sarcoma and metastatic, nonseminomatous testicular cancer.
- COSMEGEN is indicated as a single agent, or as part of a combination chemotherapy regimen, for the treatment of gestational trophoblastic neoplasia.
- COSMEGEN, as a component of regional perfusion, is indicated for the palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies.
### Dosage
- Not for oral administration: Toxic reactions due to COSMEGEN are frequent and may be severe, thus limiting in many instances the amount that may be administered. However, the severity of toxicity varies markedly and is only partly dependent on the dose employed.
- Careful calculation of the dosage should be performed prior to administration of each dose.
- The dosage of COSMEGEN varies depending on the tolerance of the patient, the size and location of the neoplasm, and the use of other forms of therapy. It may be necessary to decrease the usual dosages suggested below when additional chemotherapy or radiation therapy is used concomitantly or has been used previously.
- The dosage for COSMEGEN is calculated in micrograms (mcg). The dose intensity per 2-week cycle for adults or children should not exceed 15 mcg/kg/day or 400-600 mcg/m2/day intravenously for five days. Calculation of the dosage for obese or edematous patients should be performed on the basis of surface area in an effort to more closely relate dosage to lean body mass.
- A wide variety of single agent and combination chemotherapy regimens with COSMEGEN may be employed. Because chemotherapeutic regimens are constantly changing, dosing and administration should be performed under the direct supervision of physicians familiar with current oncologic practices and new advances in therapy. The following suggested regimens are based upon a review of current literature concerning therapy with COSMEGEN and are on a per cycle basis.
- Regimens of 15 mcg/kg intravenously daily for five days administered in various combinations and schedules with other chemotherapeutic agents have been utilized in the treatment of Wilms’ tumor, rhabdomyosarcoma and Ewing’s sarcoma.
- 1000 mcg/m2 intravenously on Day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin.
- 12 mcg/kg intravenously daily for five days as a single agent.
- 500 mcg intravenously on Days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin.
- The dosage schedules and the technique itself vary from one investigator to another; the published literature, therefore, should be consulted for details. * In general, the following doses are suggested:
- 50 mcg (0.05 mg) per kilogram of body weight for lower extremity or pelvis.
- 35 mcg (0.035 mg) per kilogram of body weight for upper extremity.
- It may be advisable to use lower doses in obese patients, or when previous chemotherapy or radiation therapy has been employed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dactinomycin in adult patients.
### Non–Guideline-Supported Use
- Kaposi's sarcoma[1][2]
- Sarcoma[3][4]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The greater frequency of toxic effects of COSMEGEN in infants suggest that this drug should be administered to infants only over the age of 6 to 12 months.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dactinomycin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dactinomycin in pediatric patients.
# Contraindications
- Hypersensitivity to any component of this product.
- COSMEGEN should not be given at or about the time of infection with chickenpox or herpes zoster because of the risk of severe generalized disease which may result in death.
# Warnings
- Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as COSMEGEN. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.
### Precautions
- This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Since COSMEGEN is extremely corrosive to soft tissues, it is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling COSMEGEN. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse .
- As with all antineoplastic agents, COSMEGEN is a toxic drug and very careful and frequent observation of the patient for adverse reactions is necessary. These reactions may involve any tissue of the body, most commonly the hematopoietic system resulting in myelosuppression. As such, live virus vaccines should not be administered during therapy with COSMEGEN. The possibility of an anaphylactoid reaction should be borne in mind.
- It is extremely important to observe the patient daily for toxic side effects when combination chemotherapy is employed, since a full course of therapy occasionally is not tolerated. If stomatitis, diarrhea, or severe hematopoietic depression appear during therapy, these drugs should be discontinued until the patient has recovered.
- Veno-occlusive disease (primarily hepatic) may result in fatality, particularly in children younger than 48 months.
- An increased incidence of gastrointestinal toxicity and marrow suppression has been reported with combined therapy incorporating COSMEGEN and radiation. Moreover, the normal skin, as well as the buccal and pharyngeal mucosa, may show early erythema. A smaller than usual radiation dose administered in combination with COSMEGEN causes erythema and vesiculation, which progress more rapidly through the stages of tanning and desquamation. Healing may occur in four to six weeks rather than two to three months. Erythema from previous radiation therapy may be reactivated by COSMEGEN alone, even when radiotherapy was administered many months earlier, and especially when the interval between the two forms of therapy is brief. This potentiation of radiation effect represents a special problem when the radiotherapy involves the mucous membrane. When irradiation is directed toward the nasopharynx, the combination may produce severe oropharyngeal mucositis. Severe reactions may ensue if high doses of both COSMEGEN and radiation therapy are used or if the patient is particularly sensitive to such combined therapy.
- Particular caution is necessary when administering COSMEGEN within two months of irradiation for the treatment of right-sided Wilms’ tumor, since hepatomegaly and elevated AST levels have been noted. In general, COSMEGEN should not be concomitantly administered with radiotherapy in the treatment of Wilms’ tumor unless the benefit outweighs the risk.
- Complications of the perfusion technique are related mainly to the amount of drug that escapes into the systemic circulation and may consist of hematopoietic depression, absorption of toxic products from massive destruction of neoplastic tissue, increased susceptibility to infection, impaired wound healing, and superficial ulceration of the gastric mucosa. Other side effects may include edema of the extremity involved, damage to soft tissues of the perfused area, and (potentially) venous thrombosis.
- Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic diseases receiving COSMEGEN. Renal, hepatic, and bone marrow functions should be assessed frequently.
# Adverse Reactions
## Clinical Trials Experience
- Toxic effects (excepting nausea and vomiting) usually do not become apparent until two to four days after a course of therapy is stopped, and may not peak until one to two weeks have elapsed. Deaths have been reported. However, adverse reactions are usually reversible on discontinuance of therapy. They include the following:
- Sepsis (including neutropenic sepsis) with fatal outcome, infection, malaise, fatigue, lethargy, fever, myalgia, proctitis, hypocalcemia and growth retardation.
- cheilitis, dysphagia, esophagitis, ulcerative stomatitis, pharyngitis.
- pneumonitis.
- anorexia, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal ulceration. Nausea and vomiting, which occur early during the first few hours after administration, may be alleviated by the administration of anti-emetics.
- liver toxicity including liver function test abnormalities, ascites, hepatomegaly, hepatitis, hepatic failure with reports of death, hepatic veno-occlusive disease which may be associated with intravascular clotting disorder and multi-organ failure .
- anemia, even to the point of aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia. Platelet and white cell counts should be performed frequently to detect severe hematopoietic depression. If either count markedly decreases, the drug should be withheld to allow marrow recovery. This often takes up to three weeks.
- alopecia, skin eruptions, acne, erythema multiforme, flare-up of erythema or increased pigmentation of previously irradiated skin. Toxic Epidermal Necrolysis (TEN) and Stevens Johnson Syndrome (SJS) have been observed from postmarketing experience.
- Dactinomycin is extremely corrosive. If extravasation occurs during intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms. Epidermolysis, erythema, and edema, at times severe, have been reported with regional limb perfusion.
- Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic diseases receiving COSMEGEN. Renal, hepatic, and bone marrow functions should be assessed frequently.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Dactinomycin in the drug label.
# Drug Interactions
- Dactinomycin may interfere with bioassay procedures for the determination of antibacterial drug levels.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- COSMEGEN may cause fetal harm when administered to a pregnant woman. COSMEGEN has been shown to cause malformations and embryotoxicity in rat, rabbit, and hamster when given in doses of 50-100 mcg/kg (approximately 0.5-2 times the maximum recommended daily human dose on a body surface area basis). If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential must be warned to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dactinomycin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dactinomycin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COSMEGEN, a decision should be made as to discontinuation of nursing and/or drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The greater frequency of toxic effects of COSMEGEN in infants suggest that this drug should be administered to infants only over the age of 6 to 12 months.
### Geriatic Use
- Clinical studies of COSMEGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, a published meta-analysis of all studies performed by the Eastern Cooperative Oncology Group (ECOG) over a 13-year period suggests that administration of COSMEGEN to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Dactinomycin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dactinomycin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dactinomycin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dactinomycin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dactinomycin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dactinomycin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see BOXED WARNING and HOW SUPPLIED, SPECIAL HANDLING). Since COSMEGEN is extremely corrosive to soft tissues, it is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling COSMEGEN. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse. (See HOW SUPPLIED, SPECIAL HANDLING.)
- Reconstitute COSMEGEN by adding 1.1 mL of Sterile Water for Injection (without preservative) using aseptic precautions. The resulting solution of COSMEGEN will contain approximately 500 mcg (0.5 mg) per mL.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstituted, COSMEGEN is a clear, gold-colored solution.
- Once reconstituted, the solution of COSMEGEN can be added to infusion solutions of Dextrose Injection 5 percent or Sodium Chloride Injection either directly or to the tubing of a running intravenous infusion.
- Although reconstituted COSMEGEN is chemically stable, the product does not contain a preservative and accidental microbial contamination might result. Any unused portion should be discarded. Use of water containing preservatives (benzyl alcohol or parabens) to reconstitute COSMEGEN for Injection, results in the formation of a precipitate.
- Studies conducted on dactinomycin lyophilized powder for injection demonstrate that drug product diluted at concentrations of 10 mcg/mL or higher in WFI, 0.9% saline and 5% dextrose in glass or PVC infusion containers are chemically stable for up to 10 hours when stored at ambient room temperature. Drug product diluted to concentrations lower than 10 mcg/mL and stored at ambient room temperature showed significantly lower recoveries. Therefore, only drug product diluted at concentrations greater than 10 mcg/mL are recommended for administration. Since the product contains no preservatives, the final prepared product (which has undergone reconstitution and dilution) must be used within 4 hours of initial reconstitution when stored at ambient room temperature.
- Partial removal of COSMEGEN from intravenous solutions by cellulose ester membrane filters used in some intravenous in-line filters has been reported.
- Since dactinomycin is extremely corrosive to soft tissue, precautions for materials of this nature should be observed.
- If the drug is given directly into the vein without the use of an infusion, the “two-needle technique” should be used. Reconstitute and withdraw the calculated dose from the vial with one sterile needle. Use another sterile needle for direct injection into the vein.
- Discard any unused portion of the COSMEGEN solution.
- Care in the administration of COSMEGEN will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of COSMEGEN, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 minutes 4 times daily for 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.
### Monitoring
- Renal, hepatic, and bone marrow functions should be assessed frequently.
# IV Compatibility
There is limited information regarding IV Compatibility of Dactinomycin in the drug label.
# Overdosage
- Dactinomycin was lethal to mice and rats at intravenous doses of 700 and 500 mcg/kg, respectively (approximately 3.8 and 5.4 times the maximum recommended daily human dose on a body surface area basis, respectively). The oral LD50 of dactinomycin is 7.8 mg/kg and 7.2 mg/kg in the mouse and rat, respectively.
- Manifestations of overdose in patients have included nausea, vomiting, diarrhea, mucositis including stomatitis, gastrointestinal ulceration, severe skin disorders including skin exfoliation, exanthema, desquamation and epidermolysis, severe hematopoietic depression, veno-occlusive disease, acute renal failure, sepsis (including neutropenic sepsis) with fatal outcome and death. No specific information is available on the treatment of overdosage with COSMEGEN. Treatment is symptomatic and supportive. It is advisable to check skin and mucous membrane integrity as well as renal, hepatic, and bone marrow functions frequently.
# Pharmacology
## Mechanism of Action
- Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases.
- Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implants. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.
## Structure
- Dactinomycin is one of the actinomycins, a group of antibiotics produced by various species of Streptomyces. Dactinomycin is the principal component of the mixture of actinomycins produced by Streptomyces parvullus. Unlike other species of Streptomyces, this organism yields an essentially pure substance that contains only traces of similar compounds differing in the amino acid content of the peptide side chains. The empirical formula is C62H86N12O16 and the structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dactinomycin in the drug label.
## Pharmacokinetics
- Results of a study in patients with malignant melanoma indicate that dactinomycin (3H actinomycin D) is minimally metabolized, is concentrated in nucleated cells, and does not penetrate the blood-brain barrier. Approximately 30% of the dose was recovered in urine and feces in one week. The terminal plasma half-life for radioactivity was approximately 36 hours.
## Nonclinical Toxicology
- Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as COSMEGEN. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.
- The International Agency on Research on Cancer has judged that dactinomycin is a positive carcinogen in animals. Local sarcomas were produced in mice and rats after repeated subcutaneous or intraperitoneal injection. Mesenchymal tumors occurred in male F344 rats given intraperitoneal injections of 50 mcg/kg, 2 to 5 times per week for 18 weeks. The first tumor appeared at 23 weeks.
- Dactinomycin has been shown to be mutagenic in a number of test systems in vitro and in vivo including human fibroblasts and leukocytes, and HeLa cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat.
- Adequate fertility studies have not been reported, although, reports suggest an increased incidence of infertility following treatment with other antineoplastic agents.
# Clinical Studies
- A wide variety of single agent and combination chemotherapy regimens with COSMEGEN have been studied. Because chemotherapeutic regimens are constantly changing, the decision to employ COSMEGEN should be directly supervised by physicians familiar with current oncologic practices and new advances in therapy.
- The neoplasm responding most frequently to COSMEGEN is Wilms’ tumor. Data from the National Wilms’ Tumor Studies (NWTS-1, NWTS-2, NWTS-3 and NWTS-4) support the use of COSMEGEN in Wilms’ tumor. The NWTS-3 evaluated results in 1,439 patients randomized to various regimens incorporating COSMEGEN (see table below).
- It should be noted that the complete results from NWTS-4 have not yet been published. Changes in NWTS-4 and NWTS-5 have consisted of alterations in duration as well as dose intensity of COSMEGEN. As a consequence, appropriate consultation with physicians experienced in the management of Wilms’ tumor should be sought.
- The Third Intergroup Rhabdomyosarcoma Study (IRS-III) studied 1,062 previously untreated pediatric patients and young adults (≤21 years of age) and compared outcomes amongst a number of treatment regimens.
- COSMEGEN was included in all arms as a standard component of the treatment regimen; thus, comparative data are not available from this study. Nevertheless, it does provide information on treatment outcomes in a large group of closely studied patients. For treatment purposes, patients were stratified according to clinical group, histologic subtype, and site of disease. Patients in most strata were randomized, but clinical group I patients with favorable histology were not randomized and treated according to a single regimen.
- Combinations of vinblastine, cyclophosphamide, COSMEGEN, bleomycin and cisplatin (VAB-6 regimen) have been employed in the treatment of metastatic nonseminomatous testicular cancer. In a retrospective analysis of 142 evaluable patients with primary advanced stage II or clinical stage III testicular cancer 112 (79%) achieved a complete response (CR) after treatment with VAB-6 alone or in combination with surgery. Relapses were uncommon (12%) and 117 of 166 patients (71%) were categorized as alive without evidence of disease during the four years covered by the study.
- COSMEGEN in conjunction with vincristine, doxorubicin, cyclophosphamide and radiotherapy has been used in the management of both metastatic and non-metastatic Ewing’s sarcoma. Of 120 previously untreated patients with non-metastatic disease treated with COSMEGEN as part of maintenance therapy in the United Kingdom Children’s Cancer Study Group Ewing’s Tumor Study (ET-1), 49 (41%) were free of disease at 5 years and 53 (44%) were alive at 5 years. Outcomes in regional and metastatic disease for previously untreated patients administered COSMEGEN resulted in 31 of 44 patients (70%) achieving a CR after a median time on study of 83 weeks. Eight of 44 (18%) patients achieved a partial response (PR) and the remaining 5 (11%) demonstrated no response to the regimen.
- Single agent COSMEGEN has been used in the management of nonmetastatic gestational trophoblastic neoplasia. In a series of 31 patients with nonmetastatic disease, complete and sustained remissions were achieved with COSMEGEN alone in 94% of treated patients. Alternating combination regimens incorporating COSMEGEN in conjunction with etoposide, methotrexate, vincristine and cyclophosphamide (EMA-CO regimen) have also been used in the treatment of poor prognosis gestational trophoblastic neoplasia. Administration of EMA-CO to 148 women with poor prognosis gestational trophoblastic neoplasia resulted in 110 (80%) complete and 25 (18%) partial responses after a mean follow-up of 50.4 months. Overall survival during the study period was 85% and relapses were uncommon (5.4%). Meticulous monitoring of beta-hCG (human chorionic gonadotropin) must be incorporated into the treatment regimen.
- COSMEGEN, as a component of regional perfusion, has been administered as palliative treatment and as an adjunct to tumor resection in the management of locally recurrent and locoregional sarcomas, carcinomas and adenocarcinomas.
# How Supplied
- COSMEGEN for Injection is a lyophilized powder. In the dry form the compound is an amorphous yellow to orange powder. The solution is clear, gold-colored and essentially free from visible particles. COSMEGEN for Injection is supplied in vials containing 0.5 mg (500 micrograms) of dactinomycin and 20.0 mg of mannitol.
NDC 55292-811-55
## Storage
- Store at 20-25ºC (68-77ºF). See USP controlled room temperature. Protect from light and humidity.
- Animal studies have shown dactinomycin to be corrosive to skin, irritating to the eyes and mucous membranes of the respiratory tract and highly toxic by the oral route. It has also been shown to be carcinogenic, mutagenic, embryotoxic and teratogenic. Due to the drug’s toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of COSMEGEN for parenteral administration. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. The National Institutes of Health presently recommends that the preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers. Additional body garments should be used based upon the task being performed (e.g., sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapors and dust. Appropriate techniques should be used to remove potentially contaminated clothing.
- Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered.[1]-[4]
- Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 55292-811-55 12 Single Dose Vials
Cosmegen® for Injection
(dactinomycin for injection)
500 mcg (0.5 mg)
Store at 20-25ºC (68-77ºF).
See USP controlled room temperature.
Protect from light and humidity.
RECORDATI RARE DISEASES GROUP
Rx only
Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany
For: Recordati Rare Diseases Inc., Lebanon, NJ 08833, U.S.A.
® Trademark of Recordati Rare Diseases Inc.
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Dactinomycin in the drug label.
# Precautions with Alcohol
- Alcohol-Dactinomycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cosmegen®[5]
# Look-Alike Drug Names
There is limited information regarding Dactinomycin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dactinomycin | |
a52efe835c1457518bdebaea5da5c996e390c992 | wikidoc | Dale Pendell | Dale Pendell
Dale Pendell is a contemporary author who combines science and poetry in his explications of the relationship between psychoactive compounds and human beings. A long time student of ethnobotany, Pendell discusses historical and cultural uses of "power plants" in his works. He reads and distills the literature of pharmacology and neuroscience, of ethnobotany and anthropology, of mythology and political economics as they intersect with the direct experience of human psychoactive use.
His publications include the Pharmako Trilogy: Pharmako/Poeia (1994), Pharmako/Dynamis (2002), and Pharmako/Gnosis (2005), all published by Mercury House. He covers all the major categories of psychoactives and details the use, the pharmacology, the chemistry, the political and social historical implications and effects of the use of psychoactives.
He his also well regarded as a myth critic. Certain of his works contained detailed scholarship on the origins of cultural myths.
Dale Pendell is highly regarded for his expertise on psychoactive plants and drugs and as a writer and poet; one of his works is used as a textbook for a lower division course in the University of California, Berkeley's Molecular and Cell Biology department. | Dale Pendell
Dale Pendell is a contemporary author who combines science and poetry in his explications of the relationship between psychoactive compounds and human beings. A long time student of ethnobotany, Pendell discusses historical and cultural uses of "power plants" in his works. He reads and distills the literature of pharmacology and neuroscience, of ethnobotany and anthropology, of mythology and political economics as they intersect with the direct experience of human psychoactive use.
His publications include the Pharmako Trilogy: Pharmako/Poeia (1994), Pharmako/Dynamis (2002), and Pharmako/Gnosis (2005), all published by Mercury House. He covers all the major categories of psychoactives and details the use, the pharmacology, the chemistry, the political and social historical implications and effects of the use of psychoactives.
He his also well regarded as a myth critic. Certain of his works contained detailed scholarship on the origins of cultural myths.
Dale Pendell is highly regarded for his expertise on psychoactive plants and drugs and as a writer and poet; one of his works is used as a textbook for a lower division course in the University of California, Berkeley's Molecular and Cell Biology department.
# External links
- Erowid's Dale Pendell vault
- Erowid review of Pharmako/Gnosis
audio recordings of Dale Pendell discussing his favorite plant allies can be found at botanicalpreservationcorps.com
Template:US-nonfiction-writer-stub
Template:US-poet-stub
Template:Hallucinogen-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dale_Pendell | |
270dcee5c2987d73bff4bd3e3dfdb711c7a81ee8 | wikidoc | Danger space | Danger space
# Overview
The danger space is a region of the neck.
# Anatomy
It is bounded superiorly by the skull base, anteriorly by the alar fascia and posteriorly by the prevertebral fascia. It comes to an end at the level of the diaphragm.
The retropharyngeal space is found anterior to the danger zone, between the buccopharnygeal fascia and alar fascia. There exists a midline raphe in this space so some infections of this space appear unilateral.
# History
It was first characterized in 1938.
# Clinical significance
It gets its common name from the risk that an infection in this space can spread directly to the thorax, it is sometimes also referred to as the Alar space. It is a median space without a midline raphe and hence infection can spread easily to either side. | Danger space
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The danger space is a region of the neck.[1]
# Anatomy
It is bounded superiorly by the skull base, anteriorly by the alar fascia and posteriorly by the prevertebral fascia. It comes to an end at the level of the diaphragm.
The retropharyngeal space is found anterior to the danger zone, between the buccopharnygeal fascia and alar fascia. There exists a midline raphe in this space so some infections of this space appear unilateral.
# History
It was first characterized in 1938.[2][3]
# Clinical significance
It gets its common name from the risk that an infection in this space can spread directly to the thorax, it is sometimes also referred to as the Alar space. It is a median space without a midline raphe and hence infection can spread easily to either side. | https://www.wikidoc.org/index.php/Danger_space | |
63206070d57f30284b3b8754d085649d528c13f9 | wikidoc | Datura metel | Datura metel
Datura metel, commonly known as Devil's trumpet, metel, or downy thorn-apple is a shrub-like annual herb with large flowers, typically white or yellow. Native to China, it is now used in landscaping and gardening in North America.
# Medicinal use
D. metel is one of the 50 fundamental herbs used in Chinese herbology, where it is called yáng jīn huā (洋金花).
# Toxicity
This plant may be toxic if ingested in any quantity, symptomatically expressed as flushed skin, headaches, hallucinations, and possibly convulsions or even a coma. The principal toxic elements are tropane alkaloids. Accidentally (or intentionally) ingesting even a single leaf could lead to severe side effects. | Datura metel
Datura metel, commonly known as Devil's trumpet, metel, or downy thorn-apple is a shrub-like annual herb with large flowers, typically white or yellow. Native to China, it is now used in landscaping and gardening in North America.
# Medicinal use
D. metel is one of the 50 fundamental herbs used in Chinese herbology, where it is called yáng jīn huā (洋金花).
# Toxicity
This plant may be toxic if ingested in any quantity, symptomatically expressed as flushed skin, headaches, hallucinations, and possibly convulsions or even a coma. The principal toxic elements are tropane alkaloids. Accidentally (or intentionally) ingesting even a single leaf could lead to severe side effects. | https://www.wikidoc.org/index.php/Datura_metel | |
f7dffe5a4a4dfd00654a994881bcbba34111b62f | wikidoc | David Singer | David Singer
David Singer, DC, is a chiropractor, a Scientologist, and the founder, in 1981, of the controversial consulting firm now known as David Singer Enterprises. Singer is an accomplished speaker primarily engaged in training chiropractors to increase the efficiency and Profit (accounting)of their practices. The firm and its predecessor Singer Consulting, however, have also brought hundreds of new members into the Church of Scientology, triggering a nationwide controversy among chiropractors over concerns that it may be, largely or in part, a Proselytizing front group for the church. Since the 1980s, Singer has held seminars throughout the United States promoting Scientology founder L. Ron Hubbard's business methods, which revolve around 'management by statistics'.
# David Singer Enterprises
Singer has had a major impact on the approaches taken by chiropractors to building their practices. Singer offers one-on-one consulting programs, media products, and practice expansion seminars. The Singer System was developed, ostensibly, "to help natural healthcare providers achieve their personal and practice goals, despite managed care and other influences."
Singer Consultants was once licensed, by Scientology's World Institute of Scientology Enterprises (WISE) to sell Hubbard's management techniques, before merging with another Scientology management company in 1988 to form Singer Enterprises, itself a member of WISE since 1992. Singer Consulting was once ranked as one of the fastest growing private businesses in the United States, and was twice named among Inc. Magazine's Top 100 Fastest Growing Companies. In 1987, officials of David Singer Consultants said that 20 percent of the chiropractors who sign up for management consulting also wind up in Scientology courses.
# Notes
- ↑ Sappell, Joel (1990-06-27). "Church Seeks Influence in Schools, Business, Science". Los Angeles Times. p. A1:1. Retrieved 2007-09-14. It brought hundreds of new members into the church and triggered a nationwide controversy among chiropractors over its links to Scientology. Unknown parameter |coauthors= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Additional convenience link at .
- ↑ Koff, Stephen (1987-09-29). "Chiropractors seeking advice find Scientology-influenced seminars". St. Petersburg Times. Retrieved 2007-09-14. | David Singer
David Singer, DC, is a chiropractor, a Scientologist, and the founder, in 1981, of the controversial consulting firm now known as David Singer Enterprises. Singer is an accomplished speaker primarily engaged in training chiropractors to increase the efficiency and Profit (accounting)of their practices. The firm and its predecessor Singer Consulting, however, have also brought hundreds of new members into the Church of Scientology, triggering a nationwide controversy among chiropractors over concerns that it may be, largely or in part, a Proselytizing front group for the church.[1] Since the 1980s, Singer has held seminars throughout the United States promoting Scientology founder L. Ron Hubbard's business methods, which revolve around 'management by statistics'.
# David Singer Enterprises
Singer has had a major impact on the approaches taken by chiropractors to building their practices. Singer offers one-on-one consulting programs, media products, and practice expansion seminars. The Singer System was developed, ostensibly, "to help natural healthcare providers achieve their personal and practice goals, despite managed care and other influences."[2]
Singer Consultants was once licensed, by Scientology's World Institute of Scientology Enterprises (WISE) to sell Hubbard's management techniques, before merging with another Scientology management company in 1988 to form Singer Enterprises, itself a member of WISE since 1992. Singer Consulting was once ranked as one of the fastest growing private businesses in the United States, and was twice named among Inc. Magazine's Top 100 Fastest Growing Companies. In 1987, officials of David Singer Consultants said that 20 percent of the chiropractors who sign up for management consulting also wind up in Scientology courses.[2]
# Notes
- ↑ Sappell, Joel (1990-06-27). "Church Seeks Influence in Schools, Business, Science". Los Angeles Times. p. A1:1. Retrieved 2007-09-14. It brought hundreds of new members into the church and triggered a nationwide controversy among chiropractors over its links to Scientology. Unknown parameter |coauthors= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Additional convenience link at [1].
- ↑ Koff, Stephen (1987-09-29). "Chiropractors seeking advice find Scientology-influenced seminars". St. Petersburg Times. Retrieved 2007-09-14. | https://www.wikidoc.org/index.php/David_Singer | |
af969516550ec4663a94869a13462cb5af563197 | wikidoc | Hepatomegaly | Hepatomegaly
For patient information on this topic, click here.
Synonyms and keywords: Enlarged liver; liver enlargement
# Overview
The liver is an organ present in vertebrates and some other animals. The adult human liver normally weighs between 1.4 to 1.6 kilograms (3.1 to 3.5 pounds), and it is a soft, pinkish-brown "boomerang shaped" organ. It is located on the right side of the upper abdomen below the diaphragm. The size of the liver increases with age and ranges between 5 cm to 15 cm in adulthood. A normal liver is less than 16 cm on ultrasound evaluation. Hepatomegaly may be found during physical examination or on imaging studies. Imaging is more accurate in determining liver size. In some conditions normal liver may be palpated as enlarged liver including thin people, during deep inspiration, right pleural effusion, and emphysema resulting in hyperinflation of the chest with diaphragmatic descent and downward displacement of the liver. Common pathological causes that may result in hepatomegaly are hepatitis, storage disorders, impaired venous outflow, infiltrative disorders, and biliary obstruction.
# Causes
Various causes of hepatomegaly may be classified on the basis of etiology into hepatitis, storage disorders, impaired venous outflow, infiltrative, and obstructive causes.
# Differential Diagnosis
Patients with hepatomegaly need to be differentiated from other patients presenting with similar complaints such as abdominal pain.
Abbreviations:
RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram, US = Ultrasound | Hepatomegaly
For patient information on this topic, click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Seyedmahdi Pahlavani, M.D. [2],Iqra Qamar M.D.[3]
Synonyms and keywords: Enlarged liver; liver enlargement
# Overview
The liver is an organ present in vertebrates and some other animals. The adult human liver normally weighs between 1.4 to 1.6 kilograms (3.1 to 3.5 pounds), and it is a soft, pinkish-brown "boomerang shaped" organ. It is located on the right side of the upper abdomen below the diaphragm. The size of the liver increases with age and ranges between 5 cm to 15 cm in adulthood. A normal liver is less than 16 cm on ultrasound evaluation. Hepatomegaly may be found during physical examination or on imaging studies. Imaging is more accurate in determining liver size.[1][2] In some conditions normal liver may be palpated as enlarged liver including thin people, during deep inspiration, right pleural effusion, and emphysema resulting in hyperinflation of the chest with diaphragmatic descent and downward displacement of the liver. Common pathological causes that may result in hepatomegaly are hepatitis, storage disorders, impaired venous outflow, infiltrative disorders, and biliary obstruction.
# Causes
Various causes of hepatomegaly may be classified on the basis of etiology into hepatitis, storage disorders, impaired venous outflow, infiltrative, and obstructive causes.[3][4][5][6][7][8][9][10][11][12][13][14]
# Differential Diagnosis
Patients with hepatomegaly need to be differentiated from other patients presenting with similar complaints such as abdominal pain.[3][4][5][6][7][8][9][10][11][12][13][14]
Abbreviations:
RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram, US = Ultrasound | https://www.wikidoc.org/index.php/Ddx:Hepatomegaly | |
7616af51d22fa92bc7c97c61d906c5cb059f6761 | wikidoc | Nail changes | Nail changes
Synonyms and keywords: Nail abnormality; nail disorders; nail signs
# Overview
Nail diseases are distinct from diseases of the skin. Although nails are a skin appendage, they have their own signs and symptoms which may relate to other medical conditions. Nail conditions that show signs of infection or inflammation require medical assistance and cannot be treated at a beauty parlor. Deformity or disease of the nails may be referred to as onychosis.
There are many examples of how nail changes can play a role in helping to diagnose certain conditions. For example, short, small nail beds, and redness are associated with various heart conditions.
# Classification Scheme
Some images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
Acral lentiginous melanomaDoctor definition: Acral lentiginous melanoma is a kind of skin melanoma, and it is also known as subungual melanoma.Patient definition: Acral lentiginous melanoma is a kind of skin cancer, and it is also know as a skin cancer that manifests under the nail.
AcrocyanosisDoctor definition: Acrocyanosis is a persistent blue or cyanotic discoloration of the digits. Patient definition: Acrocyanosis is a blue discoloration (cyanosis) of the fingers and the fingernails.
AtherosclerosisDoctor definition: Atherosclerosis is a disease affecting arterial blood vessels and it can cause changes to the nail beds. Patient definition: Atherosclerosis is a disease affecting arterial blood vessels and it can cause changes to the nail beds.
Beau's linesDoctor definition: Beau's lines are deep grooved lines that run from side to side on the fingernail.Patient definition: Beau's lines are deep grooved lines that run from side to side on the fingernail.
Bowen's diseaseDoctor definition: Bowen's disease is a sunlight induced skin disease considered either as an early stage or intraepidermal form of squamous cell carcinoma.Patient definition: Bowen's disease is a sunlight induced skin disease considered an early stage for of skin cancer.
Brittle nailsDoctor definition: Brittle nails is a condition where the nails are fragile and break frequently.Patient definition: Brittle nails is a condition where the nails are fragile and break frequently.
Digital clubbingDoctor definition: Digital clubbing is a deformity of the fingers and fingernails that is associated with a number of diseases, mostly of the heart and lungs.Patient definition: Digital clubbing is a deformity of the fingers and fingernails that is associated with a number of diseases, mostly of the heart and lungs.
Half and half nailsDoctor definition: Half and half nails refer to a change in the appearance of the nails due to internal diseases and nutritional deficits.Patient definition Half and half nails refer to a change in the appearance of the nails due to internal diseases and nutritional deficits.
Herpes simplexDoctor definition: Herpes simplex is a viral disease caused by Herpes simplex viruses.Patient definition: Herpes simplex is a viral disease caused by Herpes simplex viruses.
IschemiaDoctor definition: Ischemia is a restriction in blood supply, generally due to factors in the blood vessels, which result in damage or dysfunction of tissue.Patient definition: Ischemia is a restriction in blood supply, generally due to factors in the blood vessels, which result in damage or dysfunction of tissue.
KoilonychiaDoctor definition: Koilonychia refers to nails (usually of the hand) which have lost their convexity, becoming flat or even concave in shape.Patient defintion: Koilonychia literally means spoon nails. It is when your nails become flat or sunken in.
LeukonychiaDoctor definition: Leukonychia is a medical term for white discoloration appearing on nails. Patient defintion: Leukonychia is a medical term for white discoloration appearing on nails.
Lichen planus nail changes Doctor definition: Lichen planus is an inflammatory disease that affects the skin and the oral mucosa.Patient definition: Lichen planus is an inflammatory disease that affects the skin and the mouth.
Mee's linesDoctor definition: Mees' lines are lines of discoloration across the nails of the fingers and toes after an episode of poisoning with arsenic or thallium or other heavy metals. Patient definition: Mees' lines are lines of discoloration across the nails of the fingers and toes after an episode of poisoning with arsenic or thallium or other heavy metals.
MelanonychiaDoctor definition: Melanonychia is a black or brown pigmentation of the normal nail plate that can present as horizontal or longitudinal bands.Patient definition: Melanonychia is a black or brown pigmentation of the normal nail plate that can present as horizontal or longitudinal bands.
Muehrcke's linesDoctor definition: Muehrcke's lines are white lines across the nail associated with hypoalbuminemia.Patient definition: Muehrcke's lines are white lines across the nail associated with low levels of the most abundant blood protein (albumin).
OnychiaDoctor definition: Onychia is an inflammation of the matrix of the nail with formation of pus and shedding of the nail.Patient definition: Onychia is an inflammation of the surrounding tissue (matrix) of the nail with formation of pus and shedding of the nail.
OnychocryptosisDoctor definition: Onychocryptosis is a painful condition in which the nail grows or cuts into one or both sides of the nail bed.Patient defintion: Onychocryptosis is a painful condition in which the nail grows or cuts into one or both sides of the nail bed.
OnychodystrophyDoctor definition: Onychodystrophy is a deformation of the nails that can result from cancer chemotherapy which includes bleomycin, hydroxyurea, or 5-fluorouracil. Patient definition: Onychodystrophy is a deformation of the nails that can result from certain cancer drugs (bleomycin, hydroxyurea, or 5-fluorouracil).
OnychogryphosisDoctor definition: Onychogryposis, also called "ram's-horn nail", is a thickening and increase in curvature of the nail.Patient definition: Onychogryposis, also called "ram's-horn nail", is a thickening and increase in curvature of the nail.
OnycholysisDoctor definition: Onycholysis is a loosening of the exposed portion of the nail from the nail bed, usually beginning at the free edge and continuing to the lunula. Patient definition: Onycholysis is a loosening of the exposed portion of the nail from the nail bed, usually beginning at the free edge and continuing to the crescent-shaped whitish area of the bed of a fingernail or toenail.
OnychomadesisDoctor definition: Onychomadesis is a periodic idiopathic shedding of the nails beginning at its proximal end.Patient definition: Onychomadesis is a periodic, spontaneous shedding of the nails beginning at the end closer to the finger.
OnychomycosisDoctor definition: Onychomycosis is a fungal infection of the nails. Patient definition: Onychomycosis is a fungal infection of the nails.
OnychophosisDoctor definition: Onychophosis is a localized or diffuse hyperkeratotic tissue that develops on the lateral or proximal nailfolds, within the space between the nailfolds and the nail plate.Patient definition: Onychophosis is a localized or diffuse excess of the nail proteins that develops on the side of the nail closer to the finger. This forms specifically in the space between the nail folds and nail plate.
OnychoptosisDoctor definition: Onychoptosis is the periodic shedding of the nails.Patient definition: Onychoptosis is the periodic shedding of the nails.
PachyonychiaDoctor definition: Pachyonychia is an autosomal dominant skin disorder.Patient definition: Pachyonychia is a skin disorder that is expressed when the specific gene is present.
Paronychia Doctor defintion: Paronychia is an often tender bacterial or fungal infection where the nail and skin meet at the side or the base of a finger or toenail. Patient definition: Paronychia is an often tender infection where the nail and skin meet at the side or the base of a finger or toenail.
Pitted nails Doctor definition: Pitted nails are pinpoint depressions in the nails.Patient definition: Pitted nails are pinpoint depressions in the nails.
Platonychia Doctor definition: Platonychia is characterized by an abnormally flat and broad nail. Patient definition: Platonychia is characterized by an abnormally flat and broad nail.
Psoriatic nails Doctor definition: Psoriatic nails is a common nail disease associated with people who have psoriasis. Patient definition: Psoriatic nails is a common nail disease associated with people who have a scaly skin rash (psoriasis).
SclerodermaDoctor definition: Scleroderma is a rare, chronic disease characterized by excessive deposits of collagen in the skin or other organs.Patient definition: Scleroderma is a rare, long lasting disease characterized by excessive deposits of a structural protein in the skin or other organs.
Skin cancerDoctor definition: Skin cancer is a malignant growth on the skin which can have many causes.Patient definition: Skin cancer is invasive, spreading cancer on the skin which can have many causes.
Splinter hemorrhage Doctor defintion: Splinter hemorrhages are tiny lines that run vertically under the nails.Patient definition: Splinter hemorrhages are tiny lines that run vertically under the nails.
Subungual hematomaDoctor definition: A subungal hematoma is a hematoma underneath a toenail or fingernail which often results from a traumatic injury such as slamming a finger in a door.Patient definition: A subungal hematoma is a collection of blood underneath a toenail or fingernail which often results from a traumatic injury such as slamming a finger in a door.
Terry's nailsDoctor definition: Terry's nails is a physical finding in which fingernails and/or toenails appear white with a characteristic "ground glass" appearance, with no lunula.Patient definition: Terry's nails is a physical finding in which fingernails and/or toenails appear white with a characteristic "ground glass" appearance, with no white crescent shaped area at the bottom of the nail.
TraumaDoctor definition: Trauma refers to a physical injury.Patient definition: Trauma refers to a physical injury.
Tuberous sclerosisDoctor definition: Tuberous sclerosis is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. Patient definition: Tuberous sclerosis is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.
WartDoctor definition: A wart is generally a small, rough tumor, typically on hands and feet, that can resemble a cauliflower or a solid blister.Patient definition: A wart is generally a small, rough tumor, typically on hands and feet, that can resemble a cauliflower or a solid blister.
Yellow nail syndromeDoctor definition: Yellow nail syndrome is characterized by yellow nails that lack a cuticle, grow slowly, and are loose or detached (onycholysis). Patient definition: Yellow nail syndrome is characterized by yellow nails that lack a cuticle, grow slowly, and are loose or detached (onycholysis). | Nail changes
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Michael Maddaleni, B.S.
Synonyms and keywords: Nail abnormality; nail disorders; nail signs
# Overview
Nail diseases are distinct from diseases of the skin. Although nails are a skin appendage, they have their own signs and symptoms which may relate to other medical conditions. Nail conditions that show signs of infection or inflammation require medical assistance and cannot be treated at a beauty parlor. Deformity or disease of the nails may be referred to as onychosis.
There are many examples of how nail changes can play a role in helping to diagnose certain conditions. For example, short, small nail beds, and redness are associated with various heart conditions.
# Classification Scheme
Some images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
Acral lentiginous melanomaDoctor definition: Acral lentiginous melanoma is a kind of skin melanoma, and it is also known as subungual melanoma.Patient definition: Acral lentiginous melanoma is a kind of skin cancer, and it is also know as a skin cancer that manifests under the nail.
AcrocyanosisDoctor definition: Acrocyanosis is a persistent blue or cyanotic discoloration of the digits. Patient definition: Acrocyanosis is a blue discoloration (cyanosis) of the fingers and the fingernails.
AtherosclerosisDoctor definition: Atherosclerosis is a disease affecting arterial blood vessels and it can cause changes to the nail beds. Patient definition: Atherosclerosis is a disease affecting arterial blood vessels and it can cause changes to the nail beds.
Beau's linesDoctor definition: Beau's lines are deep grooved lines that run from side to side on the fingernail.Patient definition: Beau's lines are deep grooved lines that run from side to side on the fingernail.
Bowen's diseaseDoctor definition: Bowen's disease is a sunlight induced skin disease considered either as an early stage or intraepidermal form of squamous cell carcinoma.Patient definition: Bowen's disease is a sunlight induced skin disease considered an early stage for of skin cancer.
Brittle nailsDoctor definition: Brittle nails is a condition where the nails are fragile and break frequently.Patient definition: Brittle nails is a condition where the nails are fragile and break frequently.
Digital clubbingDoctor definition: Digital clubbing is a deformity of the fingers and fingernails that is associated with a number of diseases, mostly of the heart and lungs.Patient definition: Digital clubbing is a deformity of the fingers and fingernails that is associated with a number of diseases, mostly of the heart and lungs.
Half and half nailsDoctor definition: Half and half nails refer to a change in the appearance of the nails due to internal diseases and nutritional deficits.Patient definition Half and half nails refer to a change in the appearance of the nails due to internal diseases and nutritional deficits.
Herpes simplexDoctor definition: Herpes simplex is a viral disease caused by Herpes simplex viruses.Patient definition: Herpes simplex is a viral disease caused by Herpes simplex viruses.
IschemiaDoctor definition: Ischemia is a restriction in blood supply, generally due to factors in the blood vessels, which result in damage or dysfunction of tissue.Patient definition: Ischemia is a restriction in blood supply, generally due to factors in the blood vessels, which result in damage or dysfunction of tissue.
KoilonychiaDoctor definition: Koilonychia refers to nails (usually of the hand) which have lost their convexity, becoming flat or even concave in shape.Patient defintion: Koilonychia literally means spoon nails. It is when your nails become flat or sunken in.
LeukonychiaDoctor definition: Leukonychia is a medical term for white discoloration appearing on nails. Patient defintion: Leukonychia is a medical term for white discoloration appearing on nails.
Lichen planus nail changes Doctor definition: Lichen planus is an inflammatory disease that affects the skin and the oral mucosa.Patient definition: Lichen planus is an inflammatory disease that affects the skin and the mouth.
Mee's linesDoctor definition: Mees' lines are lines of discoloration across the nails of the fingers and toes after an episode of poisoning with arsenic or thallium or other heavy metals. Patient definition: Mees' lines are lines of discoloration across the nails of the fingers and toes after an episode of poisoning with arsenic or thallium or other heavy metals.
MelanonychiaDoctor definition: Melanonychia is a black or brown pigmentation of the normal nail plate that can present as horizontal or longitudinal bands.Patient definition: Melanonychia is a black or brown pigmentation of the normal nail plate that can present as horizontal or longitudinal bands.
Muehrcke's linesDoctor definition: Muehrcke's lines are white lines across the nail associated with hypoalbuminemia.Patient definition: Muehrcke's lines are white lines across the nail associated with low levels of the most abundant blood protein (albumin).
OnychiaDoctor definition: Onychia is an inflammation of the matrix of the nail with formation of pus and shedding of the nail.Patient definition: Onychia is an inflammation of the surrounding tissue (matrix) of the nail with formation of pus and shedding of the nail.
OnychocryptosisDoctor definition: Onychocryptosis is a painful condition in which the nail grows or cuts into one or both sides of the nail bed.Patient defintion: Onychocryptosis is a painful condition in which the nail grows or cuts into one or both sides of the nail bed.
OnychodystrophyDoctor definition: Onychodystrophy is a deformation of the nails that can result from cancer chemotherapy which includes bleomycin, hydroxyurea, or 5-fluorouracil. Patient definition: Onychodystrophy is a deformation of the nails that can result from certain cancer drugs (bleomycin, hydroxyurea, or 5-fluorouracil).
OnychogryphosisDoctor definition: Onychogryposis, also called "ram's-horn nail", is a thickening and increase in curvature of the nail.Patient definition: Onychogryposis, also called "ram's-horn nail", is a thickening and increase in curvature of the nail.
OnycholysisDoctor definition: Onycholysis is a loosening of the exposed portion of the nail from the nail bed, usually beginning at the free edge and continuing to the lunula. Patient definition: Onycholysis is a loosening of the exposed portion of the nail from the nail bed, usually beginning at the free edge and continuing to the crescent-shaped whitish area of the bed of a fingernail or toenail.
OnychomadesisDoctor definition: Onychomadesis is a periodic idiopathic shedding of the nails beginning at its proximal end.Patient definition: Onychomadesis is a periodic, spontaneous shedding of the nails beginning at the end closer to the finger.
OnychomycosisDoctor definition: Onychomycosis is a fungal infection of the nails. Patient definition: Onychomycosis is a fungal infection of the nails.
OnychophosisDoctor definition: Onychophosis is a localized or diffuse hyperkeratotic tissue that develops on the lateral or proximal nailfolds, within the space between the nailfolds and the nail plate.Patient definition: Onychophosis is a localized or diffuse excess of the nail proteins that develops on the side of the nail closer to the finger. This forms specifically in the space between the nail folds and nail plate.
OnychoptosisDoctor definition: Onychoptosis is the periodic shedding of the nails.Patient definition: Onychoptosis is the periodic shedding of the nails.
PachyonychiaDoctor definition: Pachyonychia is an autosomal dominant skin disorder.Patient definition: Pachyonychia is a skin disorder that is expressed when the specific gene is present.
Paronychia Doctor defintion: Paronychia is an often tender bacterial or fungal infection where the nail and skin meet at the side or the base of a finger or toenail. Patient definition: Paronychia is an often tender infection where the nail and skin meet at the side or the base of a finger or toenail.
Pitted nails Doctor definition: Pitted nails are pinpoint depressions in the nails.Patient definition: Pitted nails are pinpoint depressions in the nails.
Platonychia Doctor definition: Platonychia is characterized by an abnormally flat and broad nail. Patient definition: Platonychia is characterized by an abnormally flat and broad nail.
Psoriatic nails Doctor definition: Psoriatic nails is a common nail disease associated with people who have psoriasis. Patient definition: Psoriatic nails is a common nail disease associated with people who have a scaly skin rash (psoriasis).
SclerodermaDoctor definition: Scleroderma is a rare, chronic disease characterized by excessive deposits of collagen in the skin or other organs.Patient definition: Scleroderma is a rare, long lasting disease characterized by excessive deposits of a structural protein in the skin or other organs.
Skin cancerDoctor definition: Skin cancer is a malignant growth on the skin which can have many causes.Patient definition: Skin cancer is invasive, spreading cancer on the skin which can have many causes.
Splinter hemorrhage Doctor defintion: Splinter hemorrhages are tiny lines that run vertically under the nails.Patient definition: Splinter hemorrhages are tiny lines that run vertically under the nails.
Subungual hematomaDoctor definition: A subungal hematoma is a hematoma underneath a toenail or fingernail which often results from a traumatic injury such as slamming a finger in a door.Patient definition: A subungal hematoma is a collection of blood underneath a toenail or fingernail which often results from a traumatic injury such as slamming a finger in a door.
Terry's nailsDoctor definition: Terry's nails is a physical finding in which fingernails and/or toenails appear white with a characteristic "ground glass" appearance, with no lunula.Patient definition: Terry's nails is a physical finding in which fingernails and/or toenails appear white with a characteristic "ground glass" appearance, with no white crescent shaped area at the bottom of the nail.
TraumaDoctor definition: Trauma refers to a physical injury.Patient definition: Trauma refers to a physical injury.
Tuberous sclerosisDoctor definition: Tuberous sclerosis is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. Patient definition: Tuberous sclerosis is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.
WartDoctor definition: A wart is generally a small, rough tumor, typically on hands and feet, that can resemble a cauliflower or a solid blister.Patient definition: A wart is generally a small, rough tumor, typically on hands and feet, that can resemble a cauliflower or a solid blister.
Yellow nail syndromeDoctor definition: Yellow nail syndrome is characterized by yellow nails that lack a cuticle, grow slowly, and are loose or detached (onycholysis). Patient definition: Yellow nail syndrome is characterized by yellow nails that lack a cuticle, grow slowly, and are loose or detached (onycholysis).
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744b057e7c6886b38d0bb25a9d42ebf579f8027e | wikidoc | Oral lesions | Oral lesions
Synonyms and keywords: Oral cavity lesions, Oral cavity ulcers, Oral cavity infections, Mouth ulcers, Mouth lesions.
# Overview
In many cases, mouth sores are attributed to herpes simplex virus and idiopathic aphthous stomatitis. Oral lesions can be indicative of a more serious underlying condition. A full review of the systems and a full skin exam are necessary to obtain an accurate diagnosis.
# Pathophysiology
# Differential diagnosis of oral cavity lesions
- ↑ Jahanbani J, Sandvik L, Lyberg T, Ahlfors E (March 2009). "Evaluation of oral mucosal lesions in 598 referred Iranian patients". Open Dent J. 3: 42–7. doi:10.2174/1874210600903010042. PMID 19444343..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Abidullah M, Raghunath V, Karpe T, Akifuddin S, Imran S, Dhurjati VN, Aleem MA, Khatoon F (February 2016). "Clinicopathologic Correlation of White, Non scrapable Oral Mucosal Surface Lesions: A Study of 100 Cases". J Clin Diagn Res. 10 (2): ZC38–41. doi:10.7860/JCDR/2016/16950.7226. PMC 4800649. PMID 27042583.
- ↑ Lee JH, Lee JH, Kwon NH, Yu DS, Kim GM, Park CJ, Lee JD, Kim SY (February 2012). "Clinicopathologic Manifestations of Patients with Fordyce's Spots". Ann Dermatol. 24 (1): 103–6. doi:10.5021/ad.2012.24.1.103. PMC 3283840. PMID 22363169.
- ↑ Olivier JH (March 2006). "Fordyce granules on the prolabial and oral mucous membranes of a selected population". SADJ. 61 (2): 072–4. PMID 16711559.
- ↑ De Felice C, Parrini S, Chitano G, Gentile M, Dipaola L, Latini G (September 2005). "Fordyce granules and hereditary non-polyposis colorectal cancer syndrome". Gut. 54 (9): 1279–82. doi:10.1136/gut.2005.064881. PMID 15879014.
- ↑ Ponti G, Meschieri A, Pollio A, Ruini C, Manfredini M, Longo C, Mandel VD, Ciardo S, Tomasi A, Giannetti L, Pellacani G (August 2015). "Fordyce granules and hyperplastic mucosal sebaceous glands as distinctive stigmata in Muir-Torre syndrome patients: characterization with reflectance confocal microscopy". J. Oral Pathol. Med. 44 (7): 552–7. doi:10.1111/jop.12256. PMID 25213213.
- ↑ Assimakopoulos D, Patrikakos G, Fotika C, Elisaf M (December 2002). "Benign migratory glossitis or geographic tongue: an enigmatic oral lesion". Am. J. Med. 113 (9): 751–5. PMID 12517366.
- ↑ Picciani BL, Domingos TA, Teixeira-Souza T, Santos Vde C, Gonzaga HF, Cardoso-Oliveira J, Gripp AC, Dias EP, Carneiro S (2016). "Geographic tongue and psoriasis: clinical, histopathological, immunohistochemical and genetic correlation - a literature review". An Bras Dermatol. 91 (4): 410–21. doi:10.1590/abd1806-4841.20164288. PMC 4999097. PMID 27579734.
- ↑ Tarakji B, Umair A, Babaker Z, Sn A, Gazal G, Sarraj F (November 2014). "Relation between psoriasis and geographic tongue". J Clin Diagn Res. 8 (11): ZE06–7. doi:10.7860/JCDR/2014/9101.5171. PMC 4290356. PMID 25584342.
- ↑ Kobayashi K, Takei Y, Sawada M, Ishizaki S, Ito H, Tanaka M (2010). "Dermoscopic features of a black hairy tongue in 2 Japanese patients". Dermatol Res Pract. 2010. doi:10.1155/2010/145878. PMC 2913535. PMID 20706544.
- ↑ Jhaj R, Gour PR, Asati DP (2016). "Black hairy tongue with a fixed dose combination of olanzapine and fluoxetine". Indian J Pharmacol. 48 (3): 318–20. doi:10.4103/0253-7613.182894. PMC 4900008. PMID 27298505.
- ↑ Gurvits GE, Tan A (August 2014). "Black hairy tongue syndrome". World J. Gastroenterol. 20 (31): 10845–50. doi:10.3748/wjg.v20.i31.10845. PMC 4138463. PMID 25152586.
- ↑ Erriu M, Pili FM, Denotti G, Garau V (2016). "Black hairy tongue in a patient with amyotrophic lateral sclerosis". J Int Soc Prev Community Dent. 6 (1): 80–3. doi:10.4103/2231-0762.175408. PMC 4784070. PMID 27011938.
- ↑ Kreuter A, Wieland U (May 2011). "Oral hairy leukoplakia: a clinical indicator of immunosuppression". CMAJ. 183 (8): 932. doi:10.1503/cmaj.100841. PMC 3091903. PMID 21398239.
- ↑ Greenspan JS, Greenspan D, Webster-Cyriaque J (April 2016). "Hairy leukoplakia; lessons learned: 30-plus years". Oral Dis. 22 Suppl 1: 120–7. doi:10.1111/odi.12393. PMID 27109280.
- ↑ Aghbali A, Pouralibaba F, Eslami H, Pakdel F, Jamali Z (2009). "White sponge nevus: a case report". J Dent Res Dent Clin Dent Prospects. 3 (2): 70–2. doi:10.5681/joddd.2009.017. PMC 3517290. PMID 23230487.
- ↑ Nichols GE, Cooper PH, Underwood PB, Greer KE (September 1990). "White sponge nevus". Obstet Gynecol. 76 (3 Pt 2): 545–8. PMID 2381643.
- ↑ Gorouhi F, Davari P, Fazel N (2014). "Cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis". ScientificWorldJournal. 2014: 742826. doi:10.1155/2014/742826. PMC 3929580. PMID 24672362.
- ↑ Gupta S, Jawanda MK (2015). "Oral Lichen Planus: An Update on Etiology, Pathogenesis, Clinical Presentation, Diagnosis and Management". Indian J Dermatol. 60 (3): 222–9. doi:10.4103/0019-5154.156315. PMC 4458931. PMID 26120146.
- ↑ Cam K, Santoro A, Lee JB (2012). "Oral frictional hyperkeratosis (morsicatio buccarum): an entity to be considered in the differential diagnosis of white oral mucosal lesions". Skinmed. 10 (2): 114–5. PMID 22545331.
- ↑ Mignogna MD, Fortuna G, Leuci S, Adamo D, Siano M, Makary C, Cafiero C (May 2011). "Frictional keratoses on the facial attached gingiva are rare clinical findings and do not belong to the category of leukoplakia". J. Oral Maxillofac. Surg. 69 (5): 1367–74. doi:10.1016/j.joms.2010.05.087. PMID 21216078.
- ↑ Carlos-Bregni R, Contreras E, Netto AC, Mosqueda-Taylor A, Vargas PA, Jorge J, León JE, de Almeida OP (September 2007). "Oral melanoacanthoma and oral melanotic macule: a report of 8 cases, review of the literature, and immunohistochemical analysis". Med Oral Patol Oral Cir Bucal. 12 (5): E374–9. PMID 17767102.
- ↑ Pais S, Hegde SK, Bhat SS (June 2004). "Oral melanotic macule--a case report". J Indian Soc Pedod Prev Dent. 22 (2): 73–5. PMID 15491090.
- ↑ Cantudo-Sanagustín E, Gutiérrez-Corrales A, Vigo-Martínez M, Serrera-Figallo MÁ, Torres-Lagares D, Gutiérrez-Pérez JL (July 2016). "Pathogenesis and clinicohistopathological caractheristics of melanoacanthoma: A systematic review". J Clin Exp Dent. 8 (3): e327–36. doi:10.4317/jced.52860. PMC 4930645. PMID 27398186.
- ↑ Peters SM, Mandel L, Perrino MA (March 2018). "Oral melanoacanthoma of the palate: An unusual presentation of an uncommon entity". JAAD Case Rep. 4 (2): 138–139. doi:10.1016/j.jdcr.2017.11.023. PMID 29387765.
- ↑ Gupta AA, Nainani P, Upadhyay B, Kavle P (September 2012). "Oral melanoacanthoma: A rare case of diffuse oral pigmentation". J Oral Maxillofac Pathol. 16 (3): 441–3. doi:10.4103/0973-029X.102514. PMID 23248484.
- ↑ Monteiro LS, Costa JA, da Câmara MI, Albuquerque R, Martins M, Pacheco JJ, Salazar F, Figueira F (2015). "Aesthetic Depigmentation of Gingival Smoker's Melanosis Using Carbon Dioxide Lasers". Case Rep Dent. 2015: 510589. doi:10.1155/2015/510589. PMC 4410537. PMID 25954535.
- ↑ Moravej-Salehi E, Moravej-Salehi E, Hajifattahi F (2015). "Relationship of Gingival Pigmentation with Passive Smoking in Women". Tanaffos. 14 (2): 107–14. PMC 4629424. PMID 26528364.
- ↑ Brown FH, Houston GD (August 1991). "Smoker's melanosis. A case report". J. Periodontol. 62 (8): 524–7. doi:10.1902/jop.1991.62.8.524. PMID 1920020.
- ↑ Puttanna A, Cunningham AR, Dainty P (July 2013). "Addison's disease and its associations". BMJ Case Rep. 2013. doi:10.1136/bcr-2013-010473. PMC 3736622. PMID 23893277.
- ↑ Sarkar SB, Sarkar S, Ghosh S, Bandyopadhyay S (October 2012). "Addison's disease". Contemp Clin Dent. 3 (4): 484–6. doi:10.4103/0976-237X.107450. PMC 3636818. PMID 23633816.
- ↑ Mozaffari HR, Rezaei F, Sharifi R, Mirbahari SG (2016). "Seven-Year Follow-Up of Peutz-Jeghers Syndrome". Case Rep Dent. 2016: 6052181. doi:10.1155/2016/6052181. PMC 4852371. PMID 27195155.
- ↑ Choi HS, Park YJ, Park JG (February 1999). "Peutz-Jeghers syndrome: a new understanding". J. Korean Med. Sci. 14 (1): 2–7. doi:10.3346/jkms.1999.14.1.2. PMC 3054160. PMID 10102516.
- ↑ Janardhanan M, Rakesh S, Vinod Kumar R (January 2011). "Intraoral presentation of multiple malignant peripheral nerve sheath tumors associated with neurofibromatosis-1". J Oral Maxillofac Pathol. 15 (1): 46–51. doi:10.4103/0973-029X.80025. PMC 3125655. PMID 21731277.
- ↑ Thammaiah S, Manjunath M, Rao K, Uma DH (January 2011). "Intraoral plexiform neurofibroma involving the maxilla - pathognomonic of neurofibromatosis type I". J Pediatr Neurosci. 6 (1): 65–8. doi:10.4103/1817-1745.84413. PMC 3173921. PMID 21977094.
- ↑ Janardhanan M, Rakesh S, Vinod Kumar R (January 2011). "Intraoral presentation of multiple malignant peripheral nerve sheath tumors associated with neurofibromatosis-1". J Oral Maxillofac Pathol. 15 (1): 46–51. doi:10.4103/0973-029X.80025. PMC 3125655. PMID 21731277.
- ↑ Thammaiah S, Manjunath M, Rao K, Uma DH (January 2011). "Intraoral plexiform neurofibroma involving the maxilla - pathognomonic of neurofibromatosis type I". J Pediatr Neurosci. 6 (1): 65–8. doi:10.4103/1817-1745.84413. PMC 3173921. PMID 21977094.
- ↑ Lundin K, Schmidt G, Bonde C (2013). "Amalgam tattoo mimicking mucosal melanoma: a diagnostic dilemma revisited". Case Rep Dent. 2013: 787294. doi:10.1155/2013/787294. PMC 3606745. PMID 23533829.
- ↑ Buchner A, Hansen LS (February 1980). "Amalgam pigmentation (amalgam tattoo) of the oral mucosa. A clinicopathologic study of 268 cases". Oral Surg. Oral Med. Oral Pathol. 49 (2): 139–47. PMID 6928285.
- ↑ Mohan RP, Verma S, Singh U, Agarwal N (July 2013). "Acute primary herpetic gingivostomatitis". BMJ Case Rep. 2013. doi:10.1136/bcr-2013-200074. PMC 3736476. PMID 23839615.
- ↑ Tovaru S, Parlatescu I, Tovaru M, Cionca L (February 2009). "Primary herpetic gingivostomatitis in children and adults". Quintessence Int. 40 (2): 119–24. PMID 19169443.
- ↑ Amir J, Nussinovitch M, Kleper R, Cohen HA, Varsano I (1997). "Primary herpes simplex virus type 1 gingivostomatitis in pediatric personnel". Infection. 25 (5): 310–2. PMID 9334868.
- ↑ Mohan RP, Verma S, Singh U, Agarwal N (June 2013). "Herpes zoster". BMJ Case Rep. 2013. doi:10.1136/bcr-2013-010246. PMC 3702907. PMID 23771975.
- ↑ Patil S, Srinivas K, Reddy BS, Gupta M (March 2013). "Prodromal herpes zoster mimicking odontalgia--a diagnostic challenge". Ethiop J Health Sci. 23 (1): 73–7. PMC 3613819. PMID 23559842.
- ↑ Kolokotronis A, Louloudiadis K, Fotiou G, Matiais A (2001). "Oral manifestations of infections of infections due to varicella zoster virus in otherwise healthy children". J Clin Pediatr Dent. 25 (2): 107–12. PMID 11314207.
- ↑ Muppa R, Bhupatiraju P, Duddu M, Dandempally A (2011). "Hand, foot and mouth disease". J Indian Soc Pedod Prev Dent. 29 (2): 165–7. doi:10.4103/0970-4388.84692. PMID 21911958.
- ↑ Kashyap RR, Kashyap RS (April 2015). "Hand, foot and mouth disease - a short case report". J Clin Exp Dent. 7 (2): e336–8. doi:10.4317/jced.52031. PMC 4483348. PMID 26155357.
- ↑ Liu B, Luo L, Yan S, Wen T, Bai W, Li H, Zhang G, Lu X, Liu Y, He L (2015). "Clinical Features for Mild Hand, Foot and Mouth Disease in China". PLoS ONE. 10 (8): e0135503. doi:10.1371/journal.pone.0135503. PMC 4547800. PMID 26302092.
- ↑ Odumade OA, Hogquist KA, Balfour HH (January 2011). "Progress and problems in understanding and managing primary Epstein-Barr virus infections". Clin. Microbiol. Rev. 24 (1): 193–209. doi:10.1128/CMR.00044-10. PMC 3021204. PMID 21233512.
- ↑ Grimm JM, Schmeling DO, Dunmire SK, Knight JA, Mullan BD, Ed JA, Brundage RC, Hogquist KA, Balfour HH (August 2016). "Prospective studies of infectious mononucleosis in university students". Clin Transl Immunology. 5 (8): e94. doi:10.1038/cti.2016.48. PMID 27588199.
- ↑ Omal P, Jacob V, Prathap A, Thomas NG (March 2012). "Prevalence of oral, skin, and oral and skin lesions of lichen planus in patients visiting a dental school in southern India". Indian J Dermatol. 57 (2): 107–9. doi:10.4103/0019-5154.94276. PMC 3352630. PMID 22615505.
- ↑ Belal MH (2015). "Management of symptomatic erosive-ulcerative lesions of oral lichen planus in an adult Egyptian population using Selenium-ACE combined with topical corticosteroids plus antifungal agent". Contemp Clin Dent. 6 (4): 454–60. doi:10.4103/0976-237X.169837. PMC 4678540. PMID 26681847.
- ↑ Chitturi RT, Sindhuja P, Parameswar RA, Nirmal RM, Reddy BV, Dineshshankar J, Yoithapprabhunath TR (August 2015). "A clinical study on oral lichen planus with special emphasis on hyperpigmentation". J Pharm Bioallied Sci. 7 (Suppl 2): S495–8. doi:10.4103/0975-7406.163513. PMC 4606647. PMID 26538905.
- ↑ Williams D, Lewis M (January 2011). "Pathogenesis and treatment of oral candidosis". J Oral Microbiol. 3. doi:10.3402/jom.v3i0.5771. PMC 3087208. PMID 21547018.
- ↑ Warrier SA, Sathasivasubramanian S (August 2015). "Human immunodeficiency virus induced oral candidiasis". J Pharm Bioallied Sci. 7 (Suppl 2): S812–4. doi:10.4103/0975-7406.163577. PMC 4606720. PMID 26538978.
- ↑ Byadarahally Raju S, Rajappa S (2011). "Isolation and identification of Candida from the oral cavity". ISRN Dent. 2011: 487921. doi:10.5402/2011/487921. PMC 3205665. PMID 22111010.
- ↑ Chatterjee D, Chatterjee A, Agarwal M, Mathur M, Mathur S, Mallikarjun R, Banerjee S (2017). "Disseminated Histoplasmosis with Oral Manifestation in an Immunocompetent Patient". Case Rep Dent. 2017: 1323514. doi:10.1155/2017/1323514. PMC 5306962. PMID 28255468.
- ↑ Vidyanath S, Shameena P, Sudha S, Nair RG (January 2013). "Disseminated histoplasmosis with oral and cutaneous manifestations". J Oral Maxillofac Pathol. 17 (1): 139–42. doi:10.4103/0973-029X.110722. PMC 3687172. PMID 23798850.
- ↑ Patil K, Mahima VG, Prathibha Rani RM (September 2009). "Oral histoplasmosis". J Indian Soc Periodontol. 13 (3): 157–9. doi:10.4103/0972-124X.60230. PMC 2848788. PMID 20379415.
- ↑ Brazão-Silva MT, Mancusi GW, Bazzoun FV, Ishisaki GY, Marcucci M (January 2013). "A gingival manifestation of histoplasmosis leading diagnosis". Contemp Clin Dent. 4 (1): 97–101. doi:10.4103/0976-237X.111621. PMC 3703707. PMID 23853464.
- ↑ Souza BC, Munerato MC (2017). "Oral manifestation of histoplasmosis on the palate". An Bras Dermatol. 92 (5 Suppl 1): 107–109. doi:10.1590/abd1806-4841.20175751. PMC 5726694. PMID 29267463.
- ↑ Kruse AL, Zwahlen RA, Bredell MG, Gengler C, Dannemann C, Grätz KW (January 2010). "Primary blastomycosis of oral cavity". J Craniofac Surg. 21 (1): 121–3. doi:10.1097/SCS.0b013e3181c4680c. PMID 20072023.
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# Causes
## Causes in Alphabetical Order
- Agranulocytosis
- Aphthous stomatitis
- Allergic contact dermatitis
- Behcet's disease
- Bollus disease
- Chemotherapy drugs
- Erythema multiforme
- Herpes stomatitis
- Histoplasmosis
- Primary syphilis
- Self limited viral disease
- Squamous cell carcinoma
# Diagnosis
## History and Symptoms
- Past medical/medicinal history
- If the lesions occur in the same locations every time, culpit is HSV
- Consider the patients sexual history
- Evaluate open and mucosal lesions
- Lichen planus - lacy white plaques
## Laboratory Findings
- Culture for HSV-1
- RPR
- CBC
- Punch biopsy
# Treatment
## Medical Therapy
### Acute Pharmacotherapies
- Orabase and topical steroids can increase speed of healing
- Aphthous stomatitis - intralesional triamcinalone injections
- HSV (recurrent) - acyclovir
- Bollous disease - corticosteroids | Oral lesions
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2] Aditya Ganti M.B.B.S. [3]
Synonyms and keywords: Oral cavity lesions, Oral cavity ulcers, Oral cavity infections, Mouth ulcers, Mouth lesions.
# Overview
In many cases, mouth sores are attributed to herpes simplex virus and idiopathic aphthous stomatitis. Oral lesions can be indicative of a more serious underlying condition. A full review of the systems and a full skin exam are necessary to obtain an accurate diagnosis.
# Pathophysiology
# Differential diagnosis of oral cavity lesions
- ↑ Jahanbani J, Sandvik L, Lyberg T, Ahlfors E (March 2009). "Evaluation of oral mucosal lesions in 598 referred Iranian patients". Open Dent J. 3: 42–7. doi:10.2174/1874210600903010042. PMID 19444343..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Abidullah M, Raghunath V, Karpe T, Akifuddin S, Imran S, Dhurjati VN, Aleem MA, Khatoon F (February 2016). "Clinicopathologic Correlation of White, Non scrapable Oral Mucosal Surface Lesions: A Study of 100 Cases". J Clin Diagn Res. 10 (2): ZC38–41. doi:10.7860/JCDR/2016/16950.7226. PMC 4800649. PMID 27042583.
- ↑ Lee JH, Lee JH, Kwon NH, Yu DS, Kim GM, Park CJ, Lee JD, Kim SY (February 2012). "Clinicopathologic Manifestations of Patients with Fordyce's Spots". Ann Dermatol. 24 (1): 103–6. doi:10.5021/ad.2012.24.1.103. PMC 3283840. PMID 22363169.
- ↑ Olivier JH (March 2006). "Fordyce granules on the prolabial and oral mucous membranes of a selected population". SADJ. 61 (2): 072–4. PMID 16711559.
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- ↑ Picciani BL, Domingos TA, Teixeira-Souza T, Santos Vde C, Gonzaga HF, Cardoso-Oliveira J, Gripp AC, Dias EP, Carneiro S (2016). "Geographic tongue and psoriasis: clinical, histopathological, immunohistochemical and genetic correlation - a literature review". An Bras Dermatol. 91 (4): 410–21. doi:10.1590/abd1806-4841.20164288. PMC 4999097. PMID 27579734.
- ↑ Tarakji B, Umair A, Babaker Z, Sn A, Gazal G, Sarraj F (November 2014). "Relation between psoriasis and geographic tongue". J Clin Diagn Res. 8 (11): ZE06–7. doi:10.7860/JCDR/2014/9101.5171. PMC 4290356. PMID 25584342.
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- ↑ Thammaiah S, Manjunath M, Rao K, Uma DH (January 2011). "Intraoral plexiform neurofibroma involving the maxilla - pathognomonic of neurofibromatosis type I". J Pediatr Neurosci. 6 (1): 65–8. doi:10.4103/1817-1745.84413. PMC 3173921. PMID 21977094.
- ↑ Janardhanan M, Rakesh S, Vinod Kumar R (January 2011). "Intraoral presentation of multiple malignant peripheral nerve sheath tumors associated with neurofibromatosis-1". J Oral Maxillofac Pathol. 15 (1): 46–51. doi:10.4103/0973-029X.80025. PMC 3125655. PMID 21731277.
- ↑ Thammaiah S, Manjunath M, Rao K, Uma DH (January 2011). "Intraoral plexiform neurofibroma involving the maxilla - pathognomonic of neurofibromatosis type I". J Pediatr Neurosci. 6 (1): 65–8. doi:10.4103/1817-1745.84413. PMC 3173921. PMID 21977094.
- ↑ Lundin K, Schmidt G, Bonde C (2013). "Amalgam tattoo mimicking mucosal melanoma: a diagnostic dilemma revisited". Case Rep Dent. 2013: 787294. doi:10.1155/2013/787294. PMC 3606745. PMID 23533829.
- ↑ Buchner A, Hansen LS (February 1980). "Amalgam pigmentation (amalgam tattoo) of the oral mucosa. A clinicopathologic study of 268 cases". Oral Surg. Oral Med. Oral Pathol. 49 (2): 139–47. PMID 6928285.
- ↑ Mohan RP, Verma S, Singh U, Agarwal N (July 2013). "Acute primary herpetic gingivostomatitis". BMJ Case Rep. 2013. doi:10.1136/bcr-2013-200074. PMC 3736476. PMID 23839615.
- ↑ Tovaru S, Parlatescu I, Tovaru M, Cionca L (February 2009). "Primary herpetic gingivostomatitis in children and adults". Quintessence Int. 40 (2): 119–24. PMID 19169443.
- ↑ Amir J, Nussinovitch M, Kleper R, Cohen HA, Varsano I (1997). "Primary herpes simplex virus type 1 gingivostomatitis in pediatric personnel". Infection. 25 (5): 310–2. PMID 9334868.
- ↑ Mohan RP, Verma S, Singh U, Agarwal N (June 2013). "Herpes zoster". BMJ Case Rep. 2013. doi:10.1136/bcr-2013-010246. PMC 3702907. PMID 23771975.
- ↑ Patil S, Srinivas K, Reddy BS, Gupta M (March 2013). "Prodromal herpes zoster mimicking odontalgia--a diagnostic challenge". Ethiop J Health Sci. 23 (1): 73–7. PMC 3613819. PMID 23559842.
- ↑ Kolokotronis A, Louloudiadis K, Fotiou G, Matiais A (2001). "Oral manifestations of infections of infections due to varicella zoster virus in otherwise healthy children". J Clin Pediatr Dent. 25 (2): 107–12. PMID 11314207.
- ↑ Muppa R, Bhupatiraju P, Duddu M, Dandempally A (2011). "Hand, foot and mouth disease". J Indian Soc Pedod Prev Dent. 29 (2): 165–7. doi:10.4103/0970-4388.84692. PMID 21911958.
- ↑ Kashyap RR, Kashyap RS (April 2015). "Hand, foot and mouth disease - a short case report". J Clin Exp Dent. 7 (2): e336–8. doi:10.4317/jced.52031. PMC 4483348. PMID 26155357.
- ↑ Liu B, Luo L, Yan S, Wen T, Bai W, Li H, Zhang G, Lu X, Liu Y, He L (2015). "Clinical Features for Mild Hand, Foot and Mouth Disease in China". PLoS ONE. 10 (8): e0135503. doi:10.1371/journal.pone.0135503. PMC 4547800. PMID 26302092.
- ↑ Odumade OA, Hogquist KA, Balfour HH (January 2011). "Progress and problems in understanding and managing primary Epstein-Barr virus infections". Clin. Microbiol. Rev. 24 (1): 193–209. doi:10.1128/CMR.00044-10. PMC 3021204. PMID 21233512.
- ↑ Grimm JM, Schmeling DO, Dunmire SK, Knight JA, Mullan BD, Ed JA, Brundage RC, Hogquist KA, Balfour HH (August 2016). "Prospective studies of infectious mononucleosis in university students". Clin Transl Immunology. 5 (8): e94. doi:10.1038/cti.2016.48. PMID 27588199.
- ↑ Omal P, Jacob V, Prathap A, Thomas NG (March 2012). "Prevalence of oral, skin, and oral and skin lesions of lichen planus in patients visiting a dental school in southern India". Indian J Dermatol. 57 (2): 107–9. doi:10.4103/0019-5154.94276. PMC 3352630. PMID 22615505.
- ↑ Belal MH (2015). "Management of symptomatic erosive-ulcerative lesions of oral lichen planus in an adult Egyptian population using Selenium-ACE combined with topical corticosteroids plus antifungal agent". Contemp Clin Dent. 6 (4): 454–60. doi:10.4103/0976-237X.169837. PMC 4678540. PMID 26681847.
- ↑ Chitturi RT, Sindhuja P, Parameswar RA, Nirmal RM, Reddy BV, Dineshshankar J, Yoithapprabhunath TR (August 2015). "A clinical study on oral lichen planus with special emphasis on hyperpigmentation". J Pharm Bioallied Sci. 7 (Suppl 2): S495–8. doi:10.4103/0975-7406.163513. PMC 4606647. PMID 26538905.
- ↑ Williams D, Lewis M (January 2011). "Pathogenesis and treatment of oral candidosis". J Oral Microbiol. 3. doi:10.3402/jom.v3i0.5771. PMC 3087208. PMID 21547018.
- ↑ Warrier SA, Sathasivasubramanian S (August 2015). "Human immunodeficiency virus induced oral candidiasis". J Pharm Bioallied Sci. 7 (Suppl 2): S812–4. doi:10.4103/0975-7406.163577. PMC 4606720. PMID 26538978.
- ↑ Byadarahally Raju S, Rajappa S (2011). "Isolation and identification of Candida from the oral cavity". ISRN Dent. 2011: 487921. doi:10.5402/2011/487921. PMC 3205665. PMID 22111010.
- ↑ Chatterjee D, Chatterjee A, Agarwal M, Mathur M, Mathur S, Mallikarjun R, Banerjee S (2017). "Disseminated Histoplasmosis with Oral Manifestation in an Immunocompetent Patient". Case Rep Dent. 2017: 1323514. doi:10.1155/2017/1323514. PMC 5306962. PMID 28255468.
- ↑ Vidyanath S, Shameena P, Sudha S, Nair RG (January 2013). "Disseminated histoplasmosis with oral and cutaneous manifestations". J Oral Maxillofac Pathol. 17 (1): 139–42. doi:10.4103/0973-029X.110722. PMC 3687172. PMID 23798850.
- ↑ Patil K, Mahima VG, Prathibha Rani RM (September 2009). "Oral histoplasmosis". J Indian Soc Periodontol. 13 (3): 157–9. doi:10.4103/0972-124X.60230. PMC 2848788. PMID 20379415.
- ↑ Brazão-Silva MT, Mancusi GW, Bazzoun FV, Ishisaki GY, Marcucci M (January 2013). "A gingival manifestation of histoplasmosis leading diagnosis". Contemp Clin Dent. 4 (1): 97–101. doi:10.4103/0976-237X.111621. PMC 3703707. PMID 23853464.
- ↑ Souza BC, Munerato MC (2017). "Oral manifestation of histoplasmosis on the palate". An Bras Dermatol. 92 (5 Suppl 1): 107–109. doi:10.1590/abd1806-4841.20175751. PMC 5726694. PMID 29267463.
- ↑ Kruse AL, Zwahlen RA, Bredell MG, Gengler C, Dannemann C, Grätz KW (January 2010). "Primary blastomycosis of oral cavity". J Craniofac Surg. 21 (1): 121–3. doi:10.1097/SCS.0b013e3181c4680c. PMID 20072023.
- ↑ Thomas J, Munson E, Christianson JC (August 2014). "Unexpected Blastomyces dermatitidis etiology of fungal sinusitis and erosive palatal infection in a diabetic patient". J. Clin. Microbiol. 52 (8): 3130–3. doi:10.1128/JCM.01392-14. PMC 4136175. PMID 24899035.
- ↑ Webber LP, Martins MD, de Oliveira MG, Munhoz EA, Carrard VC (April 2014). "Disseminated paracoccidioidomycosis diagnosis based on oral lesions". Contemp Clin Dent. 5 (2): 213–6. doi:10.4103/0976-237X.132340. PMC 4067786. PMID 24963249.
- ↑ Mendez LA, Flores SA, Martinez R, de Almeida OP (2017). "Ulcerated Lesion of the Tongue as Manifestation of Systemic Coccidioidomycosis". Case Rep Med. 2017: 1489501. doi:10.1155/2017/1489501. PMC 5366790. PMID 28386282.
- ↑ Rodriguez RA, Konia T (January 2005). "Coccidioidomycosis of the tongue". Arch. Pathol. Lab. Med. 129 (1): e4–6. doi:10.1043/1543-2165(2005)129<e4:COTT>2.0.CO;2. PMID 15628927.
- ↑ McConnell MF, Shi A, Lasco TM, Yoon L (March 2017). "Disseminated coccidioidomycosis with multifocal musculoskeletal disease involvement". Radiol Case Rep. 12 (1): 141–145. doi:10.1016/j.radcr.2016.11.017. PMC 5310389. PMID 28228898.
- ↑ Valdivia L, Nix D, Wright M, Lindberg E, Fagan T, Lieberman D, Stoffer T, Ampel NM, Galgiani JN (June 2006). "Coccidioidomycosis as a common cause of community-acquired pneumonia". Emerging Infect. Dis. 12 (6): 958–62. PMC 3373055. PMID 16707052.
- ↑ Arpita R, Monica A, Venkatesh N, Atul S, Varun M (October 2015). "Oral Pemphigus Vulgaris: Case Report". Ethiop J Health Sci. 25 (4): 367–72. PMID 26949302.
- ↑ Kumar SJ, Nehru Anand SP, Gunasekaran N, Krishnan R (2016). "Oral pemphigus vulgaris: A case report with direct immunofluorescence study". J Oral Maxillofac Pathol. 20 (3): 549. doi:10.4103/0973-029X.190979. PMID 27721634.
- ↑ Rath SK, Reenesh M (October 2012). "Gingival pemphigus vulgaris preceding cutaneous lesion: A rare case report". J Indian Soc Periodontol. 16 (4): 588–91. doi:10.4103/0972-124X.106922. PMC 3590732. PMID 23493851.
- ↑ Vijayan V, Paul A, Babu K, Madhan B (2016). "Desquamative gingivitis as only presenting sign of mucous membrane pemphigoid". J Indian Soc Periodontol. 20 (3): 340–3. doi:10.4103/0972-124X.182602. PMID 27563211.
- ↑ Trimarchi M, Bellini C, Fabiano B, Gerevini S, Bussi M (August 2009). "Multiple mucosal involvement in cicatricial pemphigoid". Acta Otorhinolaryngol Ital. 29 (4): 222–5. PMC 2816372. PMID 20161882.
- ↑ Schellinck AE, Rees TD, Plemons JM, Kessler HP, Rivera-Hidalgo F, Solomon ES (November 2009). "A comparison of the periodontal status in patients with mucous membrane pemphigoid: a 5-year follow-up". J. Periodontol. 80 (11): 1765–73. doi:10.1902/jop.2009.090244. PMID 19905946.
- ↑ Altenburg A, El-Haj N, Micheli C, Puttkammer M, Abdel-Naser MB, Zouboulis CC (October 2014). "The treatment of chronic recurrent oral aphthous ulcers". Dtsch Arztebl Int. 111 (40): 665–73. doi:10.3238/arztebl.2014.0665. PMC 4215084. PMID 25346356.
- ↑ Vaillant L, Samimi M (February 2016). "[Aphthous ulcers and oral ulcerations]". Presse Med (in French). 45 (2): 215–26. doi:10.1016/j.lpm.2016.01.005. PMID 26880080.CS1 maint: Unrecognized language (link)
- ↑ Bucci P, Carile F, Sangianantoni A, Sangianantoni A, D'Angiò F, Santarelli A, Lo Muzio L (February 2006). "Oral aphthous ulcers and dental enamel defects in children with coeliac disease". Acta Paediatr. 95 (2): 203–7. doi:10.1080/08035250500355022. PMID 16449028.
- ↑ Scully C, Bagan J (March 2008). "Oral mucosal diseases: erythema multiforme". Br J Oral Maxillofac Surg. 46 (2): 90–5. doi:10.1016/j.bjoms.2007.07.202. PMID 17767983.
- ↑ Joseph TI, Vargheese G, George D, Sathyan P (January 2012). "Drug induced oral erythema multiforme: A rare and less recognized variant of erythema multiforme". J Oral Maxillofac Pathol. 16 (1): 145–8. doi:10.4103/0973-029X.92995. PMC 3303512. PMID 22434953.
- ↑ Speight PM (September 2007). "Update on oral epithelial dysplasia and progression to cancer". Head Neck Pathol. 1 (1): 61–6. doi:10.1007/s12105-007-0014-5. PMC 2807503. PMID 20614284.
- ↑ Zhang GZ, Zhang GQ, Xiu JM, Wang XM (October 2012). "Intraoral multifocal and multinodular adult rhabdomyoma: report of a case". J. Oral Maxillofac. Surg. 70 (10): 2480–5. doi:10.1016/j.joms.2011.12.006. PMID 22305873.
- ↑ da Silva WB, Ribeiro AL, de Menezes SA, de Jesus Viana Pinheiro J, de Melo Alves-Junior S (December 2014). "Oral capillary hemangioma: a clinical protocol of diagnosis and treatment in adults". Oral Maxillofac Surg. 18 (4): 431–7. doi:10.1007/s10006-013-0436-z. PMID 24263242.
- ↑ Dilsiz A, Aydin T, Gursan N (September 2009). "Capillary hemangioma as a rare benign tumor of the oral cavity: a case report". Cases J. 2: 8622. doi:10.1186/1757-1626-0002-0000008622. PMC 2827094. PMID 20181211.
- ↑ Agarwal S (September 2012). "Treatment of oral hemangioma with 3% sodium tetradecyl sulfate: study of 20 cases". Indian J Otolaryngol Head Neck Surg. 64 (3): 205–7. doi:10.1007/s12070-011-0249-z. PMC 3431531. PMID 23998020.
- ↑ Arul AS, Kumar AR, Verma S, Arul AS (2015). "Oral Kaposi's sarcoma: Sole presentation in HIV seropositive patient". J Nat Sci Biol Med. 6 (2): 459–61. doi:10.4103/0976-9668.160041. PMID 26283853.
- ↑ Mehta S, Garg A, Gupta LK, Mittal A, Khare AK, Kuldeep CM (July 2011). "Kaposi's sarcoma as a presenting manifestation of HIV". Indian J Sex Transm Dis AIDS. 32 (2): 108–10. doi:10.4103/0253-7184.85415. PMC 3195171. PMID 22021973.
- ↑ Meng GZ, Zhang HY, Bu H, Zhang XL, Pang ZG, Ke Q, Liu X, Yang G (March 2007). "Myofibroblastic sarcomas: a clinicopathological study of 20 cases". Chin. Med. J. 120 (5): 363–9. PMID 17376304.
- ↑ Mentzel T, Dry S, Katenkamp D, Fletcher CD (October 1998). "Low-grade myofibroblastic sarcoma: analysis of 18 cases in the spectrum of myofibroblastic tumors". Am. J. Surg. Pathol. 22 (10): 1228–38. PMID 9777985.
- ↑ Yamada T, Yoshimura T, Kitamura N, Sasabe E, Ohno S, Yamamoto T (September 2012). "Low-grade myofibroblastic sarcoma of the palate". Int J Oral Sci. 4 (3): 170–3. doi:10.1038/ijos.2012.49. PMID 22935748.
- ↑ Castillo JJ, Bibas M, Miranda RN (April 2015). "The biology and treatment of plasmablastic lymphoma". Blood. 125 (15): 2323–30. doi:10.1182/blood-2014-10-567479. PMID 25636338.
- ↑ Vega F, Chang CC, Medeiros LJ, Udden MM, Cho-Vega JH, Lau CC, Finch CJ, Vilchez RA, McGregor D, Jorgensen JL (June 2005). "Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles". Mod. Pathol. 18 (6): 806–15. doi:10.1038/modpathol.3800355. PMID 15578069.
- ↑ Castillo J, Pantanowitz L, Dezube BJ (October 2008). "HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases". Am. J. Hematol. 83 (10): 804–9. doi:10.1002/ajh.21250. PMID 18756521.
- ↑ Aricò M, Girschikofsky M, Généreau T, Klersy C, McClain K, Grois N, Emile JF, Lukina E, De Juli E, Danesino C (November 2003). "Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society". Eur. J. Cancer. 39 (16): 2341–8. PMID 14556926.
- ↑ Piattelli A, Paolantonio M (August 1995). "Eosinophilic granuloma of the mandible involving the periodontal tissues. A case report". J. Periodontol. 66 (8): 731–6. doi:10.1902/jop.1995.66.8.731. PMID 7473016.
- ↑ Eckardt A, Schultze A (October 2003). "Maxillofacial manifestations of Langerhans cell histiocytosis: a clinical and therapeutic analysis of 10 patients". Oral Oncol. 39 (7): 687–94. PMID 12907208.
- ↑ Kurdoğlu B, Oztemel A, Barış E, Sengüven B (September 2013). "Primary oral myeloid sarcoma: Report of a case". J Oral Maxillofac Pathol. 17 (3): 413–6. doi:10.4103/0973-029X.125209. PMC 3927345. PMID 24574662.
- ↑ Kumar P, Singh H, Khurana N, Urs AB, Augustine J, Tomar R (March 2017). "Diagnostic challenges with intraoral myeloid sarcoma: report of two cases & review of world literature". Exp. Oncol. 39 (1): 78–85. PMID 28361861.
- ↑ Papamanthos MK, Kolokotronis AE, Skulakis HE, Fericean AM, Zorba MT, Matiakis AT (June 2010). "Acute myeloid leukaemia diagnosed by intra-oral myeloid sarcoma. A case report". Head Neck Pathol. 4 (2): 132–5. doi:10.1007/s12105-010-0163-9. PMC 2878628. PMID 20512638.
- ↑ Bosanquet D, Roblin G (2009). "Congenital epulis: a case report and estimation of incidence". Int J Otolaryngol. 2009: 508780. doi:10.1155/2009/508780. PMC 2809329. PMID 20130770.
- ↑ Vered M, Dobriyan A, Buchner A (March 2009). "Congenital granular cell epulis presents an immunohistochemical profile that distinguishes it from the granular cell tumor of the adult". Virchows Arch. 454 (3): 303–10. doi:10.1007/s00428-009-0733-y. PMID 19205730.
- ↑ Angiero F (November 2010). "Ectomesenchymal chondromyxoid tumour of the tongue. A review of histological and immunohistochemical features". Anticancer Res. 30 (11): 4685–9. PMID 21115924.
- ↑ Kannan R, Damm DD, White DK, Marsh W, Allen CM (October 1996). "Ectomesenchymal chondromyxoid tumor of the anterior tongue: a report of three cases". Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 82 (4): 417–22. PMID 8899780.
- ↑ Sykara M, Ntovas P, Kalogirou EM, Tosios KI, Sklavounou A (August 2017). "Oral lymphoepithelial cyst: A clinicopathological study of 26 cases and review of the literature". J Clin Exp Dent. 9 (8): e1035–e1043. doi:10.4317/jced.54072. PMC 5601105. PMID 28936296.
- ↑ Stramandinoli-Zanicotti RT, de Castro Ávila LF, de Azevedo Izidoro AC, Izidoro FA, Schussel JL (2012). "Lymphoepithelial cysts of oral mucosa: two cases in different regions". Bull. Tokyo Dent. Coll. 53 (1): 17–22. PMID 22452887.
- ↑ De Ponte FS, Brunelli A, Marchetti E, Bottini DJ (March 2002). "Sublingual epidermoid cyst". J Craniofac Surg. 13 (2): 308–10. PMID 12000893.
- ↑ Ozan F, Polat HB, Ay S, Goze F (March 2007). "Epidermoid cyst of the buccal mucosa: a case report". J Contemp Dent Pract. 8 (3): 90–6. PMID 17351686.
- ↑ Puranik SR, Puranik RS, Prakash S, Bimba M (2016). "Epidermoid cyst: Report of two cases". J Oral Maxillofac Pathol. 20 (3): 546. doi:10.4103/0973-029X.190965. PMC 5051311. PMID 27721628.
- ↑ Urao M, Teitelbaum DH, Miyano T (November 1996). "Lingual thyroglossal duct cyst: a unique surgical approach". J. Pediatr. Surg. 31 (11): 1574–6. PMID 8943128.
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# Causes
## Causes in Alphabetical Order[1][2]
- Agranulocytosis
- Aphthous stomatitis
- Allergic contact dermatitis
- Behcet's disease
- Bollus disease
- Chemotherapy drugs
- Erythema multiforme
- Herpes stomatitis
- Histoplasmosis
- Primary syphilis
- Self limited viral disease
- Squamous cell carcinoma
# Diagnosis
## History and Symptoms
- Past medical/medicinal history
- If the lesions occur in the same locations every time, culpit is HSV
- Consider the patients sexual history
- Evaluate open and mucosal lesions
- Lichen planus - lacy white plaques
## Laboratory Findings
- Culture for HSV-1
- RPR
- CBC
- Punch biopsy
# Treatment
## Medical Therapy
### Acute Pharmacotherapies
- Orabase and topical steroids can increase speed of healing
- Aphthous stomatitis - intralesional triamcinalone injections
- HSV (recurrent) - acyclovir
- Bollous disease - corticosteroids | https://www.wikidoc.org/index.php/Ddx:Oral_Lesions | |
91a5133431901d60fac62e2dbf01c7733e51e07f | wikidoc | Pancytopenia | Pancytopenia
Pancytopenia is not equivalent with bone marrow suppression. Pancytopenia is a lab finding that may related to either bone marrow suppression or peripheral sequestration/destruction. For details about bone marrow suppression click here.
# Overview
Pancytopenia is the reduction in numbers of all three bone marrow cell types, including red blood cells, white blood cells, and platelets. The prefix "pan-" means "everything," "cyto" means "cell", and the suffix "penia" means "deficiency." Pancytopenia is not a disease, but rather a laboratory finding that may related to bone marrow suppression caused by either insufficient production (aplastic anemia), inability of cells to mature (myelodysplasia), replacement of normal bone marrow with fibrosis (myelofibrosis) or peripheral sequestration that is not related to the bone marrow (e.g. splenomegaly or hypersplenism). Chemotherapy is associated with pancytopenia due to drug-mediated bone marrow suppression. Pancytopenia frequently requires a bone marrow biopsy in order to distinguish among different causes.
# Historical Perspective
The history of pancytopenia relates to the history of each of its individual sub-entities, namely anemia, thrombocytopenia, and leukopenia. Pancytopenia was not recognized as a distinct clinical entity until after each of its other subcomponents were characterized. Thus, there is no specific history for pancytopenia.
- History of aplastic anemia:
The seminal discoveries for aplastic anemia were made by Bruno Speck and Georges Mathe, who noted that immunosuppression could be used to treat aplastic anemia.
In the 1970s, matched sibling donor transplant was used for severe aplastic anemia.
- The seminal discoveries for aplastic anemia were made by Bruno Speck and Georges Mathe, who noted that immunosuppression could be used to treat aplastic anemia.
- In the 1970s, matched sibling donor transplant was used for severe aplastic anemia.
- History of paroxysmal nocturnal hemoglobinuria:
In 1882, Dr. Paul Strubing reported the case of a patient with hematuria at night that occurred periodically.
He noted that hemolysis was the reason for the patient's hematuria.
In 1925, the term paroxysmal nocturnal hemaglobinuria was coined.
In the 1930s, Dr. T.H. Ham noted that acidified serum could induce hemolysis.
Thus, the Ham's acid serum test was developed.
This became the first diagnostic test for this disease.
In the 1950s, the complement pathway was discovered, and it was determined that paroxysmal nocturnal hemoglobinuria was due to activation of complement proteins on the red blood cell membrane.
In the 1980s, the genetic defect responsible for the disease was discovered, specifically, the PIG-A gene defect leading to inability to anchor complement-inhibitory proteins onto the red blood cell membrane.
- In 1882, Dr. Paul Strubing reported the case of a patient with hematuria at night that occurred periodically.
He noted that hemolysis was the reason for the patient's hematuria.
- He noted that hemolysis was the reason for the patient's hematuria.
- In 1925, the term paroxysmal nocturnal hemaglobinuria was coined.
- In the 1930s, Dr. T.H. Ham noted that acidified serum could induce hemolysis.
Thus, the Ham's acid serum test was developed.
This became the first diagnostic test for this disease.
- Thus, the Ham's acid serum test was developed.
- This became the first diagnostic test for this disease.
- In the 1950s, the complement pathway was discovered, and it was determined that paroxysmal nocturnal hemoglobinuria was due to activation of complement proteins on the red blood cell membrane.
- In the 1980s, the genetic defect responsible for the disease was discovered, specifically, the PIG-A gene defect leading to inability to anchor complement-inhibitory proteins onto the red blood cell membrane.
# Classification
There is no classification system for pancytopenia. However, some underlying disease entities that cause pancytopenia have classification. For example, aplastic anemia is classified as moderate, severe, or very severe.
# Pathophysiology
- The pathophysiology of pancytopenia relates to the underlying etiology.
- In most cases, pancytopenia is due to a disruption in trilineage hematopoiesis.
- This means that the bone marrow is not appropriately producing erythrocytes, leukocytes, and thrombocytocytes.
- The cause of the disruption in trilineage hematopoiesis is in turn due to the underlying cause of pancytopenia.
- For example, viral-mediated pancytopenia is caused by viral particles infecting hematopoietic cells and preventing normal cell division.
- Leukemia-mediated pancytopenia is typically due to marrow replacement of normal hematopoietic precursors, a process known as myelopthisis.
- Leukemic infiltration of the bone marrow creates a "crowding-out" phenomenon.
# Causes
## Life Threatening Causes
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no life-threatening causes of pancytopenia that require acute treatment within 24 hours. However, if pancytopenia is accompanied by fever, this should be treated as a hematologic emergency with prompt administration of IV antibiotics.
## Common Causes
- Aplastic anemia
This is a condition characterized by immune-mediated reduction in all three hematopoietic cell lines with absence of hematopoietic precursors.
It is a rare condition with a prevalence of only 1-2 cases per million annually. It is most commonly diagnosed in childhood.
Epidemiologic studies have shown a greater prevalence in Southeast Asia and other countries with limited access to healthcare, as viral infection can trigger aplastic crisis.
There are three categories: moderate, severe, and very severe.
These categories are based upon the number and degree of cytopenias as well as bone marrow cellularity.
The preferred treatment of aplastic anemia is bone marrow transplantation from an HLA-matched sibling.
If there is no human leukocyte antigen (HLA)-matched sibling available, the next best option is medical management with the immunosuppressive agents anti-thymocyte globulin (ATG) and cyclosporine A.
The reason for the efficacy of immunosuppressive medications is that the pancytopenia from aplastic anemia is due to abnormal immune activation and thus destruction of hematopoietic cells.
ATG from horse has been shown to be superior compared to ATG from rabbit.
ATG is administered over 5 days, and cyclosporine A is administered orally for 6 months, after which response can be assessed.
The combination of ATG and cyclosporine A carries a response rate of 60-70%. Eltrombopag can also be added to the regimen of ATG and cyclosporine.
- This is a condition characterized by immune-mediated reduction in all three hematopoietic cell lines with absence of hematopoietic precursors.
- It is a rare condition with a prevalence of only 1-2 cases per million annually. It is most commonly diagnosed in childhood.
- Epidemiologic studies have shown a greater prevalence in Southeast Asia and other countries with limited access to healthcare, as viral infection can trigger aplastic crisis.
- There are three categories: moderate, severe, and very severe.
- These categories are based upon the number and degree of cytopenias as well as bone marrow cellularity.
- The preferred treatment of aplastic anemia is bone marrow transplantation from an HLA-matched sibling.
- If there is no human leukocyte antigen (HLA)-matched sibling available, the next best option is medical management with the immunosuppressive agents anti-thymocyte globulin (ATG) and cyclosporine A.
- The reason for the efficacy of immunosuppressive medications is that the pancytopenia from aplastic anemia is due to abnormal immune activation and thus destruction of hematopoietic cells.
- ATG from horse has been shown to be superior compared to ATG from rabbit.
- ATG is administered over 5 days, and cyclosporine A is administered orally for 6 months, after which response can be assessed.
- The combination of ATG and cyclosporine A carries a response rate of 60-70%. Eltrombopag can also be added to the regimen of ATG and cyclosporine.
- Folate deficiency
Folate is required for pyrimidine nucleotide synthesis, and thus folate deficiency can lead to decreased production of hematopoietic cells.
Folate deficiency occurs in persons who consume large amounts of alcohol.
Folate deficiency is accompanied by macrocytosis, or large-sized cells.
Treatment of folate deficiency is supplementation of folate in the diet.
- Folate is required for pyrimidine nucleotide synthesis, and thus folate deficiency can lead to decreased production of hematopoietic cells.
- Folate deficiency occurs in persons who consume large amounts of alcohol.
- Folate deficiency is accompanied by macrocytosis, or large-sized cells.
- Treatment of folate deficiency is supplementation of folate in the diet.
- Leishmaniasis
This is a rare infectious cause of pancytopenia.
- This is a rare infectious cause of pancytopenia.
- Leukemia
This can be myeloid or lymphoid, and each of these can be acute or chronic.
Acute leukemias typically cause pancytopenia via a crowding-out phenomenon, known as myelopthisis.
Diagnosis of acute leukemia is based by demonstration of blast count of 20% or greater in the bone marrow.
Treatment involves multiagent chemotherapy, such as cytarabine combined with anthracycline for acute myeloid leukemia, or vincristine-based and anthracycline-based regimen for acute lymphoblastic leukemia.
Treatment of the underlying leukemia can help improve pancytopenia.
- This can be myeloid or lymphoid, and each of these can be acute or chronic.
- Acute leukemias typically cause pancytopenia via a crowding-out phenomenon, known as myelopthisis.
- Diagnosis of acute leukemia is based by demonstration of blast count of 20% or greater in the bone marrow.
- Treatment involves multiagent chemotherapy, such as cytarabine combined with anthracycline for acute myeloid leukemia, or vincristine-based and anthracycline-based regimen for acute lymphoblastic leukemia.
- Treatment of the underlying leukemia can help improve pancytopenia.
- Megaloblastic anemia
This condition is characterized by decreased red blood cell count and increased cellular size with defective maturation.
The cause is usually deficiency of vitamin B12 or folate.
The diagnosis is made with a complete blood count showing hemoglobin less than 12 g/dl, mean corpuscular volume greater than 100 femtoliter (MCV > 100 fL), and peripheral smear showing enlarged cells.
The treatment is supplementation with vitamin B12 or folate.
- This condition is characterized by decreased red blood cell count and increased cellular size with defective maturation.
- The cause is usually deficiency of vitamin B12 or folate.
- The diagnosis is made with a complete blood count showing hemoglobin less than 12 g/dl, mean corpuscular volume greater than 100 femtoliter (MCV > 100 fL), and peripheral smear showing enlarged cells.
- The treatment is supplementation with vitamin B12 or folate.
- Myelodysplastic syndrome
This is a disease characterized by ineffective erythropoiesis and peripheral cytopenias.
It is a clonal disorder of the hematopoietic stem cell.
The subtype of myelodysplastic syndrome that causes pancytopenia is termed refractory anemia with multilineage dysplasia.
The pancytopenia of myelodysplastic syndrome is due to failure of maturation of hematopoietic precursors, leading to peripheral cytopenias.
Diagnosis of myelodysplastic syndrome is made by demonstration of at least 1 cell line with 10% of greater dysplastic cells on bone marrow biopsy.
Bone marrow biopsy should also show myeloblasts less then 20% of total leukocytes.
Clinical features of myelodysplastic syndrome include manifestations of specific cytopenias, such as fatigue if there is anemia, bleeding if there is thrombocytopenia, and infections if there is leukopenia.
The prognostication of myelodysplastic syndrome is determined by the International Prognosis Scoring System-Revised (IPSS-R), which is determined by blast count, the karyotype, and cytopenia.
This clinical tool is used to estimate the time to progression to acute myeloid leukemia.
The treatment of myelodysplastic syndrome is based on the subtype. Lenalidomide is highly effective for persons with deletion of chromosome 5q.
DNA hypomethylating agents like azacitadine and decitabine are commonly used for those with symptomatic cytopenias and without chromosome 5q deletion.
In some cases, allogeneic stem cell transplantation can be done with the goal of curing myelodysplastic syndrome and preventing progression to acute myeloid leukemia.
Adjunctive therapies include transfusion support (such as red blood cell transfusions or platelet transfusions), growth factor support (such as filgrastim), and immunosuppressive therapy, which is particularly effective in persons with PNH clones, HLA-DR15 positivity, or STAT3-mutant cytotoxic T cells.
- This is a disease characterized by ineffective erythropoiesis and peripheral cytopenias.
- It is a clonal disorder of the hematopoietic stem cell.
- The subtype of myelodysplastic syndrome that causes pancytopenia is termed refractory anemia with multilineage dysplasia.
- The pancytopenia of myelodysplastic syndrome is due to failure of maturation of hematopoietic precursors, leading to peripheral cytopenias.
- Diagnosis of myelodysplastic syndrome is made by demonstration of at least 1 cell line with 10% of greater dysplastic cells on bone marrow biopsy.
- Bone marrow biopsy should also show myeloblasts less then 20% of total leukocytes.
- Clinical features of myelodysplastic syndrome include manifestations of specific cytopenias, such as fatigue if there is anemia, bleeding if there is thrombocytopenia, and infections if there is leukopenia.
- The prognostication of myelodysplastic syndrome is determined by the International Prognosis Scoring System-Revised (IPSS-R), which is determined by blast count, the karyotype, and cytopenia.
- This clinical tool is used to estimate the time to progression to acute myeloid leukemia.
- The treatment of myelodysplastic syndrome is based on the subtype. Lenalidomide is highly effective for persons with deletion of chromosome 5q.
- DNA hypomethylating agents like azacitadine and decitabine are commonly used for those with symptomatic cytopenias and without chromosome 5q deletion.
- In some cases, allogeneic stem cell transplantation can be done with the goal of curing myelodysplastic syndrome and preventing progression to acute myeloid leukemia.
- Adjunctive therapies include transfusion support (such as red blood cell transfusions or platelet transfusions), growth factor support (such as filgrastim), and immunosuppressive therapy, which is particularly effective in persons with PNH clones, HLA-DR15 positivity, or STAT3-mutant cytotoxic T cells.
- Paroxysmal nocturnal hemoglobinuria
This is a clonal disorder of the hematopoietic stem cell characterized by hemolysis due to complement activation on the red blood cell membrane.
It is cause of bone marrow failure.
The genetic defect is a deficiency in glycosylphosphatidylinositol (GPI) which is encoded by the PIG-A gene.
This protein normally serves to anchor complement regulatory and inhibitory proteins onto the red blood cell membrane.
The two major regulatory proteins are CD55 (or decay accelerating factor (DAF)), which functions to degrade complement proteins C3 and C5 convertase, and CD59 (or membrane inhibitor of reactive lysis (MIRL)), which functions to prevent complement-mediated hemolysis via preventing formation of the membrane attack complex.
The clinical manifestations include hematuria, portal venous or hepatic venous thrombosis.
Diagnosis is made by performing flow cytometry of peripheral blood and analyzing the expression fo CD55 and CD59 on red blood cell membranes.
Treatment of this condition is eculizumab, a humanized monoclonal antibody that inhibits complement protein C5.
- This is a clonal disorder of the hematopoietic stem cell characterized by hemolysis due to complement activation on the red blood cell membrane.
- It is cause of bone marrow failure.
- The genetic defect is a deficiency in glycosylphosphatidylinositol (GPI) which is encoded by the PIG-A gene.
- This protein normally serves to anchor complement regulatory and inhibitory proteins onto the red blood cell membrane.
- The two major regulatory proteins are CD55 (or decay accelerating factor (DAF)), which functions to degrade complement proteins C3 and C5 convertase, and CD59 (or membrane inhibitor of reactive lysis (MIRL)), which functions to prevent complement-mediated hemolysis via preventing formation of the membrane attack complex.
- The clinical manifestations include hematuria, portal venous or hepatic venous thrombosis.
- Diagnosis is made by performing flow cytometry of peripheral blood and analyzing the expression fo CD55 and CD59 on red blood cell membranes.
- Treatment of this condition is eculizumab, a humanized monoclonal antibody that inhibits complement protein C5.
- Viral infections
Viruses such as HIV, EBV, or CMV can cause pancytopenia.
The diagnosis can be made by checking viral loads via PCR of peripheral blood or by checking antibody titers to the viruses.
For example, EBV can be diagnosed by assessing for EBV DNA PCR, or by assessing for IgM or IgM to EBV antigens.
- Viruses such as HIV, EBV, or CMV can cause pancytopenia.
- The diagnosis can be made by checking viral loads via PCR of peripheral blood or by checking antibody titers to the viruses.
- For example, EBV can be diagnosed by assessing for EBV DNA PCR, or by assessing for IgM or IgM to EBV antigens.
- Vitamin B12 deficiency
This can cause megaloblastic anemia.
- This can cause megaloblastic anemia.
- Copper deficiency
This is a more rare cause of pancytopenia.
- This is a more rare cause of pancytopenia.
- Zinc deficiency
This is a more rare cause of pancytopenia. Treatment is supplementation with zinc.
- This is a more rare cause of pancytopenia. Treatment is supplementation with zinc.
## Causes by Organ System
## Causes in Alphabetical Order
- Acetaminophen and Oxycodone
- Aclarubicin
- Acute lymphoblastic leukemia
- Acute myeloid leukemia
- Aggressive NK-cell leukemia
- Albendazole
- Albers-Schonberg disease
- Alemtuzumab
- Alkylating antineoplastic agent
- Amegakaryocytic thrombocytopenia
- Ankylosing spondylitis
- Anorexia nervosa
- Aplastic anemia
- Arsenic poisoning
- Arsenicals
- Ataxia telangiectasia
- Auranofin
- Autoimmune lymphoproliferative syndrome type 1
- Autoimmune lymphoproliferative syndrome type 2
- Azathioprine
- Aztreonam
- Babesiosis
- Banti's syndrome
- Benzene solvents
- Radioactive p32
- Bleeding (Excessive)
- Bloom syndrome
- Boceprevir
- Bone marrow tumor
- Brucellosis
- Busulfan
- Cancer
- Carbamazepine
- Carboplatin
- Cartilage-hair hypoplasia
- Castleman's disease
- Cefadroxil
- Ceftazidime
- Certolizumab pegol
- Chediak-Higashi disease
- Chemotherapy
- Chloramphenicol
- Chlorpromazine
- Chlorpropamide
- Chondrosarcoma
- Chronic lymphocytic leukaemia
- Chronic myeloid leukaemia
- Cidofovir
- Cirrhosis
- Clomipramine
- Colchicine toxicity
- Common variable hypogammaglobulinemia
- Common variable immune deficiency
- Copper deficiency
- Cyclical neutropenia
- Cyclophosphamide
- Cytotoxic drugs
- Dactinomycin
- Dengue
- Diamond-Blackfan anemia
- DNA repair-deficiency disorder
- Docetaxel
- Down syndrome
- Doxorubicin
- Dubowitz syndrome
- Dyskeratosis congenita
- Eosinophilic fasciitis
- Epiphyseal tumors
- Epstein-Barr virus
- Ethosuximide
- Ewing's sarcoma
- Familial histiocytic reticulosis
- Familial monosomy 7
- Familial myelofibrosis
- Fanconi anemia
- Febuxostat
- Felty's syndrome
- Flucytosine
- Folate deficiency
- Gaucher's disease
- Gemcitabine
- Gemifloxacin mesylate
- Genotoxic therapy
- Germ cell tumors
- Glue vapors
- Glutathione synthase deficiency
- Gold
- Graft versus host disease
- Granuloma
- Hairy cell leukemia
- Hematopoietic stem cell transplantation
- Hemoglobin E disease
- Hemoglobin H disease
- Hemoglobin SC disease
- Hemophagocytic lymphohistiocytosis
- Hepatitis
- Hepatosplenic T-cell lymphoma
- Histiocytosis X
- Hodgkin's lymphoma
- Hoyeraal-Hreidarsson syndrome
- Human immunodeficiency virus
- Hypersplenism
- Hypoplastic myelodysplastic syndromes
- Idarubicin
- Idiopathic
- Auto-immune disorders
- Indomethacin
- Ineffective erythropoiesis
- Infectious mononucleosis
- Infliximab
- Interferon beta-1a
- Intestinal lymphangiectasia
- Intrinsic factor deficiency
- Iron deficiency
- Jacobsen syndrome
- Kala-azar
- Kikuchi disease
- Kwashiorkor
- Langerhans cell histiocytosis
- Lassa fever
- Legionella pneumophila
- Leucoerythroblastic anemia
- Leukemia
- Lincomycin hydrochloride
- Lymphoma
- Malabsorption syndrome
- Malignant histiocytosis
- Marasmus
- Megaloblastic anemia
- Melanoma
- Metastatic neoplasm
- Minocycline hydrochloride
- Mutagen exposure
- Mutagen-detoxification (GSTq1-null)
- Mycobacterium tuberculosis
- Myelodysplastic syndrome
- Myelofibrosis
- Myeloma
- Myelopathic anemia
- Neuroblastoma
- Neurofibromatosis 1
- Niemann-Pick disease
- Non steroidal anti-inflammatory drugs
- Non-Hodgkin lymphoma
- Obesity
- Ofatumumab
- Omacetaxine
- Osteoclastoma
- Osteopetrosis lethal
- Osteopetrosis, autosomal recessive 2
- Osteoporosis
- Osteosarcoma
- Oxaprozin
- Oxcarbazepine
- Panhypopituitarism
- Paroxysmal nocturnal hemoglobinuria
- Parvovirus B19 infection
- Pearson syndrome
- Penicillamine
- Pernicious anemia
- Phenacemide
- Phenylbutazone
- Piperacillin
- Plummer-Vinson syndrome
- Portal hypertension
- Pralatrexate
- Precursor B acute lymphoblastic leukemia/lymphoma
- Pregnancy
- Propylthiouracil
- Prostate cancer
- Pyrimethamine
- Q fever
- Rabeprazole
- Radiation therapy
- Radium chloride
- Renal failure, chronic
- Reticular dysgenesis
- Reticulosis
- Rheumatoid disease
- Sarcoidosis
- Schwachman-Diamond syndrome
- Severe combined immunodeficiency
- Sickle cell disease
- Splenomegaly
- Sulfonamides
- Systemic lupus erythematosus
- Tamoxifen
- TAR syndrome
- T-cell large granular lymphocytic leukemia
- Temozolomide
- Thiothixene
- Thymoma
- Thyroid carcinoma
- Tobacco use
- Tolazamide
- Tolbutamide
- Topoisomerase II interactive agents
- Toxins
- Trifluoperazine
- Trimethadione
- Trimethoprim-sulfamethoxazole
- Trisomy 8 mosaicism
- Tuberculosis
- Valganciclovir hydrochloride
- Valproic acid poisoning
- Viral infections
- Vitamin B12 deficiency
- Vitamin C deficiency
- Whipple's disease
- Wiskott-Aldrich syndrome
- Xeroderma pigmentosum
## Causes by Pathophysiology
### Bone Marrow Failure
- Insufficient production (aplastic anemia)
- Inability of cells or mature (myelodysplasia)
- Replacement of normal bone marrow with fibrosis (myelofibrosis)
### Peripheral Sequestration/Destruction
- Splenomegaly
- Hypersplenism
## Causes by Mode of Inheritance
This is not applicable since there is no specific mode of inheritance for pancytopenia.
### Congenital
- Cartilage hair hypoplasia:
This is a bone marrow failure condition caused by ribosomal protein mutations.
Clinical manifestations include cartilage and hair loss.
- This is a bone marrow failure condition caused by ribosomal protein mutations.
- Clinical manifestations include cartilage and hair loss.
- Diamond-Blackfan syndrome:
This is a rare condition affecting 5-7 persons per million and is characterized by a macrocytic anemia and less than 5% erythroid precursors including reticulocytes.
It is the most common inherited erythrocyte failure syndrome, and it is inherited in an autosomal dominant pattern.
This condition is caused by mutations in ribosomal protein genes such as RPS19.
Though neutropenia and thrombocytopenia do not usually occur, moderate white blood cell and platelet count reductions have been described in some cases.
Fetal hemoglobin is typically increased in an effect to enhance delivery of oxygen to tissues in the setting of low hemoglobin.
Clinical manifestations usually include short statute, ocular abnormalities, skeletal abnormalities.
It is the most common inherited erythrocyte failure syndrome.
The only curative therapy is bone marrow transplantation.
- This is a rare condition affecting 5-7 persons per million and is characterized by a macrocytic anemia and less than 5% erythroid precursors including reticulocytes.
- It is the most common inherited erythrocyte failure syndrome, and it is inherited in an autosomal dominant pattern.
- This condition is caused by mutations in ribosomal protein genes such as RPS19.
- Though neutropenia and thrombocytopenia do not usually occur, moderate white blood cell and platelet count reductions have been described in some cases.
- Fetal hemoglobin is typically increased in an effect to enhance delivery of oxygen to tissues in the setting of low hemoglobin.
- Clinical manifestations usually include short statute, ocular abnormalities, skeletal abnormalities.
- It is the most common inherited erythrocyte failure syndrome.
- The only curative therapy is bone marrow transplantation.
- Dubowitz syndrome
This is a rare autosomal recessive disorder characterized by increased cancer susceptibility.
The exact genetic abnormality and etiology is yet to be identified.
Patients have DNA that is very sensitive to ionizing radiation and a few chemotherapy agents like anthracyclines and bleomycin.
There is some clinical overlap with Fanconi anemia.
Patients can develop bone marrow failure and cytopenias.
- This is a rare autosomal recessive disorder characterized by increased cancer susceptibility.
- The exact genetic abnormality and etiology is yet to be identified.
- Patients have DNA that is very sensitive to ionizing radiation and a few chemotherapy agents like anthracyclines and bleomycin.
- There is some clinical overlap with Fanconi anemia.
- Patients can develop bone marrow failure and cytopenias.
- Dyskeratosis congenita
This is a rare condition caused by short telomeres, which normally function to maintain the length and integrity of DNA.
It is characterized by skin abnormalities, nail abnormalities, and leukoplakia.
The genes implicated include DKC1 (dyskerin), TERT, and TERC.
Other genes implicated in this condition encode ribonucleoprotein enzymes.
By age 30, approximately 80% of patients with this condition will develop bone marrow failure.
- This is a rare condition caused by short telomeres, which normally function to maintain the length and integrity of DNA.
- It is characterized by skin abnormalities, nail abnormalities, and leukoplakia.
- The genes implicated include DKC1 (dyskerin), TERT, and TERC.
- Other genes implicated in this condition encode ribonucleoprotein enzymes.
- By age 30, approximately 80% of patients with this condition will develop bone marrow failure.
- Fanconi's anemia
This is a condition characterized by erythrocyte hypoproduction due to genomic instability and increased susceptibility to DNA damaging agents.
Diagnosis is made by demonstration of DNA crosslinking upon exposure to diepoxybutane (DEB) and mitomycin C (MCC).
Patients with fanconi anemia have a higher risk for development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), both of which can contribute to pancytopenia.
- This is a condition characterized by erythrocyte hypoproduction due to genomic instability and increased susceptibility to DNA damaging agents.
- Diagnosis is made by demonstration of DNA crosslinking upon exposure to diepoxybutane (DEB) and mitomycin C (MCC).
- Patients with fanconi anemia have a higher risk for development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), both of which can contribute to pancytopenia.
- Pearson syndrome
This is a relatively uncommon cause of refractory sideroblastic anemia, neutropenia, and thrombocytopenia.
Clinical features include proximal myopathy and weakness, ophthalmoplegia, ataxia. and peripheral neuropathy.
- This is a relatively uncommon cause of refractory sideroblastic anemia, neutropenia, and thrombocytopenia.
- Clinical features include proximal myopathy and weakness, ophthalmoplegia, ataxia. and peripheral neuropathy.
- Schwachman-Diamond syndrome
This is a condition that affects approximately 1 in 50000 persons and is characterized by bone marrow failure, pancreatic exocrine insufficiency, and skeletal abnormalities.
It is caused by a biallelic (two alleles) mutation in a ribosomal protein encoded by the Schwachman-Bodian-Diamond gene SBDS, located on chromosome 7.
Clinical manifestations in children usually include diarrhea and steatorrhea (due to pancreatic exocrine insufficiency).
However, there have been cases of pancytopenia from schwachman-diamond syndrome in the absence of diarrhea, so this condition should still be in the differential diagnosis of children with pancytopenia and bone marrow failure.
- This is a condition that affects approximately 1 in 50000 persons and is characterized by bone marrow failure, pancreatic exocrine insufficiency, and skeletal abnormalities.
- It is caused by a biallelic (two alleles) mutation in a ribosomal protein encoded by the Schwachman-Bodian-Diamond gene SBDS, located on chromosome 7.
- Clinical manifestations in children usually include diarrhea and steatorrhea (due to pancreatic exocrine insufficiency).
- However, there have been cases of pancytopenia from schwachman-diamond syndrome in the absence of diarrhea, so this condition should still be in the differential diagnosis of children with pancytopenia and bone marrow failure.
- TAR syndrome
This is a rare condition characterized by low platelet count (thrombocytopenia) and absent radius (a long bone of the lower arm).
It is thought to be caused by an interstitial deletion in chromosome 1q21.
Patients can have skeletal abnormalities (like absent radius, short ulna, and absence of other long bones of the arm).
The fingers are not affected.
- This is a rare condition characterized by low platelet count (thrombocytopenia) and absent radius (a long bone of the lower arm).
- It is thought to be caused by an interstitial deletion in chromosome 1q21.
- Patients can have skeletal abnormalities (like absent radius, short ulna, and absence of other long bones of the arm).
- The fingers are not affected.
### Acquired
- Albers-Schonberg disease
- Banti's Syndrome
- Bone marrow tumor
- Cirrhosis
- Drugs/Toxins
- Felty's Syndrome
- Gaucher's Disease
- Graft-versus-host disease
- Infections
- Kala-Azar
- Leukemia
- Lymphoma
- Lymphoproliferative Disorders
- Myelodysplastic syndrome
- Myelofibrosis
- Niemann-Pick Disease
- Osteoporosis
- Pernicious anemia
- Reticulosis
- Sarcoidosis
- Thymoma
- Tuberculosis
# Differentiating Pancytopenia from Other Diseases
# Epidemiology and Demographics
- Pancytopenia affects males and females equally.
- However, the underlying etiologies of pancytopenia can have a gender predilection.
- Please see above sections for epidemiology and demographics of the individual disease entities that cause pancytopenia.
# Risk Factors
- The risk factors of pancytopenia are related to the underlying cause.
- For example, leukemia-mediated pancytopenia can be related to risk factors such as chemical exposure, radiation, or family history.
- Please see above sections for risk factors of the individual disease entities that cause pancytopenia.
# Screening
- There are no suggested screening tests for pancytopenia.
- The United States Preventive Services Task Force (USPSTF) does not have any recommendations for screening for pancytopenia.
- However, if a person is suspected of having a particular condition that cause cause pancytopenia, such as viral infection, a diagnosis complete blood count (CBC) can be checked to assess for pancytopenia.
# Natural History, Complications, and Prognosis
## Natural History
- The natural history of pancytopenia is dictated by the pathophysiology of the under etiology.
- For example, viral-mediated pancytopenia is typically short-lived, pending clearance of the virus.
- Drug-induced pancytopenia typically resolves after discontinuing of the culprit drug and the drug has been metabolized by the body.
- Leukemia-mediated pancytopenia is usually a more long-term process, as marrow replacement by leukemia cells is difficult to overcome unless the leukemia is treated and the patient is in remission.
- Please see above sections for natural history of the individual disease entities that cause pancytopenia.
## Complications
- Complications of pancytopenia relate to deficits of the cell types that are affected.
- Decrease in erythrocytes causes fatigue, pallor, lightheadedness, and shortness of breath due to decrease in oxygen delivery to tissue beds.
- Decrease in leukocytes and leukocyte subsets causes infections, which can be viral, bacteria, fungal, or parasitic.
- The most concerning complication of decrease in leukocytes is called febrile neutropenia, which is a hematologic emergency.
- Decrease in thrombocytes causes bleeding, which is typically mucosal, given loss of the ability of platelets to create a hemostatic plug.
## Prognosis
- The prognosis of pancytopenia is related to the underlying etiology.
- For example, patients with unfavorable-risk leukemia will likely have a poor prognosis from a pancytopenia perspective.
- Patients with viral-mediated pancytopenia have a prognosis that is determined by the natural history of the virus.
- Epstein-Barr virus (EBV)-related pancytopenia can have a good prognosis if EBV resolves.
- Drug-induced pancytopenia has a favorable prognosis, as discontinuation of the offending agent can typically reverse the pancytopenia.
- Please see above sections for prognosis of the individual disease entities that cause pancytopenia.
# Diagnosis
## Diagnostic Criteria
The diagnosis of pancytopenia is made by assessing a complete blood count (CBC) when all of the following criteria are fulfilled:
- Anemia as defined by hemoglobin level < 12 grams per deciliter (g/dl)
- Leukopenia as defined by leukocyte count < 4000 per microliter
- Thrombocytopenia as defined by platelet count < 150000 per microliter
## History and Symptoms
Symptoms of pancytopenia are related to decrease in erythrocytes, leukocytes, and platelets.
- Decrease in erythrocytes causes fatigue, shortness of breath, decreased exercise tolerance, and pallor.
- Decrease in leukocytes causes infection, which can affect a multitude of organ systems including the central nervous system, lungs, abdomen, urinary tract, kidneys, and skin.
- Decrease in platelets causes mucocutaneous bleeding, typically of the nose, mouth, gastrointestinal tract, or genitourinary tract.
## Physical Examination
Key components of the physical exam include assessment of the conjunctiva, oral and nasal mucosa, lymph nodes (cervical, axillary, supraclavicular, inguinal), spleen size, liver size, and skin.
- The anemia component of pancytopenia can cause conjunctival pallor, mucosal pallor, skin pallor, and tachypnea.
- The leukopenia component of pancytopenia can cause variable findings depending on whether infection is present. Exam findings can include lymphadenopathy, egophony, coarse breath sounds, malodorous urine, suprapubic tenderness, costovertebral tenderness, abdominal tenderness, skin erythema, and/or skin purulence.
- The thrombocytopenia component of pancytopenia can cause petechiae (pinpoint hemorrhages in the skin), mucosal bleeding, or internal bleeding.
## Laboratory Findings
Laboratory findings in pancytopenia are, by definition:
- Hemoglobin level < 12 grams per deciliter (g/dl)
- Leukocyte count < 4000 per microliter
- Platelet count < 150000 per microliter
Other laboratory findings, depending on the underlying cause, can include:
- Elevated LDH
- Elevated indirect bilirubin
- Elevated reticulocyte count
- Decreased haptoglobin
## Imaging Findings
- There are no imaging findings associated with pancytopenia.
## Other Diagnostic Studies
- Viral polymerase chain reaction PCR testing can be done for viral-induced pancytopenia. This includes PCR for CMV DNA and EBV DNA.
# Treatment
## Medical Therapy
- The treatment of pancytopenia depends on the underlying cause.
- If pancytopenia is due to medication adverse effect, the offending agent should be discontinued.
- If pancytopenia is due to myelopthisis from leukemia, the underlying leukemia should be treated with cytotoxic chemotherapy.
- If pancytopenia is due to aplastic anemia, this should be treated with either immunosuppression with anti-thymocyte globulin (ATG) and cyclosporine A, or by hematopoietic stem cell transplantation from a matched related donor.
- Please see above sections for details of treatment of the individual disease entities that cause pancytopenia.
## Surgery
- The is no role for surgery for pancytopenia.
- However, for immune thrombocytopenia purpura (ITP) and autoimmune hemolytic anemia (AIHA), splenectomy can be considered.
## Prevention
- The prevention of pancytopenia focuses on prevention of the underlying etiologies.
- For example, viral-induced pancytopenia can be prevented by taking precautions against acquiring viral infections.
- This can include good hand hygiene, avoidance of exposures, anti-viral medications as prophylaxis.
- Prevention of leukemia-induced pancytopenia can be achieved via avoidance of risk factors of leukemia such as radiation exposure, chemical exposure, or benzene exposure.
- Drug-induced pancytopenia can be prevented by choosing an alternative medication in a similar class that does not cause pancytopenia.
- For example, in a patient who requires prophylaxis for PCP, atovaquone can be administered in place of trimethoprim-sulfamethoxazole, as atovaquone does not cause pancytopenia. | Pancytopenia
Pancytopenia is not equivalent with bone marrow suppression. Pancytopenia is a lab finding that may related to either bone marrow suppression or peripheral sequestration/destruction. For details about bone marrow suppression click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Ogheneochuko Ajari, MB.BS, MS [3], Shyam Patel [4], Sadaf Sharfaei M.D.[5]
# Overview
Pancytopenia is the reduction in numbers of all three bone marrow cell types, including red blood cells, white blood cells, and platelets. The prefix "pan-" means "everything," "cyto" means "cell", and the suffix "penia" means "deficiency." Pancytopenia is not a disease, but rather a laboratory finding that may related to bone marrow suppression caused by either insufficient production (aplastic anemia), inability of cells to mature (myelodysplasia), replacement of normal bone marrow with fibrosis (myelofibrosis) or peripheral sequestration that is not related to the bone marrow (e.g. splenomegaly or hypersplenism). Chemotherapy is associated with pancytopenia due to drug-mediated bone marrow suppression. Pancytopenia frequently requires a bone marrow biopsy in order to distinguish among different causes.
# Historical Perspective
The history of pancytopenia relates to the history of each of its individual sub-entities, namely anemia, thrombocytopenia, and leukopenia. Pancytopenia was not recognized as a distinct clinical entity until after each of its other subcomponents were characterized. Thus, there is no specific history for pancytopenia.
- History of aplastic anemia:
The seminal discoveries for aplastic anemia were made by Bruno Speck and Georges Mathe, who noted that immunosuppression could be used to treat aplastic anemia.[1]
In the 1970s, matched sibling donor transplant was used for severe aplastic anemia.[2]
- The seminal discoveries for aplastic anemia were made by Bruno Speck and Georges Mathe, who noted that immunosuppression could be used to treat aplastic anemia.[1]
- In the 1970s, matched sibling donor transplant was used for severe aplastic anemia.[2]
- History of paroxysmal nocturnal hemoglobinuria:
In 1882, Dr. Paul Strubing reported the case of a patient with hematuria at night that occurred periodically.[3]
He noted that hemolysis was the reason for the patient's hematuria.
In 1925, the term paroxysmal nocturnal hemaglobinuria was coined.[3]
In the 1930s, Dr. T.H. Ham noted that acidified serum could induce hemolysis.
Thus, the Ham's acid serum test was developed.[3]
This became the first diagnostic test for this disease.
In the 1950s, the complement pathway was discovered, and it was determined that paroxysmal nocturnal hemoglobinuria was due to activation of complement proteins on the red blood cell membrane.[3]
In the 1980s, the genetic defect responsible for the disease was discovered, specifically, the PIG-A gene defect leading to inability to anchor complement-inhibitory proteins onto the red blood cell membrane.
- In 1882, Dr. Paul Strubing reported the case of a patient with hematuria at night that occurred periodically.[3]
He noted that hemolysis was the reason for the patient's hematuria.
- He noted that hemolysis was the reason for the patient's hematuria.
- In 1925, the term paroxysmal nocturnal hemaglobinuria was coined.[3]
- In the 1930s, Dr. T.H. Ham noted that acidified serum could induce hemolysis.
Thus, the Ham's acid serum test was developed.[3]
This became the first diagnostic test for this disease.
- Thus, the Ham's acid serum test was developed.[3]
- This became the first diagnostic test for this disease.
- In the 1950s, the complement pathway was discovered, and it was determined that paroxysmal nocturnal hemoglobinuria was due to activation of complement proteins on the red blood cell membrane.[3]
- In the 1980s, the genetic defect responsible for the disease was discovered, specifically, the PIG-A gene defect leading to inability to anchor complement-inhibitory proteins onto the red blood cell membrane.
# Classification
There is no classification system for pancytopenia. However, some underlying disease entities that cause pancytopenia have classification. For example, aplastic anemia is classified as moderate, severe, or very severe.
# Pathophysiology
- The pathophysiology of pancytopenia relates to the underlying etiology.
- In most cases, pancytopenia is due to a disruption in trilineage hematopoiesis.
- This means that the bone marrow is not appropriately producing erythrocytes, leukocytes, and thrombocytocytes.
- The cause of the disruption in trilineage hematopoiesis is in turn due to the underlying cause of pancytopenia.
- For example, viral-mediated pancytopenia is caused by viral particles infecting hematopoietic cells and preventing normal cell division.
- Leukemia-mediated pancytopenia is typically due to marrow replacement of normal hematopoietic precursors, a process known as myelopthisis.
- Leukemic infiltration of the bone marrow creates a "crowding-out" phenomenon.
# Causes
## Life Threatening Causes
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no life-threatening causes of pancytopenia that require acute treatment within 24 hours. However, if pancytopenia is accompanied by fever, this should be treated as a hematologic emergency with prompt administration of IV antibiotics.
## Common Causes
- Aplastic anemia [4]
This is a condition characterized by immune-mediated reduction in all three hematopoietic cell lines with absence of hematopoietic precursors.[1]
It is a rare condition with a prevalence of only 1-2 cases per million annually. It is most commonly diagnosed in childhood.
Epidemiologic studies have shown a greater prevalence in Southeast Asia and other countries with limited access to healthcare, as viral infection can trigger aplastic crisis.[1]
There are three categories: moderate, severe, and very severe.
These categories are based upon the number and degree of cytopenias as well as bone marrow cellularity.
The preferred treatment of aplastic anemia is bone marrow transplantation from an HLA-matched sibling.
If there is no human leukocyte antigen (HLA)-matched sibling available, the next best option is medical management with the immunosuppressive agents anti-thymocyte globulin (ATG) and cyclosporine A.[1]
The reason for the efficacy of immunosuppressive medications is that the pancytopenia from aplastic anemia is due to abnormal immune activation and thus destruction of hematopoietic cells.
ATG from horse has been shown to be superior compared to ATG from rabbit.[1]
ATG is administered over 5 days, and cyclosporine A is administered orally for 6 months, after which response can be assessed.
The combination of ATG and cyclosporine A carries a response rate of 60-70%. [2] Eltrombopag can also be added to the regimen of ATG and cyclosporine.
- This is a condition characterized by immune-mediated reduction in all three hematopoietic cell lines with absence of hematopoietic precursors.[1]
- It is a rare condition with a prevalence of only 1-2 cases per million annually. It is most commonly diagnosed in childhood.
- Epidemiologic studies have shown a greater prevalence in Southeast Asia and other countries with limited access to healthcare, as viral infection can trigger aplastic crisis.[1]
- There are three categories: moderate, severe, and very severe.
- These categories are based upon the number and degree of cytopenias as well as bone marrow cellularity.
- The preferred treatment of aplastic anemia is bone marrow transplantation from an HLA-matched sibling.
- If there is no human leukocyte antigen (HLA)-matched sibling available, the next best option is medical management with the immunosuppressive agents anti-thymocyte globulin (ATG) and cyclosporine A.[1]
- The reason for the efficacy of immunosuppressive medications is that the pancytopenia from aplastic anemia is due to abnormal immune activation and thus destruction of hematopoietic cells.
- ATG from horse has been shown to be superior compared to ATG from rabbit.[1]
- ATG is administered over 5 days, and cyclosporine A is administered orally for 6 months, after which response can be assessed.
- The combination of ATG and cyclosporine A carries a response rate of 60-70%. [2] Eltrombopag can also be added to the regimen of ATG and cyclosporine.
- Folate deficiency
Folate is required for pyrimidine nucleotide synthesis, and thus folate deficiency can lead to decreased production of hematopoietic cells.[5]
Folate deficiency occurs in persons who consume large amounts of alcohol.
Folate deficiency is accompanied by macrocytosis, or large-sized cells.
Treatment of folate deficiency is supplementation of folate in the diet.
- Folate is required for pyrimidine nucleotide synthesis, and thus folate deficiency can lead to decreased production of hematopoietic cells.[5]
- Folate deficiency occurs in persons who consume large amounts of alcohol.
- Folate deficiency is accompanied by macrocytosis, or large-sized cells.
- Treatment of folate deficiency is supplementation of folate in the diet.
- Leishmaniasis
This is a rare infectious cause of pancytopenia.
- This is a rare infectious cause of pancytopenia.
- Leukemia
This can be myeloid or lymphoid, and each of these can be acute or chronic.
Acute leukemias typically cause pancytopenia via a crowding-out phenomenon, known as myelopthisis.
Diagnosis of acute leukemia is based by demonstration of blast count of 20% or greater in the bone marrow.
Treatment involves multiagent chemotherapy, such as cytarabine combined with anthracycline for acute myeloid leukemia, or vincristine-based and anthracycline-based regimen for acute lymphoblastic leukemia.
Treatment of the underlying leukemia can help improve pancytopenia.
- This can be myeloid or lymphoid, and each of these can be acute or chronic.
- Acute leukemias typically cause pancytopenia via a crowding-out phenomenon, known as myelopthisis.
- Diagnosis of acute leukemia is based by demonstration of blast count of 20% or greater in the bone marrow.
- Treatment involves multiagent chemotherapy, such as cytarabine combined with anthracycline for acute myeloid leukemia, or vincristine-based and anthracycline-based regimen for acute lymphoblastic leukemia.
- Treatment of the underlying leukemia can help improve pancytopenia.
- Megaloblastic anemia [4]
This condition is characterized by decreased red blood cell count and increased cellular size with defective maturation.[6]
The cause is usually deficiency of vitamin B12 or folate.
The diagnosis is made with a complete blood count showing hemoglobin less than 12 g/dl, mean corpuscular volume greater than 100 femtoliter (MCV > 100 fL), and peripheral smear showing enlarged cells.
The treatment is supplementation with vitamin B12 or folate.[6]
- This condition is characterized by decreased red blood cell count and increased cellular size with defective maturation.[6]
- The cause is usually deficiency of vitamin B12 or folate.
- The diagnosis is made with a complete blood count showing hemoglobin less than 12 g/dl, mean corpuscular volume greater than 100 femtoliter (MCV > 100 fL), and peripheral smear showing enlarged cells.
- The treatment is supplementation with vitamin B12 or folate.[6]
- Myelodysplastic syndrome
This is a disease characterized by ineffective erythropoiesis and peripheral cytopenias.
It is a clonal disorder of the hematopoietic stem cell.[7]
The subtype of myelodysplastic syndrome that causes pancytopenia is termed refractory anemia with multilineage dysplasia.
The pancytopenia of myelodysplastic syndrome is due to failure of maturation of hematopoietic precursors, leading to peripheral cytopenias.[7]
Diagnosis of myelodysplastic syndrome is made by demonstration of at least 1 cell line with 10% of greater dysplastic cells on bone marrow biopsy.
Bone marrow biopsy should also show myeloblasts less then 20% of total leukocytes.
Clinical features of myelodysplastic syndrome include manifestations of specific cytopenias, such as fatigue if there is anemia, bleeding if there is thrombocytopenia, and infections if there is leukopenia.[8]
The prognostication of myelodysplastic syndrome is determined by the International Prognosis Scoring System-Revised (IPSS-R), which is determined by blast count, the karyotype, and cytopenia.
This clinical tool is used to estimate the time to progression to acute myeloid leukemia.
The treatment of myelodysplastic syndrome is based on the subtype. Lenalidomide is highly effective for persons with deletion of chromosome 5q.[8]
DNA hypomethylating agents like azacitadine and decitabine are commonly used for those with symptomatic cytopenias and without chromosome 5q deletion.
In some cases, allogeneic stem cell transplantation can be done with the goal of curing myelodysplastic syndrome and preventing progression to acute myeloid leukemia.[8]
Adjunctive therapies include transfusion support (such as red blood cell transfusions or platelet transfusions), growth factor support (such as filgrastim), and immunosuppressive therapy, which is particularly effective in persons with PNH clones, HLA-DR15 positivity, or STAT3-mutant cytotoxic T cells.
- This is a disease characterized by ineffective erythropoiesis and peripheral cytopenias.
- It is a clonal disorder of the hematopoietic stem cell.[7]
- The subtype of myelodysplastic syndrome that causes pancytopenia is termed refractory anemia with multilineage dysplasia.
- The pancytopenia of myelodysplastic syndrome is due to failure of maturation of hematopoietic precursors, leading to peripheral cytopenias.[7]
- Diagnosis of myelodysplastic syndrome is made by demonstration of at least 1 cell line with 10% of greater dysplastic cells on bone marrow biopsy.
- Bone marrow biopsy should also show myeloblasts less then 20% of total leukocytes.
- Clinical features of myelodysplastic syndrome include manifestations of specific cytopenias, such as fatigue if there is anemia, bleeding if there is thrombocytopenia, and infections if there is leukopenia.[8]
- The prognostication of myelodysplastic syndrome is determined by the International Prognosis Scoring System-Revised (IPSS-R), which is determined by blast count, the karyotype, and cytopenia.
- This clinical tool is used to estimate the time to progression to acute myeloid leukemia.
- The treatment of myelodysplastic syndrome is based on the subtype. Lenalidomide is highly effective for persons with deletion of chromosome 5q.[8]
- DNA hypomethylating agents like azacitadine and decitabine are commonly used for those with symptomatic cytopenias and without chromosome 5q deletion.
- In some cases, allogeneic stem cell transplantation can be done with the goal of curing myelodysplastic syndrome and preventing progression to acute myeloid leukemia.[8]
- Adjunctive therapies include transfusion support (such as red blood cell transfusions or platelet transfusions), growth factor support (such as filgrastim), and immunosuppressive therapy, which is particularly effective in persons with PNH clones, HLA-DR15 positivity, or STAT3-mutant cytotoxic T cells.
- Paroxysmal nocturnal hemoglobinuria
This is a clonal disorder of the hematopoietic stem cell characterized by hemolysis due to complement activation on the red blood cell membrane.[9]
It is cause of bone marrow failure.
The genetic defect is a deficiency in glycosylphosphatidylinositol (GPI) which is encoded by the PIG-A gene.
This protein normally serves to anchor complement regulatory and inhibitory proteins onto the red blood cell membrane.[9]
The two major regulatory proteins are CD55 (or decay accelerating factor (DAF)), which functions to degrade complement proteins C3 and C5 convertase, and CD59 (or membrane inhibitor of reactive lysis (MIRL)), which functions to prevent complement-mediated hemolysis via preventing formation of the membrane attack complex.[9]
The clinical manifestations include hematuria, portal venous or hepatic venous thrombosis.
Diagnosis is made by performing flow cytometry of peripheral blood and analyzing the expression fo CD55 and CD59 on red blood cell membranes.[9]
Treatment of this condition is eculizumab, a humanized monoclonal antibody that inhibits complement protein C5.[9]
- This is a clonal disorder of the hematopoietic stem cell characterized by hemolysis due to complement activation on the red blood cell membrane.[9]
- It is cause of bone marrow failure.
- The genetic defect is a deficiency in glycosylphosphatidylinositol (GPI) which is encoded by the PIG-A gene.
- This protein normally serves to anchor complement regulatory and inhibitory proteins onto the red blood cell membrane.[9]
- The two major regulatory proteins are CD55 (or decay accelerating factor (DAF)), which functions to degrade complement proteins C3 and C5 convertase, and CD59 (or membrane inhibitor of reactive lysis (MIRL)), which functions to prevent complement-mediated hemolysis via preventing formation of the membrane attack complex.[9]
- The clinical manifestations include hematuria, portal venous or hepatic venous thrombosis.
- Diagnosis is made by performing flow cytometry of peripheral blood and analyzing the expression fo CD55 and CD59 on red blood cell membranes.[9]
- Treatment of this condition is eculizumab, a humanized monoclonal antibody that inhibits complement protein C5.[9]
- Viral infections
Viruses such as HIV, EBV, or CMV can cause pancytopenia.
The diagnosis can be made by checking viral loads via PCR of peripheral blood or by checking antibody titers to the viruses.
For example, EBV can be diagnosed by assessing for EBV DNA PCR, or by assessing for IgM or IgM to EBV antigens.
- Viruses such as HIV, EBV, or CMV can cause pancytopenia.
- The diagnosis can be made by checking viral loads via PCR of peripheral blood or by checking antibody titers to the viruses.
- For example, EBV can be diagnosed by assessing for EBV DNA PCR, or by assessing for IgM or IgM to EBV antigens.
- Vitamin B12 deficiency
This can cause megaloblastic anemia.[6]
- This can cause megaloblastic anemia.[6]
- Copper deficiency
This is a more rare cause of pancytopenia.
- This is a more rare cause of pancytopenia.
- Zinc deficiency
This is a more rare cause of pancytopenia. Treatment is supplementation with zinc.
- This is a more rare cause of pancytopenia. Treatment is supplementation with zinc.
## Causes by Organ System
## Causes in Alphabetical Order
- Acetaminophen and Oxycodone
- Aclarubicin
- Acute lymphoblastic leukemia [10]
- Acute myeloid leukemia [4]
- Aggressive NK-cell leukemia [11]
- Albendazole
- Albers-Schonberg disease
- Alemtuzumab
- Alkylating antineoplastic agent
- Amegakaryocytic thrombocytopenia
- Ankylosing spondylitis
- Anorexia nervosa [12]
- Aplastic anemia
- Arsenic poisoning
- Arsenicals
- Ataxia telangiectasia
- Auranofin
- Autoimmune lymphoproliferative syndrome type 1
- Autoimmune lymphoproliferative syndrome type 2
- Azathioprine [13]
- Aztreonam
- Babesiosis [14]
- Banti's syndrome
- Benzene solvents [15]
- Radioactive p32
- Bleeding (Excessive)
- Bloom syndrome
- Boceprevir
- Bone marrow tumor
- Brucellosis [16]
- Busulfan
- Cancer
- Carbamazepine
- Carboplatin
- Cartilage-hair hypoplasia
- Castleman's disease
- Cefadroxil
- Ceftazidime
- Certolizumab pegol
- Chediak-Higashi disease
- Chemotherapy
- Chloramphenicol
- Chlorpromazine
- Chlorpropamide
- Chondrosarcoma
- Chronic lymphocytic leukaemia
- Chronic myeloid leukaemia
- Cidofovir
- Cirrhosis
- Clomipramine
- Colchicine toxicity
- Common variable hypogammaglobulinemia
- Common variable immune deficiency [17]
- Copper deficiency
- Cyclical neutropenia
- Cyclophosphamide
- Cytotoxic drugs
- Dactinomycin
- Dengue
- Diamond-Blackfan anemia
- DNA repair-deficiency disorder
- Docetaxel
- Down syndrome
- Doxorubicin
- Dubowitz syndrome
- Dyskeratosis congenita [18]
- Eosinophilic fasciitis
- Epiphyseal tumors
- Epstein-Barr virus [19]
- Ethosuximide
- Ewing's sarcoma
- Familial histiocytic reticulosis
- Familial monosomy 7
- Familial myelofibrosis
- Fanconi anemia
- Febuxostat
- Felty's syndrome
- Flucytosine
- Folate deficiency [20]
- Gaucher's disease
- Gemcitabine
- Gemifloxacin mesylate
- Genotoxic therapy
- Germ cell tumors [21]
- Glue vapors
- Glutathione synthase deficiency
- Gold
- Graft versus host disease [22]
- Granuloma
- Hairy cell leukemia [23]
- Hematopoietic stem cell transplantation
- Hemoglobin E disease
- Hemoglobin H disease
- Hemoglobin SC disease
- Hemophagocytic lymphohistiocytosis [24]
- Hepatitis
- Hepatosplenic T-cell lymphoma
- Histiocytosis X
- Hodgkin's lymphoma
- Hoyeraal-Hreidarsson syndrome
- Human immunodeficiency virus
- Hypersplenism [25]
- Hypoplastic myelodysplastic syndromes [26]
- Idarubicin
- Idiopathic
- Auto-immune disorders
- Indomethacin
- Ineffective erythropoiesis
- Infectious mononucleosis
- Infliximab
- Interferon beta-1a
- Intestinal lymphangiectasia
- Intrinsic factor deficiency
- Iron deficiency
- Jacobsen syndrome [27]
- Kala-azar [28]
- Kikuchi disease
- Kwashiorkor
- Langerhans cell histiocytosis
- Lassa fever
- Legionella pneumophila
- Leucoerythroblastic anemia
- Leukemia
- Lincomycin hydrochloride
- Lymphoma
- Malabsorption syndrome
- Malignant histiocytosis
- Marasmus
- Megaloblastic anemia [29]
- Melanoma
- Metastatic neoplasm
- Minocycline hydrochloride
- Mutagen exposure
- Mutagen-detoxification (GSTq1-null)
- Mycobacterium tuberculosis
- Myelodysplastic syndrome [30]
- Myelofibrosis
- Myeloma
- Myelopathic anemia
- Neuroblastoma
- Neurofibromatosis 1
- Niemann-Pick disease
- Non steroidal anti-inflammatory drugs
- Non-Hodgkin lymphoma
- Obesity
- Ofatumumab
- Omacetaxine
- Osteoclastoma
- Osteopetrosis lethal
- Osteopetrosis, autosomal recessive 2
- Osteoporosis
- Osteosarcoma
- Oxaprozin
- Oxcarbazepine
- Panhypopituitarism
- Paroxysmal nocturnal hemoglobinuria [31]
- Parvovirus B19 infection [32]
- Pearson syndrome
- Penicillamine [33]
- Pernicious anemia [34]
- Phenacemide
- Phenylbutazone
- Piperacillin
- Plummer-Vinson syndrome
- Portal hypertension
- Pralatrexate
- Precursor B acute lymphoblastic leukemia/lymphoma
- Pregnancy
- Propylthiouracil
- Prostate cancer
- Pyrimethamine
- Q fever
- Rabeprazole
- Radiation therapy [35]
- Radium chloride
- Renal failure, chronic
- Reticular dysgenesis
- Reticulosis
- Rheumatoid disease
- Sarcoidosis [36]
- Schwachman-Diamond syndrome
- Severe combined immunodeficiency [37]
- Sickle cell disease
- Splenomegaly
- Sulfonamides
- Systemic lupus erythematosus [38]
- Tamoxifen
- TAR syndrome
- T-cell large granular lymphocytic leukemia [39]
- Temozolomide [40]
- Thiothixene
- Thymoma
- Thyroid carcinoma
- Tobacco use
- Tolazamide
- Tolbutamide
- Topoisomerase II interactive agents
- Toxins
- Trifluoperazine
- Trimethadione
- Trimethoprim-sulfamethoxazole
- Trisomy 8 mosaicism
- Tuberculosis [41]
- Valganciclovir hydrochloride
- Valproic acid poisoning [42][43]
- Viral infections
- Vitamin B12 deficiency
- Vitamin C deficiency
- Whipple's disease [44]
- Wiskott-Aldrich syndrome
- Xeroderma pigmentosum
## Causes by Pathophysiology
### Bone Marrow Failure
- Insufficient production (aplastic anemia)
- Inability of cells or mature (myelodysplasia)
- Replacement of normal bone marrow with fibrosis (myelofibrosis)
### Peripheral Sequestration/Destruction
- Splenomegaly
- Hypersplenism
## Causes by Mode of Inheritance
This is not applicable since there is no specific mode of inheritance for pancytopenia.
### Congenital
- Cartilage hair hypoplasia:
This is a bone marrow failure condition caused by ribosomal protein mutations.[45]
Clinical manifestations include cartilage and hair loss.
- This is a bone marrow failure condition caused by ribosomal protein mutations.[45]
- Clinical manifestations include cartilage and hair loss.
- Diamond-Blackfan syndrome:
This is a rare condition affecting 5-7 persons per million and is characterized by a macrocytic anemia and less than 5% erythroid precursors including reticulocytes.[46]
It is the most common inherited erythrocyte failure syndrome, and it is inherited in an autosomal dominant pattern.[45]
This condition is caused by mutations in ribosomal protein genes such as RPS19.
Though neutropenia and thrombocytopenia do not usually occur, moderate white blood cell and platelet count reductions have been described in some cases.[46]
Fetal hemoglobin is typically increased in an effect to enhance delivery of oxygen to tissues in the setting of low hemoglobin.[46]
Clinical manifestations usually include short statute, ocular abnormalities, skeletal abnormalities.
It is the most common inherited erythrocyte failure syndrome.[45]
The only curative therapy is bone marrow transplantation.
- This is a rare condition affecting 5-7 persons per million and is characterized by a macrocytic anemia and less than 5% erythroid precursors including reticulocytes.[46]
- It is the most common inherited erythrocyte failure syndrome, and it is inherited in an autosomal dominant pattern.[45]
- This condition is caused by mutations in ribosomal protein genes such as RPS19.
- Though neutropenia and thrombocytopenia do not usually occur, moderate white blood cell and platelet count reductions have been described in some cases.[46]
- Fetal hemoglobin is typically increased in an effect to enhance delivery of oxygen to tissues in the setting of low hemoglobin.[46]
- Clinical manifestations usually include short statute, ocular abnormalities, skeletal abnormalities.
- It is the most common inherited erythrocyte failure syndrome.[45]
- The only curative therapy is bone marrow transplantation.
- Dubowitz syndrome
This is a rare autosomal recessive disorder characterized by increased cancer susceptibility.[47]
The exact genetic abnormality and etiology is yet to be identified.
Patients have DNA that is very sensitive to ionizing radiation and a few chemotherapy agents like anthracyclines and bleomycin.[47]
There is some clinical overlap with Fanconi anemia.[47]
Patients can develop bone marrow failure and cytopenias.
- This is a rare autosomal recessive disorder characterized by increased cancer susceptibility.[47]
- The exact genetic abnormality and etiology is yet to be identified.
- Patients have DNA that is very sensitive to ionizing radiation and a few chemotherapy agents like anthracyclines and bleomycin.[47]
- There is some clinical overlap with Fanconi anemia.[47]
- Patients can develop bone marrow failure and cytopenias.
- Dyskeratosis congenita
This is a rare condition caused by short telomeres, which normally function to maintain the length and integrity of DNA.[48]
It is characterized by skin abnormalities, nail abnormalities, and leukoplakia.
The genes implicated include DKC1 (dyskerin), TERT, and TERC.
Other genes implicated in this condition encode ribonucleoprotein enzymes.
By age 30, approximately 80% of patients with this condition will develop bone marrow failure.[48]
- This is a rare condition caused by short telomeres, which normally function to maintain the length and integrity of DNA.[48]
- It is characterized by skin abnormalities, nail abnormalities, and leukoplakia.
- The genes implicated include DKC1 (dyskerin), TERT, and TERC.
- Other genes implicated in this condition encode ribonucleoprotein enzymes.
- By age 30, approximately 80% of patients with this condition will develop bone marrow failure.[48]
- Fanconi's anemia
This is a condition characterized by erythrocyte hypoproduction due to genomic instability and increased susceptibility to DNA damaging agents.[45] [49]
Diagnosis is made by demonstration of DNA crosslinking upon exposure to diepoxybutane (DEB) and mitomycin C (MCC).
Patients with fanconi anemia have a higher risk for development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), both of which can contribute to pancytopenia.[50]
- This is a condition characterized by erythrocyte hypoproduction due to genomic instability and increased susceptibility to DNA damaging agents.[45] [49]
- Diagnosis is made by demonstration of DNA crosslinking upon exposure to diepoxybutane (DEB) and mitomycin C (MCC).
- Patients with fanconi anemia have a higher risk for development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), both of which can contribute to pancytopenia.[50]
- Pearson syndrome
This is a relatively uncommon cause of refractory sideroblastic anemia, neutropenia, and thrombocytopenia.[51]
Clinical features include proximal myopathy and weakness, ophthalmoplegia, ataxia. and peripheral neuropathy.[51]
- This is a relatively uncommon cause of refractory sideroblastic anemia, neutropenia, and thrombocytopenia.[51]
- Clinical features include proximal myopathy and weakness, ophthalmoplegia, ataxia. and peripheral neuropathy.[51]
- Schwachman-Diamond syndrome
This is a condition that affects approximately 1 in 50000 persons and is characterized by bone marrow failure, pancreatic exocrine insufficiency, and skeletal abnormalities.[52]
It is caused by a biallelic (two alleles) mutation in a ribosomal protein encoded by the Schwachman-Bodian-Diamond gene SBDS, located on chromosome 7.[52]
Clinical manifestations in children usually include diarrhea and steatorrhea (due to pancreatic exocrine insufficiency).[53]
However, there have been cases of pancytopenia from schwachman-diamond syndrome in the absence of diarrhea, so this condition should still be in the differential diagnosis of children with pancytopenia and bone marrow failure.
- This is a condition that affects approximately 1 in 50000 persons and is characterized by bone marrow failure, pancreatic exocrine insufficiency, and skeletal abnormalities.[52]
- It is caused by a biallelic (two alleles) mutation in a ribosomal protein encoded by the Schwachman-Bodian-Diamond gene SBDS, located on chromosome 7.[52]
- Clinical manifestations in children usually include diarrhea and steatorrhea (due to pancreatic exocrine insufficiency).[53]
- However, there have been cases of pancytopenia from schwachman-diamond syndrome in the absence of diarrhea, so this condition should still be in the differential diagnosis of children with pancytopenia and bone marrow failure.
- TAR syndrome
This is a rare condition characterized by low platelet count (thrombocytopenia) and absent radius (a long bone of the lower arm).[54]
It is thought to be caused by an interstitial deletion in chromosome 1q21.
Patients can have skeletal abnormalities (like absent radius, short ulna, and absence of other long bones of the arm).[54]
The fingers are not affected.
- This is a rare condition characterized by low platelet count (thrombocytopenia) and absent radius (a long bone of the lower arm).[54]
- It is thought to be caused by an interstitial deletion in chromosome 1q21.
- Patients can have skeletal abnormalities (like absent radius, short ulna, and absence of other long bones of the arm).[54]
- The fingers are not affected.
### Acquired
- Albers-Schonberg disease
- Banti's Syndrome
- Bone marrow tumor
- Cirrhosis
- Drugs/Toxins
- Felty's Syndrome
- Gaucher's Disease
- Graft-versus-host disease
- Infections
- Kala-Azar
- Leukemia
- Lymphoma
- Lymphoproliferative Disorders
- Myelodysplastic syndrome
- Myelofibrosis
- Niemann-Pick Disease
- Osteoporosis
- Pernicious anemia
- Reticulosis
- Sarcoidosis
- Thymoma
- Tuberculosis
# Differentiating Pancytopenia from Other Diseases
# Epidemiology and Demographics
- Pancytopenia affects males and females equally.
- However, the underlying etiologies of pancytopenia can have a gender predilection.
- Please see above sections for epidemiology and demographics of the individual disease entities that cause pancytopenia.
# Risk Factors
- The risk factors of pancytopenia are related to the underlying cause.
- For example, leukemia-mediated pancytopenia can be related to risk factors such as chemical exposure, radiation, or family history.
- Please see above sections for risk factors of the individual disease entities that cause pancytopenia.
# Screening
- There are no suggested screening tests for pancytopenia.
- The United States Preventive Services Task Force (USPSTF) does not have any recommendations for screening for pancytopenia.
- However, if a person is suspected of having a particular condition that cause cause pancytopenia, such as viral infection, a diagnosis complete blood count (CBC) can be checked to assess for pancytopenia.
# Natural History, Complications, and Prognosis
## Natural History
- The natural history of pancytopenia is dictated by the pathophysiology of the under etiology.
- For example, viral-mediated pancytopenia is typically short-lived, pending clearance of the virus.
- Drug-induced pancytopenia typically resolves after discontinuing of the culprit drug and the drug has been metabolized by the body.
- Leukemia-mediated pancytopenia is usually a more long-term process, as marrow replacement by leukemia cells is difficult to overcome unless the leukemia is treated and the patient is in remission.
- Please see above sections for natural history of the individual disease entities that cause pancytopenia.
## Complications
- Complications of pancytopenia relate to deficits of the cell types that are affected.
- Decrease in erythrocytes causes fatigue, pallor, lightheadedness, and shortness of breath due to decrease in oxygen delivery to tissue beds.
- Decrease in leukocytes and leukocyte subsets causes infections, which can be viral, bacteria, fungal, or parasitic.
- The most concerning complication of decrease in leukocytes is called febrile neutropenia, which is a hematologic emergency.
- Decrease in thrombocytes causes bleeding, which is typically mucosal, given loss of the ability of platelets to create a hemostatic plug.
## Prognosis
- The prognosis of pancytopenia is related to the underlying etiology.
- For example, patients with unfavorable-risk leukemia will likely have a poor prognosis from a pancytopenia perspective.
- Patients with viral-mediated pancytopenia have a prognosis that is determined by the natural history of the virus.
- Epstein-Barr virus (EBV)-related pancytopenia can have a good prognosis if EBV resolves.
- Drug-induced pancytopenia has a favorable prognosis, as discontinuation of the offending agent can typically reverse the pancytopenia.
- Please see above sections for prognosis of the individual disease entities that cause pancytopenia.
# Diagnosis
## Diagnostic Criteria
The diagnosis of pancytopenia is made by assessing a complete blood count (CBC) when all of the following criteria are fulfilled:
- Anemia as defined by hemoglobin level < 12 grams per deciliter (g/dl)
- Leukopenia as defined by leukocyte count < 4000 per microliter
- Thrombocytopenia as defined by platelet count < 150000 per microliter
## History and Symptoms
Symptoms of pancytopenia are related to decrease in erythrocytes, leukocytes, and platelets.
- Decrease in erythrocytes causes fatigue, shortness of breath, decreased exercise tolerance, and pallor.
- Decrease in leukocytes causes infection, which can affect a multitude of organ systems including the central nervous system, lungs, abdomen, urinary tract, kidneys, and skin.
- Decrease in platelets causes mucocutaneous bleeding, typically of the nose, mouth, gastrointestinal tract, or genitourinary tract.
## Physical Examination
Key components of the physical exam include assessment of the conjunctiva, oral and nasal mucosa, lymph nodes (cervical, axillary, supraclavicular, inguinal), spleen size, liver size, and skin.
- The anemia component of pancytopenia can cause conjunctival pallor, mucosal pallor, skin pallor, and tachypnea.
- The leukopenia component of pancytopenia can cause variable findings depending on whether infection is present. Exam findings can include lymphadenopathy, egophony, coarse breath sounds, malodorous urine, suprapubic tenderness, costovertebral tenderness, abdominal tenderness, skin erythema, and/or skin purulence.
- The thrombocytopenia component of pancytopenia can cause petechiae (pinpoint hemorrhages in the skin), mucosal bleeding, or internal bleeding.
## Laboratory Findings
Laboratory findings in pancytopenia are, by definition:
- Hemoglobin level < 12 grams per deciliter (g/dl)
- Leukocyte count < 4000 per microliter
- Platelet count < 150000 per microliter
Other laboratory findings, depending on the underlying cause, can include:
- Elevated LDH
- Elevated indirect bilirubin
- Elevated reticulocyte count
- Decreased haptoglobin
## Imaging Findings
- There are no imaging findings associated with pancytopenia.
## Other Diagnostic Studies
- Viral polymerase chain reaction PCR testing can be done for viral-induced pancytopenia. This includes PCR for CMV DNA and EBV DNA.
# Treatment
## Medical Therapy
- The treatment of pancytopenia depends on the underlying cause.
- If pancytopenia is due to medication adverse effect, the offending agent should be discontinued.
- If pancytopenia is due to myelopthisis from leukemia, the underlying leukemia should be treated with cytotoxic chemotherapy.
- If pancytopenia is due to aplastic anemia, this should be treated with either immunosuppression with anti-thymocyte globulin (ATG) and cyclosporine A, or by hematopoietic stem cell transplantation from a matched related donor.
- Please see above sections for details of treatment of the individual disease entities that cause pancytopenia.
## Surgery
- The is no role for surgery for pancytopenia.
- However, for immune thrombocytopenia purpura (ITP) and autoimmune hemolytic anemia (AIHA), splenectomy can be considered.
## Prevention
- The prevention of pancytopenia focuses on prevention of the underlying etiologies.
- For example, viral-induced pancytopenia can be prevented by taking precautions against acquiring viral infections.
- This can include good hand hygiene, avoidance of exposures, anti-viral medications as prophylaxis.
- Prevention of leukemia-induced pancytopenia can be achieved via avoidance of risk factors of leukemia such as radiation exposure, chemical exposure, or benzene exposure.
- Drug-induced pancytopenia can be prevented by choosing an alternative medication in a similar class that does not cause pancytopenia.
- For example, in a patient who requires prophylaxis for PCP, atovaquone can be administered in place of trimethoprim-sulfamethoxazole, as atovaquone does not cause pancytopenia. | https://www.wikidoc.org/index.php/Ddx:Pancytopenia | |
331f501f695978b6850f35df4f1bb8c0753656c9 | wikidoc | Pollakisuria | Pollakisuria
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Pollakisuria or pollakiuria is frequent urge to urinate, which is also known as urgency.
# Differential Diagnosis
In alphabetical order:
- Cystitis
- Descensus uteri
- Diabetes Insipidus
- Diabetes Mellitus
- Endometriosis
- Heart Failure
- Hyperhydration
- Irritable bladder
- Multiple Sclerosis
- Pregnancy
- Prostatitis
- Prostate carcinoma
- Prostate hyperplasia
- Urethritis
- Vesicle calculus | Pollakisuria
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Pollakisuria or pollakiuria is frequent urge to urinate, which is also known as urgency.
# Differential Diagnosis
In alphabetical order: [1] [2]
- Cystitis
- Descensus uteri
- Diabetes Insipidus
- Diabetes Mellitus
- Endometriosis
- Heart Failure
- Hyperhydration
- Irritable bladder
- Multiple Sclerosis
- Pregnancy
- Prostatitis
- Prostate carcinoma
- Prostate hyperplasia
- Urethritis
- Vesicle calculus | https://www.wikidoc.org/index.php/Ddx:Pollakisuria | |
c6ae656b705dc3e1d0baf8ea34b52471ef5aa0a2 | wikidoc | Deborah Mash | Deborah Mash
Dr. Deborah Mash is an American professor of neurology and of molecular and cellular pharmacology at the University of Miami School of Medicine and director of the university's Brain Endowment Bank. She is one of the world's foremost scientific experts on the hallucinogenic drug, ibogaine.
Dr. Mash has been on the scientific advisory board for the Life Extension Foundation, located in Florida.
# Education
After obtaining her B.A. from the Florida State University, Tallahassee, she received her Ph.D from the University of Miami School of Medicine in Miami. She has also done work as a post-doctoral fellow at the Harvard Medical School Beth Israel Hospital in Boston, Massachusetts. | Deborah Mash
Dr. Deborah Mash is an American professor of neurology and of molecular and cellular pharmacology at the University of Miami School of Medicine and director of the university's Brain Endowment Bank. She is one of the world's foremost scientific experts on the hallucinogenic drug, ibogaine.
Dr. Mash has been on the scientific advisory board for the Life Extension Foundation, located in Florida.
# Education
After obtaining her B.A. from the Florida State University, Tallahassee, she received her Ph.D from the University of Miami School of Medicine in Miami. She has also done work as a post-doctoral fellow at the Harvard Medical School Beth Israel Hospital in Boston, Massachusetts.[1] | https://www.wikidoc.org/index.php/Deborah_Mash | |
a213cdcd6b5197524eb21c85b8b8e349ff9d2db4 | wikidoc | Deceleration | Deceleration
Synonyms and keywords: deceleration of diastolic flow; deceleration time of diastolic flow velocity (DDT)
# Overview
The deceleration time of diastolic flow may be a parameter to evaluate the degree of microvasculature damage that might predict the residual myocardial viability assessed by angiography.
# Definition
- Deceleration is defined as when dye flow down in the artery is slowed at any point during the course of flow.
- The diastolic deceleration rate (m/s2) refers to the calculation of the rate of decline in flow velocity in diastole.
# Pathophysiology
Microvascular ischemic damage after epicardial coronary artery occlusion affects coronary vascular resistance and may result in perivascular edema in which the generation of capillary leukocyte plugging contributes to prevention of full restoration of myocardial perfusion. Thus, the deceleration time of diastolic flow velocity may be explained as an increase in coronary vascular resistance caused by such ischemic microvascular impedance which significantly affects total coronary resistance in patients without severe coronary stenosis. Hence, this fact explains the reduction in postprocedural coronary systolic flow velocity in patients with no-reflow and is also the reason for a significantly increase in total coronary resistance in patients without severe coronary stenosis.
The deceleration time of diastolic flow velocity might reflect the coronary blood flow and is represented by a high ratio of perfused myocardium per functioning coronary microvasculature. So, the degree of reduced systolic antegrade flow or the deceleration time of diastolic flow evidence the level of microvasculature damage and be predictive of residual myocardial viability. Thus, the coronary blood flow velocity pattern seems almost normal in viable myocardium but is reduced in nonviable myocardium due to a systolic retrograde flow and a rapid deceleration of diastolic flow velocity.
# Clinical Significance
The coronary blood flow velocity pattern of no-reflow in patients with reperfused AMI is characterized by the occurrence of:
- Systolic retrograde flow.
- Diminished systolic antegrade flow.
- Rapid deceleration of diastolic flow.
- May occur immediately after reperfusion or shortly thereafter.
Disturbances are present during the deceleration phase of systole related to mild to moderate stenosis.
# Example | Deceleration
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Vanessa Cherniauskas, M.D. [2]
Synonyms and keywords: deceleration of diastolic flow; deceleration time of diastolic flow velocity (DDT)
# Overview
The deceleration time of diastolic flow may be a parameter to evaluate the degree of microvasculature damage that might predict the residual myocardial viability assessed by angiography.
# Definition
- Deceleration is defined as when dye flow down in the artery is slowed at any point during the course of flow.
- The diastolic deceleration rate (m/s2) refers to the calculation of the rate of decline in flow velocity in diastole.[1]
# Pathophysiology
Microvascular ischemic damage after epicardial coronary artery occlusion affects coronary vascular resistance and may result in perivascular edema in which the generation of capillary leukocyte plugging contributes to prevention of full restoration of myocardial perfusion.[2][3][4] Thus, the deceleration time of diastolic flow velocity may be explained as an increase in coronary vascular resistance caused by such ischemic microvascular impedance which significantly affects total coronary resistance in patients without severe coronary stenosis.[2][3][4][5][6] Hence, this fact explains the reduction in postprocedural coronary systolic flow velocity in patients with no-reflow and is also the reason for a significantly increase in total coronary resistance in patients without severe coronary stenosis.[1][7]
The deceleration time of diastolic flow velocity might reflect the coronary blood flow and is represented by a high ratio of perfused myocardium per functioning coronary microvasculature. So, the degree of reduced systolic antegrade flow or the deceleration time of diastolic flow evidence the level of microvasculature damage and be predictive of residual myocardial viability. Thus, the coronary blood flow velocity pattern seems almost normal in viable myocardium but is reduced in nonviable myocardium due to a systolic retrograde flow and a rapid deceleration of diastolic flow velocity.[5]
# Clinical Significance
The coronary blood flow velocity pattern of no-reflow in patients with reperfused AMI is characterized by the occurrence of:
- Systolic retrograde flow.[1]
- Diminished systolic antegrade flow.[1]
- Rapid deceleration of diastolic flow.[1]
- May occur immediately after reperfusion or shortly thereafter.[8]
Disturbances are present during the deceleration phase of systole related to mild to moderate stenosis.[9]
# Example | https://www.wikidoc.org/index.php/Deceleration | |
d7f2a985e06eb0027dd548b11af10da723302923 | wikidoc | Decongestant | Decongestant
# Overview
A decongestant is a broad class of medications used to relieve nasal congestion. Generally, they work by reducing swelling of the mucous membranes in the nasal passages.
# Mechanism
Most decongestants cause response from adrenoreceptor a1, chiefly responsible for vasoconstriction (a2 modulates adrenaline/noradrenaline levels, b1 is the most stimulating and increases cardiac output, b2 dilates the bronchial walls, and b3 induces lipolysis). The effects are not limited to the nose and these medicines can increase hypertension (blood pressure) through vasoconstriction, but most decongestants are not pronounced stimulants due to lack of response from the other adrenoreceptors.
These are normally paired with antihistamines to lessen this effect, but they don't always even each other out.
# Administration
These agents are usually administered topically (by the intranasal route) or orally.
# Examples
The most common oral decongestants are pseudoephedrine and phenylephrine; phenylpropanolamine (PPA) is another, although it's no longer available in the US. Oxymetazoline and phenylephrine are a commonly available topical decongestants (nasal sprays). | Decongestant
# Overview
A decongestant is a broad class of medications used to relieve nasal congestion. Generally, they work by reducing swelling of the mucous membranes in the nasal passages.
# Mechanism
Most decongestants cause response from adrenoreceptor a1, chiefly responsible for vasoconstriction (a2 modulates adrenaline/noradrenaline levels, b1 is the most stimulating and increases cardiac output, b2 dilates the bronchial walls, and b3 induces lipolysis). The effects are not limited to the nose and these medicines can increase hypertension (blood pressure) through vasoconstriction, but most decongestants are not pronounced stimulants due to lack of response from the other adrenoreceptors.
These are normally paired with antihistamines to lessen this effect, but they don't always even each other out.
# Administration
These agents are usually administered topically (by the intranasal route) or orally.
# Examples
The most common oral decongestants are pseudoephedrine and phenylephrine; phenylpropanolamine (PPA) is another, although it's no longer available in the US. Oxymetazoline and phenylephrine are a commonly available topical decongestants (nasal sprays). | https://www.wikidoc.org/index.php/Decongestant | |
0dc438fdc78fca91c8eca0f81e2cd6b9906ed87f | wikidoc | Deferoxamine | Deferoxamine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Deferoxamine is a heavy metal chelator , toxicology-antidote agent that is FDA approved for the treatment of acute iron intoxication, chronic iron overload. Common adverse reactions include injection site pain, generalized rash, urticaria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Deferoxamine mesylate is indicated for the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias.
- Deferoxamine mesylate is an adjunct to, and not a substitute for, standard measures used in treating acute iron intoxication, which may include the following: induction of emesis with syrup of ipecac; gastric lavage; suction and maintenance of a clear airway; control of shock with intravenous fluids, blood, oxygen, and vasopressors; and correction of acidosis.
- Deferoxamine mesylate can promote iron excretion in patients with secondary iron overload from multiple transfusions (as may occur in the treatment of some chronic anemias, including thalassemia). Long-term therapy with deferoxamine mesylate slows accumulation of hepatic iron and retards or eliminates progression of hepatic fibrosis.
- Iron mobilization with deferoxamine mesylate is relatively poor in patients under the age of 3 years with relatively little iron overload. The drug should ordinarily not be given to such patients unless significant iron mobilization (e.g., 1 mg or more of iron per day) can be demonstrated.
- Deferoxamine mesylate is not indicated for the treatment of primary hemochromatosis, since phlebotomy is the method of choice for removing excess iron in this disorder.
### Dosing Information
- Intramuscular Administration:
- This route is preferred and should be used for ALL PATIENTS NOT IN SHOCK.
- A dose of 1000 mg should be administered initially. This may be followed by 500 mg every 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered every 4 to 12 hours. The total amount administered should not exceed 6000 mg in 24 hours. For reconstitution instructions for intramuscular administration see Table 1.
- Intravenous Administration:
- THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION. THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1000 MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT A SLOWER RATE, NOT TO EXCEED 125 MG/HR.
- For reconstitution instructions for intravenous administration see Table 2. The reconstituted solution is added to physiologic saline (e.g., 0.9% sodium chloride, 0.45% sodium chloride), glucose in water, or Ringer’s lactate solution.
- An initial dose of 1000 mg should be administered at a rate NOT TO EXCEED 15 mg/kg/hr. This may be followed by 500 mg over 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered over 4 to 12 hours. The total amount administered should not exceed 6000 mg in 24 hours.
- As soon as the clinical condition of the patient permits, intravenous administration should be discontinued and the drug should be administered intramuscularly.
- Subcutaneous Administration:
- A daily dose of 1000 to 2000 mg (20 to 40 mg/kg/day) should be administered over 8 to 24 hours, utilizing a small portable pump capable of providing continuous mini-infusion. The duration of infusion must be individualized. In some patients, as much iron will be excreted after a short infusion of 8 to 12 hours as with the same dose given over 24 hours. For reconstitution instructions for subcutaneous administration see Table 3.
- The standard recommended method of deferoxamine mesylate administration is via slow subcutaneous infusion over 8 to 12 hours. In patients with intravenous access, the daily dose of deferoxamine mesylate can be administered intravenously. The standard dose is 20 to 40 mg/kg/day for children and 40 to 50 mg/kg/day over 8 to 12 hours in adults for 5 to 7 days per week. In children, average doses should not exceed 40 mg/kg/day until growth has ceased. In adults, average doses should not exceed 60 mg/kg/day. The intravenous infusion rate should not exceed 15 mg/kg/hour. For reconstitution instructions for intravenous administration see Table 2.
- In patients who are poorly compliant, deferoxamine mesylate may be administered prior to or following same day blood transfusion (for example 1 gram over 4 hours on the day of transfusion); however, the contribution of this mode of administration to iron balance is limited. Deferoxamine mesylate should not be administered concurrently with the blood transfusion as this can lead to errors in interpreting side effects such as rash, anaphylaxis and hypotension.
- A daily dose of 500 to 1000 mg may be administered intramuscularly. The total daily dose should not exceed 1000 mg. For reconstitution instructions for intramuscular administration see Table 1.
- The reconstituted deferoxamine mesylate for injection solution is an isotonic, clear and colorless to slightly yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Deferoxamine mesylate reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion.
- The product should be used immediately after reconstitution (commencement of treatment within 3 hours) for microbiological safety. When reconstitution is carried out under validated aseptic conditions (in a sterile laminar flow hood using aseptic technique), the product may be stored at room temperature for a maximum period of 24 hours before use. Do not refrigerate reconstituted solution. Reconstituting deferoxamine mesylate for injection in solvents or under conditions other than indicated may result in precipitation. Turbid solutions should not be used.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Deferoxamine in adult patients.
### Non–Guideline-Supported Use
- Renal dialysis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Dosage
There is limited information regarding FDA-Labeled Use of Deferoxamine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Deferoxamine in pediatric patients.
### Non–Guideline-Supported Use
- Renal dialysis
# Contraindications
- Known hypersensitivity to the active substance.
- Deferoxamine mesylate is contraindicated in patients with severe renal disease or anuria, since the drug and the iron chelate are excreted primarily by the kidney.
# Warnings
- Ocular and auditory disturbances have been reported when deferoxamine mesylate was administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. The ocular disturbances observed have been blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory abnormalities reported have been tinnitus and hearing loss including high frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment.
- Visual acuity tests, slit-lamp examinations, funduscopy and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early.
- Increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders, associated with the administration of deferoxamine, have been reported in postmarketing experience (see ADVERSE REACTIONS). Monitor patients for changes in renal function.
- High doses of deferoxamine mesylate and concomitant low ferritin levels have also been associated with growth retardation. After reduction of deferoxamine mesylate dose, growth velocity may partially resume to pretreatment rates.
- Adult respiratory distress syndrome, also reported in children, has been described following treatment with excessively high intravenous doses of deferoxamine mesylate in patients with acute iron intoxication or thalassemia.
### Precautions
- Flushing of the skin, urticaria, hypotension, and shock have occurred in a few patients when deferoxamine mesylate was administered by rapid intravenous injection. THEREFORE, DEFEROXAMINE MESYLATE SHOULD BE GIVEN INTRAMUSCULARLY OR BY SLOW SUBCUTANEOUS OR INTRAVENOUS INFUSION.
- Iron overload increases susceptibility of patients to Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In some rare cases, treatment with deferoxamine mesylate has enhanced this susceptibility, resulting in generalized infections by providing these bacteria with a siderophore otherwise missing. In such cases, deferoxamine mesylate treatment should be discontinued until the infection is resolved.
- In patients receiving deferoxamine mesylate, rare cases of mucormycosis, some with a fatal outcome, have been reported. If any of the suspected signs or symptoms occur, deferoxamine mesylate should be discontinued, mycological tests carried out and appropriate treatment instituted immediately.
- In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with deferoxamine mesylate and high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and deferoxamine mesylate are to be used concomitantly:
- Vitamin C supplements should not be given to patients with cardiac failure.
- Start supplemental vitamin C only after an initial month of regular treatment with deferoxamine mesylate.
- Give vitamin C only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.
- Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses.
- Clinical monitoring of cardiac function is advisable during such combined therapy.
In patients with aluminum-related encephalopathy and receiving dialysis, deferoxamine mesylate may cause neurological dysfunction (seizures), possibly due to an acute increase in circulating aluminum. Deferoxamine mesylate may precipitate the onset of dialysis dementia. Treatment with deferoxamine mesylate in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency.
- At the Injection Site: Localized irritation, pain, burning, swelling, induration, infiltration, pruritus, erythema, wheal formation, eschar, crust, vesicles, local edema. Injection site reactions may be associated with systemic allergic reactions (see Body as a Whole below).
- Generalized rash, urticaria, anaphylactic reaction with or without shock, angioedema.
- Local injection site reactions may be accompanied by systemic reactions like arthralgia, fever, headache, myalgia, nausea, vomiting, abdominal pain, or asthma.
- Infections with Yersinia and Mucormycosis have been reported in association with deferoxamine mesylate use (see PRECAUTIONS).
- Tachycardia, hypotension, shock.
- Abdominal discomfort, diarrhea, nausea, vomiting.
- Blood dyscrasia (thrombocytopenia, leukopenia).
- Increased transaminases, hepatic dysfunction.
- Muscle spasms. Growth retardation and bone changes (e.g., metaphyseal dysplasia) are common in chelated patients given doses above 60 mg/kg, especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk may be reduced.
- Neurological disturbances including dizziness, peripheral sensory, motor, or mixed neuropathy, paresthesias, seizures; exacerbation or precipitation of aluminum-related dialysis encephalopathy (see PRECAUTIONS, INFORMATION FOR PATIENTS).
- High-frequency sensorineural hearing loss and/or tinnitus are uncommon if dosage guidelines are not exceeded and if dose is reduced when ferritin levels decline. Visual disturbances are rare if dosage guidelines are not exceeded. These may include decreased acuity, blurred vision, loss of vision, dyschromatopsia, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration), optic neuritis, and cataracts (see WARNINGS).
- Acute respiratory distress syndrome (with dyspnea, cyanosis, and/or interstitial infiltrates).
- Very rare generalized rash.
- Dysuria, acute renal failure, increased serum creatinine and renal tubular disorders.
## Postmarketing Experience
- There are postmarketing reports of deferoxamine-associated renal dysfunction, including renal failure.
- Monitor patients for changes in renal function (e.g., increased serum creatinine).
# Drug Interactions
- Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with deferoxamine mesylate (see PRECAUTIONS). Vitamin C increases availability of iron for chelation. In general, 50 mg daily suffices for children under 10 years old and 100 mg daily for older children. Larger doses of vitamin C fail to produce any additional increase in excretion of iron complex.
- Concurrent treatment with deferoxamine mesylate and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness.
- Imaging results may be distorted because of the rapid urinary excretion of deferoxamine mesylate-bound gallium-67. Discontinuation of deferoxamine mesylate 48 hours prior to scintigraphy is advisable.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Delayed ossification in mice and skeletal anomalies in rabbits were observed after deferoxamine mesylate was administered in daily doses up to 4.5 times the maximum daily human dose. No adverse effects were observed in similar studies in rats.
- There are no adequate and well-controlled studies in pregnant women. Deferoxamine mesylate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Deferoxamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Deferoxamine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when deferoxamine mesylate is administered to a nursing woman.
### Pediatric Use
- Pediatric patients receiving deferoxamine mesylate should be monitored for body weight and growth every 3 months.
- Safety and effectiveness in pediatric patients under the age of 3 years have not been established.
### Geriatic Use
- Clinical studies of deferoxamine mesylate did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from the younger subjects. Postmarketing reports suggest a possible trend for an increased risk of eye disorders in the geriatric population, specifically the occurrence of color blindness, maculopathy, and scotoma. However, it is unclear if these eye disorders were dose related. Although the number of reports was very small, certain elderly patients may be predisposed to eye disorders when taking deferoxamine mesylate. Postmarketing reports also suggest that there may be an increased risk of deafness and hearing loss in the geriatric population). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Deferoxamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Deferoxamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Deferoxamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Deferoxamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Deferoxamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Deferoxamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
- Intravenous
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Deferoxamine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Deferoxamine in the drug label.
# Overdosage
- Intravenous LD50s (mg/kg): mice, 287; rats, 329.
- Inadvertent administration of an overdose or inadvertent intravenous bolus administration/rapid intravenous infusion may be associated with hypotension, tachycardia and gastrointestinal disturbances; acute but transient loss of vision, aphasia, agitation, headache, nausea, pallor, CNS depression including coma, bradycardia and acute renal failure have been reported.
- Acute respiratory distress syndrome has been reported following treatment with excessively high intravenous doses of deferoxamine mesylate in patients with acute iron intoxication and in patients with thalassemia.
- There is no specific antidote. Deferoxamine mesylate should be discontinued and appropriate symptomatic measures undertaken.
- Deferoxamine mesylate is readily dialyzable.
# Pharmacology
There is limited information regarding Deferoxamine Pharmacology in the drug label.
## Mechanism of Action
- Deferoxamine mesylate chelates iron by forming a stable complex that prevents the iron from entering into further chemical reactions. It readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it does not combine with the iron from cytochromes and hemoglobin. Deferoxamine mesylate does not cause any demonstrable increase in the excretion of electrolytes or trace metals. Theoretically, 100 parts by weight of deferoxamine mesylate is capable of binding approximately 8.5 parts by weight of ferric iron.
## Structure
- Deferoxamine Mesylate for Injection, USP, is an iron-chelating agent, available in vials for intramuscular, subcutaneous, and intravenous administration. Deferoxamine mesylate for injection is supplied as vials containing 500 mg and 2 g of deferoxamine mesylate in sterile, lyophilized form.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Deferoxamine in the drug label.
## Pharmacokinetics
- Deferoxamine mesylate is metabolized principally by plasma enzymes, but the pathways have not yet been defined. The chelate is readily soluble in water and passes easily through the kidney, giving the urine a characteristic reddish color. Some is also excreted in the feces via the bile.
## Nonclinical Toxicology
- Long-term carcinogenicity studies in animals have not been performed with deferoxamine mesylate.
- Cytotoxicity may occur, since deferoxamine mesylate has been shown to inhibit DNA synthesis in vitro.
# Clinical Studies
There is limited information regarding Clinical Studies of Deferoxamine in the drug label.
# How Supplied
- This container closure is not made with natural rubber latex.
## Storage
- Store at 20º to 25°C (68º to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
NDC 63323-597-10
Deferoxamine Mesylate for Injection, USP
500 mg/vial
For SC, IM, or IV Use
Rx only
NDC 63323-597-10
Deferoxamine Mesylate for Injection, USP
500 mg/vial
For SC, IM or IV Use
Rx only
NDC 63323-599-30
Deferoxamine Mesylate for Injection, USP
2 g/vial
For SC, IM, or IV Use
Rx only
Single Use Only
NDC 63323-599-30
Deferoxamine Mesylate for Injection, USP
2 g/vial
For SC, IM or IV Use
Rx only
Single Use Only
# Patient Counseling Information
- Patients experiencing dizziness or other nervous system disturbances, or impairment of vision or hearing, should refrain from driving or operating potentially hazardous machines.
- Patients should be informed that occasionally their urine may show a reddish discoloration.
# Precautions with Alcohol
- Alcohol-Deferoxamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Desferal®
# Look-Alike Drug Names
There is limited information regarding Deferoxamine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Deferoxamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Deferoxamine is a heavy metal chelator , toxicology-antidote agent that is FDA approved for the treatment of acute iron intoxication, chronic iron overload. Common adverse reactions include injection site pain, generalized rash, urticaria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Deferoxamine mesylate is indicated for the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias.
- Deferoxamine mesylate is an adjunct to, and not a substitute for, standard measures used in treating acute iron intoxication, which may include the following: induction of emesis with syrup of ipecac; gastric lavage; suction and maintenance of a clear airway; control of shock with intravenous fluids, blood, oxygen, and vasopressors; and correction of acidosis.
- Deferoxamine mesylate can promote iron excretion in patients with secondary iron overload from multiple transfusions (as may occur in the treatment of some chronic anemias, including thalassemia). Long-term therapy with deferoxamine mesylate slows accumulation of hepatic iron and retards or eliminates progression of hepatic fibrosis.
- Iron mobilization with deferoxamine mesylate is relatively poor in patients under the age of 3 years with relatively little iron overload. The drug should ordinarily not be given to such patients unless significant iron mobilization (e.g., 1 mg or more of iron per day) can be demonstrated.
- Deferoxamine mesylate is not indicated for the treatment of primary hemochromatosis, since phlebotomy is the method of choice for removing excess iron in this disorder.
### Dosing Information
- Intramuscular Administration:
- This route is preferred and should be used for ALL PATIENTS NOT IN SHOCK.
- A dose of 1000 mg should be administered initially. This may be followed by 500 mg every 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered every 4 to 12 hours. The total amount administered should not exceed 6000 mg in 24 hours. For reconstitution instructions for intramuscular administration see Table 1.
- Intravenous Administration:
- THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION. THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1000 MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT A SLOWER RATE, NOT TO EXCEED 125 MG/HR.
- For reconstitution instructions for intravenous administration see Table 2. The reconstituted solution is added to physiologic saline (e.g., 0.9% sodium chloride, 0.45% sodium chloride), glucose in water, or Ringer’s lactate solution.
- An initial dose of 1000 mg should be administered at a rate NOT TO EXCEED 15 mg/kg/hr. This may be followed by 500 mg over 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered over 4 to 12 hours. The total amount administered should not exceed 6000 mg in 24 hours.
- As soon as the clinical condition of the patient permits, intravenous administration should be discontinued and the drug should be administered intramuscularly.
- Subcutaneous Administration:
- A daily dose of 1000 to 2000 mg (20 to 40 mg/kg/day) should be administered over 8 to 24 hours, utilizing a small portable pump capable of providing continuous mini-infusion. The duration of infusion must be individualized. In some patients, as much iron will be excreted after a short infusion of 8 to 12 hours as with the same dose given over 24 hours. For reconstitution instructions for subcutaneous administration see Table 3.
- The standard recommended method of deferoxamine mesylate administration is via slow subcutaneous infusion over 8 to 12 hours. In patients with intravenous access, the daily dose of deferoxamine mesylate can be administered intravenously. The standard dose is 20 to 40 mg/kg/day for children and 40 to 50 mg/kg/day over 8 to 12 hours in adults for 5 to 7 days per week. In children, average doses should not exceed 40 mg/kg/day until growth has ceased. In adults, average doses should not exceed 60 mg/kg/day. The intravenous infusion rate should not exceed 15 mg/kg/hour. For reconstitution instructions for intravenous administration see Table 2.
- In patients who are poorly compliant, deferoxamine mesylate may be administered prior to or following same day blood transfusion (for example 1 gram over 4 hours on the day of transfusion); however, the contribution of this mode of administration to iron balance is limited. Deferoxamine mesylate should not be administered concurrently with the blood transfusion as this can lead to errors in interpreting side effects such as rash, anaphylaxis and hypotension.
- A daily dose of 500 to 1000 mg may be administered intramuscularly. The total daily dose should not exceed 1000 mg. For reconstitution instructions for intramuscular administration see Table 1.
- The reconstituted deferoxamine mesylate for injection solution is an isotonic, clear and colorless to slightly yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Deferoxamine mesylate reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion.
- The product should be used immediately after reconstitution (commencement of treatment within 3 hours) for microbiological safety. When reconstitution is carried out under validated aseptic conditions (in a sterile laminar flow hood using aseptic technique), the product may be stored at room temperature for a maximum period of 24 hours before use. Do not refrigerate reconstituted solution. Reconstituting deferoxamine mesylate for injection in solvents or under conditions other than indicated may result in precipitation. Turbid solutions should not be used.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Deferoxamine in adult patients.
### Non–Guideline-Supported Use
- Renal dialysis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Dosage
There is limited information regarding FDA-Labeled Use of Deferoxamine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Deferoxamine in pediatric patients.
### Non–Guideline-Supported Use
- Renal dialysis
# Contraindications
- Known hypersensitivity to the active substance.
- Deferoxamine mesylate is contraindicated in patients with severe renal disease or anuria, since the drug and the iron chelate are excreted primarily by the kidney.
# Warnings
- Ocular and auditory disturbances have been reported when deferoxamine mesylate was administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. The ocular disturbances observed have been blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory abnormalities reported have been tinnitus and hearing loss including high frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment.
- Visual acuity tests, slit-lamp examinations, funduscopy and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early.
- Increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders, associated with the administration of deferoxamine, have been reported in postmarketing experience (see ADVERSE REACTIONS). Monitor patients for changes in renal function.
- High doses of deferoxamine mesylate and concomitant low ferritin levels have also been associated with growth retardation. After reduction of deferoxamine mesylate dose, growth velocity may partially resume to pretreatment rates.
- Adult respiratory distress syndrome, also reported in children, has been described following treatment with excessively high intravenous doses of deferoxamine mesylate in patients with acute iron intoxication or thalassemia.
### Precautions
- Flushing of the skin, urticaria, hypotension, and shock have occurred in a few patients when deferoxamine mesylate was administered by rapid intravenous injection. THEREFORE, DEFEROXAMINE MESYLATE SHOULD BE GIVEN INTRAMUSCULARLY OR BY SLOW SUBCUTANEOUS OR INTRAVENOUS INFUSION.
- Iron overload increases susceptibility of patients to Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In some rare cases, treatment with deferoxamine mesylate has enhanced this susceptibility, resulting in generalized infections by providing these bacteria with a siderophore otherwise missing. In such cases, deferoxamine mesylate treatment should be discontinued until the infection is resolved.
- In patients receiving deferoxamine mesylate, rare cases of mucormycosis, some with a fatal outcome, have been reported. If any of the suspected signs or symptoms occur, deferoxamine mesylate should be discontinued, mycological tests carried out and appropriate treatment instituted immediately.
- In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with deferoxamine mesylate and high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and deferoxamine mesylate are to be used concomitantly:
- Vitamin C supplements should not be given to patients with cardiac failure.
- Start supplemental vitamin C only after an initial month of regular treatment with deferoxamine mesylate.
- Give vitamin C only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.
- Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses.
- Clinical monitoring of cardiac function is advisable during such combined therapy.
In patients with aluminum-related encephalopathy and receiving dialysis, deferoxamine mesylate may cause neurological dysfunction (seizures), possibly due to an acute increase in circulating aluminum. Deferoxamine mesylate may precipitate the onset of dialysis dementia. Treatment with deferoxamine mesylate in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency.
- At the Injection Site: Localized irritation, pain, burning, swelling, induration, infiltration, pruritus, erythema, wheal formation, eschar, crust, vesicles, local edema. Injection site reactions may be associated with systemic allergic reactions (see Body as a Whole below).
- Generalized rash, urticaria, anaphylactic reaction with or without shock, angioedema.
- Local injection site reactions may be accompanied by systemic reactions like arthralgia, fever, headache, myalgia, nausea, vomiting, abdominal pain, or asthma.
- Infections with Yersinia and Mucormycosis have been reported in association with deferoxamine mesylate use (see PRECAUTIONS).
- Tachycardia, hypotension, shock.
- Abdominal discomfort, diarrhea, nausea, vomiting.
- Blood dyscrasia (thrombocytopenia, leukopenia).
- Increased transaminases, hepatic dysfunction.
- Muscle spasms. Growth retardation and bone changes (e.g., metaphyseal dysplasia) are common in chelated patients given doses above 60 mg/kg, especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk may be reduced.
- Neurological disturbances including dizziness, peripheral sensory, motor, or mixed neuropathy, paresthesias, seizures; exacerbation or precipitation of aluminum-related dialysis encephalopathy (see PRECAUTIONS, INFORMATION FOR PATIENTS).
- High-frequency sensorineural hearing loss and/or tinnitus are uncommon if dosage guidelines are not exceeded and if dose is reduced when ferritin levels decline. Visual disturbances are rare if dosage guidelines are not exceeded. These may include decreased acuity, blurred vision, loss of vision, dyschromatopsia, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration), optic neuritis, and cataracts (see WARNINGS).
- Acute respiratory distress syndrome (with dyspnea, cyanosis, and/or interstitial infiltrates).
- Very rare generalized rash.
- Dysuria, acute renal failure, increased serum creatinine and renal tubular disorders.
## Postmarketing Experience
- There are postmarketing reports of deferoxamine-associated renal dysfunction, including renal failure.
- Monitor patients for changes in renal function (e.g., increased serum creatinine).
# Drug Interactions
- Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with deferoxamine mesylate (see PRECAUTIONS). Vitamin C increases availability of iron for chelation. In general, 50 mg daily suffices for children under 10 years old and 100 mg daily for older children. Larger doses of vitamin C fail to produce any additional increase in excretion of iron complex.
- Concurrent treatment with deferoxamine mesylate and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness.
- Imaging results may be distorted because of the rapid urinary excretion of deferoxamine mesylate-bound gallium-67. Discontinuation of deferoxamine mesylate 48 hours prior to scintigraphy is advisable.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Delayed ossification in mice and skeletal anomalies in rabbits were observed after deferoxamine mesylate was administered in daily doses up to 4.5 times the maximum daily human dose. No adverse effects were observed in similar studies in rats.
- There are no adequate and well-controlled studies in pregnant women. Deferoxamine mesylate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Deferoxamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Deferoxamine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when deferoxamine mesylate is administered to a nursing woman.
### Pediatric Use
- Pediatric patients receiving deferoxamine mesylate should be monitored for body weight and growth every 3 months.
- Safety and effectiveness in pediatric patients under the age of 3 years have not been established.
### Geriatic Use
- Clinical studies of deferoxamine mesylate did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from the younger subjects. Postmarketing reports suggest a possible trend for an increased risk of eye disorders in the geriatric population, specifically the occurrence of color blindness, maculopathy, and scotoma. However, it is unclear if these eye disorders were dose related. Although the number of reports was very small, certain elderly patients may be predisposed to eye disorders when taking deferoxamine mesylate. Postmarketing reports also suggest that there may be an increased risk of deafness and hearing loss in the geriatric population). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Deferoxamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Deferoxamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Deferoxamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Deferoxamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Deferoxamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Deferoxamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
- Intravenous
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Deferoxamine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Deferoxamine in the drug label.
# Overdosage
- Intravenous LD50s (mg/kg): mice, 287; rats, 329.
- Inadvertent administration of an overdose or inadvertent intravenous bolus administration/rapid intravenous infusion may be associated with hypotension, tachycardia and gastrointestinal disturbances; acute but transient loss of vision, aphasia, agitation, headache, nausea, pallor, CNS depression including coma, bradycardia and acute renal failure have been reported.
- Acute respiratory distress syndrome has been reported following treatment with excessively high intravenous doses of deferoxamine mesylate in patients with acute iron intoxication and in patients with thalassemia.
- There is no specific antidote. Deferoxamine mesylate should be discontinued and appropriate symptomatic measures undertaken.
- Deferoxamine mesylate is readily dialyzable.
# Pharmacology
There is limited information regarding Deferoxamine Pharmacology in the drug label.
## Mechanism of Action
- Deferoxamine mesylate chelates iron by forming a stable complex that prevents the iron from entering into further chemical reactions. It readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it does not combine with the iron from cytochromes and hemoglobin. Deferoxamine mesylate does not cause any demonstrable increase in the excretion of electrolytes or trace metals. Theoretically, 100 parts by weight of deferoxamine mesylate is capable of binding approximately 8.5 parts by weight of ferric iron.
## Structure
- Deferoxamine Mesylate for Injection, USP, is an iron-chelating agent, available in vials for intramuscular, subcutaneous, and intravenous administration. Deferoxamine mesylate for injection is supplied as vials containing 500 mg and 2 g of deferoxamine mesylate in sterile, lyophilized form.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Deferoxamine in the drug label.
## Pharmacokinetics
- Deferoxamine mesylate is metabolized principally by plasma enzymes, but the pathways have not yet been defined. The chelate is readily soluble in water and passes easily through the kidney, giving the urine a characteristic reddish color. Some is also excreted in the feces via the bile.
## Nonclinical Toxicology
- Long-term carcinogenicity studies in animals have not been performed with deferoxamine mesylate.
- Cytotoxicity may occur, since deferoxamine mesylate has been shown to inhibit DNA synthesis in vitro.
# Clinical Studies
There is limited information regarding Clinical Studies of Deferoxamine in the drug label.
# How Supplied
- This container closure is not made with natural rubber latex.
## Storage
- Store at 20º to 25°C (68º to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
NDC 63323-597-10
509710
Deferoxamine Mesylate for Injection, USP
500 mg/vial
For SC, IM, or IV Use
Rx only
NDC 63323-597-10
509710
Deferoxamine Mesylate for Injection, USP
500 mg/vial
For SC, IM or IV Use
Rx only
NDC 63323-599-30
509930
Deferoxamine Mesylate for Injection, USP
2 g/vial
For SC, IM, or IV Use
Rx only
Single Use Only
NDC 63323-599-30
509930
Deferoxamine Mesylate for Injection, USP
2 g/vial
For SC, IM or IV Use
Rx only
Single Use Only
# Patient Counseling Information
- Patients experiencing dizziness or other nervous system disturbances, or impairment of vision or hearing, should refrain from driving or operating potentially hazardous machines.
- Patients should be informed that occasionally their urine may show a reddish discoloration.
# Precautions with Alcohol
- Alcohol-Deferoxamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Desferal®
# Look-Alike Drug Names
There is limited information regarding Deferoxamine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Deferoxamine | |
70a32d8a6a7af2e3facc8d3c18b1c86dd998b0cf | wikidoc | Delafloxacin | Delafloxacin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Delafloxacin is a a fluoroquinolone antibacterial that is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible bacteria. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, diarrhea, headache, transaminase elevations, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Acute Bacterial Skin and Skin Structure Infections
- Delafloxacin is indicated in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following:
- Gram-positive organisms: Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis.
- Gram-negative organisms: Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of delafloxacin and other antibacterial drugs, delafloxacin should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- For treatment of adults with ABSSSI, the recommended dosage regimen of delafloxacin is as follows:
- Administer 300 mg of delafloxacin for Injection every 12 hours over 60 minutes by intravenous infusion for 5 to 14 days or,
- Administer 300 mg of delafloxacin for Injection every 12 hours over 60 minutes by intravenous infusion, then switch to a 450 mg delafloxacin tablet orally every 12 hours at the discretion of the physician for a total duration of 5 to 14 days or,
- Administer a 450 mg delafloxacin tablet orally every 12 hours for a total duration of 5 to 14 days.
- Table 1 below describes the dosage modification based on the estimated glomerular filtration rate (eGFR) that is recommended in patients with renal impairment. Dosage adjustment is required for patients with severe renal impairment (eGFR 15-29 mL/min/1.73m2).
- In patients with severe renal impairment receiving delafloxacin intravenously, closely monitor serum creatinine levels and eGFR. If serum creatinine level increases, consider switching to delafloxacin Tablets. Discontinue delafloxacin if eGFR decreases to <15 mL/min/1.73 m2.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding delafloxacin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding delafloxacin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Pediatric studies were not conducted because risk-benefit considerations do not support the use of delafloxacin for ABSSSI in this population. Fluoroquinolones cause arthropathy in juvenile animals.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding delafloxacin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding delafloxacin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Delafloxacin is contraindicated in patients with known hypersensitivity to delafloxacin or any of the fluoroquinolone class of antibacterial drugs, or any of the components of delafloxacin
# Warnings
- Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions could occur within hours to weeks after starting a fluoroquinolone. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.
- Discontinue delafloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including delafloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.
- Fluoroquinolones have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting a fluoroquinolone, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.
- This risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over age 60 years of age, in patients taking corticosteroid drugs, and, in patients with kidney, heart, and lung transplant. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors.
- Discontinue delafloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Advise patients, at the first sign of tendon pain, swelling, or inflammation, to stop taking delafloxacin, to avoid exercise and use of the affected area, and to promptly contact their healthcare provider about changing to a non-quinolone antimicrobial drug. Avoid delafloxacin in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.
- Fluoroquinolones have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias, and weakness have been reported in patients receiving fluoroquinolones, including delafloxacin. Symptoms may occur soon after initiation of fluoroquinolones and may be irreversible in some patients.
- Discontinue delafloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including delafloxacin in patients who have previously experienced peripheral neuropathy.
- Fluoroquinolones have been associated with an increased risk of central nervous system (CNS) reactions, including: convulsions and increased intracranial pressure (including pseudotumor cerebri) and toxic psychosis. Fluoroquinolones, including delafloxicin, may also cause CNS reactions of nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or acts. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving delafloxicin, discontinue delafloxicin immediately and institute appropriate measures. As with all fluoroquinolones, use delafloxicin when the benefits of treatment exceed the risks in patients with known or suspected CNS disorders (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold.
- Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse reactions, including death and requirement for ventilator support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid delafloxicin in patients with known history of myasthenia gravis.
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Hypersensitivity reactions have been reported in patients receiving delafloxicin. These reactions may occur after first or subsequent doses of delafloxicin. Discontinue delafloxicin at the first appearance of a skin rash or any other sign of hypersensitivity.
- Clostridium difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including delafloxicin, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon, and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Prescribing delafloxacin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of delafloxacin cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.
- Delafloxacin was evaluated in two multicenter, multinational, randomized, double-blind, double-dummy, non-inferiority trials (Trial 1 and Trial 2) in adults with ABSSSI. In Trial 1 patients received delafloxacin 300 mg by intravenous infusion every 12 hours and in Trial 2 the patients received delafloxacin 300 mg by intravenous infusion every 12 hours for 6 doses then were switched to delafloxacin 450 mg tablets every 12 hours. The total treatment duration was 5 to 14 days. Adverse reactions were evaluated for 741 patients treated with delafloxacin and 751 patients treated with comparator antibacterial drugs. The median age of patients treated with delafloxacin was 49 years, ranging between 18 and 94 years old; 15% were age 65 years and older. Patients treated with delafloxacin were predominantly male (62%) and Caucasian (86%). The delafloxacin treated population included 44% obese patients (BMI ≥ 30 kg/m2), 11% with diabetes, and 16% with baseline renal impairment (calculated creatinine clearance less than 90 mL/min).
- Serious adverse reactions occurred in 3/741 (0.4%) of patients treated with delafloxacin and in 6/751 (0.8%) of patients treated with the comparator.
- Delafloxacin was discontinued due to an adverse reaction in 7/741 (0.9%) patients and the comparator was discontinued due to an adverse reaction in 21/751 (2.8%) patients. The most commonly reported adverse reactions leading to study discontinuation in the delafloxacin arm included urticaria (2/741; 0.3%) and hypersensitivity (2/741; 0.3%); whereas, the most commonly reported adverse reactions leading to study discontinuation in the comparator arm included urticaria (5/751; 0.7%), rash (4/751; 0.5%), hypersensitivity and infusion site extravasation (2/751; 0.3%).
- The most common adverse reactions in patients treated with delafloxacin were nausea (8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). Table 3 lists selected adverse reactions occurring in ≥ 2 % of patients receiving delafloxacin in the pooled adult Phase 3 clinical trials.
- The following selected adverse reactions were reported in delafloxacin-treated patients at a rate of less than 2% in these clinical trials.
- Cardiac Disorders: sinus tachycardia, palpitations, bradycardia
- Ear and Labyrinth Disorders: tinnitus, vertigo
- Eye Disorders: vision blurred
- General disorders and administration site conditions: infusion site extravasation, infusion site bruise, discomfort, edema, erythema, irritation, pain, phlebitis, swelling, or thrombosis
- Gastrointestinal Disorders: abdominal pain, dyspepsia
- Immune System Disorders: hypersensitivity
- Infections and Infestations: Clostridium difficile infection, fungal infection, oral candidiasis, vulvovaginal candidiasis
- Laboratory Investigations: blood alkaline phosphatase increased, blood creatinine increased, blood creatine phosphokinase increased
- Metabolism and Nutrition Disorders: hyperglycemia, hypoglycemia
- Musculoskeletal and Connective Tissue Disorders: myalgia
- Nervous System Disorders: dizziness, hypoesthesia, paraesthesia, dysgeusia, presyncope, syncope
- Psychiatric Disorders: anxiety, insomnia, abnormal dreams
- Renal and Urinary: renal impairment, renal failure
- Skin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis, rash
- Vascular Disorders: flushing, hypotension, hypertension, phlebitis
## Postmarketing Experience
There is limited information regarding Delafloxacin Postmarketing Experience in the drug label.
# Drug Interactions
- Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins
- Fluoroquinolones form chelates with alkaline earth and transition metal cations. Oral administration of delafloxacin with antacids containing aluminum or magnesium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as didanosine buffered tablets for oral suspension or the pediatric powder for oral solution, may substantially interfere with the absorption of delafloxacin, resulting in systemic concentrations considerably lower than desired. Therefore, delafloxacin should be taken at least 2 hours before or 6 hours after these agents.
- There are no data concerning an interaction of intravenous delafloxacin with oral antacids, sucralfate, multivitamins, didanosine, or metal cations. However, delafloxacin should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- The limited available data with delafloxacin use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriages. When delafloxacin (as the N-methyl glucamine salt) was administered orally to rats during the period of organogenesis, no malformations or fetal death were observed at up to 7 times the estimated clinical exposure based on AUC. When rats were dosed intravenously in late pregnancy and through lactation, there were no adverse effects on offspring at exposures approximating the clinical intravenous (IV) exposure based on AUC.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
- In embryo-fetal studies, oral administration of delafloxacin to pregnant rats during the period of major organogenesis resulted in maternal toxicity and reduced fetal body weights at the highest dose (1600 mg/kg/day) and fetal ossification delays at all doses. No malformations were reported up to the highest dose tested (approximately 7 times the estimated human plasma exposure based on AUC). The lowest dose, 200 mg/kg/day (approximately 2.5 times the estimated human plasma exposure based on AUC), was still toxic to the fetus, based on ossification delays. In rabbits, a species known to be extremely sensitive to maternal toxicity of antibacterial drugs, no embryo-fetal developmental toxicity was observed up to the highest dose which induced maternal toxicity (1.6 mg/kg/day, or approximately 0.01 times the estimated human plasma exposure based on AUC). In a pre-postnatal study in rats of IV administered delafloxacin, dams at the highest dose tested (120 mg/kg/day) exhibited slightly lower body weights and slightly longer gestation length than control animals. Exposure at that dose was estimated to be approximately 5 times human plasma exposure based on AUC, as determined in a separate shorter term study at an earlier stage of pregnancy. Effects on pups at that dose included increased mortality during lactation, small stature, and lower body weights, but no changes in learning and memory, sensory function, locomotor activity, developmental landmarks, or reproductive performance were reported. The No Adverse Effect Level (NOAEL) for maternal toxicity pup development in that study was 60 mg/kg/day (approximately 580 mg/day IV for a 60 kg patient, or just below the clinical IV dose).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Delafloxacin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Delafloxacin during labor and delivery.
### Nursing Mothers
- There are no data available on the presence of delafloxacin in human milk, the effects on the breast-fed infant, or the effects on milk production. Delafloxacin is excreted in the breast milk of rats . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for delafloxacin and any potential adverse effects on the breast-fed child from delafloxacin or from the underlying maternal condition.
- After single oral dose of 20 mg/kg (approximately 194 mg for a 60 kg patient) 14C labeled delafloxacin on post-natal day 11, the radioactivity was transferred into the milk of lactating rats. The mean milk/plasma radioactivity concentration ratios in dams at 4 and 8 hours after dosing were 8.5 and 4.0, respectively, and essentially background by 24 hours. The rate of elimination of radioactivity was similar in milk and plasma. Absorption of radioactive drug by rat pups following nursing was observed.
### Pediatric Use
- Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Pediatric studies were not conducted because risk-benefit considerations do not support the use of delafloxacin for ABSSSI in this population. Fluoroquinolones cause arthropathy in juvenile animals.
### Geriatic Use
- Of the 754 adults patients treated with delafloxacin in the Phase 3 ABSSSI trials, 111 (15%) were ≥ 65 years of age. The clinical response rates at 48-72 hours in the delafloxacin group (ITT Population) in patients aged ≥ 65 years old were 75.7% and 82.3% in patients aged < 65 years old; comparator response rates were 71.3% in patients aged ≥ 65 years old and 82.1% in patients aged < 65 years old.
- In the safety population, of the 741 adult patients treated with delafloxacin, 110 (16.4%) patients aged ≥ 65 years old and 146 (23.1%) patients aged < 65 years old had at least one adverse drug reaction.
- Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolones. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing delafloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue delafloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur .
- In elderly subjects (≥ 65 years), the mean Cmax and AUC∞ of delafloxacin were about 35% higher compared with young adults, which is not considered clinically significant.
### Gender
There is no FDA guidance on the use of Delafloxacin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Delafloxacin with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment of delafloxacin is necessary in patients with mild (eGFR 60-89 mL/min/1.73 m2) or moderate (eGFR 30-59 mL/min/1.73 m2) renal impairment. The dose of delafloxacin intravenous IV infusion in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) should be decreased to 200 mg intravenously every 12 hours; the dose of oral delafloxacin in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) is 450mg orally every 12 hours. delafloxacin is not recommended in patients with End Stage Renal Disease (eGFR of <15 mL/min/1.73 m2).
- In patients with severe renal impairment or ESRD (eGFR of < 15 mL/min/1.73 m2), accumulation of the intravenous vehicle, sulfobutylether-β-cyclodextrin (SBECD) occurs. Serum creatinine levels should be closely monitored in patients with severe renal impairment receiving intravenous delafloxacin. If serum creatinine level increases occur, consideration should be given to changing to oral delafloxacin. If eGFR decreases to <15 mL/min/1.73 m2, delafloxacin should be discontinued.
### Hepatic Impairment
- No dosage adjustment is necessary for delafloxacin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Delafloxacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Delafloxacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer delafloxacin at least 2 hours before or 6 hours after antacids containing magnesium, or aluminum, with sucralfate, with metal cations such as iron, or with multivitamin preparations containing zinc or iron, or with didanosine buffered tablets for oral suspension or the pediatric powder for oral solution
- Delafloxacin Tablets can be taken with or without food.
- If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose.
- Do NOT administer delafloxacin for Injection with any solution containing multivalent cations, e.g., calcium and magnesium, through the same intravenous line. Do NOT Co-infuse delafloxacin for Injection with other medications.
- Delafloxacin must be reconstituted and then further diluted under aseptic conditions. Reconstitute the powder in the delafloxacin vial using 10.5 mL of 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride Injection for each 300 mg vial. Shake the vial vigorously until contents are completely dissolved. The reconstituted vial contains 300 mg per 12 mL (25 mg/mL) of delafloxacin as a clear yellow to amber colored solution.
- The reconstituted solution must then be diluted to a total volume of 250 mL using either 0.9% Sodium Chloride or D5W to achieve a concentration of 1.2 mg/mL, prior to administration. Prepare the required dose for intravenous infusion by withdrawing the appropriate volume from the reconstituted vial per Table 2 below:
- Aseptically transfer the required volume of delafloxacin reconstituted solution from the vial to an intravenous bag to achieve a 250 mL volume of infusion solution. Discard any unused portion of the reconstituted solution.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Reconstituted vials, as described above, may be stored either refrigerated at 2°C to 8°C (36°F to 46°F), or at controlled room temperature 20°C to 25°C (68°F to 77°F) for up to 24 hours. Do not freeze.
- Once diluted into the intravenous bag, as described above, delafloxacin may be stored either refrigerated at 2°C to 8°C (36°F to 46°F) or at a controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 24 hours. Do not freeze.
- After reconstitution and dilution, administer delafloxacin by intravenous infusion, using a total infusion time of 60 minutes.
- The compatibility of reconstituted delafloxacin with intravenous medications, additives, or substances other than D5W or 0.9% Sodium Chloride Injection has not been established. If a common intravenous line is being used to administer other drugs in addition to delafloxacin the line should be flushed before and after each delafloxacin infusion with 0.9% Sodium Chloride Injection or D5W.
### Monitoring
- Improvement in signs, symptoms, or laboratory markers of infection may be indicative of efficacy
- (Injection) Serum creatinine in patients with severe renal impairment: Monitor closely
# IV Compatibility
There is limited information regarding the compatibility of Delafloxacin and IV administrations.
# Overdosage
- Treatment of overdose with delafloxacin should consist of observation and general supportive measures. Hemodialysis removed about 19% of delafloxacin and 56% of SBECD (Sulfobutylether β cyclodextrin) after intravenous administration of delafloxacin.
# Pharmacology
## Mechanism of Action
- Delafloxacin belongs to the fluoroquinolone class of antibacterial drugs and is anionic in nature. The antibacterial activity of delafloxacin is due to the inhibition of both bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes which are required for bacterial DNA replication, transcription, repair, and recombination. Delafloxacin exhibits a concentration-dependent bactericidal activity against gram-positive and gram-negative bacteria in vitro.
## Structure
## Pharmacodynamics
- The antibacterial activity of delafloxacin appears to best correlate with the ratio of area under the concentration-time curve of free delafloxacin to minimal inhibitory concentration (fAUC/MIC) for Gram-positive organisms such as Staphylococcus aureus and Gram-negative organisms such as Escherichia coli based on animal models of infection.
- In a randomized, positive- and placebo-controlled, thorough QT/QTc study, 51 healthy subjects received delafloxacin 300 mg IV, delafloxacin 900 mg IV, oral moxifloxacin 400 mg, or placebo. Neither delafloxacin 300 mg nor delafloxacin 900 mg (three times the intravenous therapeutic dose) had any clinically relevant adverse effect on cardiac repolarization.
- A study of photosensitizing potential to ultraviolet (UVA and UVB) and visible radiation was conducted in 52 healthy volunteers (originally 13 subjects per treatment group). delafloxacin, at 200 mg/day and 400 mg/day (0.22 and 0.44 times the approved recommended daily oral dosage, respectively) for 7 days, and placebo did not demonstrate clinically significant phototoxic potential at any wavelengths tested (295 nm to 430 nm), including solar simulation. The active comparator (lomefloxacin) demonstrated a moderate degree of phototoxicity at UVA 335 nm and 365 nm and solar simulation wavelengths.
## Pharmacokinetics
- The pharmacokinetic parameters of delafloxacin following single- and multiple-dose (every 12 hours) oral (450 mg) and intravenous (300 mg) administration are shown in Table 4. Steady-state was achieved within approximately three days with accumulation of approximately 10% and 36% following IV and oral administration, respectively.
- The absolute bioavailability for delafloxacin 450 mg oral tablet administered as a single dose was 58.8%. The AUC of delafloxacin following administration of a single 450 mg oral (tablet) dose was comparable to that following a single 300 mg intravenous dose. The Cmax of delafloxacin was achieved within about 1 hour after oral administration under fasting condition. Food (kcal:917, Fat: 58.5%, Protein: 15.4%, Carbohydrate: 26.2%). did not affect the bioavailability of delafloxacin.
- The steady state volume of distribution of delafloxacin is 30–48 L which approximates total body water. The plasma protein binding of delafloxacin is approximately 84%; delafloxacin primarily binds to albumin. Plasma protein binding of delafloxacin is not significantly affected by renal impairment.
- In a mass balance study, the mean half-life for delafloxacin was 3.7 hours (SD 0.7 hour) after a single dose intravenous administration. The mean half-life values for delafloxacin ranged from 4.2 to 8.5 hours following multiple oral administrations. Following administration of a single 300 mg intravenous dose of delafloxacin, the mean clearance (CL) of delafloxacin was 16.3 L/h (SD 3.7 L/h), and the renal clearance (CLr) of delafloxacin accounts for 35-45% of the total clearance.
- Glucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing about 1% of an administered dose. The glucuronidation of delafloxacin is mediated mainly by UGT1A1, UGT1A3, and UGT2B15. Unchanged parent drug is the predominant component in plasma. There are no significant circulating metabolites in humans.
- After single intravenous dose of 14C-labeled delafloxacin, 65% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 28% was excreted in feces as unchanged delafloxacin. Following a single oral dose of 14C-labeled delafloxacin, 50% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 48% was excreted in feces as unchanged delafloxacin.
- Based on a population pharmacokinetic analysis, the pharmacokinetics of delafloxacin were not significantly impacted by age, sex, race, weight, body mass index, and disease state (ABSSSI).
Patients with Hepatic Impairment
- No clinically meaningful changes in delafloxacin Cmax and AUC were observed, following administration of a single 300-mg intravenous dose of delafloxacin to patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, and C) compared to matched healthy control subjects.
Patients with Renal Impairment
- Following a single intravenous (300 mg) administration of delafloxacin to subjects with mild (eGFR = 51-80 mL/min/1.73 m2), moderate (eGFR = 31–50 mL/min/1.73 m2), severe (eGFR = 15-29 mL/min/1.73 m2) renal impairment, and ESRD on hemodialysis receiving intravenous delafloxacin within 1 hour before and 1 hour after hemodialysis, mean total exposure (AUCt) of delafloxacin was 1.3, 1.6, 1.8, 2.1, and 2.6-fold higher, respectively than that for matched normal control subjects. The mean dialysate clearance (CLd) of delafloxacin was 4.21 L/h (SD 1.56 L/h). After about 4 hours of hemodialysis, the mean fraction of administered delafloxacin recovered in the dialysate was about 19%.
- Following a single oral (400 mg) administration of delafloxacin to subjects with mild (eGFR = 51-80 mL/min/1.73 m2), moderate (eGFR = 31-50mL/min/1.73m2), or severe (eGFR = 15-29 mL/min/1.73m2) renal impairment, the mean total exposure (AUCt) of delafloxacin was about 1.5-fold higher for subjects with moderate and severe renal impairment compared with healthy subjects, whereas total systemic exposures of delafloxacin in subjects with mild renal impairment were comparable with healthy subjects.
- In patients with moderate (eGFR = 31–50 mL/min/1.73 m2), or severe (eGFR = 15–29 mL/min/1.73 m2) renal impairment or ESRD on hemodialysis, accumulation of the intravenous vehicle SBECD occurs. The mean systemic exposure (AUC) increased 2-fold, 5-fold, 7.5-fold, and 27-fold for patients with moderate impairment, severe impairment, ESRD on hemodialysis receiving intravenous delafloxacin within 1 hour before, and 1 hour after hemodialysis respectively, compared to the healthy control group. In subjects with ESRD undergoing hemodialysis, SBECD is dialyzed with a clearance of 4.74 L/h. When hemodialysis occurred 1 hour after the delafloxacin infusion in subjects with ESRD, the mean fraction of SBECD recovered in the dialysate was 56.1% over approximately 4 hours.
Geriatric Patients
- Following single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC∞ values in elderly subjects (≥ 65 years) were about 35% higher compared to values obtained in young adults (18 to 40 years). This difference is not considered clinically relevant. A population pharmacokinetic analysis of patients with ABSSSI showed no significant impact of age on delafloxacin pharmacokinetics.
Male and Female Patients
- Following single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC∞ values in male subjects were comparable to female subjects. Results from a population pharmacokinetic analysis showed that females have a 24% lower AUC than males. This difference is not considered clinically relevant.
Drug Metabolizing Enzymes
- Delafloxacin at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes. At a delafloxacin concentration (500 µM) well above clinically relevant exposures, the activity of CYP2E1was increased.
- In human hepatocytes, delafloxacin showed no potential for in vitro induction of CYP1A2, 2B6, 2C19, or 2C8 but was a mild inducer of CYP2C9 at a concentration of 100 µM and CYP3A4 at a clinically relevant concentration. Administration of delafloxacin 450 mg every 12 hours for 5 days to healthy male and female subjects (n = 22) prior to and on Day 6 with a single oral 5-mg dose of midazolam (a sensitive CYP3A substrate), did not affect the Cmax and AUC values for midazolam or 1-hydroxy midazolam compared to administration of midazolam alone.
- Delafloxacin was not an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, OCT1 and OCT2. Delafloxacin was not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1 or OATP. Delafloxacin was shown to be a substrate of P-gp and BCRP in vitro. The clinical relevance of co-administration of delafloxacin and P-gp and/or BCRP inhibitors is unknown.
## Nonclinical Toxicology
- Long-term carcinogenicity studies have not been conducted with delafloxacin.
- Delafloxacin was not mutagenic in a bacterial reverse mutation (Ames) assay, and was not clastogenic in a mouse bone marrow micronucleus test at ≥ 15 times the estimated human plasma exposure based on AUC. In an in vitro clastogenicity assay using isolated human lymphocytes, delafloxacin was negative in short incubations (~3 hours) and, at high cytotoxic concentrations (> 1.0 mM), was positive in a long incubation (~19 hours).
- Delafloxacin did not affect the fertility of male and female rats up to the highest intravenous dose tested (120 mg/kg/day); female rats were dosed 2 weeks prior to mating and through gestation day 7 and male rats were treated for 28 days prior to mating and beyond for a total of 58-59 days. AUC in male and female (non-pregnant and pregnant) rats at 120 mg/kg/day delafloxacin intravenous was estimated to be approximately 5 times the estimated human plasma exposure based on AUC in separate intravenous toxicology studies in rats, one of which was a 2-week study that used a different vehicle for delafloxacin than in the fertility study, and another was an 8-day study in nonpregnant and pregnant (gestation day 13) rats that used the same vehicle for delafloxacin as in the fertility study.
- Fluoroquinolone antibacterials are associated with degenerative changes in articular cartilage and arthropathy in skeletally immature animals. In a toxicology study of the formulated tablet in dogs, the femoral head of one of three high dose (480 mg/kg/day) females had minimal focal degeneration of the superficial articular cartilage and a small focal cleft in the articular cartilage. No other joints were examined.
# Clinical Studies
- A total of 1510 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in 2 multicenter, multinational, double-blind, double-dummy, non-inferiority trials. Trial 1 compared delafloxacin 300 mg via intravenous infusion every 12 hours to comparator. In Trial 2, patients received delafloxacin 300 mg via intravenous infusion every12 hours for 6 doses then made a mandatory switch to oral delafloxacin 450 mg every 12 hours. In both studies, the comparator was the intravenous combination of vancomycin 15 mg/kg actual body weight and aztreonam. Aztreonam therapy was discontinued if no gram-negative pathogens were identified in the baseline cultures.
- In Trial 1, 331 patients with ABSSSI were randomized to delafloxacin and 329 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (39%), wound infection (35%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion as measured by digital planimetry was 307 cm2. The average age of patients was 46 years (range 18 to 94 years). Patients were predominately male (63%) and White (91%); 32% had BMI ≥ 30 kg/m2. The population studied in Trial 1 included a distribution of patients with associated comorbidities such as hypertension (21%), diabetes (9%), and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 55% of patients. Bacteremia was documented at baseline in 2% of patients.
- In Trial 2, 423 patients were randomized to delafloxacin and 427 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (48%), wound infection (26%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion, as measured by digital planimetry, was 353 cm2. The average age of patients was 51 years (range 18 to 93 years). Patients were predominately male (63%) and White (83%); 50 % had a BMI ≥ 30 kg/m2. The population studied in Trial 2 included a distribution of patients with associated comorbidities such as hypertension (31%), diabetes (13%) and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 30% of patients. Bacteremia was documented at baseline in 2% of patients.
- In both trials, objective clinical response at 48 to 72 hours post initiation of treatment was defined as a 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema. Table 5 summarizes the objective clinical response rates in both of these trials.
- In both trials, an investigator assessment of response was made at Follow-up (Day 14 ± 1) in the ITT and CE populations. Success was defined as "cure + improved," where patients had complete or near resolution of signs and symptoms, with no further antibacterial needed. The success rates in the ITT and CE populations are shown in Table 6.
- Six delafloxacin patients had baseline S. aureus bacteremia with ABSSSI. Five of these 6 patients (83.3%) were clinical responders at 48 to 72 hours and 5/6 (83.3%) were considered clinical success for ABSSSI at Day 14 ± 1. Two delafloxacin patients had baseline Gram-negative bacteremia (K. pneumoniae and P. aeruginosa), and both were clinical responders and successes.
- The investigator assessments of clinical success rates were also similar between treatment groups at Late Follow-up (LFU, day 21-28).
- Objective clinical response and investigator-assessed success by baseline pathogens from the primary infection site or blood cultures for the microbiological ITT (MITT) patient population pooled across Trial 1 and Trial 2 are presented in Table 7.
# How Supplied
- Delafloxacin is supplied as a sterile, lyophilized powder in single-dose clear glass vials of 300 mg delafloxacin (equivalent to 433 mg delafloxacin meglumine). The lyophilized powder is a light yellow to tan cake, which may exhibit cracking and shrinkage and slight variation in texture and color.
- They are supplied as follows: 300-mg single-dose vials (NDC 70842-102-01), packaged in cartons of 10 vials (NDC 70842-102-03).
- Delafloxacin Tablets contain 450 mg delafloxacin (equivalent to 649 mg delafloxacin meglumine); each modified capsule-shaped tablet in beige to mottled beige color is debossed with RX3341 on one side. They are supplied as follows:
- Bottles of 20 tablets with child-resistant closure (NDC 70842-101-01)
- Unit dose blister packs which contain 20 tablets (2 blister cards of 10 tablets each) (20 tablet blister pack: NDC 70842-101-02, 10 tablet blister card: NDC 70842-101-03)
## Storage
- Delafloxacin Tablets and delafloxacin for Injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
- The reconstituted powder may be stored for up to 24 hours under refrigerated or controlled room temperature and then further diluted for intravenous infusion. The reconstituted solution in the infusion bag may be stored under refrigerated or controlled room temperature conditions for up to 24 hours. Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling
Serious Adverse Reactions
- Advise patients to stop taking delafloxacin if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.
- Inform patients of the following serious adverse reactions that have been associated with delafloxacin or other fluoroquinolone use:
- Disabling and Potentially Irreversible Serious Adverse Reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of fluoroquinolones and may occur together in the same patient. Inform patients to stop taking delafloxacin immediately if they experience an adverse reaction and to call their healthcare provider.
- Tendinitis and Tendon Rupture: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue delafloxacin treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
- Peripheral Neuropathy: Inform patients that peripheral neuropathies have been associated with delafloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue delafloxacin and tell them to contact their physician.
- Central Nervous System Effects: (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to delafloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
- Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
- Hypersensitivity Reactions: Inform patients that delafloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue delafloxacin at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
- Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.
- Antibacterial Resistance: Inform patients that antibacterial drugs including delafloxacin Tablets and Injection should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When delafloxacin Tablets and delafloxacin Injection are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by delafloxacin Tablets and delafloxacin Injection or other antibacterial drugs in the future.
Administration with Food and Concomitant Medications
- Inform patients that delafloxacin Tablets may be taken with or without food and without any dietary restrictions
- Inform patients that delafloxacin Tablets should be taken at least 2 hours before or 6 hours after antacids containing magnesium, or aluminum, with sucralfate, with metal cations such as iron, or with multivitamin preparations containing zinc or iron, or with didanosine buffered tablets for oral suspension or the pediatric powder for oral solution.
# Precautions with Alcohol
Alcohol-Delafloxacin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Baxdela
# Look-Alike Drug Names
There is limited information regarding Delafloxacin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Delafloxacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand, Anmol Pitliya, M.B.B.S. M.D.[2]
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# Black Box Warning
# Overview
Delafloxacin is a a fluoroquinolone antibacterial that is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible bacteria. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, diarrhea, headache, transaminase elevations, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Acute Bacterial Skin and Skin Structure Infections
- Delafloxacin is indicated in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following:
- Gram-positive organisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis.
- Gram-negative organisms: Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of delafloxacin and other antibacterial drugs, delafloxacin should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- For treatment of adults with ABSSSI, the recommended dosage regimen of delafloxacin is as follows:
- Administer 300 mg of delafloxacin for Injection every 12 hours over 60 minutes by intravenous infusion for 5 to 14 days or,
- Administer 300 mg of delafloxacin for Injection every 12 hours over 60 minutes by intravenous infusion, then switch to a 450 mg delafloxacin tablet orally every 12 hours at the discretion of the physician for a total duration of 5 to 14 days or,
- Administer a 450 mg delafloxacin tablet orally every 12 hours for a total duration of 5 to 14 days.
- Table 1 below describes the dosage modification based on the estimated glomerular filtration rate (eGFR) that is recommended in patients with renal impairment. Dosage adjustment is required for patients with severe renal impairment (eGFR 15-29 mL/min/1.73m2).
- In patients with severe renal impairment receiving delafloxacin intravenously, closely monitor serum creatinine levels and eGFR. If serum creatinine level increases, consider switching to delafloxacin Tablets. Discontinue delafloxacin if eGFR decreases to <15 mL/min/1.73 m2.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding delafloxacin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding delafloxacin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Pediatric studies were not conducted because risk-benefit considerations do not support the use of delafloxacin for ABSSSI in this population. Fluoroquinolones cause arthropathy in juvenile animals.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding delafloxacin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding delafloxacin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Delafloxacin is contraindicated in patients with known hypersensitivity to delafloxacin or any of the fluoroquinolone class of antibacterial drugs, or any of the components of delafloxacin
# Warnings
- Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions could occur within hours to weeks after starting a fluoroquinolone. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.
- Discontinue delafloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including delafloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.
- Fluoroquinolones have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting a fluoroquinolone, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.
- This risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over age 60 years of age, in patients taking corticosteroid drugs, and, in patients with kidney, heart, and lung transplant. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors.
- Discontinue delafloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Advise patients, at the first sign of tendon pain, swelling, or inflammation, to stop taking delafloxacin, to avoid exercise and use of the affected area, and to promptly contact their healthcare provider about changing to a non-quinolone antimicrobial drug. Avoid delafloxacin in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.
- Fluoroquinolones have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias, and weakness have been reported in patients receiving fluoroquinolones, including delafloxacin. Symptoms may occur soon after initiation of fluoroquinolones and may be irreversible in some patients.
- Discontinue delafloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including delafloxacin in patients who have previously experienced peripheral neuropathy.
- Fluoroquinolones have been associated with an increased risk of central nervous system (CNS) reactions, including: convulsions and increased intracranial pressure (including pseudotumor cerebri) and toxic psychosis. Fluoroquinolones, including delafloxicin, may also cause CNS reactions of nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or acts. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving delafloxicin, discontinue delafloxicin immediately and institute appropriate measures. As with all fluoroquinolones, use delafloxicin when the benefits of treatment exceed the risks in patients with known or suspected CNS disorders (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold.
- Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse reactions, including death and requirement for ventilator support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid delafloxicin in patients with known history of myasthenia gravis.
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Hypersensitivity reactions have been reported in patients receiving delafloxicin. These reactions may occur after first or subsequent doses of delafloxicin. Discontinue delafloxicin at the first appearance of a skin rash or any other sign of hypersensitivity.
- Clostridium difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including delafloxicin, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon, and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Prescribing delafloxacin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of delafloxacin cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.
- Delafloxacin was evaluated in two multicenter, multinational, randomized, double-blind, double-dummy, non-inferiority trials (Trial 1 and Trial 2) in adults with ABSSSI. In Trial 1 patients received delafloxacin 300 mg by intravenous infusion every 12 hours and in Trial 2 the patients received delafloxacin 300 mg by intravenous infusion every 12 hours for 6 doses then were switched to delafloxacin 450 mg tablets every 12 hours. The total treatment duration was 5 to 14 days. Adverse reactions were evaluated for 741 patients treated with delafloxacin and 751 patients treated with comparator antibacterial drugs. The median age of patients treated with delafloxacin was 49 years, ranging between 18 and 94 years old; 15% were age 65 years and older. Patients treated with delafloxacin were predominantly male (62%) and Caucasian (86%). The delafloxacin treated population included 44% obese patients (BMI ≥ 30 kg/m2), 11% with diabetes, and 16% with baseline renal impairment (calculated creatinine clearance less than 90 mL/min).
- Serious adverse reactions occurred in 3/741 (0.4%) of patients treated with delafloxacin and in 6/751 (0.8%) of patients treated with the comparator.
- Delafloxacin was discontinued due to an adverse reaction in 7/741 (0.9%) patients and the comparator was discontinued due to an adverse reaction in 21/751 (2.8%) patients. The most commonly reported adverse reactions leading to study discontinuation in the delafloxacin arm included urticaria (2/741; 0.3%) and hypersensitivity (2/741; 0.3%); whereas, the most commonly reported adverse reactions leading to study discontinuation in the comparator arm included urticaria (5/751; 0.7%), rash (4/751; 0.5%), hypersensitivity and infusion site extravasation (2/751; 0.3%).
- The most common adverse reactions in patients treated with delafloxacin were nausea (8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). Table 3 lists selected adverse reactions occurring in ≥ 2 % of patients receiving delafloxacin in the pooled adult Phase 3 clinical trials.
- The following selected adverse reactions were reported in delafloxacin-treated patients at a rate of less than 2% in these clinical trials.
- Cardiac Disorders: sinus tachycardia, palpitations, bradycardia
- Ear and Labyrinth Disorders: tinnitus, vertigo
- Eye Disorders: vision blurred
- General disorders and administration site conditions: infusion site extravasation, infusion site bruise, discomfort, edema, erythema, irritation, pain, phlebitis, swelling, or thrombosis
- Gastrointestinal Disorders: abdominal pain, dyspepsia
- Immune System Disorders: hypersensitivity
- Infections and Infestations: Clostridium difficile infection, fungal infection, oral candidiasis, vulvovaginal candidiasis
- Laboratory Investigations: blood alkaline phosphatase increased, blood creatinine increased, blood creatine phosphokinase increased
- Metabolism and Nutrition Disorders: hyperglycemia, hypoglycemia
- Musculoskeletal and Connective Tissue Disorders: myalgia
- Nervous System Disorders: dizziness, hypoesthesia, paraesthesia, dysgeusia, presyncope, syncope
- Psychiatric Disorders: anxiety, insomnia, abnormal dreams
- Renal and Urinary: renal impairment, renal failure
- Skin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis, rash
- Vascular Disorders: flushing, hypotension, hypertension, phlebitis
## Postmarketing Experience
There is limited information regarding Delafloxacin Postmarketing Experience in the drug label.
# Drug Interactions
- Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins
- Fluoroquinolones form chelates with alkaline earth and transition metal cations. Oral administration of delafloxacin with antacids containing aluminum or magnesium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as didanosine buffered tablets for oral suspension or the pediatric powder for oral solution, may substantially interfere with the absorption of delafloxacin, resulting in systemic concentrations considerably lower than desired. Therefore, delafloxacin should be taken at least 2 hours before or 6 hours after these agents.
- There are no data concerning an interaction of intravenous delafloxacin with oral antacids, sucralfate, multivitamins, didanosine, or metal cations. However, delafloxacin should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- The limited available data with delafloxacin use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriages. When delafloxacin (as the N-methyl glucamine salt) was administered orally to rats during the period of organogenesis, no malformations or fetal death were observed at up to 7 times the estimated clinical exposure based on AUC. When rats were dosed intravenously in late pregnancy and through lactation, there were no adverse effects on offspring at exposures approximating the clinical intravenous (IV) exposure based on AUC.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
- In embryo-fetal studies, oral administration of delafloxacin to pregnant rats during the period of major organogenesis resulted in maternal toxicity and reduced fetal body weights at the highest dose (1600 mg/kg/day) and fetal ossification delays at all doses. No malformations were reported up to the highest dose tested (approximately 7 times the estimated human plasma exposure based on AUC). The lowest dose, 200 mg/kg/day (approximately 2.5 times the estimated human plasma exposure based on AUC), was still toxic to the fetus, based on ossification delays. In rabbits, a species known to be extremely sensitive to maternal toxicity of antibacterial drugs, no embryo-fetal developmental toxicity was observed up to the highest dose which induced maternal toxicity (1.6 mg/kg/day, or approximately 0.01 times the estimated human plasma exposure based on AUC). In a pre-postnatal study in rats of IV administered delafloxacin, dams at the highest dose tested (120 mg/kg/day) exhibited slightly lower body weights and slightly longer gestation length than control animals. Exposure at that dose was estimated to be approximately 5 times human plasma exposure based on AUC, as determined in a separate shorter term study at an earlier stage of pregnancy. Effects on pups at that dose included increased mortality during lactation, small stature, and lower body weights, but no changes in learning and memory, sensory function, locomotor activity, developmental landmarks, or reproductive performance were reported. The No Adverse Effect Level (NOAEL) for maternal toxicity pup development in that study was 60 mg/kg/day (approximately 580 mg/day IV for a 60 kg patient, or just below the clinical IV dose).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Delafloxacin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Delafloxacin during labor and delivery.
### Nursing Mothers
- There are no data available on the presence of delafloxacin in human milk, the effects on the breast-fed infant, or the effects on milk production. Delafloxacin is excreted in the breast milk of rats [see DATA]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for delafloxacin and any potential adverse effects on the breast-fed child from delafloxacin or from the underlying maternal condition.
- After single oral dose of 20 mg/kg (approximately 194 mg for a 60 kg patient) 14C labeled delafloxacin on post-natal day 11, the radioactivity was transferred into the milk of lactating rats. The mean milk/plasma radioactivity concentration ratios in dams at 4 and 8 hours after dosing were 8.5 and 4.0, respectively, and essentially background by 24 hours. The rate of elimination of radioactivity was similar in milk and plasma. Absorption of radioactive drug by rat pups following nursing was observed.
### Pediatric Use
- Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Pediatric studies were not conducted because risk-benefit considerations do not support the use of delafloxacin for ABSSSI in this population. Fluoroquinolones cause arthropathy in juvenile animals.
### Geriatic Use
- Of the 754 adults patients treated with delafloxacin in the Phase 3 ABSSSI trials, 111 (15%) were ≥ 65 years of age. The clinical response rates at 48-72 hours in the delafloxacin group (ITT Population) in patients aged ≥ 65 years old were 75.7% and 82.3% in patients aged < 65 years old; comparator response rates were 71.3% in patients aged ≥ 65 years old and 82.1% in patients aged < 65 years old.
- In the safety population, of the 741 adult patients treated with delafloxacin, 110 (16.4%) patients aged ≥ 65 years old and 146 (23.1%) patients aged < 65 years old had at least one adverse drug reaction.
- Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolones. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing delafloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue delafloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see WARNINGS AND PRECAUTIONS (5.1)].
- In elderly subjects (≥ 65 years), the mean Cmax and AUC∞ of delafloxacin were about 35% higher compared with young adults, which is not considered clinically significant.
### Gender
There is no FDA guidance on the use of Delafloxacin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Delafloxacin with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment of delafloxacin is necessary in patients with mild (eGFR 60-89 mL/min/1.73 m2) or moderate (eGFR 30-59 mL/min/1.73 m2) renal impairment. The dose of delafloxacin intravenous IV infusion in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) should be decreased to 200 mg intravenously every 12 hours; the dose of oral delafloxacin in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) is 450mg orally every 12 hours. delafloxacin is not recommended in patients with End Stage Renal Disease [ESRD] (eGFR of <15 mL/min/1.73 m2).
- In patients with severe renal impairment or ESRD (eGFR of < 15 mL/min/1.73 m2), accumulation of the intravenous vehicle, sulfobutylether-β-cyclodextrin (SBECD) occurs. Serum creatinine levels should be closely monitored in patients with severe renal impairment receiving intravenous delafloxacin. If serum creatinine level increases occur, consideration should be given to changing to oral delafloxacin. If eGFR decreases to <15 mL/min/1.73 m2, delafloxacin should be discontinued.
### Hepatic Impairment
- No dosage adjustment is necessary for delafloxacin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Delafloxacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Delafloxacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer delafloxacin at least 2 hours before or 6 hours after antacids containing magnesium, or aluminum, with sucralfate, with metal cations such as iron, or with multivitamin preparations containing zinc or iron, or with didanosine buffered tablets for oral suspension or the pediatric powder for oral solution
- Delafloxacin Tablets can be taken with or without food.
- If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose.
- Do NOT administer delafloxacin for Injection with any solution containing multivalent cations, e.g., calcium and magnesium, through the same intravenous line. Do NOT Co-infuse delafloxacin for Injection with other medications.
- Delafloxacin must be reconstituted and then further diluted under aseptic conditions. Reconstitute the powder in the delafloxacin vial using 10.5 mL of 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride Injection for each 300 mg vial. Shake the vial vigorously until contents are completely dissolved. The reconstituted vial contains 300 mg per 12 mL (25 mg/mL) of delafloxacin as a clear yellow to amber colored solution.
- The reconstituted solution must then be diluted to a total volume of 250 mL using either 0.9% Sodium Chloride or D5W to achieve a concentration of 1.2 mg/mL, prior to administration. Prepare the required dose for intravenous infusion by withdrawing the appropriate volume from the reconstituted vial per Table 2 below:
- Aseptically transfer the required volume of delafloxacin reconstituted solution from the vial to an intravenous bag to achieve a 250 mL volume of infusion solution. Discard any unused portion of the reconstituted solution.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Reconstituted vials, as described above, may be stored either refrigerated at 2°C to 8°C (36°F to 46°F), or at controlled room temperature 20°C to 25°C (68°F to 77°F) for up to 24 hours. Do not freeze.
- Once diluted into the intravenous bag, as described above, delafloxacin may be stored either refrigerated at 2°C to 8°C (36°F to 46°F) or at a controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 24 hours. Do not freeze.
- After reconstitution and dilution, administer delafloxacin by intravenous infusion, using a total infusion time of 60 minutes.
- The compatibility of reconstituted delafloxacin with intravenous medications, additives, or substances other than D5W or 0.9% Sodium Chloride Injection has not been established. If a common intravenous line is being used to administer other drugs in addition to delafloxacin the line should be flushed before and after each delafloxacin infusion with 0.9% Sodium Chloride Injection or D5W.
### Monitoring
- Improvement in signs, symptoms, or laboratory markers of infection may be indicative of efficacy
- (Injection) Serum creatinine in patients with severe renal impairment: Monitor closely
# IV Compatibility
There is limited information regarding the compatibility of Delafloxacin and IV administrations.
# Overdosage
- Treatment of overdose with delafloxacin should consist of observation and general supportive measures. Hemodialysis removed about 19% of delafloxacin and 56% of SBECD (Sulfobutylether β cyclodextrin) after intravenous administration of delafloxacin.
# Pharmacology
## Mechanism of Action
- Delafloxacin belongs to the fluoroquinolone class of antibacterial drugs and is anionic in nature. The antibacterial activity of delafloxacin is due to the inhibition of both bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes which are required for bacterial DNA replication, transcription, repair, and recombination. Delafloxacin exhibits a concentration-dependent bactericidal activity against gram-positive and gram-negative bacteria in vitro.
## Structure
## Pharmacodynamics
- The antibacterial activity of delafloxacin appears to best correlate with the ratio of area under the concentration-time curve of free delafloxacin to minimal inhibitory concentration (fAUC/MIC) for Gram-positive organisms such as Staphylococcus aureus and Gram-negative organisms such as Escherichia coli based on animal models of infection.
- In a randomized, positive- and placebo-controlled, thorough QT/QTc study, 51 healthy subjects received delafloxacin 300 mg IV, delafloxacin 900 mg IV, oral moxifloxacin 400 mg, or placebo. Neither delafloxacin 300 mg nor delafloxacin 900 mg (three times the intravenous therapeutic dose) had any clinically relevant adverse effect on cardiac repolarization.
- A study of photosensitizing potential to ultraviolet (UVA and UVB) and visible radiation was conducted in 52 healthy volunteers (originally 13 subjects per treatment group). delafloxacin, at 200 mg/day and 400 mg/day (0.22 and 0.44 times the approved recommended daily oral dosage, respectively) for 7 days, and placebo did not demonstrate clinically significant phototoxic potential at any wavelengths tested (295 nm to 430 nm), including solar simulation. The active comparator (lomefloxacin) demonstrated a moderate degree of phototoxicity at UVA 335 nm and 365 nm and solar simulation wavelengths.
## Pharmacokinetics
- The pharmacokinetic parameters of delafloxacin following single- and multiple-dose (every 12 hours) oral (450 mg) and intravenous (300 mg) administration are shown in Table 4. Steady-state was achieved within approximately three days with accumulation of approximately 10% and 36% following IV and oral administration, respectively.
- The absolute bioavailability for delafloxacin 450 mg oral tablet administered as a single dose was 58.8%. The AUC of delafloxacin following administration of a single 450 mg oral (tablet) dose was comparable to that following a single 300 mg intravenous dose. The Cmax of delafloxacin was achieved within about 1 hour after oral administration under fasting condition. Food (kcal:917, Fat: 58.5%, Protein: 15.4%, Carbohydrate: 26.2%). did not affect the bioavailability of delafloxacin.
- The steady state volume of distribution of delafloxacin is 30–48 L which approximates total body water. The plasma protein binding of delafloxacin is approximately 84%; delafloxacin primarily binds to albumin. Plasma protein binding of delafloxacin is not significantly affected by renal impairment.
- In a mass balance study, the mean half-life for delafloxacin was 3.7 hours (SD 0.7 hour) after a single dose intravenous administration. The mean half-life values for delafloxacin ranged from 4.2 to 8.5 hours following multiple oral administrations. Following administration of a single 300 mg intravenous dose of delafloxacin, the mean clearance (CL) of delafloxacin was 16.3 L/h (SD 3.7 L/h), and the renal clearance (CLr) of delafloxacin accounts for 35-45% of the total clearance.
- Glucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing about 1% of an administered dose. The glucuronidation of delafloxacin is mediated mainly by UGT1A1, UGT1A3, and UGT2B15. Unchanged parent drug is the predominant component in plasma. There are no significant circulating metabolites in humans.
- After single intravenous dose of 14C-labeled delafloxacin, 65% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 28% was excreted in feces as unchanged delafloxacin. Following a single oral dose of 14C-labeled delafloxacin, 50% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 48% was excreted in feces as unchanged delafloxacin.
- Based on a population pharmacokinetic analysis, the pharmacokinetics of delafloxacin were not significantly impacted by age, sex, race, weight, body mass index, and disease state (ABSSSI).
Patients with Hepatic Impairment
- No clinically meaningful changes in delafloxacin Cmax and AUC were observed, following administration of a single 300-mg intravenous dose of delafloxacin to patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, and C) compared to matched healthy control subjects.
Patients with Renal Impairment
- Following a single intravenous (300 mg) administration of delafloxacin to subjects with mild (eGFR = 51-80 mL/min/1.73 m2), moderate (eGFR = 31–50 mL/min/1.73 m2), severe (eGFR = 15-29 mL/min/1.73 m2) renal impairment, and ESRD on hemodialysis receiving intravenous delafloxacin within 1 hour before and 1 hour after hemodialysis, mean total exposure (AUCt) of delafloxacin was 1.3, 1.6, 1.8, 2.1, and 2.6-fold higher, respectively than that for matched normal control subjects. The mean dialysate clearance (CLd) of delafloxacin was 4.21 L/h (SD 1.56 L/h). After about 4 hours of hemodialysis, the mean fraction of administered delafloxacin recovered in the dialysate was about 19%.
- Following a single oral (400 mg) administration of delafloxacin to subjects with mild (eGFR = 51-80 mL/min/1.73 m2), moderate (eGFR = 31-50mL/min/1.73m2), or severe (eGFR = 15-29 mL/min/1.73m2) renal impairment, the mean total exposure (AUCt) of delafloxacin was about 1.5-fold higher for subjects with moderate and severe renal impairment compared with healthy subjects, whereas total systemic exposures of delafloxacin in subjects with mild renal impairment were comparable with healthy subjects.
- In patients with moderate (eGFR = 31–50 mL/min/1.73 m2), or severe (eGFR = 15–29 mL/min/1.73 m2) renal impairment or ESRD on hemodialysis, accumulation of the intravenous vehicle SBECD occurs. The mean systemic exposure (AUC) increased 2-fold, 5-fold, 7.5-fold, and 27-fold for patients with moderate impairment, severe impairment, ESRD on hemodialysis receiving intravenous delafloxacin within 1 hour before, and 1 hour after hemodialysis respectively, compared to the healthy control group. In subjects with ESRD undergoing hemodialysis, SBECD is dialyzed with a clearance of 4.74 L/h. When hemodialysis occurred 1 hour after the delafloxacin infusion in subjects with ESRD, the mean fraction of SBECD recovered in the dialysate was 56.1% over approximately 4 hours.
Geriatric Patients
- Following single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC∞ values in elderly subjects (≥ 65 years) were about 35% higher compared to values obtained in young adults (18 to 40 years). This difference is not considered clinically relevant. A population pharmacokinetic analysis of patients with ABSSSI showed no significant impact of age on delafloxacin pharmacokinetics.
Male and Female Patients
- Following single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC∞ values in male subjects were comparable to female subjects. Results from a population pharmacokinetic analysis showed that females have a 24% lower AUC than males. This difference is not considered clinically relevant.
Drug Metabolizing Enzymes
- Delafloxacin at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes. At a delafloxacin concentration (500 µM) well above clinically relevant exposures, the activity of CYP2E1was increased.
- In human hepatocytes, delafloxacin showed no potential for in vitro induction of CYP1A2, 2B6, 2C19, or 2C8 but was a mild inducer of CYP2C9 at a concentration of 100 µM and CYP3A4 at a clinically relevant concentration. Administration of delafloxacin 450 mg every 12 hours for 5 days to healthy male and female subjects (n = 22) prior to and on Day 6 with a single oral 5-mg dose of midazolam (a sensitive CYP3A substrate), did not affect the Cmax and AUC values for midazolam or 1-hydroxy midazolam compared to administration of midazolam alone.
- Delafloxacin was not an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, OCT1 and OCT2. Delafloxacin was not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1 or OATP. Delafloxacin was shown to be a substrate of P-gp and BCRP in vitro. The clinical relevance of co-administration of delafloxacin and P-gp and/or BCRP inhibitors is unknown.
## Nonclinical Toxicology
- Long-term carcinogenicity studies have not been conducted with delafloxacin.
- Delafloxacin was not mutagenic in a bacterial reverse mutation (Ames) assay, and was not clastogenic in a mouse bone marrow micronucleus test at ≥ 15 times the estimated human plasma exposure based on AUC. In an in vitro clastogenicity assay using isolated human lymphocytes, delafloxacin was negative in short incubations (~3 hours) and, at high cytotoxic concentrations (> 1.0 mM), was positive in a long incubation (~19 hours).
- Delafloxacin did not affect the fertility of male and female rats up to the highest intravenous dose tested (120 mg/kg/day); female rats were dosed 2 weeks prior to mating and through gestation day 7 and male rats were treated for 28 days prior to mating and beyond for a total of 58-59 days. AUC in male and female (non-pregnant and pregnant) rats at 120 mg/kg/day delafloxacin intravenous was estimated to be approximately 5 times the estimated human plasma exposure based on AUC in separate intravenous toxicology studies in rats, one of which was a 2-week study that used a different vehicle for delafloxacin than in the fertility study, and another was an 8-day study in nonpregnant and pregnant (gestation day 13) rats that used the same vehicle for delafloxacin as in the fertility study.
- Fluoroquinolone antibacterials are associated with degenerative changes in articular cartilage and arthropathy in skeletally immature animals. In a toxicology study of the formulated tablet in dogs, the femoral head of one of three high dose (480 mg/kg/day) females had minimal focal degeneration of the superficial articular cartilage and a small focal cleft in the articular cartilage. No other joints were examined.
# Clinical Studies
- A total of 1510 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in 2 multicenter, multinational, double-blind, double-dummy, non-inferiority trials. Trial 1 compared delafloxacin 300 mg via intravenous infusion every 12 hours to comparator. In Trial 2, patients received delafloxacin 300 mg via intravenous infusion every12 hours for 6 doses then made a mandatory switch to oral delafloxacin 450 mg every 12 hours. In both studies, the comparator was the intravenous combination of vancomycin 15 mg/kg actual body weight and aztreonam. Aztreonam therapy was discontinued if no gram-negative pathogens were identified in the baseline cultures.
- In Trial 1, 331 patients with ABSSSI were randomized to delafloxacin and 329 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (39%), wound infection (35%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion as measured by digital planimetry was 307 cm2. The average age of patients was 46 years (range 18 to 94 years). Patients were predominately male (63%) and White (91%); 32% had BMI ≥ 30 kg/m2. The population studied in Trial 1 included a distribution of patients with associated comorbidities such as hypertension (21%), diabetes (9%), and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 55% of patients. Bacteremia was documented at baseline in 2% of patients.
- In Trial 2, 423 patients were randomized to delafloxacin and 427 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (48%), wound infection (26%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion, as measured by digital planimetry, was 353 cm2. The average age of patients was 51 years (range 18 to 93 years). Patients were predominately male (63%) and White (83%); 50 % had a BMI ≥ 30 kg/m2. The population studied in Trial 2 included a distribution of patients with associated comorbidities such as hypertension (31%), diabetes (13%) and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 30% of patients. Bacteremia was documented at baseline in 2% of patients.
- In both trials, objective clinical response at 48 to 72 hours post initiation of treatment was defined as a 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema. Table 5 summarizes the objective clinical response rates in both of these trials.
- In both trials, an investigator assessment of response was made at Follow-up (Day 14 ± 1) in the ITT and CE populations. Success was defined as "cure + improved," where patients had complete or near resolution of signs and symptoms, with no further antibacterial needed. The success rates in the ITT and CE populations are shown in Table 6.
- Six delafloxacin patients had baseline S. aureus bacteremia with ABSSSI. Five of these 6 patients (83.3%) were clinical responders at 48 to 72 hours and 5/6 (83.3%) were considered clinical success for ABSSSI at Day 14 ± 1. Two delafloxacin patients had baseline Gram-negative bacteremia (K. pneumoniae and P. aeruginosa), and both were clinical responders and successes.
- The investigator assessments of clinical success rates were also similar between treatment groups at Late Follow-up (LFU, day 21-28).
- Objective clinical response and investigator-assessed success by baseline pathogens from the primary infection site or blood cultures for the microbiological ITT (MITT) patient population pooled across Trial 1 and Trial 2 are presented in Table 7.
# How Supplied
- Delafloxacin is supplied as a sterile, lyophilized powder in single-dose clear glass vials of 300 mg delafloxacin (equivalent to 433 mg delafloxacin meglumine). The lyophilized powder is a light yellow to tan cake, which may exhibit cracking and shrinkage and slight variation in texture and color.
- They are supplied as follows: 300-mg single-dose vials (NDC 70842-102-01), packaged in cartons of 10 vials (NDC 70842-102-03).
- Delafloxacin Tablets contain 450 mg delafloxacin (equivalent to 649 mg delafloxacin meglumine); each modified capsule-shaped tablet in beige to mottled beige color is debossed with RX3341 on one side. They are supplied as follows:
- Bottles of 20 tablets with child-resistant closure (NDC 70842-101-01)
- Unit dose blister packs which contain 20 tablets (2 blister cards of 10 tablets each) (20 tablet blister pack: NDC 70842-101-02, 10 tablet blister card: NDC 70842-101-03)
## Storage
- Delafloxacin Tablets and delafloxacin for Injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
- The reconstituted powder may be stored for up to 24 hours under refrigerated or controlled room temperature and then further diluted for intravenous infusion. The reconstituted solution in the infusion bag may be stored under refrigerated or controlled room temperature conditions for up to 24 hours. Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling
Serious Adverse Reactions
- Advise patients to stop taking delafloxacin if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.
- Inform patients of the following serious adverse reactions that have been associated with delafloxacin or other fluoroquinolone use:
- Disabling and Potentially Irreversible Serious Adverse Reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of fluoroquinolones and may occur together in the same patient. Inform patients to stop taking delafloxacin immediately if they experience an adverse reaction and to call their healthcare provider.
- Tendinitis and Tendon Rupture: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue delafloxacin treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
- Peripheral Neuropathy: Inform patients that peripheral neuropathies have been associated with delafloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue delafloxacin and tell them to contact their physician.
- Central Nervous System Effects: (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to delafloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
- Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
- Hypersensitivity Reactions: Inform patients that delafloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue delafloxacin at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
- Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.
- Antibacterial Resistance: Inform patients that antibacterial drugs including delafloxacin Tablets and Injection should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When delafloxacin Tablets and delafloxacin Injection are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by delafloxacin Tablets and delafloxacin Injection or other antibacterial drugs in the future.
Administration with Food and Concomitant Medications
- Inform patients that delafloxacin Tablets may be taken with or without food and without any dietary restrictions
- Inform patients that delafloxacin Tablets should be taken at least 2 hours before or 6 hours after antacids containing magnesium, or aluminum, with sucralfate, with metal cations such as iron, or with multivitamin preparations containing zinc or iron, or with didanosine buffered tablets for oral suspension or the pediatric powder for oral solution.
# Precautions with Alcohol
Alcohol-Delafloxacin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Baxdela
# Look-Alike Drug Names
There is limited information regarding Delafloxacin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Delafloxacin | |
4cec4b3aecc361a1693e565e8c7dcbc92260b0b0 | wikidoc | Demographics | Demographics
Demographics refers to selected population characteristics as used in government, marketing or opinion research, or the demographic profiles used in such research. (Note the distinction from demography, see below.) Commonly-used demographics include race, age, income, disabilities, mobility (in terms of travel time to work or number of vehicles available), educational attainment, home ownership, employment status, and even location. Distributions of values within a demographic variable, and across households, are both of interest, as well as trends over time. Demographics are frequently used in economic and marketing research.
Demographic trends describe the changes in demographics in a population over time. For example, the average age of a population may increase. It may decrease as well as certain restrictions may be in place, for instance like in China if the population is high.
# Demographics vs Demography
The term demographics as a noun is often used erroneously in place of demography, the study of human population, its structure and change. Although there is no absolute delineation, demography focuses on population structure, processes and dynamics, whereas demographics is most often used in the fields of media studies, advertising, marketing, and polling, and should not be used interchangeably with the term "demography" or (more broadly) "population studies". 'Demographic' as an adjective can refer to either, e.g., demographic transition
# Demographic variables
Demographic Marketers and other social scientists often group populations into categories based on demographic variables. Some frequently used demographic variables are:
- Age
- Sex / Gender
- Race/ Ethnicity
- Location of residence
- Socioeconomic status (SES)
- Religion
- Marital status
- Ownership (home, car, pet, etc.)
- Language
- Mobility
- Life cycles (fertility, mortality, migration)
# Demographic profiles in marketing
Marketers typically combine several variables to define a demographic profile. A demographic profile (often shortened to "a demographic") provides enough information about the typical member of this group to create a mental picture of this hypothetical aggregate. For example, a marketer might speak of the single, female, middle-class, age 18 to 24 demographic.
Marketing researchers typically have two objectives in this regard: first to determine what segments or subgroups exist in the overall population; and secondly to create a clear and complete picture of the characteristics of a typical member of each of these segments. Once these profiles are constructed, they can be used to develop a marketing strategy and marketing plan.
# Generational cohorts
A generational cohort has been defined as "the aggregation of individuals (within some population definition) who experience the same event within the same time interval". The notion of a group of people bound together by the sharing of the experience of common historical events due to their birth in a particular period of time was first introduced by Karl Mannheim in the early 1920s. Today the concept has found its way into popular culture through well known epitomes like "baby boomer" and "gen-Xer".
# Cohorts in the United States
A study by William Strauss and Neil Howe, in their books Generations and Fourth Turning, looked at generational similarities and differences going back to the 15th century and concluded that over 80 year spans, generations proceed through 4 stages of about 20 years each. The first phase consists of times of relative crisis and the people born during this period were called "artists". The next phase was a "high" period and those born in this period were called "prophets". The next phase was an "awakening period" and people born in this period were called "nomads". The final stage was the "unraveling period" and people born in this period were called "heroes". The most recent "high period" occurred in the 50s and 60s (hence baby boomers are the most recent crop of "prophets").
The most definitive recent study of US generational cohorts was done by Schuman and Scott (1989) in 1985 in which a broad sample of adults of all ages were asked, "What world events over the past 50 years were especially important to them?". They found that 33 events were mentioned with great frequency. When the ages of the respondents were correlated with the expressed importance rankings, seven distinct cohorts became evident. Today the following descriptors are frequently used for these cohorts:
- Depression cohort (born from 1912 to 1921)
Memorable events: The Great Depression, high levels of unemployment, poverty, lack of creature comforts, financial uncertainty
Key characteristics: strive for financial security, risk averse, waste-not-want-not attitude, strive for comfort
- Memorable events: The Great Depression, high levels of unemployment, poverty, lack of creature comforts, financial uncertainty
- Key characteristics: strive for financial security, risk averse, waste-not-want-not attitude, strive for comfort
- Pre 'World War II cohort' (born from 1922 to 1927)
Memorable events: men leaving to go to war and many not returning, the personal experience of the war, women working in factories, focus on defeating a common enemy
Key characteristics: the nobility of sacrifice for the common good, patriotism, team player
- Memorable events: men leaving to go to war and many not returning, the personal experience of the war, women working in factories, focus on defeating a common enemy
- Key characteristics: the nobility of sacrifice for the common good, patriotism, team player
- World War II cohort (born from 1928 to 1945)
Memorable events: sustained economic growth, social tranquility, The Cold War, McCarthyism
Key characteristics: conformity, conservatism, traditional family values
- Memorable events: sustained economic growth, social tranquility, The Cold War, McCarthyism
- Key characteristics: conformity, conservatism, traditional family values
- Baby Boomer cohort #1 (born from 1946 to 1954)
Memorable events: assassinations of JFK, Robert Kennedy, and Martin Luther King, political unrest, walk on the moon, Vietnam War, anti-war protests, social experimentation, sexual freedom, civil rights movement, environmental movement, women's movement, protests and riots, experimentation with various intoxicating recreational substances
Key characteristics: experimental, individualism, free spirited, social cause oriented
- Memorable events: assassinations of JFK, Robert Kennedy, and Martin Luther King, political unrest, walk on the moon, Vietnam War, anti-war protests, social experimentation, sexual freedom, civil rights movement, environmental movement, women's movement, protests and riots, experimentation with various intoxicating recreational substances
- Key characteristics: experimental, individualism, free spirited, social cause oriented
- Baby Boomer cohort #2 (born from 1955 to 1964)
Memorable events: Watergate, Nixon resigns, the cold war, the oil embargo, raging inflation, gasoline shortages
Key characteristics: less optimistic, distrust of government, general cynicism
- Memorable events: Watergate, Nixon resigns, the cold war, the oil embargo, raging inflation, gasoline shortages
- Key characteristics: less optimistic, distrust of government, general cynicism
- Generation X cohort (born from 1965 to 1979)
Memorable events: Challenger explosion, Iran-Contra, social malaise, Reaganomics, AIDS, safe sex, fall of Berlin Wall, single parent families
Key characteristics: quest for emotional security, independent, informality, entrepreneurial
- Memorable events: Challenger explosion, Iran-Contra, social malaise, Reaganomics, AIDS, safe sex, fall of Berlin Wall, single parent families
- Key characteristics: quest for emotional security, independent, informality, entrepreneurial
- Generation Y cohort also called N Generation (born from 1980 to 2001)
Memorable events: rise of the internet, September 11 attacks, cultural diversity, 2 wars in Iraq
Key characteristics: quest for physical security and safety, patriotism, heightened fears, acceptance of change, technically savvy, environmental issues
- Memorable events: rise of the internet, September 11 attacks, cultural diversity, 2 wars in Iraq
- Key characteristics: quest for physical security and safety, patriotism, heightened fears, acceptance of change, technically savvy, environmental issues
### US Demographic birth cohorts
The US Census Bureau considers the following demographic birth cohorts based on birth rate, which is statistically measurable:
- Classics (born from 1900 to 1920)
(the last American cohort in which the population pyramid takes on the standard "step" form for males and females)
- (the last American cohort in which the population pyramid takes on the standard "step" form for males and females)
- Baby Bust (I) (born from 1921 to 1945)
early cohort (born from 1921 to 1933)
late cohort (born from 1934 to 1945)
- early cohort (born from 1921 to 1933)
- late cohort (born from 1934 to 1945)
- Baby Boomers (born from 1946 to 1964)
Leading Edge Boomers (born from 1946 to 1957)
Trailing Edge Boomers (born from 1958 to 1964)
- Leading Edge Boomers (born from 1946 to 1957)
- Trailing Edge Boomers (born from 1958 to 1964)
- Baby Bust (II) (born from 1965 to 1976)
- Echo Boomers (born from 1977 to 1994)
Leading Edge (born from 1977 to 1990)
- Leading Edge (born from 1977 to 1990)
Subdivided groups are present when peak boom years or inverted peak bust years are present, and may be represented by a normal or inverted bell-shaped curve (rather than a straight curve). The boom subdivided cohorts may be considered as "pre-peak" (including peak year) and "post-peak". The year 1957 was the baby boom peak with 4.3 million births and 122.7 fertility rate. Although post-peak births (such as trailing edge boomers) are in decline, and sometimes referred to as a "bust", there are still a relative large number of births. The dearth-in-birth bust cohorts include those up to the valley birth year, and those including and beyond, leading up to the subsequent normal birth rate.
# Criticisms and qualifications of demographic profiling
Demographic profiling is essentially an exercise in making generalizations about groups of people. As with all such generalizations many individuals within these groups will not conform to the profile - demographic information is aggregate and probabilistic information about groups, not about specific individuals. Critics of demographic profiling argue that such broad-brush generalizations can only offer such limited insight that their practical usefulness is debatable.
Most demographic information is also culturally based. The generational cohort information above, for example, applies primarily to North America (and to a lesser extent to Western Europe) and it may be unfruitful to generalise conclusions more widely. | Demographics
Demographics refers to selected population characteristics as used in government, marketing or opinion research, or the demographic profiles used in such research. (Note the distinction from demography, see below.) Commonly-used demographics include race, age, income, disabilities, mobility (in terms of travel time to work or number of vehicles available), educational attainment, home ownership, employment status, and even location. Distributions of values within a demographic variable, and across households, are both of interest, as well as trends over time. Demographics are frequently used in economic and marketing research.
Demographic trends describe the changes in demographics in a population over time. For example, the average age of a population may increase. It may decrease as well as certain restrictions may be in place, for instance like in China if the population is high.
# Demographics vs Demography
The term demographics as a noun is often used erroneously in place of demography, the study of human population, its structure and change. Although there is no absolute delineation, demography focuses on population structure, processes and dynamics, whereas demographics is most often used in the fields of media studies, advertising, marketing, and polling, and should not be used interchangeably with the term "demography" or (more broadly) "population studies".[citation needed] 'Demographic' as an adjective can refer to either, e.g., demographic transition
# Demographic variables
Demographic Marketers and other social scientists often group populations into categories based on demographic variables. Some frequently used demographic variables are:
- Age
- Sex / Gender
- Race/ Ethnicity
- Location of residence
- Socioeconomic status (SES)
- Religion
- Marital status
- Ownership (home, car, pet, etc.)
- Language
- Mobility
- Life cycles (fertility, mortality, migration)
# Demographic profiles in marketing
Marketers typically combine several variables to define a demographic profile. A demographic profile (often shortened to "a demographic") provides enough information about the typical member of this group to create a mental picture of this hypothetical aggregate. For example, a marketer might speak of the single, female, middle-class, age 18 to 24 demographic.
Marketing researchers typically have two objectives in this regard: first to determine what segments or subgroups exist in the overall population; and secondly to create a clear and complete picture of the characteristics of a typical member of each of these segments. Once these profiles are constructed, they can be used to develop a marketing strategy and marketing plan.
# Generational cohorts
Template:Globalize
A generational cohort has been defined as "the aggregation of individuals (within some population definition) who experience the same event within the same time interval"[1]. The notion of a group of people bound together by the sharing of the experience of common historical events due to their birth in a particular period of time was first introduced by Karl Mannheim in the early 1920s. Today the concept has found its way into popular culture through well known epitomes like "baby boomer" and "gen-Xer".
# Cohorts in the United States
A study by William Strauss and Neil Howe, in their books Generations and Fourth Turning, looked at generational similarities and differences going back to the 15th century and concluded that over 80 year spans, generations proceed through 4 stages of about 20 years each. The first phase consists of times of relative crisis and the people born during this period were called "artists". The next phase was a "high" period and those born in this period were called "prophets". The next phase was an "awakening period" and people born in this period were called "nomads". The final stage was the "unraveling period" and people born in this period were called "heroes". The most recent "high period" occurred in the 50s and 60s (hence baby boomers are the most recent crop of "prophets").
The most definitive recent study of US generational cohorts was done by Schuman and Scott (1989) in 1985 in which a broad sample of adults of all ages were asked, "What world events over the past 50 years were especially important to them?"[2]. They found that 33 events were mentioned with great frequency. When the ages of the respondents were correlated with the expressed importance rankings, seven distinct cohorts became evident. Today the following descriptors are frequently used for these cohorts:
- Depression cohort (born from 1912 to 1921)
Memorable events: The Great Depression, high levels of unemployment, poverty, lack of creature comforts, financial uncertainty
Key characteristics: strive for financial security, risk averse, waste-not-want-not attitude, strive for comfort
- Memorable events: The Great Depression, high levels of unemployment, poverty, lack of creature comforts, financial uncertainty
- Key characteristics: strive for financial security, risk averse, waste-not-want-not attitude, strive for comfort
- Pre 'World War II cohort' (born from 1922 to 1927)
Memorable events: men leaving to go to war and many not returning, the personal experience of the war, women working in factories, focus on defeating a common enemy
Key characteristics: the nobility of sacrifice for the common good, patriotism, team player
- Memorable events: men leaving to go to war and many not returning, the personal experience of the war, women working in factories, focus on defeating a common enemy
- Key characteristics: the nobility of sacrifice for the common good, patriotism, team player
- World War II cohort (born from 1928 to 1945)
Memorable events: sustained economic growth, social tranquility, The Cold War, McCarthyism
Key characteristics: conformity, conservatism, traditional family values
- Memorable events: sustained economic growth, social tranquility, The Cold War, McCarthyism
- Key characteristics: conformity, conservatism, traditional family values
- Baby Boomer cohort #1 (born from 1946 to 1954)
Memorable events: assassinations of JFK, Robert Kennedy, and Martin Luther King, political unrest, walk on the moon, Vietnam War, anti-war protests, social experimentation, sexual freedom, civil rights movement, environmental movement, women's movement, protests and riots, experimentation with various intoxicating recreational substances
Key characteristics: experimental, individualism, free spirited, social cause oriented
- Memorable events: assassinations of JFK, Robert Kennedy, and Martin Luther King, political unrest, walk on the moon, Vietnam War, anti-war protests, social experimentation, sexual freedom, civil rights movement, environmental movement, women's movement, protests and riots, experimentation with various intoxicating recreational substances
- Key characteristics: experimental, individualism, free spirited, social cause oriented
- Baby Boomer cohort #2 (born from 1955 to 1964)
Memorable events: Watergate, Nixon resigns, the cold war, the oil embargo, raging inflation, gasoline shortages
Key characteristics: less optimistic, distrust of government, general cynicism
- Memorable events: Watergate, Nixon resigns, the cold war, the oil embargo, raging inflation, gasoline shortages
- Key characteristics: less optimistic, distrust of government, general cynicism
- Generation X cohort (born from 1965 to 1979)
Memorable events: Challenger explosion, Iran-Contra, social malaise, Reaganomics, AIDS, safe sex, fall of Berlin Wall, single parent families
Key characteristics: quest for emotional security, independent, informality, entrepreneurial
- Memorable events: Challenger explosion, Iran-Contra, social malaise, Reaganomics, AIDS, safe sex, fall of Berlin Wall, single parent families
- Key characteristics: quest for emotional security, independent, informality, entrepreneurial
- Generation Y cohort also called N Generation (born from 1980 to 2001)
Memorable events: rise of the internet, September 11 attacks, cultural diversity, 2 wars in Iraq
Key characteristics: quest for physical security and safety, patriotism, heightened fears, acceptance of change, technically savvy, environmental issues
- Memorable events: rise of the internet, September 11 attacks, cultural diversity, 2 wars in Iraq
- Key characteristics: quest for physical security and safety, patriotism, heightened fears, acceptance of change, technically savvy, environmental issues
### US Demographic birth cohorts
The US Census Bureau considers the following demographic birth cohorts based on birth rate, which is statistically measurable:
- Classics (born from 1900 to 1920)
(the last American cohort in which the population pyramid takes on the standard "step" form for males and females)
- (the last American cohort in which the population pyramid takes on the standard "step" form for males and females)
- Baby Bust (I) (born from 1921 to 1945)
early cohort (born from 1921 to 1933)
late cohort (born from 1934 to 1945)
- early cohort (born from 1921 to 1933)
- late cohort (born from 1934 to 1945)
- Baby Boomers (born from 1946 to 1964)
Leading Edge Boomers (born from 1946 to 1957)
Trailing Edge Boomers (born from 1958 to 1964)
- Leading Edge Boomers (born from 1946 to 1957)
- Trailing Edge Boomers (born from 1958 to 1964)
- Baby Bust (II) (born from 1965 to 1976)
- Echo Boomers (born from 1977 to 1994)
Leading Edge (born from 1977 to 1990)
- Leading Edge (born from 1977 to 1990)
Subdivided groups are present when peak boom years or inverted peak bust years are present, and may be represented by a normal or inverted bell-shaped curve (rather than a straight curve). The boom subdivided cohorts may be considered as "pre-peak" (including peak year) and "post-peak". The year 1957 was the baby boom peak with 4.3 million births and 122.7 fertility rate. Although post-peak births (such as trailing edge boomers) are in decline, and sometimes referred to as a "bust", there are still a relative large number of births. The dearth-in-birth bust cohorts include those up to the valley birth year, and those including and beyond, leading up to the subsequent normal birth rate.
# Criticisms and qualifications of demographic profiling
Demographic profiling is essentially an exercise in making generalizations about groups of people. As with all such generalizations many individuals within these groups will not conform to the profile - demographic information is aggregate and probabilistic information about groups, not about specific individuals. Critics of demographic profiling argue that such broad-brush generalizations can only offer such limited insight that their practical usefulness is debatable.
Most demographic information is also culturally based. The generational cohort information above, for example, applies primarily to North America (and to a lesser extent to Western Europe) and it may be unfruitful to generalise conclusions more widely. | https://www.wikidoc.org/index.php/Demographics | |
bb5ae336a03db4581c22503d8d961f41fbb93cfc | wikidoc | Dental drill | Dental drill
# Overview
A dental drill (or dentist's drill) is a small, high-speed drill used in dentistry to remove decayed tooth material prior to the insertion of a dental filling. Dental drills are used in the treatment of dental caries. The term "dental drill" is considered the more colloquial form of the term "dental handpiece," although it can also be construed as to include to the power source for one or more handpieces, a "dental engine." "Handpiece" and "engine" are more generic and euphemistic terms for generic dental tools.
Modern dental drills can rotate at up to 800,000 rpm, and generally use hard metal alloy bits (actually small rotary files) known as 'burs'. Dental burs come in a great variety of shapes designed for specific applications. They are often made of steel with a tungsten carbide coating, or of tungsten carbide entirely. The bur may also have a diamond coating.
Dental drills, which have a distinctive, shrill sound, are often a prominent factor in many people's fear of dentistry (dentophobia).
# History
Archeological researches in the area of the Indus Valley Civilization Mergarh, Pakistan / India, resulted in the finding of eleven human teeth that were treated with flintstone tools. Cavities of 3.5 mm depth with concentric groovings indicate the usage of a drill tool. The age of the teeth has been estimated with 9000 years. In later times, mechanical hand drills were used. Like most hand drills, they were quite slow, with speeds of up to 15 rpm. In 1864, British dentist George Fellows Harrington invented a clockwork dental drill named Erado. The device was much faster than earlier drills, but also very noisy. In 1868, American dentist George F. Green came up with a pneumatic dental drill powered with pedal-operated bellows. James B. Morrison devised a pedal-powered bur drill in 1871.
The first electric dental drill was patented in 1875 by Dr. Green, a development that revolutionized dentistry. By 1914, electric dental drills could reach speeds of up to 3,000 rpm. A second wave of rapid development occurred in the 1950s and 60s, including the development of the air turbine drill.
The modern incarnation of the dental drill is the air turbine handpiece, developed by John Patrick Walsh (later knighted) and members of the staff of the Dominion Physical Laboratory (DPL) Wellington , New Zealand. The first application for a provisional patent for the handpiece was granted in October 1949. This handpiece was driven by compressed air. The final model is held by the Commonwealth Inventions development Board in Canada. The New Zealand patent number is No/104611. The patent was granted in November to John Patrick Walsh who conceived the idea of the contra angle air turbine handpiece after he had used a small commercial type air grinder as a straight handpiece. Dr. John Borden developed it in America and it was first commercially manufactured and distributed by the DENTSPLY Company as the Borden Airotor in 1957.
Current iterations can operate at up to 800,000 rpm, however, most common is a 400,000 rpm "High Speed" Handpiece for precision work complimented with a "Low Speed" Handpiece operating at 20,000 rpm for applications requiring higher torque than a high speed handpiece can deliver.
# Alternatives
Starting in the 1990s, a number of alternatives to conventional rotary dental drills have been developed. These include laser ablation systems and air abrasion devices (essentially miniature sand blasters).
# Other uses
Dental drills and drill bits are commonly used by jewellers and hobbyists for high-precision drilling work. | Dental drill
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A dental drill (or dentist's drill) is a small, high-speed drill used in dentistry to remove decayed tooth material prior to the insertion of a dental filling. Dental drills are used in the treatment of dental caries. The term "dental drill" is considered the more colloquial form of the term "dental handpiece," although it can also be construed as to include to the power source for one or more handpieces, a "dental engine." "Handpiece" and "engine" are more generic and euphemistic terms for generic dental tools.
Modern dental drills can rotate at up to 800,000 rpm, and generally use hard metal alloy bits (actually small rotary files) known as 'burs'. Dental burs come in a great variety of shapes designed for specific applications. They are often made of steel with a tungsten carbide coating, or of tungsten carbide entirely. The bur may also have a diamond coating.
Dental drills, which have a distinctive, shrill sound, are often a prominent factor in many people's fear of dentistry (dentophobia).
# History
Archeological researches in the area of the Indus Valley Civilization Mergarh, Pakistan / India, resulted in the finding of eleven human teeth that were treated with flintstone tools.[1] Cavities of 3.5 mm depth with concentric groovings indicate the usage of a drill tool. The age of the teeth has been estimated with 9000 years. In later times, mechanical hand drills were used. Like most hand drills, they were quite slow, with speeds of up to 15 rpm. In 1864, British dentist George Fellows Harrington invented a clockwork dental drill named Erado. The device was much faster than earlier drills, but also very noisy. In 1868, American dentist George F. Green came up with a pneumatic dental drill powered with pedal-operated bellows. James B. Morrison devised a pedal-powered bur drill in 1871.
The first electric dental drill was patented in 1875 by Dr. Green, a development that revolutionized dentistry. By 1914, electric dental drills could reach speeds of up to 3,000 rpm. A second wave of rapid development occurred in the 1950s and 60s, including the development of the air turbine drill.
The modern incarnation of the dental drill is the air turbine handpiece, developed by John Patrick Walsh (later knighted) and members of the staff of the Dominion Physical Laboratory (DPL) Wellington , New Zealand. The first application for a provisional patent for the handpiece was granted in October 1949. This handpiece was driven by compressed air. The final model is held by the Commonwealth Inventions development Board in Canada. The New Zealand patent number is No/104611. The patent was granted in November to John Patrick Walsh who conceived the idea of the contra angle air turbine handpiece after he had used a small commercial type air grinder as a straight handpiece. Dr. John Borden developed it in America and it was first commercially manufactured and distributed by the DENTSPLY Company as the Borden Airotor in 1957.
Current iterations can operate at up to 800,000 rpm, however, most common is a 400,000 rpm "High Speed" Handpiece for precision work complimented with a "Low Speed" Handpiece operating at 20,000 rpm for applications requiring higher torque than a high speed handpiece can deliver. [2]
# Alternatives
Starting in the 1990s, a number of alternatives to conventional rotary dental drills have been developed. These include laser ablation systems and air abrasion devices (essentially miniature sand blasters).
# Other uses
Dental drills and drill bits are commonly used by jewellers and hobbyists for high-precision drilling work. | https://www.wikidoc.org/index.php/Dental_drill | |
614e7d8051beb00a23456d762075b71e9f086e50 | wikidoc | Tooth enamel | Tooth enamel
# Overview
Tooth enamel is the hardest and most highly mineralized substance of the body, and with dentin, cementum, and dental pulp is one of the four major tissues which make up the tooth. It is the normally visible dental tissue of a tooth and must be supported by underlying dentin. Ninety-six percent of enamel consists of mineral, with water and organic material composing the rest. The normal color of enamel varies from light yellow to grayish white. At the edges of teeth where there is no dentin underlying the enamel, the color sometimes has a slightly blue tone. Since enamel is semitranslucent, the color of dentin and any restorative dental material underneath the enamel strongly affects the appearance of a tooth. Enamel varies in thickness over the surface of the tooth and is often thickest at the cusp, up to 2.5 mm, and thinnest at its border, which is seen clinically as the cementoenamel junction (CEJ).
Enamel's primary mineral is hydroxyapatite, which is a crystalline calcium phosphate. The large amount of minerals in enamel accounts not only for its strength but also for its brittleness. Tooth enamel is the hardest substance in the human body, ranking a 5 on Mohs hardness scale. Dentin, less mineralized and less brittle, 3-4 in hardness, compensates for enamel and is necessary as a support.
Unlike dentin and bone, enamel does not contain collagen. Instead, it has two unique classes of proteins called amelogenins and enamelins. While the role of these proteins is not fully understood, it is believed that they aid in the development of enamel by serving as a framework support, among other functions.
# Structure
The basic unit of enamel is called an enamel rod. Measuring 4 μm - 8 μm in diameter an enamel rod, formerly called an enamel prism, is a tightly packed mass of hydroxyapatite crystals in an organized pattern. In cross section, it is best compared to a keyhole, with the top, or head, oriented toward the crown of the tooth, and the bottom, or tail, oriented toward the root of the tooth.
The arrangement of the crystals within each enamel rod is highly complex. Both ameloblasts (the cells which initiate enamel formation) and Tomes' processes affect the crystals' pattern. Enamel crystals in the head of the enamel rod are oriented parallel to the long axis of the rod. When found in the tail of the enamel rod, the crystals' orientation diverges slightly from the long axis.
The arrangement of enamel rods is understood more clearly than their internal structure. Enamel rods are found in rows along the tooth, and within each row, the long axis of the enamel rod is generally perpendicular to the underlying dentin. In permanent teeth, the enamel rods near the cementoenamel junction (CEJ) tilt slightly toward the root of the tooth. Understanding enamel orientation is very important in restorative dentistry, because enamel unsupported by underlying dentin is prone to fracture.
The area around the enamel rod is known as interrod enamel. Interrod enamel has the same composition as enamel rod, however a histologic distinction is made between the two because crystal orientation is different in each. The border where the crystals of enamel rods and crystals of interrod enamel meet is called the rod sheath.
Striae of Retzius are stripes that appear on enamel when viewed microscopically in cross section. Formed from changes in diameter of Tomes’ processes, these stripes demonstrate the growth of enamel, similar to the annual rings on a tree. Perikymata are shallow furrows where the striae of Retzius end. Darker than the other stripes, the neonatal line is a stripe that separates enamel formed before and after birth.
Gnarled enamel is found at the cusps of teeth. Its twisted appearance results from the orientation of enamel rods and the rows in which they lie.
# Development
Enamel formation is part of the overall process of tooth development. When the tissues of the developing tooth are seen under a microscope, different cellular aggregations can be identified, including structures known as the enamel organ, dental lamina, and dental papilla. The generally recognized stages of tooth development are the bud stage, cap stage, bell stage, and crown, or calcification, stage. Enamel formation is first seen in the crown stage.
Amelogenesis, or enamel formation, occurs after the first establishment of dentin, via cells known as ameloblasts. Human enamel forms at a rate of around 4 μm per day, beginning at the future location of cusps, around the third or fourth month of pregnancy. As in all human processes, the creation of enamel is complex, but can generally be divided into two stages. The first stage, called the secretory stage, involves proteins and an organic matrix forming a partially mineralized enamel. The second stage, called the maturation stage, completes enamel mineralization.
In the secretory stage, ameloblasts are polarized columnar cells. In the rough endoplasmic reticulum of these cells, enamel proteins are released into the surrounding area and contribute to what is known as the enamel matrix, which is then partially mineralized by the enzyme alkaline phosphatase. When this first layer is formed, the ameloblasts move away from the dentin, allowing for the development of Tomes’ processes at the apical pole of the cell. Enamel formation continues around the adjoining ameloblasts, resulting in a walled area, or pit, that houses a Tomes’ process, and also around the end of each Tomes’ process, resulting in a deposition of enamel matrix inside of each pit. The matrix within the pit will eventually become an enamel rod, and the walls will eventually become interrod enamel. The only distinguishing factor between the two is the orientation of the calcium phosphate crystals.
In the maturation stage, the ameloblasts transport substances used in the formation of enamel. Histologically, the most notable aspect of this phase is that these cells become striated, or have a ruffled border. These signs demonstrate that the ameloblasts have changed their function from production, as in the secretory stage, to transportation. Proteins used for the final mineralization process compose most of the transported material. The noteworthy proteins involved are amelogenins, ameloblastins, enamelins, and tuftelins. During this process, amelogenins and ameloblastins are removed after use, leaving enamelins and tuftelin in the enamel. By the end of this stage, the enamel has completed its mineralization.
At some point before the tooth erupts into the mouth, but after the maturation stage, the ameloblasts are broken down. Consequently, enamel, unlike many other tissues of the body, has no way to regenerate itself. After destruction of enamel from decay or injury, neither the body nor a dentist can restore the enamel tissue. Enamel can be affected further by non-pathologic processes. The discoloration of teeth over time can result from exposure to substances such as tobacco, coffee, and tea. This is partly due to material building up in the enamel, but is also an effect of the underlying dentin becoming sclerotic. As a result, tooth color gradually darkens with age. Additionally, enamel becomes less permeable to fluids, less soluble to acid, and contains less water.
# Destruction
The high mineral content of enamel, which makes this tissue the hardest in the human body, also makes it susceptible to a demineralization process which often occurs as dental caries, otherwise known as cavities. Demineralization occurs for several reasons, but the most important cause of tooth decay is the ingestion of sugars.
Tooth cavities are caused when acids dissolve tooth enamel:
Sugars from candies, soft drinks, and even fruit juices play a significant role in tooth decay, and consequently in enamel destruction. The mouth contains a great number and variety of bacteria, and when sucrose, the most common of sugars, coats the surface of the mouth, some intraoral bacteria interact with it and form lactic acid, which decreases the pH in the mouth. Then, the hydroxyapatite crystals of enamel demineralize, allowing for greater bacterial invasion deeper into the tooth. The most important bacterium involved with tooth decay is Streptococcus mutans, but the number and type of bacteria varies with the progress of tooth destruction.
Furthermore, tooth morphology dictates that the most common site for the initiation of dental caries is in the deep grooves, pits, and fissures of enamel. This is expected because these locations are impossible to reach with a toothbrush and allow for bacteria to reside there. When demineralization of enamel occurs, a dentist can use a sharp instrument, such as a dental explorer, and "feel a stick" at the location of the decay. As enamel continues to become less mineralized and is unable to prevent the encroachment of bacteria, the underlying dentin becomes affected as well. When dentin, which normally supports enamel, is destroyed by a physiologic condition or by decay, enamel is unable to compensate for its brittleness and breaks away from the tooth easily.
The extent to which tooth decay is likely, known as cariogenicity, depends on factors such as how long the sugar remains in the mouth. Contrary to common belief, it is not the amount of sugar ingested but the frequency of sugar ingestion that is the most important factor in the causation of tooth decay. When the pH in the mouth initially decreases from the ingestion of sugars, the enamel is demineralized and left vulnerable for about 30 minutes. Eating a greater quantity of sugar in one sitting does not increase the time of demineralization. Similarly, eating a lesser quantity of sugar in one sitting does not decrease the time of demineralization. Thus, eating a great quantity of sugar at one time in the day is less detrimental than is a very small quantity ingested in many intervals throughout the day. For example, in terms of oral health, it is better to eat a single dessert at dinner time than to snack on a bag of candy throughout the day.
In addition to bacterial invasion, enamel is also susceptible to other destructive forces. Bruxism, also known as clenching of or grinding on teeth, destroys enamel very quickly. The wear rate of enamel, called attrition, is 8 micrometers a year from normal factors. A common misconception is that enamel wears away mostly from chewing, but actually teeth rarely touch during chewing. Furthermore, normal tooth contact is compensated physiologically by the periodontal ligaments (pdl) and the arrangement of dental occlusion. The truly destructive forces are the parafunctional movements, as found in bruxism, which can cause irreversible damage to the enamel.
Other nonbacterial processes of enamel destruction include abrasion (involving foreign elements, such as toothbrushes), erosion (involving chemical processes, such as lemon juice), and possibly abfraction (involving compressive and tensile forces).
# Oral hygiene and fluoride
Considering the vulnerability of enamel to demineralization and the daily menace of sugar ingestion, prevention of tooth decay is the best way to maintain the health of teeth. Most countries have wide use of toothbrushes, which can reduce the number of bacteria and food particles on enamel. Some isolated societies do not have access to toothbrushes, but it is common for those people to use other objects, such as sticks, to clean their teeth. In between two adjacent teeth, floss is used to wipe the enamel surfaces free of plaque and food particles to discourage bacterial growth. Although neither floss nor toothbrushes can penetrate the deep grooves and pits of enamel, good general oral health habits can usually prevent enough bacterial growth to keep tooth decay from starting.
These methods of oral hygiene have been helped greatly by the use of fluoride. Fluoride can be found in many locations naturally, such as the ocean and other water sources. Consequently, many seafood dishes contain fluoride. The recommended dosage of fluoride in drinking water is 1 part per million (ppm). Fluoride helps prevent dental decay by binding to the hydroxyapatite crystals in enamel. The incorporated fluoride makes enamel more resistant to demineralization and, thus, resistant to decay. Fluoride therapy is used to help teeth prevent dental decay.
Many groups of people have spoken out against fluoridated drinking water. One example used by these advocates is the damage fluoride can do as fluorosis. Fluorosis is a condition resulting from the overexposure to fluoride, especially between the ages of 6 months to 5 years, and appears as mottled enamel. Consequently, the teeth look unsightly and, indeed, the incidence of dental decay in those teeth is very small. However, it is important to note that most substances, even beneficial ones, are detrimental when taken in extreme doses. Where fluoride is found naturally in high concentrations, filters are often used to decrease the amount of fluoride in water. For this reason, codes have been developed by dental professionals to limit the amount of fluoride a person should take. These codes are supported by the American Dental Association and the American Academy of Pediatric Dentistry. The acute toxic dose of fluoride is ~5 mg/kg of body weight. Furthermore, whereas topical fluoride, found in toothpaste and mouthwashes, does not cause fluorosis, its effects are also less pervasive and not as long-lasting as those of systemic fluoride, such as when drinking fluorinated water. For instance, all of a tooth's enamel gains the benefits of fluoride when it is ingested systemically, through fluoridated water or salt fluoridation (a common alternative in Europe). Only some of the outer surfaces of enamel can be reached by topical fluoride. Thus, despite fluoridation's detractors, most dental health care professionals and organizations agree that the inclusion of fluoride in public water has been one of the most effective methods of decreasing the prevalence of tooth decay.
# Effects of dental procedures
## Dental restorations
Most dental restorations involve the removal of enamel. Frequently, the purpose of removal is to gain access to the underlying decay in the dentin or inflammation in the pulp. This is typically the case in amalgam restorations and endodontic treatment.
Nonetheless, enamel can sometimes be removed before there is any decay present. The most popular example is the dental sealant. The process of placing dental sealants in the past involved removing enamel in the deep fissures and grooves of a tooth and replacing it with a restorative material. Presently, it is more common to only remove decayed enamel if present. In spite of this, there are still cases where deep fissures and grooves in enamel are removed in order to prevent decay, and a sealant may or may not be placed depending on the situation. Sealants are unique in that they are preventative restorations for protection from future decay and have shown to reduce the risk of decay by 55% over 7 years.
Aesthetics is another reason for the removal of enamel. Removing enamel is necessary when placing crowns and veneers to enhance the appearance of teeth. In both of these instances, it is important to keep in mind the orientation of enamel rods because it is possible to leave enamel unsupported by underlying dentin, leaving that portion of the prepared teeth more vulnerable to fracture.
## Acid-etching techniques
Invented in 1955, acid-etching employs dental etchants and is used frequently when bonding dental restoration to teeth. This is important for long-term use of some materials, such as composites and sealants. By dissolving minerals in enamel, etchants remove the outer 10 micrometers on the enamel surface and makes a porous layer 5–50 micrometers deep. This roughens the enamel microscopically and results in a greater surface area on which to bond.
The effects of acid-etching on enamel can vary. Important variables are the amount of time the etchant is applied, the type of etchant used, and the current condition of the enamel.
There are three types of patterns formed by acid-etching. Type 1 is a pattern where predominantly the enamel rods are dissolved; type 2 is a pattern where predominantly the area around the enamel rods are dissolved; and type 3 is a pattern where there is no evidence left of any enamel rods. Besides concluding that type 1 is the most favorable pattern and type 3 the least, the explanation for these different patterns is not known for certain but is most commonly attributed to different crystal orientation in the enamel.
## Tooth whitening
Tooth whitening or tooth bleaching are procedures that attempt to lighten a tooth's color in either of two ways: by chemical or mechanical action.
Working chemically, a bleaching agent is used to carry out an oxidation reaction in the enamel and dentin. The agents most commonly used to intrinsically change the color of teeth are hydrogen peroxide and carbamide peroxide. A tooth whitening product with an overall low pH can put enamel at risk for decay or destruction by demineralization. Consequently, care should be taken and risk evaluated when choosing a product which is very acidic.
Tooth whiteners in toothpastes work through a mechanical action. They have mild abrasives which aid in the removal of stains on enamel. Although this can be an effective method, it does not alter the intrinsic color of teeth.
Microabrasion techniques employ both methods. An acid is used first to weaken the outer 22–27 micrometers of enamel in order to weaken it enough for the subsequent abrasive force. This allows for removal of superficial stains in the enamel. If the discoloration is deeper or in the dentin, this method of tooth whitening will not be successful.
# Systemic conditions affecting enamel
There are many different types of Amelogenesis imperfecta. The hypocalcification type, which is the most common, is an autosomal dominant condition that results in enamel that is not completely mineralized. Consequently, enamel easily flakes off the teeth, which appear yellow because of the revealed dentin. The hypoplastic type is X-linked and results in normal enamel that appears in too little quantity, having the same effect as the most common type.
Chronic bilirubin encephalopathy, which can result from erythroblastosis fetalis, is a disease which has numerous effects on an infant, but it can also cause enamel hypoplasia and green staining of enamel.
Enamel hypoplasia is broadly defined to encompass all deviations from normal enamel in its various degrees of absence. The missing enamel could be localized, forming a small pit, or it could be completely absent.
Erythropoietic porphyria is a genetic disease resulting in the deposition of porphyrins throughout the body. These deposits also occur in enamel and leave an appearance described as red in color and fluorescent.
Fluorosis leads to mottled enamel and occurs from overexposure to fluoride.
Tetracycline staining leads to brown bands on the areas of developing enamel. Children up to age 8 can develop mottled enamel from taking tetracylicne. As a result, tetracycline is contraindicated in pregnant women.
Celiac disease, an auto-immune disorder triggered by gluten allergies, also commonly results in demineralization of the enamel. | Tooth enamel
# Overview
Tooth enamel is the hardest and most highly mineralized substance of the body,[1] and with dentin, cementum, and dental pulp is one of the four major tissues which make up the tooth. It is the normally visible dental tissue of a tooth and must be supported by underlying dentin. Ninety-six percent of enamel consists of mineral, with water and organic material composing the rest.[2] The normal color of enamel varies from light yellow to grayish white. At the edges of teeth where there is no dentin underlying the enamel, the color sometimes has a slightly blue tone. Since enamel is semitranslucent, the color of dentin and any restorative dental material underneath the enamel strongly affects the appearance of a tooth. Enamel varies in thickness over the surface of the tooth and is often thickest at the cusp, up to 2.5 mm, and thinnest at its border, which is seen clinically as the cementoenamel junction (CEJ).[3]
Enamel's primary mineral is hydroxyapatite, which is a crystalline calcium phosphate.[4] The large amount of minerals in enamel accounts not only for its strength but also for its brittleness.[5] Tooth enamel is the hardest substance in the human body, ranking a 5 on Mohs hardness scale. Dentin, less mineralized and less brittle, 3-4 in hardness, compensates for enamel and is necessary as a support.[4]
Unlike dentin and bone, enamel does not contain collagen. Instead, it has two unique classes of proteins called amelogenins and enamelins. While the role of these proteins is not fully understood, it is believed that they aid in the development of enamel by serving as a framework support, among other functions.[6]
# Structure
The basic unit of enamel is called an enamel rod.[4] Measuring 4 μm - 8 μm in diameter an enamel rod, formerly called an enamel prism, is a tightly packed mass of hydroxyapatite crystals in an organized pattern.[1] In cross section, it is best compared to a keyhole, with the top, or head, oriented toward the crown of the tooth, and the bottom, or tail, oriented toward the root of the tooth.
The arrangement of the crystals within each enamel rod is highly complex. Both ameloblasts (the cells which initiate enamel formation) and Tomes' processes affect the crystals' pattern. Enamel crystals in the head of the enamel rod are oriented parallel to the long axis of the rod.[3][1] When found in the tail of the enamel rod, the crystals' orientation diverges slightly from the long axis.[1]
The arrangement of enamel rods is understood more clearly than their internal structure. Enamel rods are found in rows along the tooth, and within each row, the long axis of the enamel rod is generally perpendicular to the underlying dentin.[7] In permanent teeth, the enamel rods near the cementoenamel junction (CEJ) tilt slightly toward the root of the tooth. Understanding enamel orientation is very important in restorative dentistry, because enamel unsupported by underlying dentin is prone to fracture.[7]
The area around the enamel rod is known as interrod enamel. Interrod enamel has the same composition as enamel rod, however a histologic distinction is made between the two because crystal orientation is different in each.[3] The border where the crystals of enamel rods and crystals of interrod enamel meet is called the rod sheath.[8]
Striae of Retzius are stripes that appear on enamel when viewed microscopically in cross section.[7] Formed from changes in diameter of Tomes’ processes, these stripes demonstrate the growth of enamel, similar to the annual rings on a tree. Perikymata are shallow furrows where the striae of Retzius end.[9] Darker than the other stripes, the neonatal line is a stripe that separates enamel formed before and after birth.[10]
Gnarled enamel is found at the cusps of teeth.[11] Its twisted appearance results from the orientation of enamel rods and the rows in which they lie.
# Development
Enamel formation is part of the overall process of tooth development. When the tissues of the developing tooth are seen under a microscope, different cellular aggregations can be identified, including structures known as the enamel organ, dental lamina, and dental papilla.[12] The generally recognized stages of tooth development are the bud stage, cap stage, bell stage, and crown, or calcification, stage. Enamel formation is first seen in the crown stage.
Amelogenesis, or enamel formation, occurs after the first establishment of dentin, via cells known as ameloblasts. Human enamel forms at a rate of around 4 μm per day, beginning at the future location of cusps, around the third or fourth month of pregnancy.[7] As in all human processes, the creation of enamel is complex, but can generally be divided into two stages.[13] The first stage, called the secretory stage, involves proteins and an organic matrix forming a partially mineralized enamel. The second stage, called the maturation stage, completes enamel mineralization.
In the secretory stage, ameloblasts are polarized columnar cells. In the rough endoplasmic reticulum of these cells, enamel proteins are released into the surrounding area and contribute to what is known as the enamel matrix, which is then partially mineralized by the enzyme alkaline phosphatase.[14] When this first layer is formed, the ameloblasts move away from the dentin, allowing for the development of Tomes’ processes at the apical pole of the cell. Enamel formation continues around the adjoining ameloblasts, resulting in a walled area, or pit, that houses a Tomes’ process, and also around the end of each Tomes’ process, resulting in a deposition of enamel matrix inside of each pit.[15] The matrix within the pit will eventually become an enamel rod, and the walls will eventually become interrod enamel. The only distinguishing factor between the two is the orientation of the calcium phosphate crystals.
In the maturation stage, the ameloblasts transport substances used in the formation of enamel. Histologically, the most notable aspect of this phase is that these cells become striated, or have a ruffled border.[14] These signs demonstrate that the ameloblasts have changed their function from production, as in the secretory stage, to transportation. Proteins used for the final mineralization process compose most of the transported material. The noteworthy proteins involved are amelogenins, ameloblastins, enamelins, and tuftelins.[16] During this process, amelogenins and ameloblastins are removed after use, leaving enamelins and tuftelin in the enamel.[17] By the end of this stage, the enamel has completed its mineralization.
At some point before the tooth erupts into the mouth, but after the maturation stage, the ameloblasts are broken down. Consequently, enamel, unlike many other tissues of the body, has no way to regenerate itself.[18] After destruction of enamel from decay or injury, neither the body nor a dentist can restore the enamel tissue. Enamel can be affected further by non-pathologic processes. The discoloration of teeth over time can result from exposure to substances such as tobacco, coffee, and tea.[19] This is partly due to material building up in the enamel, but is also an effect of the underlying dentin becoming sclerotic.[20] As a result, tooth color gradually darkens with age. Additionally, enamel becomes less permeable to fluids, less soluble to acid, and contains less water.[20]
# Destruction
The high mineral content of enamel, which makes this tissue the hardest in the human body, also makes it susceptible to a demineralization process which often occurs as dental caries, otherwise known as cavities.[12] Demineralization occurs for several reasons, but the most important cause of tooth decay is the ingestion of sugars.
Tooth cavities are caused when acids dissolve tooth enamel:[22]
Sugars from candies, soft drinks, and even fruit juices play a significant role in tooth decay, and consequently in enamel destruction. The mouth contains a great number and variety of bacteria, and when sucrose, the most common of sugars, coats the surface of the mouth, some intraoral bacteria interact with it and form lactic acid, which decreases the pH in the mouth.[23] Then, the hydroxyapatite crystals of enamel demineralize, allowing for greater bacterial invasion deeper into the tooth. The most important bacterium involved with tooth decay is Streptococcus mutans, but the number and type of bacteria varies with the progress of tooth destruction.[23]
Furthermore, tooth morphology dictates that the most common site for the initiation of dental caries is in the deep grooves, pits, and fissures of enamel. This is expected because these locations are impossible to reach with a toothbrush and allow for bacteria to reside there. When demineralization of enamel occurs, a dentist can use a sharp instrument, such as a dental explorer, and "feel a stick" at the location of the decay. As enamel continues to become less mineralized and is unable to prevent the encroachment of bacteria, the underlying dentin becomes affected as well. When dentin, which normally supports enamel, is destroyed by a physiologic condition or by decay, enamel is unable to compensate for its brittleness and breaks away from the tooth easily.
The extent to which tooth decay is likely, known as cariogenicity, depends on factors such as how long the sugar remains in the mouth. Contrary to common belief, it is not the amount of sugar ingested but the frequency of sugar ingestion that is the most important factor in the causation of tooth decay.[24] When the pH in the mouth initially decreases from the ingestion of sugars, the enamel is demineralized and left vulnerable for about 30 minutes. Eating a greater quantity of sugar in one sitting does not increase the time of demineralization. Similarly, eating a lesser quantity of sugar in one sitting does not decrease the time of demineralization. Thus, eating a great quantity of sugar at one time in the day is less detrimental than is a very small quantity ingested in many intervals throughout the day. For example, in terms of oral health, it is better to eat a single dessert at dinner time than to snack on a bag of candy throughout the day.
In addition to bacterial invasion, enamel is also susceptible to other destructive forces. Bruxism, also known as clenching of or grinding on teeth, destroys enamel very quickly. The wear rate of enamel, called attrition, is 8 micrometers a year from normal factors. A common misconception is that enamel wears away mostly from chewing, but actually teeth rarely touch during chewing. Furthermore, normal tooth contact is compensated physiologically by the periodontal ligaments (pdl) and the arrangement of dental occlusion. The truly destructive forces are the parafunctional movements, as found in bruxism, which can cause irreversible damage to the enamel.
Other nonbacterial processes of enamel destruction include abrasion (involving foreign elements, such as toothbrushes), erosion (involving chemical processes, such as lemon juice), and possibly abfraction (involving compressive and tensile forces).[25]
# Oral hygiene and fluoride
Considering the vulnerability of enamel to demineralization and the daily menace of sugar ingestion, prevention of tooth decay is the best way to maintain the health of teeth. Most countries have wide use of toothbrushes, which can reduce the number of bacteria and food particles on enamel. Some isolated societies do not have access to toothbrushes, but it is common for those people to use other objects, such as sticks, to clean their teeth. In between two adjacent teeth, floss is used to wipe the enamel surfaces free of plaque and food particles to discourage bacterial growth. Although neither floss nor toothbrushes can penetrate the deep grooves and pits of enamel, good general oral health habits can usually prevent enough bacterial growth to keep tooth decay from starting.
These methods of oral hygiene have been helped greatly by the use of fluoride. Fluoride can be found in many locations naturally, such as the ocean and other water sources. Consequently, many seafood dishes contain fluoride. The recommended dosage of fluoride in drinking water is 1 part per million (ppm).[26] Fluoride helps prevent dental decay by binding to the hydroxyapatite crystals in enamel.[27] The incorporated fluoride makes enamel more resistant to demineralization and, thus, resistant to decay.[23] Fluoride therapy is used to help teeth prevent dental decay.
Many groups of people have spoken out against fluoridated drinking water. One example used by these advocates is the damage fluoride can do as fluorosis. Fluorosis is a condition resulting from the overexposure to fluoride, especially between the ages of 6 months to 5 years, and appears as mottled enamel.[28] Consequently, the teeth look unsightly and, indeed, the incidence of dental decay in those teeth is very small. However, it is important to note that most substances, even beneficial ones, are detrimental when taken in extreme doses. Where fluoride is found naturally in high concentrations, filters are often used to decrease the amount of fluoride in water. For this reason, codes have been developed by dental professionals to limit the amount of fluoride a person should take.[29] These codes are supported by the American Dental Association and the American Academy of Pediatric Dentistry. The acute toxic dose of fluoride is ~5 mg/kg of body weight. Furthermore, whereas topical fluoride, found in toothpaste and mouthwashes, does not cause fluorosis, its effects are also less pervasive and not as long-lasting as those of systemic fluoride, such as when drinking fluorinated water.[30] For instance, all of a tooth's enamel gains the benefits of fluoride when it is ingested systemically, through fluoridated water or salt fluoridation (a common alternative in Europe). Only some of the outer surfaces of enamel can be reached by topical fluoride. Thus, despite fluoridation's detractors, most dental health care professionals and organizations agree that the inclusion of fluoride in public water has been one of the most effective methods of decreasing the prevalence of tooth decay.
# Effects of dental procedures
## Dental restorations
Most dental restorations involve the removal of enamel. Frequently, the purpose of removal is to gain access to the underlying decay in the dentin or inflammation in the pulp. This is typically the case in amalgam restorations and endodontic treatment.
Nonetheless, enamel can sometimes be removed before there is any decay present. The most popular example is the dental sealant. The process of placing dental sealants in the past involved removing enamel in the deep fissures and grooves of a tooth and replacing it with a restorative material.[31] Presently, it is more common to only remove decayed enamel if present. In spite of this, there are still cases where deep fissures and grooves in enamel are removed in order to prevent decay, and a sealant may or may not be placed depending on the situation. Sealants are unique in that they are preventative restorations for protection from future decay and have shown to reduce the risk of decay by 55% over 7 years.[32]
Aesthetics is another reason for the removal of enamel. Removing enamel is necessary when placing crowns and veneers to enhance the appearance of teeth. In both of these instances, it is important to keep in mind the orientation of enamel rods because it is possible to leave enamel unsupported by underlying dentin, leaving that portion of the prepared teeth more vulnerable to fracture.[33]
## Acid-etching techniques
Invented in 1955, acid-etching employs dental etchants and is used frequently when bonding dental restoration to teeth.[34] This is important for long-term use of some materials, such as composites and sealants.[12] By dissolving minerals in enamel, etchants remove the outer 10 micrometers on the enamel surface and makes a porous layer 5–50 micrometers deep.[35] This roughens the enamel microscopically and results in a greater surface area on which to bond.
The effects of acid-etching on enamel can vary. Important variables are the amount of time the etchant is applied, the type of etchant used, and the current condition of the enamel.[35]
There are three types of patterns formed by acid-etching.[35] Type 1 is a pattern where predominantly the enamel rods are dissolved; type 2 is a pattern where predominantly the area around the enamel rods are dissolved; and type 3 is a pattern where there is no evidence left of any enamel rods. Besides concluding that type 1 is the most favorable pattern and type 3 the least, the explanation for these different patterns is not known for certain but is most commonly attributed to different crystal orientation in the enamel.[36]
## Tooth whitening
Tooth whitening or tooth bleaching are procedures that attempt to lighten a tooth's color in either of two ways: by chemical or mechanical action.[37]
Working chemically, a bleaching agent is used to carry out an oxidation reaction in the enamel and dentin.[38] The agents most commonly used to intrinsically change the color of teeth are hydrogen peroxide and carbamide peroxide.[39] A tooth whitening product with an overall low pH can put enamel at risk for decay or destruction by demineralization. Consequently, care should be taken and risk evaluated when choosing a product which is very acidic.[40]
Tooth whiteners in toothpastes work through a mechanical action. They have mild abrasives which aid in the removal of stains on enamel. Although this can be an effective method, it does not alter the intrinsic color of teeth.[37]
Microabrasion techniques employ both methods. An acid is used first to weaken the outer 22–27 micrometers of enamel in order to weaken it enough for the subsequent abrasive force.[41] This allows for removal of superficial stains in the enamel. If the discoloration is deeper or in the dentin, this method of tooth whitening will not be successful.
# Systemic conditions affecting enamel
There are many different types of Amelogenesis imperfecta. The hypocalcification type, which is the most common, is an autosomal dominant condition that results in enamel that is not completely mineralized.[42] Consequently, enamel easily flakes off the teeth, which appear yellow because of the revealed dentin. The hypoplastic type is X-linked and results in normal enamel that appears in too little quantity, having the same effect as the most common type.[42]
Chronic bilirubin encephalopathy, which can result from erythroblastosis fetalis, is a disease which has numerous effects on an infant, but it can also cause enamel hypoplasia and green staining of enamel.[43]
Enamel hypoplasia is broadly defined to encompass all deviations from normal enamel in its various degrees of absence.[44] The missing enamel could be localized, forming a small pit, or it could be completely absent.
Erythropoietic porphyria is a genetic disease resulting in the deposition of porphyrins throughout the body. These deposits also occur in enamel and leave an appearance described as red in color and fluorescent.[45]
Fluorosis leads to mottled enamel and occurs from overexposure to fluoride.[23]
Tetracycline staining leads to brown bands on the areas of developing enamel. Children up to age 8 can develop mottled enamel from taking tetracylicne. As a result, tetracycline is contraindicated in pregnant women.
Celiac disease, an auto-immune disorder triggered by gluten allergies, also commonly results in demineralization of the enamel. | https://www.wikidoc.org/index.php/Dental_enamel | |
4001683981302f4c4db7d680964bb7bb1821d64c | wikidoc | Dental floss | Dental floss
# Overview
Dental floss is either a bundle of thin nylon filaments or a plastic (teflon or polyethylene) ribbon used to remove food and dental plaque from teeth. The floss is gently inserted between the teeth and scraped along the teeth sides, especially close to the gums. Dental floss may be flavored or unflavored, and waxed or unwaxed.
# History
Levi Spear Parmly, a dentist from New Orleans, is credited with inventing the first form of dental floss. He had been recommending that people should clean their teeth with silk floss since 1815.
Dental floss was still unavailable to the consumer until the Codman and Shurtleft company started producing human-usable unwaxed silk floss in 1882. In 1898, the Johnson & Johnson Corporation received the first patent for dental floss. Other early brands included Red Cross, Salter Sill Co. and Brunswick.
A character is depicted using dental floss in James Joyce's famous novel
Ulysses (serialised 1918-1920) - an early mention of the practice in literary fiction.
The adoption of floss was poor before World War II. It was around this time, however, that Dr. Charles C. Bass developed nylon floss. Nylon floss was found to be better than silk because of its greater abrasion resistance and elasticity.
Dentists and dental hygienists urge the daily oral hygiene regimen of toothbrushing and flossing. Nearly all Americans brush their teeth. However, the ADA indicates that only about 12 percent of Americans floss daily, 39 percent floss less than daily, and 49 percent do not floss at all.
# Use
Dental floss is commonly supplied in plastic dispensers that contain 10 to 50 meters of floss. After pulling out the desired amount, the floss is pulled against a small protected blade in the dispenser to sever it.
The dental floss is held between the fingers. It can be difficult to grasp floss due to the tension required to push between certain teeth, and reducing friction as the fingers and floss become wet from saliva. To keep a hold, the floss can be wrapped around one or both fingers. Doing this on or above the first joint allows that finger to be used in conjunction with the thumb in a traditional pinch grip, to reduce excessive tension on the skin. Wrapping dental floss too tight as a tourniquet reduces circulation. So it is wise to loosen the wraparound when alternating to a fresh segment of floss. An alternative way to make the floss easier to handle is to make a loop and tie the ends together using a couple of knots. The resulting ring is easy to handle even in wet conditions and does not put as much tension on the skin as when wrapping it around the fingers. By rotating the loop, a clean section of floss can be used to clean each tooth to avoid transmitting plaque bacteria from one tooth to another.
Specialized plastic wands have been produced to hold the floss. These may be attached to or separate from a floss dispenser. While not pinching the finger, using a wand may be awkward and also make it difficult to floss at all the angles possible with a finger. At the same time, the enhanced reach can make flossing the back teeth easier, which are generally the more neglected teeth in dental care.
The floss is gently slid between the teeth. Dental floss is used to clear both particles of food stuck between teeth and dent-bacterial plaque adhered to such teeth surfaces. Ideally using a C-shape, when the floss is curved around a tooth and then moved away from the gumline, the floss scrapes the side of each tooth, and can also clean the front or back of the tooth. Gently moving the floss from below the gumline to away from the gumline removes dento-bacterial plaque attached to teeth surfaces above and below the gumline.
Occasional flossing and/or improper flossing can typically lead to bleeding gums. The main cause of the bleeding is inflammation of the gingival tissue due to gingivitis.
# Directions
The American Dental Association (ADA) advises to floss once or more per day. It should be noted that gental or incorrect flossing can result in tooth decay. For proper flossing, the Association advises to curve the floss against the side of the tooth in a 'C' shape, and then to wipe the tooth from under the gumline (very roughly, the more blood the better) to the tip two or three times, repeated on adjacent tooth and on all other teeth too.
Dental floss does not clean the interproximal areas beneath the contact point, because the area is concave.
For best results, use mouthwash as soon as gums bleed.
# Vibration
Some power flossers utilize vibration which transfers through the floss, originating from the ends. This is likely inspired by the similar use of vibration of the bristles in modern electric toothbrushes. As the vibration causes subtle movement, the floss will find the path of least resistance when pressed down. The movement would also help in temporarily separating tooth and gum for floss to get through.
This allows easier penetration under the gumline, with less force applied to push into the gap between teeth. With less force applied, more control of flossing is possible. In normal flossing, sure may be applied until the floss 'pops' through the teeth, and the momentum can carry on and painfully impact the gum tissue. With more control, this can be reduced or avoided totally.
Many consider vibrations to be soothing; it is a common technique in massage and orthopedic devices. Much like electric toothbrushes are soothing to the teeth and gums, vibrating floss can sooth and massage the gumline.
Cuts become less likely as the floss will not press against as isolated an area, and more pressure is applied. Any abrasions to the gum would be more evenly distributed, leading to more equal adaptation of the tissue.
# Benefits
Flossing in combination with toothbrushing can prevent gum disease, halitosis, and dental caries. | Dental floss
# Overview
Dental floss is either a bundle of thin nylon filaments or a plastic (teflon or polyethylene) ribbon used to remove food and dental plaque from teeth. The floss is gently inserted between the teeth and scraped along the teeth sides, especially close to the gums. Dental floss may be flavored or unflavored, and waxed or unwaxed.
# History
Levi Spear Parmly, a dentist from New Orleans, is credited with inventing the first form of dental floss. He had been recommending that people should clean their teeth with silk floss since 1815.[1]
Dental floss was still unavailable to the consumer until the Codman and Shurtleft company started producing human-usable unwaxed silk floss in 1882. In 1898, the Johnson & Johnson Corporation received the first patent for dental floss. Other early brands included Red Cross, Salter Sill Co. and Brunswick.
A character is depicted using dental floss in James Joyce's famous novel
Ulysses (serialised 1918-1920) - an early mention of the practice in literary fiction.
The adoption of floss was poor before World War II. It was around this time, however, that Dr. Charles C. Bass developed nylon floss. Nylon floss was found to be better than silk because of its greater abrasion resistance and elasticity.
Dentists and dental hygienists urge the daily oral hygiene regimen of toothbrushing and flossing. Nearly all Americans brush their teeth. However, the ADA indicates that only about 12 percent of Americans floss daily, 39 percent floss less than daily, and 49 percent do not floss at all.
# Use
Dental floss is commonly supplied in plastic dispensers that contain 10 to 50 meters of floss. After pulling out the desired amount, the floss is pulled against a small protected blade in the dispenser to sever it.
The dental floss is held between the fingers. It can be difficult to grasp floss due to the tension required to push between certain teeth, and reducing friction as the fingers and floss become wet from saliva. To keep a hold, the floss can be wrapped around one or both fingers. Doing this on or above the first joint allows that finger to be used in conjunction with the thumb in a traditional pinch grip, to reduce excessive tension on the skin. Wrapping dental floss too tight as a tourniquet reduces circulation. So it is wise to loosen the wraparound when alternating to a fresh segment of floss. An alternative way to make the floss easier to handle is to make a loop and tie the ends together using a couple of knots. The resulting ring is easy to handle even in wet conditions and does not put as much tension on the skin as when wrapping it around the fingers. By rotating the loop, a clean section of floss can be used to clean each tooth to avoid transmitting plaque bacteria from one tooth to another.
Specialized plastic wands have been produced to hold the floss. These may be attached to or separate from a floss dispenser. While not pinching the finger, using a wand may be awkward and also make it difficult to floss at all the angles possible with a finger. At the same time, the enhanced reach can make flossing the back teeth easier, which are generally the more neglected teeth in dental care.
The floss is gently slid between the teeth. Dental floss is used to clear both particles of food stuck between teeth and dent-bacterial plaque adhered to such teeth surfaces. Ideally using a C-shape, when the floss is curved around a tooth and then moved away from the gumline, the floss scrapes the side of each tooth, and can also clean the front or back of the tooth. Gently moving the floss from below the gumline to away from the gumline removes dento-bacterial plaque attached to teeth surfaces above and below the gumline.
Occasional flossing and/or improper flossing can typically lead to bleeding gums. The main cause of the bleeding is inflammation of the gingival tissue due to gingivitis.
# Directions
The American Dental Association (ADA) advises to floss once or more per day. It should be noted that gental or incorrect flossing can result in tooth decay. For proper flossing, the Association advises to curve the floss against the side of the tooth in a 'C' shape, and then to wipe the tooth from under the gumline (very roughly, the more blood the better) to the tip two or three times, repeated on adjacent tooth and on all other teeth too.
Dental floss does not clean the interproximal areas beneath the contact point, because the area is concave.
For best results, use mouthwash as soon as gums bleed.
# Vibration
Some power flossers utilize vibration which transfers through the floss, originating from the ends. This is likely inspired by the similar use of vibration of the bristles in modern electric toothbrushes. As the vibration causes subtle movement, the floss will find the path of least resistance when pressed down. The movement would also help in temporarily separating tooth and gum for floss to get through.
This allows easier penetration under the gumline, with less force applied to push into the gap between teeth. With less force applied, more control of flossing is possible. In normal flossing, sure may be applied until the floss 'pops' through the teeth, and the momentum can carry on and painfully impact the gum tissue. With more control, this can be reduced or avoided totally.
Many consider vibrations to be soothing; it is a common technique in massage and orthopedic devices. Much like electric toothbrushes are soothing to the teeth and gums, vibrating floss can sooth and massage the gumline.
Cuts become less likely as the floss will not press against as isolated an area, and more pressure is applied. Any abrasions to the gum would be more evenly distributed, leading to more equal adaptation of the tissue.
# Benefits
Flossing in combination with toothbrushing can prevent gum disease, halitosis, and dental caries.[2] | https://www.wikidoc.org/index.php/Dental_floss | |
aed429e664c808a2b94e128c325fbae5fa81e24c | wikidoc | Oral hygiene | Oral hygiene
# Overview
Oral hygiene is the practice of keeping the mouth and teeth clean in order to prevent dental problems and bad breath.
# Teeth cleaning
Teeth cleaning is the removal of dental plaque and tartar from teeth in order to prevent cavities, gingivitis, and gum disease. The latter causes at least one-third of adult tooth loss.
Dentists recommend that teeth be cleaned professionally at least twice per year. Professional cleaning includes tooth scaling, tooth polishing, and if too much tartar has built up, debridement. This is usually followed by a fluoride treatment.
However, in between cleanings by a dental hygienist, good oral hygiene is essential for preventing tartar build-up which causes the problems mentioned above. This is done by carefully and frequently brushing with a toothbrush and the use of dental floss, which helps prevent build-up of plaque-producing bacteria on the teeth.
# Gum care
Massaging gums is generally recommended for good oral health.
# Food and drink in relation to oral hygiene
Foods that help muscles and bones also help teeth and gums. Dairy contributes vitamin D, strengthening teeth. Breads and cereals are rich in vitamin B while fruits and vegetables contain vitamin C, both of which contribute to healthy gum tissue.(8) Lean meat, fish, and poultry provide magnesium and zinc for teeth. Some people recommend that teeth be brushed after every meal and at bedtime, and flossed at least once per day, preferably at night before sleep. For some people, flossing might be recommended after every meal.
Some foods may protect against cavities. Milk and cheese appear to be able to raise pH values in the mouth, and so reduce tooth exposure to acid. They are also rich in calcium and phosphate, and may also encourage remineralisation. All foods increase saliva production, and since saliva contains buffer chemicals this helps to stabilise the pH at just above 7 in the mouth. Foods high in fiber may also help to increase the flow of saliva. Unsweetened (sugar free) chewing gum stimulates saliva production, and helps to clean the surface of the tooth.(8)
Sugars are commonly associated with dental cavities. Other carbohydrates, especially cooked starches, e.g. crisps/potato chips, may also damage teeth, although to a much lesser degree. This is because starch is not an ideal food for the bacteria. It has to be converted by enzymes in saliva first.
Sucrose (table sugar) is most commonly associated with cavities, although glucose and maltose seem equally likely to cause cavities. The amount of sugar consumed at any one time is less important than how often food and drinks that contain sugar are consumed. The more frequently sugars are consumed, the greater the time during which the tooth is exposed to low pH levels, at which point demineralisation occurs. It is important therefore to try to encourage infrequent consumption of food and drinks containing sugar so that teeth have a chance to repair themselves. Obviously, limiting sugar-containing foods and drinks to meal times is one way to reduce the incidence of cavities.
Artificially refined sugar is not the only type that can promote dental cavities. There are also sugars found in fresh fruit and fruit juices. These foods (oranges, lemons, limes, apples, etc.) also contain acids which lower the pH level. On the other hand, carbonic acid found in soda water is very weakly acidic (pH 6.1), and not associated with dental cavities (provided the soft drink is sugar free, of course). That said, soft drinks are not as healthy for the teeth as milk, because of their lower pH and calcium. Drinking sugared soft drinks throughout the day raises the risk of dental cavities tremendously.
Another factor which affects the risk of developing cavities is the stickiness of foods. Some foods or sweets may stick to the teeth and so reduce the pH in the mouth for an extended time, particularly if they are sugary. It is important that teeth be cleaned at least twice a day, preferably with a toothbrush and fluoride toothpaste, to remove any food sticking to the teeth. Regular brushing and the use of dental floss also removes the dental plaque coating the tooth surface.
Chewing gum assists oral irrigation between and around the teeth, cleaning and removing particles, but for teeth in poor condition it may damage or remove loose fillings as well.(5)
Smoking and chewing tobacco are both linked with multiple dental hazards. Regular vomiting, as seen in those who practice bulimia, also causes significant damage.
# Other
Mouthwash or mouth rinse improve oral hygiene. Dental gums claim to improve dental health.
Retainers- can be cleaned in mouthwash or denture cleaning fluid. Dental braces may be recommended by a dentist for best oral hygiene and health.
Dentures, retainers, and other appliances must be kept extremely clean. This includes regular brushing and may include soaking them in a cleansing solution. | Oral hygiene
# Overview
Oral hygiene is the practice of keeping the mouth and teeth clean in order to prevent dental problems and bad breath.
# Teeth cleaning
Teeth cleaning is the removal of dental plaque and tartar from teeth in order to prevent cavities, gingivitis, and gum disease. The latter causes at least one-third of adult tooth loss.
Dentists recommend that teeth be cleaned professionally at least twice per year. Professional cleaning includes tooth scaling, tooth polishing, and if too much tartar has built up, debridement. This is usually followed by a fluoride treatment.
However, in between cleanings by a dental hygienist, good oral hygiene is essential for preventing tartar build-up which causes the problems mentioned above. This is done by carefully and frequently brushing with a toothbrush and the use of dental floss, which helps prevent build-up of plaque-producing bacteria on the teeth.[1]
# Gum care
Massaging gums is generally recommended for good oral health.
# Food and drink in relation to oral hygiene
Foods that help muscles and bones also help teeth and gums. Dairy contributes vitamin D, strengthening teeth. Breads and cereals are rich in vitamin B while fruits and vegetables contain vitamin C, both of which contribute to healthy gum tissue.(8) Lean meat, fish, and poultry provide magnesium and zinc for teeth. Some people recommend that teeth be brushed after every meal and at bedtime, and flossed at least once per day, preferably at night before sleep. For some people, flossing might be recommended after every meal.
Some foods may protect against cavities. Milk and cheese appear to be able to raise pH values in the mouth, and so reduce tooth exposure to acid. They are also rich in calcium and phosphate, and may also encourage remineralisation. All foods increase saliva production, and since saliva contains buffer chemicals this helps to stabilise the pH at just above 7 in the mouth. Foods high in fiber may also help to increase the flow of saliva. Unsweetened (sugar free) chewing gum stimulates saliva production, and helps to clean the surface of the tooth.(8)
Sugars are commonly associated with dental cavities. Other carbohydrates, especially cooked starches, e.g. crisps/potato chips, may also damage teeth, although to a much lesser degree. This is because starch is not an ideal food for the bacteria. It has to be converted by enzymes in saliva first.[2]
Sucrose (table sugar) is most commonly associated with cavities, although glucose and maltose seem equally likely to cause cavities. The amount of sugar consumed at any one time is less important than how often food and drinks that contain sugar are consumed. The more frequently sugars are consumed, the greater the time during which the tooth is exposed to low pH levels, at which point demineralisation occurs. It is important therefore to try to encourage infrequent consumption of food and drinks containing sugar so that teeth have a chance to repair themselves. Obviously, limiting sugar-containing foods and drinks to meal times is one way to reduce the incidence of cavities.
Artificially refined sugar is not the only type that can promote dental cavities. There are also sugars found in fresh fruit and fruit juices. These foods (oranges, lemons, limes, apples, etc.) also contain acids which lower the pH level. On the other hand, carbonic acid found in soda water is very weakly acidic (pH 6.1), and not associated with dental cavities (provided the soft drink is sugar free, of course). That said, soft drinks are not as healthy for the teeth as milk, because of their lower pH and calcium. Drinking sugared soft drinks throughout the day raises the risk of dental cavities tremendously.
Another factor which affects the risk of developing cavities is the stickiness of foods. Some foods or sweets may stick to the teeth and so reduce the pH in the mouth for an extended time, particularly if they are sugary. It is important that teeth be cleaned at least twice a day, preferably with a toothbrush and fluoride toothpaste, to remove any food sticking to the teeth. Regular brushing and the use of dental floss also removes the dental plaque coating the tooth surface.
Chewing gum assists oral irrigation between and around the teeth, cleaning and removing particles, but for teeth in poor condition it may damage or remove loose fillings as well.(5)
Smoking and chewing tobacco are both linked with multiple dental hazards. Regular vomiting, as seen in those who practice bulimia, also causes significant damage.
# Other
Mouthwash or mouth rinse improve oral hygiene. Dental gums claim to improve dental health.
Retainers- can be cleaned in mouthwash or denture cleaning fluid.[3] Dental braces may be recommended by a dentist for best oral hygiene and health.
Dentures, retainers, and other appliances must be kept extremely clean. This includes regular brushing and may include soaking them in a cleansing solution.[4] | https://www.wikidoc.org/index.php/Dental_hygiene | |
dec67084acd8f526dc240320b99875a4f097cf54 | wikidoc | Denver Scale | Denver Scale
# Overview
The Denver Developmental Screening Test (DDST), commonly known as the Denver Scale, is a test for screening cognitive and behavioural problems in preschool children. It was developed by William K. Frankenburg and first introduced by him and J.B. Dobbs in 1967. The test is currently marketed by Denver Developmental Materials, Inc., in Denver, Colorado, hence the name.
The scale reflects what percentage of a certain age group is able to perform a certain task. In a test to be administered by a pediatrician or other health or social service professional, a subject's performance against the regular age distribution is noted. Tasks are grouped into four categories (social contact, fine motor skill, language, and gross motor skill) and include items such as smiles spontaneously (performed by 90% of three-month-olds), knocks two building blocks against each other (90% of 13-month-olds), speaks three words other than "mom" and "dad" (90% of 21-month-olds), or hops on one leg (90% of 5-year-olds).
According to a study commissioned by the Public Health Agency of Canada, the DDST is the most widely used test for screening developmental problems in children. While this study acknowledges the test's utility for detecting severe developmental problems, the test has been criticized to be unreliable in predicting less severe or specific problems. The same criticism has been upheld for the currently marketed revised version of the Denver Scale, the Denver-II.. Frankenburg has replied to such criticism by pointing out that the Denver Scale is not a tool of final diagnosis, but a quick method to process large numbers of children in order to identify those that should be further evaluated.
This revised definition of the Denver's function remains commensurate with what screening tests are designed to do: sort those who probably have problems from those who probably don't. Thus standards for screening test construction still apply to the Denver. Although the instrument has proven reliability, it was not constructed on a large, current, nationally representative sample. It has not been studied for validity (given along side diagnostic measures to view their relationship or researched for the kinds of problems it may or may not detect). As a consequence, the measure was not studied by its authors for the most critical attribute of any screen, its accuracy. Studies by other researchers showed it to detect only about 50% of children with disabilities, although its specificity in identifying normally developing children is high (when questionables are grouped with normal scores) and the converse when questionable scores are grouped with abnormal results. Since 1991, researchers have appealed to the author to recall and improve the measure but to no avail. Currently the measure is excluded from lists of recommended tools in several states (e.g., Minnesota Department of Education. For a list of accurate alternatives see The website of the American Academy of Pediatrics' Section on Developmental and Behavioral Pediatrics | Denver Scale
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
The Denver Developmental Screening Test (DDST), commonly known as the Denver Scale, is a test for screening cognitive and behavioural problems in preschool children. It was developed by William K. Frankenburg and first introduced by him and J.B. Dobbs in 1967.[1] The test is currently marketed by Denver Developmental Materials, Inc., in Denver, Colorado, hence the name.
The scale reflects what percentage of a certain age group is able to perform a certain task. In a test to be administered by a pediatrician or other health or social service professional, a subject's performance against the regular age distribution is noted. Tasks are grouped into four categories (social contact, fine motor skill, language, and gross motor skill) and include items such as smiles spontaneously (performed by 90% of three-month-olds), knocks two building blocks against each other (90% of 13-month-olds), speaks three words other than "mom" and "dad" (90% of 21-month-olds), or hops on one leg (90% of 5-year-olds).
According to a study commissioned by the Public Health Agency of Canada, the DDST is the most widely used test for screening developmental problems in children.[2] While this study acknowledges the test's utility for detecting severe developmental problems, the test has been criticized to be unreliable in predicting less severe or specific problems. The same criticism has been upheld for the currently marketed revised version of the Denver Scale, the Denver-II.[3]. Frankenburg has replied to such criticism by pointing out that the Denver Scale is not a tool of final diagnosis, but a quick method to process large numbers of children in order to identify those that should be further evaluated.[4]
This revised definition of the Denver's function remains commensurate with what screening tests are designed to do: sort those who probably have problems from those who probably don't. Thus standards for screening test construction still apply to the Denver. Although the instrument has proven reliability, it was not constructed on a large, current, nationally representative sample. It has not been studied for validity (given along side diagnostic measures to view their relationship or researched for the kinds of problems it may or may not detect). As a consequence, the measure was not studied by its authors for the most critical attribute of any screen, its accuracy. Studies by other researchers showed it to detect only about 50% of children with disabilities, although its specificity in identifying normally developing children is high (when questionables are grouped with normal scores) and the converse when questionable scores are grouped with abnormal results. Since 1991, researchers have appealed to the author to recall and improve the measure but to no avail. Currently the measure is excluded from lists of recommended tools in several states (e.g., Minnesota Department of Education. For a list of accurate alternatives see The website of the American Academy of Pediatrics' Section on Developmental and Behavioral Pediatrics | https://www.wikidoc.org/index.php/Denver_Developmental_Screening_Test | |
680f8e8d2250b9508268f412a1b44aec034060d2 | wikidoc | Depo-Provera | Depo-Provera
Depot medroxyprogesterone acetate (DMPA) is a progestogen-only hormonal contraceptive birth control drug which is injected every 3 months.
Depot medroxyprogesterone acetate (DMPA) is an aqueous suspension for depot injection of the pregnane 17α-hydroxyprogesterone-derivative progestin medroxyprogesterone acetate.
Depo-Provera Contraceptive Injection is the brand name for a 150 mg aqueous suspension of medroxyprogesterone acetate for depot intramuscular injection every 3 months (12–13 weeks) manufactured by Pfizer.
depo-subQ provera 104 is the brand name for a 104 mg aqueous suspension of medroxyprogesterone acetate for depot subcutaneous injection every 3 months (12–14 weeks) manufactured by Pfizer.
depo-subQ provera 104 was approved in the United States by the FDA for contraceptive use on December 17, 2004, and for management of endometriosis-related pain on March 25, 2005.
# Mechanism of action
The mechanism of action of progestogen-only contraceptives depends on the progestogen activity and dose. High-dose progestogen-only contraceptives, such as injectable DMPA, inhibit follicular development and prevent ovulation as their primary mechanism of action.
The progestogen decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.
A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration by changes in the cervical mucus.
Inhibition of ovarian function during DMPA use causes the endometrium to become thin and atrophic. These changes in the endometrium could, theoretically, prevent implantation. However, because DMPA is highly effective in inhibiting ovulation and sperm penetration, the possibility of fertilization is negligible. No available data support prevention of implantation as a mechanism of action of DMPA.
# Effectiveness
The life-table first-year failure rates for 8,183 women using Depo-Provera in seven prospective clinical trials were: 0%, 0%, 0.1%, 0.2%, 0.2%, 0.3%, and 0.7%, with a weighted average of 0.3%.
The Pearl Index first-year failure rates for 2,042 women using depo-subQ 104 in three prospective clinical trials were: 0%, 0%, and 0%, with a weighted average of 0%.
The first-year failure rate for 209 women using Depo-Provera in one retrospective survey was: 2.6%.
- the 1995 National Survey of Family Growth (NSFG) — a retrospective survey based on a woman's recall, during a 90-minute interview, of her month-by-month contraceptive use during the preceding 4 to 5 years
## Perfect use
Trussell's estimated perfect use first-year failure rate for Depo-Provera is the weighted average of failure rates in seven clinical trials: 0.3%.
- considered perfect use because the clinical trials measured efficacy during actual use of Depo-Provera
defined as being no longer than 14 or 15 weeks after an injection (i.e., no more than 1 or 2 weeks late for a next injection)
- defined as being no longer than 14 or 15 weeks after an injection (i.e., no more than 1 or 2 weeks late for a next injection)
## Typical use
Prior to 2004, Trussell's typical use failure rate for Depo-Provera was the same as his perfect use failure rate: 0.3%.
- Depo-Provera estimated typical use first-year failure rate = 0.3% in:
Contraceptive Technology, 16th revised edition (1994)
Contraceptive Technology, 17th revised edition (1998)
adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance
- Contraceptive Technology, 16th revised edition (1994)
- Contraceptive Technology, 17th revised edition (1998)
adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance
- adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance
In 2004, using the 1995 NSFG failure rate, Trussell increased (by 10 times) his typical use failure rate for Depo-Provera from 0.3% to 3%.
- Depo-Provera estimated typical use first-year failure rate = 3% in:
Contraceptive Technology, 18th revised edition (2004)
Contraceptive Technology, 19th revised edition (2007)
- Contraceptive Technology, 18th revised edition (2004)
- Contraceptive Technology, 19th revised edition (2007)
Trussell did not use 1995 NSFG failure rates as typical use failure rates for the other two then newly available long-acting contraceptives, the Norplant implant (2.3%) and the ParaGard copper T 380A IUD (3.7%), which were (as with Depo-Provera) an order of magnitude higher than in clinical trials. Since Norplant and ParaGard allow no scope for user error, their much higher 1995 NSFG failure rates were attributed by Trussell to contraceptive overreporting at the time of a conception leading to a live birth.
# Benefits
Depo-Provera has several advantages:
- Highly effective at preventing pregnancy.
- Injected every 12 weeks. The only continuing action is to book subsequent follow-up injections every twelve weeks, and to monitor side effects to ensure that they do not require medical attention.
- No estrogen. No increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, or myocardial infarction.
- Culturally acceptable. Some cultures believe injections are especially efficacious. Injections also afford privacy because use is not detectable.
- Minimal drug interactions (compared to other hormonal contraceptives).
- Decreased risk of endometrial cancer. Depo-Provera reduces the risk of endometrial cancer by 80%. The reduced risk of endometrial cancer in Depo-Provera users is thought to be due to both the direct anti-proliferative effect of progestogen on the endometrium and the indirect reduction of estrogen levels by suppression of ovarian follicular development.
- Decreased risk of iron deficiency anemia, pelvic inflammatory disease (PID), ectopic pregnancy, and uterine fibroids.
- Decreased symptoms of endometriosis.
- Decreased incidence of primary dysmenorrhea, ovulation pain, and functional ovarian cysts.
- Decreased incidence of seizures in women with epilepsy. Additionally, unlike most other hormonal contraceptives, Depo-Provera's contraceptive effectiveness is not affected by enzyme-inducing antiepileptic drugs.
- Decreased incidence and severity of sickle cell crises in women with sickle-cell disease.
# Pregnancy and breastfeeding
Depo-Provera may be used by breast-feeding mothers. Heavy bleeding is possible if given in the immediate postpartum time and is best delayed until six weeks after birth. It may be used within five days if not breast feeding. While a study showed "no significant difference in birth weights or incidence of birth defects" and "no significant alternation of immunity to infectious disease caused by breast milk containing DMPA", a subgroup of babies whose mothers started Depo-Provera at 2 days postpartum had a 75% higher incidence of doctor visits for infectious diseases during their first year of life.
A larger study with longer follow-up concluded that "use of DMPA during pregnancy or breastfeeding does not adversely affect the long-term growth and development of children". This study also noted that "children with DMPA exposure during pregnancy and lactation had an increased risk of suboptimal growth in height," but that "after adjustment for socioeconomic factors by multiple logistic regression, there was no increased risk of impaired growth among the DMPA-exposed children." The study also noted that effects of DMPA exposure on puberty require further study, as so few children over the age of 10 were observed.
# Disadvantages and side effects
## Warnings and precautions
- Depo-Provera can require up to fourteen days to take effect. This means pregnancy can occur within fourteen days of the first Depo injection.
- Takes seven days to take effect if given after the first four days of the period cycle. Effective immediately if given during the first four days of the period cycle.
- Offers no protection against Sexually transmitted diseases (STDs).
- Depo-Provera can affect menstrual bleeding. After a year of use, 55% of women experience amenorrhoea; after 2 years, the rate rises to 68%. In the first months of use "irregular or unpredictable bleeding or spotting, or rarely, heavy or continuous bleeding" was reported.
- Delayed return of fertility. The average return to fertility is 9 to 10 months after the last injection. By 18 months after the last injection, fertility is the same as that in former users of other contraceptive methods
- Long-term studies of users of Depo-Provera have found slight or no increased overall risk of breast cancer. However, the study population did show a slightly increased risk of breast cancer in recent users (Depo use in the last four years) under age 35, similar to that seen with the use of combined oral contraceptive pills.
- A study of accidental pregnancies among poor women in Thailand found that infants who had been exposed to Depo-Provera during pregnancy had a higher risk of low birth weight and an 80% greater-than-usual chance of dying in the first year of life.
### Black box warning
While it has long been known that Depo-Provera causes bone loss, it has recently been discovered that the osteoporotic effects of the injection grow worse the longer Depo-Provera is administered, may remain long after the injections are stopped, and may be irreversible. For this reason, on November 17 2004 the United States Food and Drug Administration and Pfizer agreed to put a "black box warning" on Depo-Provera's label.
However, the World Health Organization (WHO) advises that the use of Depo-Provera should not be restricted.
It is unclear whether the bone density loss associated with Depo-Provera use is reversible, and if so, how completely. Three studies have suggested that bone loss is reversible after the discontinuation of Depo-Provera, although one notes that bone loss was not reversible in long-term users of Depo-Provera. Other studies have suggested that the effect of Depo-Provera use on post-menopausal bone density is minimal, perhaps because Depo users experience less bone loss at menopause. However, as of 2006, no study has directly examined fracture risk in post-menopausal women who have used Depo-Provera; therefore, the risk is unknown. Pfizer and the FDA recommend that Depo-Provera not be used for longer than 2 years, unless there is no viable alternative method of contraception, due to concerns over bone loss.
## Side effects
In the largest clinical trial of Depo-Provera, the most frequently reported adverse reactions (which may or may not be related to the use of Depo-Provera) were: menstrual irregularities (bleeding or amenorrhea or both), abdominal pain or discomfort, weight changes, headache, asthenia (weakness or fatigue), and nervousness. Other, less frequently reported adverse reactions are listed in the patient and physician label information for Depo-Provera.
## Related studies
- A study of 819 women in one city found an association between using Depo-Provera and higher incidence of chlamydia and gonorrhea. A second prospective study in 948 Kenyan women found that Depo-Provera use was associated with higher rates of chlamydial infection, but lower rates of trichomoniasis and pelvic inflammatory disease, when compared to women using no contraception.
- Primate studies of medroxyprogesterone have suggested that it may increase the risk of transmission of simian immunodeficiency virus (SIV), an animal model of HIV. At least one study in humans has suggested an increased rate of HIV infection in Depo-Provera users, while a number of other studies have found no such association. A large prospective clinical trial addressing the issue of Depo-Provera and HIV susceptibility is currently ongoing.
# Contraindications
The WHO Medical Eligibility Criteria for Contraceptive Use and RCOG Faculty of Family Planning & Reproductive Health Care (FFPRHC) UK Medical Eligibility Criteria for Contraceptive Use list the following as conditions where use of Depo-Provera is not usually recommended or should not be used because of an unacceptable health risk or because it is not indicated:
Conditions where the theoretical or proven risks usually outweigh the advantages of using Depo-Provera:
- Multiple risk factors for arterial cardiovascular disease
- Current deep vein thrombosis (DVT) or pulmonary embolus (PE)
- Migraine headache with aura while using Depo-Provera
- Before evaluation of unexplained vaginal bleeding suspected of being a serious condition
- Past history of breast cancer and no evidence of current disease for 5 years
- Active liver disease: (acute viral hepatitis, severe decompensated cirrhosis, benign or malignant liver tumours)
- Conditions of concern for hypo-estrogenic effects and reduced HDL levels theoretically increasing cardiovascular risk:
Hypertension with vascular disease
Current and history of ischemic heart disease
History of stroke
Diabetes for > 20 years or with nephropathy/retinopathy/neuropathy or vascular disease
- Hypertension with vascular disease
- Current and history of ischemic heart disease
- History of stroke
- Diabetes for > 20 years or with nephropathy/retinopathy/neuropathy or vascular disease
Conditions which represent an unacceptable health risk if Depo-Provera is used:
- Current or recent breast cancer (a hormonally sensitive tumour)
Conditions where use of Depo-Provera is not indicated and should not be initiated:
- Pregnancy
# Other uses
Depo-Provera is also used with male sex offenders as a form of chemical castration as it has the effect of drastically reducing sex drive in males.
# Controversy over Approval of Depo-Provera in the United States
There was a long, controversial history regarding the approval of Depo-Provera by the U.S. Food and Drug Administration. The original manufacturer, Upjohn, applied repeatedly for approval. FDA advisory committees unanimously recommended approval in 1973, 1975 and 1992, as did the FDA's professional medical staff, but the FDA repeatedly denied approval. Ultimately, on October 29 1992, the FDA approved Depo-Provera, which had by then been used by over 30 million women since 1969 and was approved and being used by nearly 9 million women in more than 90 countries, including the United Kingdom, France, Germany, Sweden, Thailand, New Zealand and Indonesia. Points in the controversy included:
- Animal testing for carcinogenicity. Depo-Provera caused breast cancer tumors in dogs. Critics of the study claimed that dogs are more sensitive to artificial progesterone, and that the doses were too high to extrapolate to humans. The FDA pointed out that all substances carcinogenic to humans are carcinogenic to animals as well, and that if a substance is not carcinogenic it does not register as a carcinogen at high doses. Levels of Depo-Provera which caused malignant mammary tumors in dogs were equivalent to 25 times the amount of the normal luteal phase progesterone level for dogs. (Which is lower than the pregnancy level of progesterone for dogs, and is species-specific.)Depo-Provera caused endometrial cancer in monkeys—2 of 12 monkeys tested, the first ever recorded cases of endometrial cancer in rhesus monkeys. However, subsequent studies have shown that in humans, Depo-Provera actually reduces the risk of endometrial cancer by approximately 80%.Speaking in comparative terms regarding animal studies of carcinogenicity for drugs, a member of the FDA's Bureau of Drugs testified at an agency Depo hearing, "...Animal data for this drug is more worrisome than any other drug we know of that is to be given to well people."
- Cervical cancer in Upjohn/NCI studies. Cervical cancer was found to be increased as high as 9-fold in the first human studies recorded by the manufacturer and the National Cancer Institute. However, numerous larger subsequent studies have shown that Depo-Provera use does not increase the risk of cervical cancer.
- Coercion and lack of informed consent. Testing/use of Depo was focused almost exclusively on women in developing countries and poor women of color in the US, raising serious questions about coercion and lack of informed consent, particularly for the illiterate and for the mentally challenged, who in some reported cases were given Depo long-term for reasons of "menstrual hygiene", in spite of the fact that they were not sexually active.
- Atlanta/Grady Study. Upjohn studied the effect of Depo for 11 years in Atlanta, mostly on black women who were receiving public assistance, but did not file any of the required follow-up reports with the FDA. Investigators who eventually visited noted that the studies were disorganized. "They found that data collection was questionable, consent forms and protocol were absent; that those women whose consent had been obtained at all were not told of possible side effects. Women whose known medical conditions indicated that use of Depo would endanger their health were given the shot. Several of the women in the study died; some of cancer, but some for other reasons, such as suicide due to depression. Over half the 13,000 women in the study were lost to followup due to sloppy record keeping." Consequently, no data from this study was usable.
- WHO Review. In 1992, the WHO presented a review of Depo in four developing countries to the FDA. The National Women's Health Network and other women's organizations testified at the hearing that the WHO was not objective, as the WHO had already distributed Depo-Provera in developing countries. Depo was approved for use in US on the basis of the WHO review of previously submitted evidence from countries such as Thailand, evidence which the FDA had deemed insufficient and too poorly designed for assessment of cancer risk at a prior hearing.The Alan Guttmacher Institute has speculated that US approval of Depo may increase its availability and acceptability in developing countries.
## Aftermath
- In 1995, several women's health groups asked the FDA to put a moratorium on Depo-Provera, and to institute standardized informed consent forms.
- In 1994, when Depo was approved in India, India's Economic and Political Weekly reported that "The FDA finally licensed the drug in 1990 in response to concerns about the population explosion in the third world and the reluctance of third world governments to license a drug not licensed in its originating country." Some scientists and women's groups in India continue to oppose Depo-Provera. In 2002, Depo was removed from the family planning protocol in India.
- One in five black teenagers using birth control in the US uses Depo-Provera, a far higher rate of use than for white teenagers. Activists claim this is because black teenagers are disproportionately targeted for the least safe contraceptives.
- The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of Depo in Canada. Since the approval of Depo in Canada in 1997, a $700 million class-action lawsuit has been filed against Pfizer by users of Depo who developed osteoporosis. In response, Pfizer argued that it had met its obligation to disclose and discuss the risks of Depo-Provera with the Canadian medical community.
# Footnotes
- ↑ Glasier, Anna (2006). "Contraception". In DeGroot, Leslie J.; Jameson, J. Larry (eds.). Endocrinology (5th edition ed.). Philadelphia: Elsevier Saunders. pp. pp. 2993-3003. ISBN 0-7216-0376-9.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed. ed.). New York: McGraw-Hill. pp. pp. 1541-1571. ISBN 0-07-142280-3.CS1 maint: Multiple names: authors list (link) CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 3.0 3.1 3.2 Hatcher, Robert A. (2004). "Depo-Provera Injections, Implants, and Progestin-Only Pills (Minipills)". In Hatcher, Robert A.; Trussell, James; Stewart, Felicia H.; Nelson, Anita L.; Cates Jr., Willard; Guest, Felicia; Kowal, Deborah. Contraceptive Technology (18th rev. ed. ed.). New York: Ardent Media. pp. pp. 461-494. ISBN 0-9664902-5-8.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 4.0 4.1 4.2 Speroff, Leon; Darney, Philip D. (2005). "Injectable Contraception". A Clinical Guide for Contraception (4th ed. ed.). Philadelphia: Lippincott Williams & Wilkins. pp. pp. 201-220. ISBN 0-7817-6488-2.CS1 maint: Multiple names: authors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 5.0 5.1 Rivera R, Yacobson I, Grimes D (1999). "The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices". Am J Obstet Gynecol. 181 (5 Pt 1): 1263–9. PMID 10561657.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 6.0 6.1 6.2 6.3 6.4 Trussell, James (2004). "Contraceptive Efficacy". In Hatcher, Robert A.; Trussell, James; Stewart, Felicia H.; Nelson, Anita L.; Cates Jr., Willard; Guest, Felicia; Kowal, Deborah. Contraceptive Technology (18th rev. ed. ed.). New York: Ardent Media. pp. pp. 773-845. ISBN 0-9664902-5-8.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ FDA (2005). "depo-subQ provera 104 Label Information: U.S. Physician Information and Patient Information" (PDF). Retrieved 2007-06-21.
- ↑ Jump up to: 8.0 8.1 Fu H, Darroch JE, Haas T, Ranjit N (1999). "Contraceptive failure rates: new estimates from the 1995 National Survey of Family Growth" (PDF). Fam Plann Perspect. 31 (2): 56–63. PMID 10224543.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 9.0 9.1 Trussell J, Vaughan B (1999). "Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth" (PDF). Fam Plann Perspect. 31 (2): 64–72, 93. PMID 10224544.
- ↑ National Center for Health Statistics (NCHS) (1995). National Survey of Family Growth (NSFG) Cycle 5 Main Study Questionnaire, CAPI Reference Version (PDF). Hyattsville, MD: NCHS.
- ↑ Jump up to: 11.0 11.1 11.2 Trussell J (2004). "Contraceptive failure in the United States". Contraception. 70 (2): 89–96. PMID 15288211.
- ↑ Trussell J, Hatcher RA, Cates W Jr, Stewart FH, Kost K (1990). "A guide to interpreting contraceptive efficacy studies". Obstet Gynecol. 76 (3 Pt 2): 558–67. PMID 2199875.CS1 maint: Multiple names: authors list (link)
- ↑ Trussell, James (1994). "Contraceptive Failure Rates". In Hatcher, Robert A.; Trussell, James; Stewart, Felicia; Stewart, Gary K.; Kowal, Deborah; Guest, Felicia; Cates Jr., Willard; Policar, Michael S. Contraceptive Technology (16th rev. ed. ed.). New York: Irvington Publishers. pp. pp. 637-688. ISBN 0-8290-3171-5.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ Trussell, James (1998). "Contraceptive Efficacy". In Hatcher, Robert A.; Trussell, James; Stewart, Felicia; Cates Jr., Willard; Stewart, Gary K.; Guest, Felicia; Kowal, Deborah. Contraceptive Technology (17th rev. ed. ed.). New York: Ardent Media. pp. pp. 779-844. ISBN 0-9664902-0-7.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ FDA (1998). "Guidance for Industry - Uniform Contraceptive Labeling" (PDF). Retrieved 2007-06-21.
- ↑ Trussell, James (2007). "Contraceptive Efficacy". In Hatcher, Robert A.; Trussell, James; Nelson, Anita L.; Cates Jr., Willard; Stewart, Felicia H.; Kowal, Deborah. Contraceptive Technology (19th rev. ed. ed.). New York: Ardent Media. Retrieved 2007-06-21.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 17.0 17.1 Westhoff C (2003). "Depot-medroxyprogesterone acetate injection (Depo-Provera): a highly effective contraceptive option with proven long-term safety". Contraception. 68 (2): 75–87. PMID 12954518.
- ↑ Mishell Jr., Daniel R. (2004). "Contraception". In Strauss, Jerome F. III; Barbieri, Robert L. (eds.). Yen and Jaffe's Reproductive Endocrinology (5th ed. ed.). Philadelphia: Elsevier Saunders. pp. pp. 899-938. ISBN 0-7216-9546-9.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 19.0 19.1 Kaunitz AM (2001). "Current options for injectable contraception in the United States". Semin Reprod Med. 19 (4): 331–7. PMID 11727175.
- ↑ Jump up to: 20.0 20.1 Bigrigg A, Evans M, Gbolade B, Newton J, Pollard L, Szarewski A, Thomas C, Walling M (1999). "Depo Provera. Position paper on clinical use, effectiveness and side effects". Br J Fam Plann. 25 (2): 69–76. PMID 10454658.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 21.0 21.1 WHO Collaborative Study of Neoplasia and Steroid Contraceptives (1991). "Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer". Int J Cancer. 49 (2): 186–90. PMID 1831802.
- ↑ Santen, Richard J. (2004). "Endocrinology of Breast and Endometrial Cancer". In Strauss, Jerome F. III; Barbieri, Robert L. (eds.). Yen and Jaffe's Reproductive Endocrinology (5th ed. ed.). Philadelphia: Elsevier Saunders. pp. pp. 787-809. ISBN 0-7216-9546-9.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link)
- ↑ O'Brien MD, Guillebaud J (2006). "Contraception for women with epilepsy". Epilepsia. 47 (9): 1419–22. PMID 16981856.
- ↑ Dahlberg K (1982). "Some effects of depo-medroxyprogesterone acetate (DMPA): observations in the nursing infant and in the long-term user". Int J Gynaecol Obstet. 20 (1): 43–8. PMID 6126406.
- ↑ Pardthaisong T, Yenchit C, Gray R (1992). "The long-term growth and development of children exposed to Depo-Provera during pregnancy or lactation". Contraception. 45 (4): 313–24. PMID 1387602.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 26.0 26.1 26.2 Pfizer (2004). "Depo-Provera Contraceptive Injection, US patient labeling" (PDF). Retrieved 2007-02-21. Unknown parameter |month= ignored (help)
- ↑ "Exposure to DMPA in pregnancy may cause low birth weight". Prog Hum Reprod Res (23): 2–3. 1992. PMID 12286194.
- ↑ Jump up to: 28.0 28.1 FDA (2004). "Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection". Retrieved 2006-05-12. Unknown parameter |month= ignored (help)
- ↑ World Health Organization (2005). "Hormonal contraception and bone health". Family Planning. Retrieved 2006-05-12. Unknown parameter |month= ignored (help)
- ↑ Curtis KM, Martins SL (2006). "Progestogen-only contraception and bone mineral density: a systematic review". Contraception. 73 (5): 470–87. PMID 16627031.
- ↑ Cundy T, Cornish J, Evans M, Roberts H, Reid I (1994). "Recovery of bone density in women who stop using medroxyprogesterone acetate". BMJ. 308 (6923): 247–8. PMID 8111260.CS1 maint: Multiple names: authors list (link)
- ↑ Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM (2002). "Injectable hormone contraception and bone density: results from a prospective study". Epidemiology. 13 (5): 581–7. PMID 12192229.CS1 maint: Multiple names: authors list (link)
- ↑ Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM (2005). "Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception". Arch Pediatr Adolesc Med. 159 (2): 139–44. PMID 15699307.CS1 maint: Multiple names: authors list (link)
- ↑ Orr-Walker B, Evans M, Ames R, Clearwater J, Cundy T, Reid I (1998). "The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women". Clin Endocrinol (Oxf). 49 (5): 615–8. PMID 10197077.CS1 maint: Multiple names: authors list (link)
- ↑ Cundy T, Cornish J, Roberts H, Reid I (2002). "Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception". Am J Obstet Gynecol. 186 (5): 978–83. PMID 12015524.CS1 maint: Multiple names: authors list (link)
- ↑ Pfizer (2004). "Depo-Provera Contraceptive Injection, US physician information" (PDF). Retrieved 2007-02-21. Unknown parameter |month= ignored (help)
- ↑ Morrison CS, Bright P, Wong EL, Kwok C, Yacobson I, Gaydos CA, Tucker HT, Blumenthal PD (2004). "Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections". Sex Transm Dis. 31 (9): 561–7. PMID 15480119.CS1 maint: Multiple names: authors list (link)
- ↑ Baeten J, Nyange P, Richardson B, Lavreys L, Chohan B, Martin H, Mandaliya K, Ndinya-Achola J, Bwayo J, Kreiss J (2001). "Hormonal contraception and risk of sexually transmitted disease acquisition: results from a prospective study". Am J Obstet Gynecol. 185 (2): 380–5. PMID 11518896.CS1 maint: Multiple names: authors list (link)
- ↑ Preston A. Marx; et al. (1996). "Progesterone implants enhance SIV vaginal transmission and early virus load". Nature Medicine. 2 (10): 1084–9. doi:10.1038/nm1096-1084. PMID 8837605.CS1 maint: Explicit use of et al. (link)
- ↑ Trunova N; et al. (2006). "Progestin-based contraceptive suppresses cellular immune responses in SHIV-infected rhesus macaques". Virology. 352 (1): 169-77. PMID 16730772.CS1 maint: Explicit use of et al. (link)
- ↑ Martin H, Nyange P, Richardson B, Lavreys L, Mandaliya K, Jackson D, Ndinya-Achola J, Kreiss J (1998). "Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1". J Infect Dis. 178 (4): 1053–9. PMID 9806034.CS1 maint: Multiple names: authors list (link)
- ↑ Bulterys M, Chao A, Habimana P, Dushimimana A, Nawrocki P, Saah A (1994). "Incident HIV-1 infection in a cohort of young women in Butare, Rwanda". AIDS. 8 (11): 1585–91. PMID 7848595.CS1 maint: Multiple names: authors list (link)
- ↑ Kiddugavu M, Makumbi F, Wawer M, Serwadda D, Sewankambo N, Wabwire-Mangen F, Lutalo T, Meehan M, Gray R (2003). "Hormonal contraceptive use and HIV-1 infection in a population-based cohort in Rakai, Uganda". AIDS. 17 (2): 233–40. PMID 12545084.CS1 maint: Multiple names: authors list (link)
- ↑ "Prospective study of hormonal contraception and women's risk of HIV infection in South Africa". Int J Epidemiol. PMID 17175547.
- ↑ Morrison C, Richardson B, Celentano D, Chipato T, Mmiro F, Mugerwa R, Padian N, Rugpao S, Salata R. "Prospective clinical trials designed to assess the use of hormonal contraceptives and risk of HIV acquisition". J Acquir Immune Defic Syndr. 38 Suppl 1: S17–8. PMID 15867602.CS1 maint: Multiple names: authors list (link)
- ↑ WHO (2004). "Progestogen-only contraceptives". Medical Eligibility Criteria for Contraceptive Use (3rd ed. ed.). Geneva: Reproductive Health and Research, WHO. ISBN 92-4-156266-8.CS1 maint: Extra text (link)
- ↑ FFPRHC (2006). "The UK Medical Eligibility Criteria for Contraceptive Use (2005/2006)" (PDF). Retrieved 2007-01-11.
- ↑ Leary, Warren E. (1992). "U.S. Approves Injectable Drug As Birth Control". The New York Times: p. A.1. PMID 11646958. Unknown parameter |month= ignored (help)CS1 maint: Extra text (link)
- ↑ Amy Goodman (1985). "The Case Against Depo-Provera - Problems in the U.S." Multinational Monitor. Volume 6 (Numbers 2 & 3). Unknown parameter |month= ignored (help)
- ↑ "Controversy over Depo-Provera". Wash Drug Device Lett. 9 (1): 2. 1977. PMID 12335988.
- ↑ Thomas D, Ye Z, Ray R (1995). "Cervical carcinoma in situ and use of depot-medroxyprogesterone acetate (DMPA). WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 51 (1): 25–31. PMID 7750280.CS1 maint: Multiple names: authors list (link)
- ↑ "Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous cell cervical cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 45 (4): 299–312. 1992. PMID 1387601.
- ↑ Thomas D, Ray R (1995). "Depot-medroxyprogesterone acetate (DMPA) and risk of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 52 (5): 307–12. PMID 8585888.
- ↑ Shapiro S, Rosenberg L, Hoffman M, Kelly J, Cooper D, Carrara H, Denny L, du Toit G, Allan B, Stander I, Williamson A (2003). "Risk of invasive cancer of the cervix in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen oral contraceptives (South Africa)". Cancer Causes Control. 14 (5): 485–95. PMID 12946044.CS1 maint: Multiple names: authors list (link)
- ↑ Kaunitz A (1996). "Depot medroxyprogesterone acetate contraception and the risk of breast and gynecologic cancer". J Reprod Med. 41 (5 Suppl): 419–27. PMID 8725705.
- ↑ Jump up to: 56.0 56.1 >Karen Hawkins, Jeff Elliott (May 5, 1996). "Seeking Approval". Albion Monitor. Retrieved 2006-11-20.
- ↑ "Sterilization of minors leads to controversy". JOICFP Rev. 2 (4): 77–8. 1973. PMID 12257656.
- ↑ Egan T, Siegert R, Fairley N (1993). "Use of hormonal contraceptives in an institutional setting: reasons for use, consent and safety in women with psychiatric and intellectual disabilities". N Z Med J. 106 (961): 338–41. PMID 8341476.CS1 maint: Multiple names: authors list (link)
- ↑ Singh S (1995). "Adolescent knowledge and use of injectable contraceptives in developing countries". J Adolesc Health. 16 (5): 396–404. PMID 7662691.
- ↑ "Clinicians clash with consumer groups over possible Depo ban". Contracept Technol Update. 16 (1): 11–4. 1995. PMID 12319319.
- ↑ "Contraceptives. Case for public enquiry". Economic and Political Weekly. 29 (15): 825-6. 1994. Popline database document number 096527.
- ↑ Sorojini, NB (2005). "Why women's groups oppose injectable contraceptives". Indian Journal of Medical Ethics. 13 (1). Unknown parameter |month= ignored (help)
- ↑ Moira Brennan (2001). "Dorothy Roberts: What we talk about when we talk about reproductive rights". Ms Magazine. Retrieved 2006-08-22. Unknown parameter |month= ignored (help)
- ↑ Madeline Boscoe (1991). "Canadian Coalition on Depo-Provera letter to The Honorable Benoit Bouchard, National Minister of Health and Welfare". Canadian Women's Health Network. Retrieved 2006-08-22. Unknown parameter |month= ignored (help)
- ↑ "Class action suit filed over birth control drug". CTV.ca. 2005. Retrieved 2006-08-22. Unknown parameter |month= ignored (help) | Depo-Provera
Template:BirthControl infobox
Depot medroxyprogesterone acetate (DMPA) is a progestogen-only hormonal contraceptive birth control drug which is injected every 3 months.
Depot medroxyprogesterone acetate (DMPA) is an aqueous suspension for depot injection of the pregnane 17α-hydroxyprogesterone-derivative progestin medroxyprogesterone acetate.
Depo-Provera Contraceptive Injection is the brand name for a 150 mg aqueous suspension of medroxyprogesterone acetate for depot intramuscular injection every 3 months (12–13 weeks) manufactured by Pfizer.
depo-subQ provera 104 is the brand name for a 104 mg aqueous suspension of medroxyprogesterone acetate for depot subcutaneous injection every 3 months (12–14 weeks) manufactured by Pfizer.
depo-subQ provera 104 was approved in the United States by the FDA for contraceptive use on December 17, 2004, and for management of endometriosis-related pain on March 25, 2005.
# Mechanism of action
The mechanism of action of progestogen-only contraceptives depends on the progestogen activity and dose. High-dose progestogen-only contraceptives, such as injectable DMPA, inhibit follicular development and prevent ovulation as their primary mechanism of action.[1][2]
The progestogen decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.[3][4]
A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration by changes in the cervical mucus.[5]
Inhibition of ovarian function during DMPA use causes the endometrium to become thin and atrophic. These changes in the endometrium could, theoretically, prevent implantation. However, because DMPA is highly effective in inhibiting ovulation and sperm penetration, the possibility of fertilization is negligible. No available data support prevention of implantation as a mechanism of action of DMPA.[5]
# Effectiveness
The life-table first-year failure rates for 8,183 women using Depo-Provera in seven prospective clinical trials were: 0%, 0%, 0.1%, 0.2%, 0.2%, 0.3%, and 0.7%, with a weighted average of 0.3%.[6]
The Pearl Index first-year failure rates for 2,042 women using depo-subQ 104 in three prospective clinical trials were: 0%, 0%, and 0%, with a weighted average of 0%.[7]
The first-year failure rate for 209 women using Depo-Provera in one retrospective survey was: 2.6%.[8][9]
- the 1995 National Survey of Family Growth (NSFG) — a retrospective survey based on a woman's recall, during a 90-minute interview, of her month-by-month contraceptive use during the preceding 4 to 5 years[8][10]
## Perfect use
Trussell's estimated perfect use first-year failure rate for Depo-Provera is the weighted average of failure rates in seven clinical trials: 0.3%.[6][11]
- considered perfect use because the clinical trials measured efficacy during actual use of Depo-Provera
defined as being no longer than 14 or 15 weeks after an injection (i.e., no more than 1 or 2 weeks late for a next injection)
- defined as being no longer than 14 or 15 weeks after an injection (i.e., no more than 1 or 2 weeks late for a next injection)
## Typical use
Prior to 2004, Trussell's typical use failure rate for Depo-Provera was the same as his perfect use failure rate: 0.3%.[12]
- Depo-Provera estimated typical use first-year failure rate = 0.3% in:
Contraceptive Technology, 16th revised edition (1994)[13]
Contraceptive Technology, 17th revised edition (1998)[14]
adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance[15]
- Contraceptive Technology, 16th revised edition (1994)[13]
- Contraceptive Technology, 17th revised edition (1998)[14]
adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance[15]
- adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance[15]
In 2004, using the 1995 NSFG failure rate, Trussell increased (by 10 times) his typical use failure rate for Depo-Provera from 0.3% to 3%.[6][11]
- Depo-Provera estimated typical use first-year failure rate = 3% in:
Contraceptive Technology, 18th revised edition (2004)[6]
Contraceptive Technology, 19th revised edition (2007)[16]
- Contraceptive Technology, 18th revised edition (2004)[6]
- Contraceptive Technology, 19th revised edition (2007)[16]
Trussell did not use 1995 NSFG failure rates as typical use failure rates for the other two then newly available long-acting contraceptives, the Norplant implant (2.3%) and the ParaGard copper T 380A IUD (3.7%), which were (as with Depo-Provera) an order of magnitude higher than in clinical trials. Since Norplant and ParaGard allow no scope for user error, their much higher 1995 NSFG failure rates were attributed by Trussell to contraceptive overreporting at the time of a conception leading to a live birth.[6][9][11]
# Benefits
Depo-Provera has several advantages:[3][4][17][18]
- Highly effective at preventing pregnancy.
- Injected every 12 weeks. The only continuing action is to book subsequent follow-up injections every twelve weeks, and to monitor side effects to ensure that they do not require medical attention.
- No estrogen. No increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, or myocardial infarction.
- Culturally acceptable. Some cultures believe injections are especially efficacious. Injections also afford privacy because use is not detectable.
- Minimal drug interactions (compared to other hormonal contraceptives).
- Decreased risk of endometrial cancer. Depo-Provera reduces the risk of endometrial cancer by 80%.[19][20][21] The reduced risk of endometrial cancer in Depo-Provera users is thought to be due to both the direct anti-proliferative effect of progestogen on the endometrium and the indirect reduction of estrogen levels by suppression of ovarian follicular development.[22]
- Decreased risk of iron deficiency anemia, pelvic inflammatory disease (PID), ectopic pregnancy, and uterine fibroids.
- Decreased symptoms of endometriosis.
- Decreased incidence of primary dysmenorrhea, ovulation pain, and functional ovarian cysts.
- Decreased incidence of seizures in women with epilepsy. Additionally, unlike most other hormonal contraceptives, Depo-Provera's contraceptive effectiveness is not affected by enzyme-inducing antiepileptic drugs.[23]
- Decreased incidence and severity of sickle cell crises in women with sickle-cell disease.[17]
# Pregnancy and breastfeeding
Depo-Provera may be used by breast-feeding mothers. Heavy bleeding is possible if given in the immediate postpartum time and is best delayed until six weeks after birth. It may be used within five days if not breast feeding. While a study showed "no significant difference in birth weights or incidence of birth defects" and "no significant alternation of immunity to infectious disease caused by breast milk containing DMPA", a subgroup of babies whose mothers started Depo-Provera at 2 days postpartum had a 75% higher incidence of doctor visits for infectious diseases during their first year of life.[24]
A larger study with longer follow-up concluded that "use of DMPA during pregnancy or breastfeeding does not adversely affect the long-term growth and development of children". This study also noted that "children with DMPA exposure during pregnancy and lactation had an increased risk of suboptimal growth in height," but that "after adjustment for socioeconomic factors by multiple logistic regression, there was no increased risk of impaired growth among the DMPA-exposed children." The study also noted that effects of DMPA exposure on puberty require further study, as so few children over the age of 10 were observed.[25]
# Disadvantages and side effects
## Warnings and precautions
- Depo-Provera can require up to fourteen days to take effect. This means pregnancy can occur within fourteen days of the first Depo injection.
- Takes seven days to take effect if given after the first four days of the period cycle. Effective immediately if given during the first four days of the period cycle.
- Offers no protection against Sexually transmitted diseases (STDs).
- Depo-Provera can affect menstrual bleeding. After a year of use, 55% of women experience amenorrhoea; after 2 years, the rate rises to 68%. In the first months of use "irregular or unpredictable bleeding or spotting, or rarely, heavy or continuous bleeding" was reported.[26]
- Delayed return of fertility. The average return to fertility is 9 to 10 months after the last injection. By 18 months after the last injection, fertility is the same as that in former users of other contraceptive methods[3][4]
- Long-term studies of users of Depo-Provera have found slight or no increased overall risk of breast cancer. However, the study population did show a slightly increased risk of breast cancer in recent users (Depo use in the last four years) under age 35, similar to that seen with the use of combined oral contraceptive pills.[26]
- A study of accidental pregnancies among poor women in Thailand found that infants who had been exposed to Depo-Provera during pregnancy had a higher risk of low birth weight and an 80% greater-than-usual chance of dying in the first year of life.[27]
### Black box warning
While it has long been known that Depo-Provera causes bone loss, it has recently been discovered that the osteoporotic effects of the injection grow worse the longer Depo-Provera is administered, may remain long after the injections are stopped, and may be irreversible. For this reason, on November 17 2004 the United States Food and Drug Administration and Pfizer agreed to put a "black box warning" on Depo-Provera's label.[28]
However, the World Health Organization (WHO) advises that the use of Depo-Provera should not be restricted.[29][30]
It is unclear whether the bone density loss associated with Depo-Provera use is reversible, and if so, how completely. Three studies have suggested that bone loss is reversible after the discontinuation of Depo-Provera, although one notes that bone loss was not reversible in long-term users of Depo-Provera.[31][32][33] Other studies have suggested that the effect of Depo-Provera use on post-menopausal bone density is minimal,[34] perhaps because Depo users experience less bone loss at menopause.[35] However, as of 2006, no study has directly examined fracture risk in post-menopausal women who have used Depo-Provera; therefore, the risk is unknown. Pfizer and the FDA recommend that Depo-Provera not be used for longer than 2 years, unless there is no viable alternative method of contraception, due to concerns over bone loss.[28]
## Side effects
In the largest clinical trial of Depo-Provera, the most frequently reported adverse reactions (which may or may not be related to the use of Depo-Provera) were: menstrual irregularities (bleeding or amenorrhea or both), abdominal pain or discomfort, weight changes, headache, asthenia (weakness or fatigue), and nervousness. Other, less frequently reported adverse reactions are listed in the patient and physician label information for Depo-Provera.[26][36]
## Related studies
- A study of 819 women in one city found an association between using Depo-Provera and higher incidence of chlamydia and gonorrhea.[37] A second prospective study in 948 Kenyan women found that Depo-Provera use was associated with higher rates of chlamydial infection, but lower rates of trichomoniasis and pelvic inflammatory disease, when compared to women using no contraception.[38]
- Primate studies of medroxyprogesterone have suggested that it may increase the risk of transmission of simian immunodeficiency virus (SIV), an animal model of HIV.[39][40] At least one study in humans has suggested an increased rate of HIV infection in Depo-Provera users,[41] while a number of other studies have found no such association.[42][43][44] A large prospective clinical trial addressing the issue of Depo-Provera and HIV susceptibility is currently ongoing.[45]
# Contraindications
The WHO Medical Eligibility Criteria for Contraceptive Use and RCOG Faculty of Family Planning & Reproductive Health Care (FFPRHC) UK Medical Eligibility Criteria for Contraceptive Use list the following as conditions where use of Depo-Provera is not usually recommended or should not be used because of an unacceptable health risk or because it is not indicated:[46][47]
Conditions where the theoretical or proven risks usually outweigh the advantages of using Depo-Provera:
- Multiple risk factors for arterial cardiovascular disease
- Current deep vein thrombosis (DVT) or pulmonary embolus (PE)
- Migraine headache with aura while using Depo-Provera
- Before evaluation of unexplained vaginal bleeding suspected of being a serious condition
- Past history of breast cancer and no evidence of current disease for 5 years
- Active liver disease: (acute viral hepatitis, severe decompensated cirrhosis, benign or malignant liver tumours)
- Conditions of concern for hypo-estrogenic effects and reduced HDL levels theoretically increasing cardiovascular risk:
Hypertension with vascular disease
Current and history of ischemic heart disease
History of stroke
Diabetes for > 20 years or with nephropathy/retinopathy/neuropathy or vascular disease
- Hypertension with vascular disease
- Current and history of ischemic heart disease
- History of stroke
- Diabetes for > 20 years or with nephropathy/retinopathy/neuropathy or vascular disease
Conditions which represent an unacceptable health risk if Depo-Provera is used:
- Current or recent breast cancer (a hormonally sensitive tumour)
Conditions where use of Depo-Provera is not indicated and should not be initiated:
- Pregnancy
# Other uses
Depo-Provera is also used with male sex offenders as a form of chemical castration as it has the effect of drastically reducing sex drive in males.[1]
# Controversy over Approval of Depo-Provera in the United States
There was a long, controversial history regarding the approval of Depo-Provera by the U.S. Food and Drug Administration. The original manufacturer, Upjohn, applied repeatedly for approval. FDA advisory committees unanimously recommended approval in 1973, 1975 and 1992, as did the FDA's professional medical staff, but the FDA repeatedly denied approval. Ultimately, on October 29 1992, the FDA approved Depo-Provera, which had by then been used by over 30 million women since 1969 and was approved and being used by nearly 9 million women in more than 90 countries, including the United Kingdom, France, Germany, Sweden, Thailand, New Zealand and Indonesia.[48] Points in the controversy included:
- Animal testing for carcinogenicity. Depo-Provera caused breast cancer tumors in dogs. Critics of the study claimed that dogs are more sensitive to artificial progesterone, and that the doses were too high to extrapolate to humans. The FDA pointed out that all substances carcinogenic to humans are carcinogenic to animals as well, and that if a substance is not carcinogenic it does not register as a carcinogen at high doses. Levels of Depo-Provera which caused malignant mammary tumors in dogs were equivalent to 25 times the amount of the normal luteal phase progesterone level for dogs. (Which is lower than the pregnancy level of progesterone for dogs, and is species-specific.)[2]Depo-Provera caused endometrial cancer in monkeys—2 of 12 monkeys tested, the first ever recorded cases of endometrial cancer in rhesus monkeys.[49] However, subsequent studies have shown that in humans, Depo-Provera actually reduces the risk of endometrial cancer by approximately 80%.[19][20][21]Speaking in comparative terms regarding animal studies of carcinogenicity for drugs, a member of the FDA's Bureau of Drugs testified at an agency Depo hearing, "...Animal data for this drug is more worrisome than any other drug we know of that is to be given to well people."
- Cervical cancer in Upjohn/NCI studies. Cervical cancer was found to be increased as high as 9-fold in the first human studies recorded by the manufacturer and the National Cancer Institute.[50] However, numerous larger subsequent studies have shown that Depo-Provera use does not increase the risk of cervical cancer.[51][52][53][54][55]
- Coercion and lack of informed consent. Testing/use of Depo was focused almost exclusively on women in developing countries and poor women of color in the US,[56] raising serious questions about coercion and lack of informed consent, particularly for the illiterate[57] and for the mentally challenged, who in some reported cases were given Depo long-term for reasons of "menstrual hygiene", in spite of the fact that they were not sexually active.[58]
- Atlanta/Grady Study. Upjohn studied the effect of Depo for 11 years in Atlanta, mostly on black women who were receiving public assistance, but did not file any of the required follow-up reports with the FDA. Investigators who eventually visited noted that the studies were disorganized. "They found that data collection was questionable, consent forms and protocol were absent; that those women whose consent had been obtained at all were not told of possible side effects. Women whose known medical conditions indicated that use of Depo would endanger their health were given the shot. Several of the women in the study died; some of cancer, but some for other reasons, such as suicide due to depression. Over half the 13,000 women in the study were lost to followup due to sloppy record keeping." Consequently, no data from this study was usable.[56]
- WHO Review. In 1992, the WHO presented a review of Depo in four developing countries to the FDA. The National Women's Health Network and other women's organizations testified at the hearing that the WHO was not objective, as the WHO had already distributed Depo-Provera in developing countries. Depo was approved for use in US on the basis of the WHO review of previously submitted evidence from countries such as Thailand, evidence which the FDA had deemed insufficient and too poorly designed for assessment of cancer risk at a prior hearing.[3]The Alan Guttmacher Institute has speculated that US approval of Depo may increase its availability and acceptability in developing countries.[4][59]
## Aftermath
- In 1995, several women's health groups asked the FDA to put a moratorium on Depo-Provera, and to institute standardized informed consent forms.[60]
- In 1994, when Depo was approved in India, India's Economic and Political Weekly reported that "The FDA finally licensed the drug in 1990 in response to concerns about the population explosion in the third world and the reluctance of third world governments to license a drug not licensed in its originating country." [61] Some scientists and women's groups in India continue to oppose Depo-Provera.[62] In 2002, Depo was removed from the family planning protocol in India.
- One in five black teenagers using birth control in the US uses Depo-Provera, a far higher rate of use than for white teenagers. Activists claim this is because black teenagers are disproportionately targeted for the least safe contraceptives.[63]
- The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of Depo in Canada.[64] Since the approval of Depo in Canada in 1997, a $700 million class-action lawsuit has been filed against Pfizer by users of Depo who developed osteoporosis. In response, Pfizer argued that it had met its obligation to disclose and discuss the risks of Depo-Provera with the Canadian medical community.[65]
# Footnotes
- ↑ Glasier, Anna (2006). "Contraception". In DeGroot, Leslie J.; Jameson, J. Larry (eds.). Endocrinology (5th edition ed.). Philadelphia: Elsevier Saunders. pp. pp. 2993-3003. ISBN 0-7216-0376-9.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed. ed.). New York: McGraw-Hill. pp. pp. 1541-1571. ISBN 0-07-142280-3.CS1 maint: Multiple names: authors list (link) CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 3.0 3.1 3.2 Hatcher, Robert A. (2004). "Depo-Provera Injections, Implants, and Progestin-Only Pills (Minipills)". In Hatcher, Robert A.; Trussell, James; Stewart, Felicia H.; Nelson, Anita L.; Cates Jr., Willard; Guest, Felicia; Kowal, Deborah. Contraceptive Technology (18th rev. ed. ed.). New York: Ardent Media. pp. pp. 461-494. ISBN 0-9664902-5-8.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 4.0 4.1 4.2 Speroff, Leon; Darney, Philip D. (2005). "Injectable Contraception". A Clinical Guide for Contraception (4th ed. ed.). Philadelphia: Lippincott Williams & Wilkins. pp. pp. 201-220. ISBN 0-7817-6488-2.CS1 maint: Multiple names: authors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 5.0 5.1 Rivera R, Yacobson I, Grimes D (1999). "The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices". Am J Obstet Gynecol. 181 (5 Pt 1): 1263–9. PMID 10561657.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 6.0 6.1 6.2 6.3 6.4 Trussell, James (2004). "Contraceptive Efficacy". In Hatcher, Robert A.; Trussell, James; Stewart, Felicia H.; Nelson, Anita L.; Cates Jr., Willard; Guest, Felicia; Kowal, Deborah. Contraceptive Technology (18th rev. ed. ed.). New York: Ardent Media. pp. pp. 773-845. ISBN 0-9664902-5-8.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ FDA (2005). "depo-subQ provera 104 Label Information: U.S. Physician Information and Patient Information" (PDF). Retrieved 2007-06-21.
- ↑ Jump up to: 8.0 8.1 Fu H, Darroch JE, Haas T, Ranjit N (1999). "Contraceptive failure rates: new estimates from the 1995 National Survey of Family Growth" (PDF). Fam Plann Perspect. 31 (2): 56–63. PMID 10224543.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 9.0 9.1 Trussell J, Vaughan B (1999). "Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth" (PDF). Fam Plann Perspect. 31 (2): 64–72, 93. PMID 10224544.
- ↑ National Center for Health Statistics (NCHS) (1995). National Survey of Family Growth (NSFG) Cycle 5 Main Study Questionnaire, CAPI Reference Version (PDF). Hyattsville, MD: NCHS.
- ↑ Jump up to: 11.0 11.1 11.2 Trussell J (2004). "Contraceptive failure in the United States". Contraception. 70 (2): 89–96. PMID 15288211.
- ↑ Trussell J, Hatcher RA, Cates W Jr, Stewart FH, Kost K (1990). "A guide to interpreting contraceptive efficacy studies". Obstet Gynecol. 76 (3 Pt 2): 558–67. PMID 2199875.CS1 maint: Multiple names: authors list (link)
- ↑ Trussell, James (1994). "Contraceptive Failure Rates". In Hatcher, Robert A.; Trussell, James; Stewart, Felicia; Stewart, Gary K.; Kowal, Deborah; Guest, Felicia; Cates Jr., Willard; Policar, Michael S. Contraceptive Technology (16th rev. ed. ed.). New York: Irvington Publishers. pp. pp. 637-688. ISBN 0-8290-3171-5.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ Trussell, James (1998). "Contraceptive Efficacy". In Hatcher, Robert A.; Trussell, James; Stewart, Felicia; Cates Jr., Willard; Stewart, Gary K.; Guest, Felicia; Kowal, Deborah. Contraceptive Technology (17th rev. ed. ed.). New York: Ardent Media. pp. pp. 779-844. ISBN 0-9664902-0-7.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ FDA (1998). "Guidance for Industry - Uniform Contraceptive Labeling" (PDF). Retrieved 2007-06-21.
- ↑ Trussell, James (2007). "Contraceptive Efficacy". In Hatcher, Robert A.; Trussell, James; Nelson, Anita L.; Cates Jr., Willard; Stewart, Felicia H.; Kowal, Deborah. Contraceptive Technology (19th rev. ed. ed.). New York: Ardent Media. Retrieved 2007-06-21.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 17.0 17.1 Westhoff C (2003). "Depot-medroxyprogesterone acetate injection (Depo-Provera): a highly effective contraceptive option with proven long-term safety". Contraception. 68 (2): 75–87. PMID 12954518.
- ↑ Mishell Jr., Daniel R. (2004). "Contraception". In Strauss, Jerome F. III; Barbieri, Robert L. (eds.). Yen and Jaffe's Reproductive Endocrinology (5th ed. ed.). Philadelphia: Elsevier Saunders. pp. pp. 899-938. ISBN 0-7216-9546-9.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 19.0 19.1 Kaunitz AM (2001). "Current options for injectable contraception in the United States". Semin Reprod Med. 19 (4): 331–7. PMID 11727175.
- ↑ Jump up to: 20.0 20.1 Bigrigg A, Evans M, Gbolade B, Newton J, Pollard L, Szarewski A, Thomas C, Walling M (1999). "Depo Provera. Position paper on clinical use, effectiveness and side effects". Br J Fam Plann. 25 (2): 69–76. PMID 10454658.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 21.0 21.1 WHO Collaborative Study of Neoplasia and Steroid Contraceptives (1991). "Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer". Int J Cancer. 49 (2): 186–90. PMID 1831802.
- ↑ Santen, Richard J. (2004). "Endocrinology of Breast and Endometrial Cancer". In Strauss, Jerome F. III; Barbieri, Robert L. (eds.). Yen and Jaffe's Reproductive Endocrinology (5th ed. ed.). Philadelphia: Elsevier Saunders. pp. pp. 787-809. ISBN 0-7216-9546-9.CS1 maint: Multiple names: editors list (link) CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link)
- ↑ O'Brien MD, Guillebaud J (2006). "Contraception for women with epilepsy". Epilepsia. 47 (9): 1419–22. PMID 16981856.
- ↑ Dahlberg K (1982). "Some effects of depo-medroxyprogesterone acetate (DMPA): observations in the nursing infant and in the long-term user". Int J Gynaecol Obstet. 20 (1): 43–8. PMID 6126406.
- ↑ Pardthaisong T, Yenchit C, Gray R (1992). "The long-term growth and development of children exposed to Depo-Provera during pregnancy or lactation". Contraception. 45 (4): 313–24. PMID 1387602.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 26.0 26.1 26.2 Pfizer (2004). "Depo-Provera Contraceptive Injection, US patient labeling" (PDF). Retrieved 2007-02-21. Unknown parameter |month= ignored (help)
- ↑ "Exposure to DMPA in pregnancy may cause low birth weight". Prog Hum Reprod Res (23): 2–3. 1992. PMID 12286194.
- ↑ Jump up to: 28.0 28.1 FDA (2004). "Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection". Retrieved 2006-05-12. Unknown parameter |month= ignored (help)
- ↑ World Health Organization (2005). "Hormonal contraception and bone health". Family Planning. Retrieved 2006-05-12. Unknown parameter |month= ignored (help)
- ↑ Curtis KM, Martins SL (2006). "Progestogen-only contraception and bone mineral density: a systematic review". Contraception. 73 (5): 470–87. PMID 16627031.
- ↑ Cundy T, Cornish J, Evans M, Roberts H, Reid I (1994). "Recovery of bone density in women who stop using medroxyprogesterone acetate". BMJ. 308 (6923): 247–8. PMID 8111260.CS1 maint: Multiple names: authors list (link)
- ↑ Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM (2002). "Injectable hormone contraception and bone density: results from a prospective study". Epidemiology. 13 (5): 581–7. PMID 12192229.CS1 maint: Multiple names: authors list (link)
- ↑ Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM (2005). "Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception". Arch Pediatr Adolesc Med. 159 (2): 139–44. PMID 15699307.CS1 maint: Multiple names: authors list (link)
- ↑ Orr-Walker B, Evans M, Ames R, Clearwater J, Cundy T, Reid I (1998). "The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women". Clin Endocrinol (Oxf). 49 (5): 615–8. PMID 10197077.CS1 maint: Multiple names: authors list (link)
- ↑ Cundy T, Cornish J, Roberts H, Reid I (2002). "Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception". Am J Obstet Gynecol. 186 (5): 978–83. PMID 12015524.CS1 maint: Multiple names: authors list (link)
- ↑ Pfizer (2004). "Depo-Provera Contraceptive Injection, US physician information" (PDF). Retrieved 2007-02-21. Unknown parameter |month= ignored (help)
- ↑ Morrison CS, Bright P, Wong EL, Kwok C, Yacobson I, Gaydos CA, Tucker HT, Blumenthal PD (2004). "Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections". Sex Transm Dis. 31 (9): 561–7. PMID 15480119.CS1 maint: Multiple names: authors list (link)
- ↑ Baeten J, Nyange P, Richardson B, Lavreys L, Chohan B, Martin H, Mandaliya K, Ndinya-Achola J, Bwayo J, Kreiss J (2001). "Hormonal contraception and risk of sexually transmitted disease acquisition: results from a prospective study". Am J Obstet Gynecol. 185 (2): 380–5. PMID 11518896.CS1 maint: Multiple names: authors list (link)
- ↑ Preston A. Marx; et al. (1996). "Progesterone implants enhance SIV vaginal transmission and early virus load". Nature Medicine. 2 (10): 1084–9. doi:10.1038/nm1096-1084. PMID 8837605.CS1 maint: Explicit use of et al. (link)
- ↑ Trunova N; et al. (2006). "Progestin-based contraceptive suppresses cellular immune responses in SHIV-infected rhesus macaques". Virology. 352 (1): 169-77. PMID 16730772.CS1 maint: Explicit use of et al. (link)
- ↑ Martin H, Nyange P, Richardson B, Lavreys L, Mandaliya K, Jackson D, Ndinya-Achola J, Kreiss J (1998). "Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1". J Infect Dis. 178 (4): 1053–9. PMID 9806034.CS1 maint: Multiple names: authors list (link)
- ↑ Bulterys M, Chao A, Habimana P, Dushimimana A, Nawrocki P, Saah A (1994). "Incident HIV-1 infection in a cohort of young women in Butare, Rwanda". AIDS. 8 (11): 1585–91. PMID 7848595.CS1 maint: Multiple names: authors list (link)
- ↑ Kiddugavu M, Makumbi F, Wawer M, Serwadda D, Sewankambo N, Wabwire-Mangen F, Lutalo T, Meehan M, Gray R (2003). "Hormonal contraceptive use and HIV-1 infection in a population-based cohort in Rakai, Uganda". AIDS. 17 (2): 233–40. PMID 12545084.CS1 maint: Multiple names: authors list (link)
- ↑ "Prospective study of hormonal contraception and women's risk of HIV infection in South Africa". Int J Epidemiol. PMID 17175547.
- ↑ Morrison C, Richardson B, Celentano D, Chipato T, Mmiro F, Mugerwa R, Padian N, Rugpao S, Salata R. "Prospective clinical trials designed to assess the use of hormonal contraceptives and risk of HIV acquisition". J Acquir Immune Defic Syndr. 38 Suppl 1: S17–8. PMID 15867602.CS1 maint: Multiple names: authors list (link)
- ↑ WHO (2004). "Progestogen-only contraceptives". Medical Eligibility Criteria for Contraceptive Use (3rd ed. ed.). Geneva: Reproductive Health and Research, WHO. ISBN 92-4-156266-8.CS1 maint: Extra text (link)
- ↑ FFPRHC (2006). "The UK Medical Eligibility Criteria for Contraceptive Use (2005/2006)" (PDF). Retrieved 2007-01-11.
- ↑ Leary, Warren E. (1992). "U.S. Approves Injectable Drug As Birth Control". The New York Times: p. A.1. PMID 11646958. Unknown parameter |month= ignored (help)CS1 maint: Extra text (link)
- ↑ Amy Goodman (1985). "The Case Against Depo-Provera - Problems in the U.S." Multinational Monitor. Volume 6 (Numbers 2 & 3). Unknown parameter |month= ignored (help)
- ↑ "Controversy over Depo-Provera". Wash Drug Device Lett. 9 (1): 2. 1977. PMID 12335988.
- ↑ Thomas D, Ye Z, Ray R (1995). "Cervical carcinoma in situ and use of depot-medroxyprogesterone acetate (DMPA). WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 51 (1): 25–31. PMID 7750280.CS1 maint: Multiple names: authors list (link)
- ↑ "Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous cell cervical cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 45 (4): 299–312. 1992. PMID 1387601.
- ↑ Thomas D, Ray R (1995). "Depot-medroxyprogesterone acetate (DMPA) and risk of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 52 (5): 307–12. PMID 8585888.
- ↑ Shapiro S, Rosenberg L, Hoffman M, Kelly J, Cooper D, Carrara H, Denny L, du Toit G, Allan B, Stander I, Williamson A (2003). "Risk of invasive cancer of the cervix in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen oral contraceptives (South Africa)". Cancer Causes Control. 14 (5): 485–95. PMID 12946044.CS1 maint: Multiple names: authors list (link)
- ↑ Kaunitz A (1996). "Depot medroxyprogesterone acetate contraception and the risk of breast and gynecologic cancer". J Reprod Med. 41 (5 Suppl): 419–27. PMID 8725705.
- ↑ Jump up to: 56.0 56.1 >Karen Hawkins, Jeff Elliott (May 5, 1996). "Seeking Approval". Albion Monitor. Retrieved 2006-11-20.
- ↑ "Sterilization of minors leads to controversy". JOICFP Rev. 2 (4): 77–8. 1973. PMID 12257656.
- ↑ Egan T, Siegert R, Fairley N (1993). "Use of hormonal contraceptives in an institutional setting: reasons for use, consent and safety in women with psychiatric and intellectual disabilities". N Z Med J. 106 (961): 338–41. PMID 8341476.CS1 maint: Multiple names: authors list (link)
- ↑ Singh S (1995). "Adolescent knowledge and use of injectable contraceptives in developing countries". J Adolesc Health. 16 (5): 396–404. PMID 7662691.
- ↑ "Clinicians clash with consumer groups over possible Depo ban". Contracept Technol Update. 16 (1): 11–4. 1995. PMID 12319319.
- ↑ "Contraceptives. Case for public enquiry". Economic and Political Weekly. 29 (15): 825-6. 1994. Popline database document number 096527.
- ↑ Sorojini, NB (2005). "Why women's groups oppose injectable contraceptives". Indian Journal of Medical Ethics. 13 (1). Unknown parameter |month= ignored (help)
- ↑ Moira Brennan (2001). "Dorothy Roberts: What we talk about when we talk about reproductive rights". Ms Magazine. Retrieved 2006-08-22. Unknown parameter |month= ignored (help)
- ↑ Madeline Boscoe (1991). "Canadian Coalition on Depo-Provera letter to The Honorable Benoit Bouchard, National Minister of Health and Welfare". Canadian Women's Health Network. Retrieved 2006-08-22. Unknown parameter |month= ignored (help)
- ↑ "Class action suit filed over birth control drug". CTV.ca. 2005. Retrieved 2006-08-22. Unknown parameter |month= ignored (help)
# External links
- Pfizer official site
- Research on Injectable contraceptives - Family Health International's fact sheet on injectables, including Depo-Provera.
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Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Depo-Provera | |
3720dc9c9b723f93a39b00b03dd4233389404c50 | wikidoc | Dermabrasion | Dermabrasion
# Overview
Dermabrasion is a cosmetic medical procedure in which the surface of the epidermis of the skin the stratum corneum is removed by abrasion (sanding).
It is used to remove sun-damaged skin and to remove or lessen scars and dark spots on the skin. The procedure is very painful and usually requires a general anaesthetic or twilight anaesthesia, in which the patient is still partly conscious Afterward, the skin is very red and raw-looking, and it takes several months for the skin to regrow and heal. Dermabrasion is useful for scar removal when the scar is raised above the surrounding skin, but is less effective with sunken scars.
In the past, dermabrasion was done using a small, sterilized, electric sander. In the past decade, it has become more common to use a CO2 or Erbium:YAG laser. Laser dermabrasion is much easier to control, much easier to gauge, and is practically bloodless compared to classic dermabrasion. | Dermabrasion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dermabrasion is a cosmetic medical procedure in which the surface of the epidermis of the skin the stratum corneum is removed by abrasion (sanding).
It is used to remove sun-damaged skin and to remove or lessen scars and dark spots on the skin. The procedure is very painful and usually requires a general anaesthetic or twilight anaesthesia, in which the patient is still partly conscious [1] Afterward, the skin is very red and raw-looking, and it takes several months for the skin to regrow and heal. Dermabrasion is useful for scar removal when the scar is raised above the surrounding skin, but is less effective with sunken scars.
In the past, dermabrasion was done using a small, sterilized, electric sander. In the past decade, it has become more common to use a CO2 or Erbium:YAG laser. Laser dermabrasion is much easier to control, much easier to gauge, and is practically bloodless compared to classic dermabrasion. | https://www.wikidoc.org/index.php/Dermabrasion | |
6f92e520235b0b0e37d42e86c317f2050e437f93 | wikidoc | Erythroderma | Erythroderma
Synonyms and keywords: Dermatitis exfoliativa; exfoliative dermatitis; exfoliative skin disease; exfoliative skin disorder; idiopathic exfoliative dermatitis; generalized exfoliative dermatitis
# Overview
Erythroderma is defined as a generalized skin disorder characterized by reddening and scaling of 100% of the skin. It is also known as erythrodermatitis, generalized exfoliative dermatitis, and red man syndrome. There may also be normal areas of skin present.
# Causes
Erythroderma is produced by several skin diseases, such as psoriasis, contact dermatitis, drug reactions, and mycosis fungoides (a cutaneous lymphoma). A dermatologist must first diagnose the cause, usually with a skin biopsy, a blood smear examined by a pathologist and patch testing (if the eruption can be temporarily cleared).
## Drug Causes
- Amobarbital sodium
- Amoxicillin
- Amifostine
- Aminophylline
- Aminosalicylic acid
- Alitretinoin
- Aztreonam
- Boceprevir
- Chlorpropamide
- Doxycycline
- Dapsone
- Flurbiprofen
- Ibritumomab tiuxetan
- Lincomycin Hydrochloride
- Nizatidine
- Oxaprozin
- Oxytetracycline
- Pembrolizumab
- Piroxicam
- Sodium aurothiomalate
- Sorafenib
- Sulfasalazine
- Sirolimus
- Tiagabine
- Trimethadione
# Treatment
The treatment is dependent on the cause. | Erythroderma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Dermatitis exfoliativa; exfoliative dermatitis; exfoliative skin disease; exfoliative skin disorder; idiopathic exfoliative dermatitis; generalized exfoliative dermatitis
# Overview
Erythroderma is defined as a generalized skin disorder characterized by reddening and scaling of 100% of the skin. It is also known as erythrodermatitis, generalized exfoliative dermatitis, and red man syndrome. There may also be normal areas of skin present.
# Causes
Erythroderma is produced by several skin diseases, such as psoriasis, contact dermatitis, drug reactions, and mycosis fungoides (a cutaneous lymphoma). A dermatologist must first diagnose the cause, usually with a skin biopsy, a blood smear examined by a pathologist and patch testing (if the eruption can be temporarily cleared).
## Drug Causes
- Amobarbital sodium
- Amoxicillin
- Amifostine
- Aminophylline
- Aminosalicylic acid
- Alitretinoin
- Aztreonam
- Boceprevir
- Chlorpropamide
- Doxycycline
- Dapsone
- Flurbiprofen
- Ibritumomab tiuxetan
- Lincomycin Hydrochloride
- Nizatidine
- Oxaprozin
- Oxytetracycline
- Pembrolizumab
- Piroxicam
- Sodium aurothiomalate
- Sorafenib
- Sulfasalazine
- Sirolimus
- Tiagabine
- Trimethadione
# Treatment
The treatment is dependent on the cause.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dermatitis_exfoliativa | |
956290bae1c35424bee59ea87d80e7626cb23d75 | wikidoc | Dermatophyte | Dermatophyte
# Overview
A dermatophyte is a parasitic fungus that infects the skin. The term embraces the imperfect fungi of the genera Epidermophyton, Microsporum and Trichophyton.
Dermatophytes (name based on the Greek for 'skin plants') are a common label for a group of three types of fungus that commonly causes skin disease in animals and humans. These anamorphic (asexual or imperfect) genera are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these three genera. Species capable of reproducing sexually belong in the teleomorphic genus, Arthroderma, of the Ascomycota. (See Teleomorph, anamorph and holomorph for more information on this type of fungal life cycle).
Dermatophytes cause infections of the skin, hair and nails due to their ability to obtain nutrients from keratinized material. The organisms colonize the keratin tissues and inflammation is caused by host response to metabolic by-products. They are usually restricted to the nonliving cornified layer of the epidermis because of their inability to penetrate viable tissue of an immunocompetent host. Invasion does elicit a host response ranging from mild to severe. Acid proteinases, elastase, keratinases, and other proteinases reportedly act as virulence factors. The development of cell-mediated immunity correlated with delayed hypersensitivity and an inflammatory response is associated with clinical cure, whereas the lack of or a defective cell-mediated immunity predisposes the host to chronic or recurrent dermatophyte infection.
Some of these infections are known as ringworm or tinea. Toe- and fingernail infection are referred to as onychomycosis. Dermatophytes usually do not invade living tissues, but colonize the outer layer of the skin. Occasionally the organisms do invade subcutaneous tissues, resulting in kerion development.
# Identification
Microscopic morphology of the micro and macroconidia is the most reliable identification character, but a good slide preparation is needed, and also needed is the stimulation of sporulation in some strains. Culture characteristics such as surface texture, topography and pigmentation are variable so they are the least reliable criteria for identification. Clinical information such as the appearance of the lesion, site, geographic location, travel history, animal contacts and race is also important, especially in identifying rare non-sporulating species like Trichophyton concentricum, Microsporum audouinii and Trichophyton schoenleinii.
# Transmission
Dermatophytes are transmitted by direct contact with infected host (human or animal) or by direct or indirect contact with infected exfoliated skin or hair in clothing, combs, hair brushes, theatre seats, caps, furniture, bed linens, towels, hotel rugs, and locker room floors. Depending on the species the organism may be viable in the environment for up to 15 months. There is an increased susceptibility to infection when there is a preexisting injury to the skin such as scars, burns, excessive temperature and humidity. Adaptation to growth on humans by most geophilic species resulted in diminished loss of sporulation, sexuality, and other soil-associated characteristics.
# Classification
Dermatophytes are classified as anthropophilic (humans), zoophilic (animals) or geophilic (soil) according to their normal habitat.
- Anthropophilic dermatophytes are restricted to human hosts and produce a mild, chronic inflammation.
- Zoophilic organisms are found primarily in animals and cause marked inflammatory reactions in humans who have contact with infected cats, dogs, cattle, horses, birds, or other animals. This is followed by a rapid termination of the infection.
- Geophilic species are usually recovered from the soil but occasionally infect humans and animals. They cause a marked inflammatory reaction, which limits the spread of the infection and may lead to a spontaneous cure but may also leave scars.
# Classification
- About 58% of the dermatophyte species isolated are Trichophyton rubrum
- 27% are T. mentagrophytes
- 7% are T. verrucosum
- 3% are T. tonsurans
- Infrequently isolated (less than 1%) are Epidermophyton floccosum, Microsporum audouinii, M. canis, M. equinum, M. nanum, M. versicolor, Trichophyton equinum, T. kanei, T. raubitschekii, and T. violaceum.
# Medications
- Lamisil
- Tea tree oil | Dermatophyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A dermatophyte is a parasitic fungus that infects the skin. The term embraces the imperfect fungi of the genera Epidermophyton, Microsporum and Trichophyton.
Dermatophytes (name based on the Greek for 'skin plants') are a common label for a group of three types of fungus that commonly causes skin disease in animals and humans. These anamorphic (asexual or imperfect) genera are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these three genera. Species capable of reproducing sexually belong in the teleomorphic genus, Arthroderma, of the Ascomycota. (See Teleomorph, anamorph and holomorph for more information on this type of fungal life cycle).
Dermatophytes cause infections of the skin, hair and nails due to their ability to obtain nutrients from keratinized material. The organisms colonize the keratin tissues and inflammation is caused by host response to metabolic by-products. They are usually restricted to the nonliving cornified layer of the epidermis because of their inability to penetrate viable tissue of an immunocompetent host. Invasion does elicit a host response ranging from mild to severe. Acid proteinases, elastase, keratinases, and other proteinases reportedly act as virulence factors. The development of cell-mediated immunity correlated with delayed hypersensitivity and an inflammatory response is associated with clinical cure, whereas the lack of or a defective cell-mediated immunity predisposes the host to chronic or recurrent dermatophyte infection.
Some of these infections are known as ringworm or tinea. Toe- and fingernail infection are referred to as onychomycosis. Dermatophytes usually do not invade living tissues, but colonize the outer layer of the skin. Occasionally the organisms do invade subcutaneous tissues, resulting in kerion development.
# Identification
Microscopic morphology of the micro and macroconidia is the most reliable identification character, but a good slide preparation is needed, and also needed is the stimulation of sporulation in some strains. Culture characteristics such as surface texture, topography and pigmentation are variable so they are the least reliable criteria for identification. Clinical information such as the appearance of the lesion, site, geographic location, travel history, animal contacts and race is also important, especially in identifying rare non-sporulating species like Trichophyton concentricum, Microsporum audouinii and Trichophyton schoenleinii.
# Transmission
Dermatophytes are transmitted by direct contact with infected host (human or animal) or by direct or indirect contact with infected exfoliated skin or hair in clothing, combs, hair brushes, theatre seats, caps, furniture, bed linens, towels, hotel rugs, and locker room floors. Depending on the species the organism may be viable in the environment for up to 15 months. There is an increased susceptibility to infection when there is a preexisting injury to the skin such as scars, burns, excessive temperature and humidity. Adaptation to growth on humans by most geophilic species resulted in diminished loss of sporulation, sexuality, and other soil-associated characteristics.
# Classification
Dermatophytes are classified as anthropophilic (humans), zoophilic (animals) or geophilic (soil) according to their normal habitat.
- Anthropophilic dermatophytes are restricted to human hosts and produce a mild, chronic inflammation.
- Zoophilic organisms are found primarily in animals and cause marked inflammatory reactions in humans who have contact with infected cats, dogs, cattle, horses, birds, or other animals. This is followed by a rapid termination of the infection.
- Geophilic species are usually recovered from the soil but occasionally infect humans and animals. They cause a marked inflammatory reaction, which limits the spread of the infection and may lead to a spontaneous cure but may also leave scars.
# Classification
- About 58% of the dermatophyte species isolated are Trichophyton rubrum
- 27% are T. mentagrophytes
- 7% are T. verrucosum
- 3% are T. tonsurans
- Infrequently isolated (less than 1%) are Epidermophyton floccosum, Microsporum audouinii, M. canis, M. equinum, M. nanum, M. versicolor, Trichophyton equinum, T. kanei, T. raubitschekii, and T. violaceum.
# Medications
- Lamisil
- Tea tree oil | https://www.wikidoc.org/index.php/Dermatophyte | |
e00af13682ffbde9277f4576ce860cc16f75ead3 | wikidoc | Tinea manuum | Tinea manuum
# Overview
Tinea Manuum is a parasitic fungal infection (mycosis) of the hand in the dermatophytosis (tinea) group. It is typically more aggressive than tinea pedis but similar in look. Itching, burning, cracking, and scaling are observable and may be transmitted sexually or otherwise, whether or not symptoms are present.
# Diagnosis
## Physical Examination
### Skin
### Hand
- Tinea manuum. Adapted from Dermatology Atlas.
- Tinea manuum. Adapted from Dermatology Atlas.
- Tinea manuum. Adapted from Dermatology Atlas.
- Tinea manuum. Adapted from Dermatology Atlas.
# Differential diagnosis
Tinea manuum must be differentiated from other diseases that cause ust be differentiated from other diseases that cause rash and eczema such as secondary syphilis and pityriasis rosea.
# Treatment
It can usually be treated with long term use of a topical antifungal cream such as selenium sulfide shampoo. However, in some cases an oral antifungal such as griseofulvin may have to be prescribed.
- ↑ Jump up to: 1.0 1.1 1.2 1.3 "Dermatology Atlas"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Mycosis Fungoides and the Sézary Syndrome Treatment (PDQ®)—Patient Version - National Cancer Institute".
- ↑ Mahajan K, Relhan V, Relhan AK, Garg VK (2016). "Pityriasis Rosea: An Update on Etiopathogenesis and Management of Difficult Aspects". Indian J Dermatol. 61 (4): 375–84. doi:10.4103/0019-5154.185699. PMC 4966395. PMID 27512182.
- ↑ Prantsidis A, Rigopoulos D, Papatheodorou G, Menounos P, Gregoriou S, Alexiou-Mousatou I, Katsambas A (2009). "Detection of human herpesvirus 8 in the skin of patients with pityriasis rosea". Acta Derm. Venereol. 89 (6): 604–6. doi:10.2340/00015555-0703. PMID 19997691.
- ↑ Smith KJ, Nelson A, Skelton H, Yeager J, Wagner KF (1997). "Pityriasis lichenoides et varioliformis acuta in HIV-1+ patients: a marker of early stage disease. The Military Medical Consortium for the Advancement of Retroviral Research (MMCARR)". Int. J. Dermatol. 36 (2): 104–9. PMID 9109005.
- ↑ Jiamton S, Tangjaturonrusamee C, Kulthanan K (2013). "Clinical features and aggravating factors in nummular eczema in Thais". Asian Pac. J. Allergy Immunol. 31 (1): 36–42. PMID 23517392.
- ↑ "STD Facts - Syphilis".
- ↑ Neagu TP, Tiglis M, Botezatu D, Enache V, Cobilinschi CO, Vâlcea-Precup MS, GrinTescu IM (2017). "Clinical, histological and therapeutic features of Bowen's disease". Rom J Morphol Embryol. 58 (1): 33–40. PMID 28523295.
- ↑ Murao K, Yoshioka R, Kubo Y (2014). "Human papillomavirus infection in Bowen disease: negative p53 expression, not p16(INK4a) overexpression, is correlated with human papillomavirus-associated Bowen disease". J. Dermatol. 41 (10): 878–84. doi:10.1111/1346-8138.12613. PMID 25201325.
- ↑ Szatkowski J, Schwartz RA (2015). "Acute generalized exanthematous pustulosis (AGEP): A review and update". J. Am. Acad. Dermatol. 73 (5): 843–8. doi:10.1016/j.jaad.2015.07.017. PMID 26354880.
- ↑ Schmid S, Kuechler PC, Britschgi M, Steiner UC, Yawalkar N, Limat A, Baltensperger K, Braathen L, Pichler WJ (2002). "Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule formation". Am. J. Pathol. 161 (6): 2079–86. doi:10.1016/S0002-9440(10)64486-0. PMC 1850901. PMID 12466124.
- ↑ Ankad BS, Beergouder SL (2016). "Hypertrophic lichen planus versus prurigo nodularis: a dermoscopic perspective". Dermatol Pract Concept. 6 (2): 9–15. doi:10.5826/dpc.0602a03. PMC 4866621. PMID 27222766.
- ↑ Shengyuan L, Songpo Y, Wen W, Wenjing T, Haitao Z, Binyou W (2009). "Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis". Arch Dermatol. 145 (9): 1040–7. doi:10.1001/archdermatol.2009.200. PMID 19770446.
- ↑ Lutz ME, Daoud MS, McEvoy MT, Gibson LE (1998). "Subcorneal pustular dermatosis: a clinical study of ten patients". Cutis. 61 (4): 203–8. PMID 9564592.
- ↑ Kasha EE, Epinette WW (1988). "Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) in association with a monoclonal IgA gammopathy: a report and review of the literature". J. Am. Acad. Dermatol. 19 (5 Pt 1): 854–8. PMID 3056995.
- ↑ Delaporte E, Colombel JF, Nguyen-Mailfer C, Piette F, Cortot A, Bergoend H (1992). "Subcorneal pustular dermatosis in a patient with Crohn's disease". Acta Derm. Venereol. 72 (4): 301–2. PMID 1357895.
- ↑ Sauder MB, Glassman SJ (2013). "Palmoplantar subcorneal pustular dermatosis following adalimumab therapy for rheumatoid arthritis". Int. J. Dermatol. 52 (5): 624–8. doi:10.1111/j.1365-4632.2012.05707.x. PMID 23489057.
- ↑ Lambert WC, Everett MA (1981). "The nosology of parapsoriasis". J. Am. Acad. Dermatol. 5 (4): 373–95. PMID 7026622.
- ↑ Väkevä L, Sarna S, Vaalasti A, Pukkala E, Kariniemi AL, Ranki A (2005). "A retrospective study of the probability of the evolution of parapsoriasis en plaques into mycosis fungoides". Acta Derm. Venereol. 85 (4): 318–23. doi:10.1080/00015550510030087. PMID 16191852.
- ↑ Janniger CK, Schwartz RA, Szepietowski JC, Reich A (2005). "Intertrigo and common secondary skin infections". Am Fam Physician. 72 (5): 833–8. PMID 16156342.
- ↑ Satter EK, High WA (2008). "Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society". Pediatr Dermatol. 25 (3): 291–5. doi:10.1111/j.1525-1470.2008.00669.x. PMID 18577030.
- ↑ Stull MA, Kransdorf MJ, Devaney KO (1992). "Langerhans cell histiocytosis of bone". Radiographics. 12 (4): 801–23. doi:10.1148/radiographics.12.4.1636041. PMID 1636041.
- ↑ Sholl LM, Hornick JL, Pinkus JL, Pinkus GS, Padera RF (2007). "Immunohistochemical analysis of langerin in langerhans cell histiocytosis and pulmonary inflammatory and infectious diseases". Am. J. Surg. Pathol. 31 (6): 947–52. doi:10.1097/01.pas.0000249443.82971.bb. PMID 17527085.
- ↑ Grois N, Pötschger U, Prosch H, Minkov M, Arico M, Braier J, Henter JI, Janka-Schaub G, Ladisch S, Ritter J, Steiner M, Unger E, Gadner H (2006). "Risk factors for diabetes insipidus in langerhans cell histiocytosis". Pediatr Blood Cancer. 46 (2): 228–33. doi:10.1002/pbc.20425. PMID 16047354.
- ↑ Al Hasan M, Fitzgerald SM, Saoudian M, Krishnaswamy G (2004). "Dermatology for the practicing allergist: Tinea pedis and its complications". Clin Mol Allergy. 2 (1): 5. doi:10.1186/1476-7961-2-5. PMC 419368. PMID 15050029.
- ↑ Schwartz RA, Janusz CA, Janniger CK (2006). "Seborrheic dermatitis: an overview". Am Fam Physician. 74 (1): 125–30. PMID 16848386.
- ↑ Misery L, Touboul S, Vinçot C, Dutray S, Rolland-Jacob G, Consoli SG, Farcet Y, Feton-Danou N, Cardinaud F, Callot V, De La Chapelle C, Pomey-Rey D, Consoli SM (2007). "". Ann Dermatol Venereol (in French). 134 (11): 833–7. PMID 18033062.CS1 maint: Unrecognized language (link) | Tinea manuum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Tinea Manuum is a parasitic fungal infection (mycosis) of the hand in the dermatophytosis (tinea) group. It is typically more aggressive than tinea pedis but similar in look. Itching, burning, cracking, and scaling are observable and may be transmitted sexually or otherwise, whether or not symptoms are present.
# Diagnosis
## Physical Examination
### Skin
### Hand
- Tinea manuum. Adapted from Dermatology Atlas.[1]
- Tinea manuum. Adapted from Dermatology Atlas.[1]
- Tinea manuum. Adapted from Dermatology Atlas.[1]
- Tinea manuum. Adapted from Dermatology Atlas.[1]
# Differential diagnosis
Tinea manuum must be differentiated from other diseases that cause ust be differentiated from other diseases that cause rash and eczema such as secondary syphilis and pityriasis rosea.
# Treatment
It can usually be treated with long term use of a topical antifungal cream such as selenium sulfide shampoo. However, in some cases an oral antifungal such as griseofulvin may have to be prescribed.
Template:Mycoses
Template:WH
Template:WikiDoc Sources
- ↑ Jump up to: 1.0 1.1 1.2 1.3 "Dermatology Atlas"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Mycosis Fungoides and the Sézary Syndrome Treatment (PDQ®)—Patient Version - National Cancer Institute".
- ↑ Mahajan K, Relhan V, Relhan AK, Garg VK (2016). "Pityriasis Rosea: An Update on Etiopathogenesis and Management of Difficult Aspects". Indian J Dermatol. 61 (4): 375–84. doi:10.4103/0019-5154.185699. PMC 4966395. PMID 27512182.
- ↑ Prantsidis A, Rigopoulos D, Papatheodorou G, Menounos P, Gregoriou S, Alexiou-Mousatou I, Katsambas A (2009). "Detection of human herpesvirus 8 in the skin of patients with pityriasis rosea". Acta Derm. Venereol. 89 (6): 604–6. doi:10.2340/00015555-0703. PMID 19997691.
- ↑ Smith KJ, Nelson A, Skelton H, Yeager J, Wagner KF (1997). "Pityriasis lichenoides et varioliformis acuta in HIV-1+ patients: a marker of early stage disease. The Military Medical Consortium for the Advancement of Retroviral Research (MMCARR)". Int. J. Dermatol. 36 (2): 104–9. PMID 9109005.
- ↑ Jiamton S, Tangjaturonrusamee C, Kulthanan K (2013). "Clinical features and aggravating factors in nummular eczema in Thais". Asian Pac. J. Allergy Immunol. 31 (1): 36–42. PMID 23517392.
- ↑ "STD Facts - Syphilis".
- ↑ Neagu TP, Tiglis M, Botezatu D, Enache V, Cobilinschi CO, Vâlcea-Precup MS, GrinTescu IM (2017). "Clinical, histological and therapeutic features of Bowen's disease". Rom J Morphol Embryol. 58 (1): 33–40. PMID 28523295.
- ↑ Murao K, Yoshioka R, Kubo Y (2014). "Human papillomavirus infection in Bowen disease: negative p53 expression, not p16(INK4a) overexpression, is correlated with human papillomavirus-associated Bowen disease". J. Dermatol. 41 (10): 878–84. doi:10.1111/1346-8138.12613. PMID 25201325.
- ↑ Szatkowski J, Schwartz RA (2015). "Acute generalized exanthematous pustulosis (AGEP): A review and update". J. Am. Acad. Dermatol. 73 (5): 843–8. doi:10.1016/j.jaad.2015.07.017. PMID 26354880.
- ↑ Schmid S, Kuechler PC, Britschgi M, Steiner UC, Yawalkar N, Limat A, Baltensperger K, Braathen L, Pichler WJ (2002). "Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule formation". Am. J. Pathol. 161 (6): 2079–86. doi:10.1016/S0002-9440(10)64486-0. PMC 1850901. PMID 12466124.
- ↑ Ankad BS, Beergouder SL (2016). "Hypertrophic lichen planus versus prurigo nodularis: a dermoscopic perspective". Dermatol Pract Concept. 6 (2): 9–15. doi:10.5826/dpc.0602a03. PMC 4866621. PMID 27222766.
- ↑ Shengyuan L, Songpo Y, Wen W, Wenjing T, Haitao Z, Binyou W (2009). "Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis". Arch Dermatol. 145 (9): 1040–7. doi:10.1001/archdermatol.2009.200. PMID 19770446.
- ↑ Lutz ME, Daoud MS, McEvoy MT, Gibson LE (1998). "Subcorneal pustular dermatosis: a clinical study of ten patients". Cutis. 61 (4): 203–8. PMID 9564592.
- ↑ Kasha EE, Epinette WW (1988). "Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) in association with a monoclonal IgA gammopathy: a report and review of the literature". J. Am. Acad. Dermatol. 19 (5 Pt 1): 854–8. PMID 3056995.
- ↑ Delaporte E, Colombel JF, Nguyen-Mailfer C, Piette F, Cortot A, Bergoend H (1992). "Subcorneal pustular dermatosis in a patient with Crohn's disease". Acta Derm. Venereol. 72 (4): 301–2. PMID 1357895.
- ↑ Sauder MB, Glassman SJ (2013). "Palmoplantar subcorneal pustular dermatosis following adalimumab therapy for rheumatoid arthritis". Int. J. Dermatol. 52 (5): 624–8. doi:10.1111/j.1365-4632.2012.05707.x. PMID 23489057.
- ↑ Lambert WC, Everett MA (1981). "The nosology of parapsoriasis". J. Am. Acad. Dermatol. 5 (4): 373–95. PMID 7026622.
- ↑ Väkevä L, Sarna S, Vaalasti A, Pukkala E, Kariniemi AL, Ranki A (2005). "A retrospective study of the probability of the evolution of parapsoriasis en plaques into mycosis fungoides". Acta Derm. Venereol. 85 (4): 318–23. doi:10.1080/00015550510030087. PMID 16191852.
- ↑ Janniger CK, Schwartz RA, Szepietowski JC, Reich A (2005). "Intertrigo and common secondary skin infections". Am Fam Physician. 72 (5): 833–8. PMID 16156342.
- ↑ Satter EK, High WA (2008). "Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society". Pediatr Dermatol. 25 (3): 291–5. doi:10.1111/j.1525-1470.2008.00669.x. PMID 18577030.
- ↑ Stull MA, Kransdorf MJ, Devaney KO (1992). "Langerhans cell histiocytosis of bone". Radiographics. 12 (4): 801–23. doi:10.1148/radiographics.12.4.1636041. PMID 1636041.
- ↑ Sholl LM, Hornick JL, Pinkus JL, Pinkus GS, Padera RF (2007). "Immunohistochemical analysis of langerin in langerhans cell histiocytosis and pulmonary inflammatory and infectious diseases". Am. J. Surg. Pathol. 31 (6): 947–52. doi:10.1097/01.pas.0000249443.82971.bb. PMID 17527085.
- ↑ Grois N, Pötschger U, Prosch H, Minkov M, Arico M, Braier J, Henter JI, Janka-Schaub G, Ladisch S, Ritter J, Steiner M, Unger E, Gadner H (2006). "Risk factors for diabetes insipidus in langerhans cell histiocytosis". Pediatr Blood Cancer. 46 (2): 228–33. doi:10.1002/pbc.20425. PMID 16047354.
- ↑ Al Hasan M, Fitzgerald SM, Saoudian M, Krishnaswamy G (2004). "Dermatology for the practicing allergist: Tinea pedis and its complications". Clin Mol Allergy. 2 (1): 5. doi:10.1186/1476-7961-2-5. PMC 419368. PMID 15050029.
- ↑ Schwartz RA, Janusz CA, Janniger CK (2006). "Seborrheic dermatitis: an overview". Am Fam Physician. 74 (1): 125–30. PMID 16848386.
- ↑ Misery L, Touboul S, Vinçot C, Dutray S, Rolland-Jacob G, Consoli SG, Farcet Y, Feton-Danou N, Cardinaud F, Callot V, De La Chapelle C, Pomey-Rey D, Consoli SM (2007). "[Stress and seborrheic dermatitis]". Ann Dermatol Venereol (in French). 134 (11): 833–7. PMID 18033062.CS1 maint: Unrecognized language (link) | https://www.wikidoc.org/index.php/Dermatophytosis_of_hand | |
da08628dda234a26ccb083a2dc2c8a32b840675d | wikidoc | Dermatoscopy | Dermatoscopy
Dermatoscopy (also known as epiluminescence microscopy) is the examination of cutaneous lesions with a dermatoscope, a magnifier with a light and a liquid medium between the instrument and the skin, thus illuminating the lesion without reflected light.
Skin surface microscopy started in 1663 by Kolhaus and was improved with the addition of immersion oil in 1878 by Abbe. The German dermatologist, Johann Saphier, added a built-in light source to the instrument. Goldman was the first dermatologist to coin the term "dermascopy" and to use the dermatoscope to evaluate pigmented cutaneous lesions.
This instrument is helpful to dermatologists in distinguishing benign from malignant lesions, especially of aid in the diagnosis of malignant melanoma.
it:Dermatoscopia
nl:Dermatoscopie | Dermatoscopy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Dermatoscopy (also known as epiluminescence microscopy) is the examination of cutaneous lesions with a dermatoscope, a magnifier with a light and a liquid medium between the instrument and the skin, thus illuminating the lesion without reflected light.
Skin surface microscopy started in 1663 by Kolhaus and was improved with the addition of immersion oil in 1878 by Abbe. The German dermatologist, Johann Saphier, added a built-in light source to the instrument. Goldman was the first dermatologist to coin the term "dermascopy" and to use the dermatoscope to evaluate pigmented cutaneous lesions.
This instrument is helpful to dermatologists in distinguishing benign from malignant lesions, especially of aid in the diagnosis of malignant melanoma.
it:Dermatoscopia
nl:Dermatoscopie
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dermatoscopy | |
08cb10210e0f3029836f61ea13c99e429e7fa693 | wikidoc | Skin disease | Skin disease
Synonyms and keywords: Dermatosis; dermatoses; disease of the skin
# Overview
In medicine, a dermatosis is a generic term for disease of the skin. The plural is dermatoses. It should be distinguished from dermatitis, which is inflammation of the skin (the two terms are related but not identical). Dermotoses covers all skin diseases, many of which are not contagious. Dermatitis is a description of symptoms (inflammation) of some dermatoses.
Many systemic diseases express symptoms through the skin such as measles, and rubella, but these are not categorized as dermatoses.
Skin diseases, or dermatoses, include, skin cancer, eczema, psoriasis, acne, impetigo, scabies, sunburn, warts, fifth disease (also called erythema infectiosum or "slapped face disease"), tinea, herpes, ulcers, and pruritis.
Some skin disorders are caused by absorption of material through the skin. Failure to use proper skin protection (gloves, aprons, overalls etc.) can result in irritation or even poisoning.
# Examples of Skin Diseases
- Acne
- Actinic keratosis
- Angioma
- Athlete's foot
- Aquagenic pruritus
- Argyria
- Atopic dermatitis
- Baldness
- Basal cell carcinoma
- Bed sore
- Behcet's disease
- Blepharitis
- Boil
- Bowen's disease
- Bullous pemphigoid
- Canker sore
- Carbuncles
- Cellulitis
- Chloracne
- Chronic dermatitis of the hands and feet
- Cold sores
- Contact dermatitis (includes poison ivy, oak, sumac)
- Creeping eruption
- Dandruff
- Dermatitis
- Dermatitis herpetiformis
- Dermatofibroma
- Diaper rash
- Dyshidrosis
- Eczema
- Epidermolysis bullosa
- Erysipelas
- Erythroderma
- Friction blister
- Genital wart
- Gestational pemphigoid
- Grover's disease
- Hemangioma
- Hidradenitis suppurativa
- Hives
- Hyperhidrosis
- Ichthyosis
- Impetigo
- Jock itch
- Kaposi's sarcoma
- Keloid
- Keratoacanthoma
- Keratosis pilaris
- Lewandowsky-Lutz dysplasia
- Lice infection
- Lichen planus
- Lichen simplex chronicus
- Lipoma
- Lymphadenitis
- Malignant melanoma
- Melasma
- Miliaria
- Molluscum contagiosum
- Nummular dermatitis
- Paget's disease of the nipple
- Pediculosis
- Pemphigus
- Perioral dermatitis
- Photoallergy
- Photosensitivity
- Pityriasis rosea
- Pityriasis rubra pilaris
- Porphyria
- Psoriasis
- Raynaud's disease
- Ringworm
- Rosacea
- Scabies
- Scleroderma
- Scrofula
- Sebaceous cyst
- Seborrheic keratosis
- Seborrhoeic dermatitis
- Shingles
- Skin cancer
- Skin Tags
- Spider veins
- Squamous cell carcinoma
- Stasis dermatitis
- Sunburn
- Tick bite
- Tinea barbae
- Tinea capitis
- Tinea corporis
- Tinea cruris
- Tinea pedis
- Tinea unguium
- Tinea versicolor
- Tinea
- Tungiasis
- Urticaria (Hives)
- Vagabond's disease
- Vitiligo
- Warts
- Wheal (aka "Weal" and "Welt") | Skin disease
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Dermatosis; dermatoses; disease of the skin
# Overview
In medicine, a dermatosis is a generic term for disease of the skin. The plural is dermatoses. It should be distinguished from dermatitis, which is inflammation of the skin (the two terms are related but not identical). Dermotoses covers all skin diseases, many of which are not contagious. Dermatitis is a description of symptoms (inflammation) of some dermatoses.
Many systemic diseases express symptoms through the skin such as measles, and rubella, but these are not categorized as dermatoses.
Skin diseases, or dermatoses, include, skin cancer, eczema, psoriasis, acne, impetigo, scabies, sunburn, warts, fifth disease (also called erythema infectiosum or "slapped face disease"), tinea, herpes, ulcers, and pruritis.
Some skin disorders are caused by absorption of material through the skin. Failure to use proper skin protection (gloves, aprons, overalls etc.) can result in irritation or even poisoning.
# Examples of Skin Diseases
- Acne
- Actinic keratosis
- Angioma
- Athlete's foot
- Aquagenic pruritus
- Argyria
- Atopic dermatitis
- Baldness
- Basal cell carcinoma
- Bed sore
- Behcet's disease
- Blepharitis
- Boil
- Bowen's disease
- Bullous pemphigoid
- Canker sore
- Carbuncles
- Cellulitis
- Chloracne
- Chronic dermatitis of the hands and feet
- Cold sores
- Contact dermatitis (includes poison ivy, oak, sumac)
- Creeping eruption
- Dandruff
- Dermatitis
- Dermatitis herpetiformis
- Dermatofibroma
- Diaper rash
- Dyshidrosis
- Eczema
- Epidermolysis bullosa
- Erysipelas
- Erythroderma
- Friction blister
- Genital wart
- Gestational pemphigoid
- Grover's disease
- Hemangioma
- Hidradenitis suppurativa
- Hives
- Hyperhidrosis
- Ichthyosis
- Impetigo
- Jock itch
- Kaposi's sarcoma
- Keloid
- Keratoacanthoma
- Keratosis pilaris
- Lewandowsky-Lutz dysplasia
- Lice infection
- Lichen planus
- Lichen simplex chronicus
- Lipoma
- Lymphadenitis
- Malignant melanoma
- Melasma
- Miliaria
- Molluscum contagiosum
- Nummular dermatitis
- Paget's disease of the nipple
- Pediculosis
- Pemphigus
- Perioral dermatitis
- Photoallergy
- Photosensitivity
- Pityriasis rosea
- Pityriasis rubra pilaris
- Porphyria
- Psoriasis
- Raynaud's disease
- Ringworm
- Rosacea
- Scabies
- Scleroderma
- Scrofula
- Sebaceous cyst
- Seborrheic keratosis
- Seborrhoeic dermatitis
- Shingles
- Skin cancer
- Skin Tags
- Spider veins
- Squamous cell carcinoma
- Stasis dermatitis
- Sunburn
- Tick bite
- Tinea barbae
- Tinea capitis
- Tinea corporis
- Tinea cruris
- Tinea pedis
- Tinea unguium
- Tinea versicolor
- Tinea
- Tungiasis
- Urticaria (Hives)
- Vagabond's disease
- Vitiligo
- Warts
- Wheal (aka "Weal" and "Welt") | https://www.wikidoc.org/index.php/Dermatosis | |
378b2bc6ffff397afbbad3c30ec6387515c91f50 | wikidoc | Epidemiology | Epidemiology
# Overview
Epidemiology is the study of factors affecting the health and illness of populations, and serves as the foundation and logic of interventions made in the interest of public health and preventive medicine. It is considered a cornerstone methodology of public health research, and is highly regarded in evidence-based medicine for identifying risk factors for disease and determining optimal treatment approaches to clinical practice.
The work of communicable and non-communicable disease epidemiologists ranges from outbreak investigation, to study design, data collection and analysis including the development of statistical models to test hypotheses and the 'writing-up' of results for submission to peer reviewed journals. Epidemiologists may draw on a number of other scientific disciplines such as biology in understanding disease processes and social science disciplines including sociology and philosophy in order to better understand proximate and distal risk factors.
# Etymology
Epidemiology, "the study of what is upon the people", is derived from the Greek terms epi = upon, among; demos = people, district; logos = study, word, discourse; suggesting that it applies only to human populations. But the term is widely used in studies of zoological populations (veterinary epidemiology), although the term 'epizoology' is available, and it has also been applied to studies of plant populations (botanical epidemiology). It is also applied to studies of micro-organisms (microbial epidemiology).
# History of epidemiology
The Greek physician Hippocrates is sometimes said to be the "father of epidemiology". He is the first person known to have examined the relationships between the occurrence of disease and environmental influences. He coined the terms endemic (for diseases usually found in some places but not in others) and epidemic (for disease that are seen at some times but not others.
One of the earliest theories on the origin of disease was that it was primarily the fault of human luxury. This was expressed by philosophers such as Plato and Rousseau, and social critics like Jonathan Swift .
In the medieval Islamic world, Muslim physicians discovered the contagious nature of infectious disease. In particular, the Persian physician Avicenna, considered a "father of modern medicine", in The Canon of Medicine (1020s), discovered the contagious nature of tuberculosis and sexually transmitted disease, and the distribution of disease through water and soil, stated that bodily secretion is contaminated by foul foreign earthly bodies before being infected, introduced the method of quarantine as a means of limiting the spread of contagious disease, the method of risk factor analysis, and the idea of a syndrome in the diagnosis of specific diseases.
When the Black Death bubonic plague reached al-Andalus in the 14th century, the Arabian physician Ibn Khatima discovered that infectious diseases are caused by microorganisms which enter the human body. Another 14th century Andalusian-Arabian physician, Ibn al-Khatib (1313-1374), wrote a treatise called On the Plague, in which he stated how infectious disease can be transmitted through bodily contact and "through garments, vessels and earrings."
In the middle of the 16th century, a famous Italian doctor from Florence named Girolamo Fracastoro was the first one who proposed a theory that very small, unseeable, live particles cause diseases. They were considered to be able to spread by air, multiply by themselves and to be destroyable by fire. In such a way he refuted Galen's theory of miasms (poison gas in sick people). In 1543 he wrote a book "De contagione et contagiosis morbis". At that time, based of his theory, he was the first to promote personal and environmental hygiene. This theory could not have been proven until the development of the first microscope by Anton van Leeuwenhoek in 1675.
John Graunt, a professional haberdasher and serious amateur scientist, published Natural and Political Observations ... upon the Bills of Mortality in 1662. In it, he used analysis of the mortality rolls in London before the Great Plague to present one of the first life tables and report time trends for many diseases, new and old. He provided statistical evidence for many theories on disease, and also refuted many widespread ideas on them.
Dr. John Snow is famous for the suppression of an 1854 outbreak of cholera in London's Soho district. He identified the cause of the outbreak as a public water pump on Broad Street and had the handle removed, thus ending the outbreak. (It has been questioned as to whether the epidemic was already in decline when Snow took action.) This has been perceived as a major event in the history of public health and can be regarded as the founding event of the science of epidemiology.
Other pioneers include Danish physician P. A. Schleisner, who in 1849 related his work on the prevention of the epidemic of tetanus neonatorum on the Vestmanna Islands in Iceland. Another important pioneer was Hungarian physician Ignaz Semmelweis, who in 1847 brought down infant mortality at a Vienna hospital by instituting a disinfection procedure. His findings were published in 1850, but his work was ill received by his colleagues, who discontinued the procedure. Disinfection did not become widely practiced until British surgeon Joseph Lister 'discovered' antiseptics in 1865 in light of the work of Louis Pasteur.
In the early 20th century, mathematical methods were introduced into epidemiology by Ronald Ross, Anderson Gray McKendrick and others.
Another breakthrough was the 1954 publication of the results of a British Doctors Study, led by Richard Doll and Austin Bradford Hill, which lent very strong statistical support to the suspicion that tobacco smoking was linked to lung cancer.
- History of emerging infectious diseases
# The profession of epidemiology
To date, few Universities offer epidemiology as a course of study at undergraduate level. Many epidemiologists, therefore, are physicians or hold other postgraduate degrees including a Master of Public Health (MPH), Master of Science or Epidemiology (MSc.) Other higher degrees confer the title of Doctor such as a Doctor of Public Health (DrPH), Doctor of Philosophy (PhD), Doctor of Science (ScD) or for those clinically trained, Doctor of Medicine (MD). In the United Kingdom, the title of 'doctor' is a honorary one conferred to those having attained the professional degrees of Bachelor of Medicine and Surgery (MBBS or MBChB). As public health/health protection practitioners, epidemiologists work in a number of different settings. Some epidemiologists work 'in the field', i.e., in the community, commonly in a public health/health protection service and are often at the forefront of investigating and combating disease outbreaks. Others work for non-profit organizations, universities, hospitals and larger government entities such as the Centers for Disease Control and Prevention (CDC), Health Protection Agency or the Public Health Agency of Canada.
# The practice of epidemiology
Epidemiologists employ a range of study designs from the observational to experimental and are generally categorized as descriptive, analytic (aiming to further examine known associations or hypothesized relationships), and experimental (a term often equated with clinical or community trials of treatments and other interventions). Epidemiological studies are aimed, where possible, at revealing unbiased relationships between exposures such as alcohol or smoking, biological agents, stress, or chemicals to mortality or morbidity. Identifying causal relationships between these exposures and outcomes are important aspects of epidemiology. Modern epidemiologist use disease informatics as a tool.
The term 'epidemiologic triangle' is used to describe the intersection of Host, Agent, and Environment in analyzing an outbreak.
# Epidemiology as causal inference
Although epidemiology is sometimes viewed as a collection of statistical tools used to elucidate the associations of exposures to health outcomes, a deeper understanding of this science is that of discovering causal relationships.
It is nearly impossible to say with perfect accuracy how even the most simple physical systems behave beyond the immediate future, much less the complex field of epidemiology, which draws on biology, sociology, mathematics, statistics, anthropology, psychology, and policy; "Correlation does not imply causation," is a common theme to much of the epidemiological literature. For epidemiologists, the key is in the term inference. Epidemiologists use gathered data and a broad range of biomedical and psychosocial theories in an iterative way to generate or expand theory, to test hypotheses, and to make educated, informed assertions about which relationships are causal, and about exactly how they are causal. Epidemiologists Rothman and Greenland emphasize that the "one cause - one effect" understanding is a simplistic mis-belief. Most outcomes — whether disease or death — are caused by a chain or web consisting of many component causes.
## Bradford-Hill criteria
In 1965 Austin Bradford Hill detailed criteria for assessing evidence of causation. These guidelines are sometimes referred to as the Bradford-Hill criteria, but this makes it seem like it is some sort of checklist. For example, Phillips and Goodman (2004) note that they are often taught or referenced as a checklist for assessing causality, despite this not being Hill's intention . Hill himself said "None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required sine qua non".
- Strength: A small association does not mean that there is not a causal effect.
- Consistency: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect.
- Specificity: Causation is likely if a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship.
- Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay).
- Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence.
- Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge).
- Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such evidence cannot nullify the epidemiological affect on associations" .
- Experiment: "Occasionally it is possible to appeal to experimental evidence" .
- Analogy: The effect of similar factors may be considered.
# Legal interpretation of epidemiological studies
In United States law, epidemiology alone cannot prove that a causal association does not exist in general. Conversely, it can be (and is in some circumstances) taken by US courts, in an individual case, to justify an inference that a causal association does exist, based upon a balance of probability. Strictly speaking, epidemiology can only go to prove that an agent could have caused but not that, in any particular case, it did cause:
"Epidemiology is concerned with the incidence of disease in populations and does not address the question of the cause of an individual’s disease. This question, sometimes referred to as specific causation, is beyond the domain of the science of epidemiology. Epidemiology has its limits at the point where an inference is made that the relationship between an agent and a disease is causal (general causation) and where the magnitude of excess risk attributed to the agent has been determined; that is, epidemiology addresses whether an agent can cause a disease, not whether an agent did cause a specific plaintiff’s disease."
# Epidemiology and advocacy
As a public health discipline, epidemiologic evidence is often used to advocate both personal measures like diet change and corporate measures like removal of junk food advertising, with study findings disseminated to the general public in order to help people to make informed decisions about their health. Often the uncertainties about these findings are not communicated well; news articles often prominently report the latest result of one study with little mention of its limitations, caveats, or context. Epidemiological tools have proved effective in establishing major causes of diseases like cholera and lung cancer but have had problems with more subtle health issues, and several recent epidemiological results on medical treatments (for example, on the effects of hormone replacement therapy) have been refuted by later randomized controlled trials.
# Epidemiology and population-based health management
Epidemiological practice and the results of epidemiological analysis make a significant contribution to emerging population-based health management frameworks.
Population-based health management encompasses the ability to:
- assess the health states and health needs of a target population;
- implement and evaluate interventions that are designed to improve the health of that population; and
- efficiently and effectively provide care for members of that population in a way that is consistent with the community’s cultural, policy and health resource values.
Modern population-based health management is complex, requiring a multiple set of skills (medical, political, technological, mathematical etc.) of which epidemiological practice and analysis is a core component, that is unified with management science to provide efficient and effective health care and health guidance to a population. This task requires the forward looking ability of modern risk management approaches that transform health risk factors, incidence, prevalence and mortality statistics (derived from epidemiological analysis) into management metrics that not only guide how a health system responds to current population health issues, but also how a health system can be managed to better respond to future potential population health issues.
Examples of organizations that use population-based health management that leverage the work and results of epidemiological practice include Canadian Strategy for Cancer Control, Health Canada Tobacco Control Programs, Rick Hansen Foundation, Canadian Tobacco Control Research Initiative.
Each of these organizations use a population-based health management framework called Life at Risk that combines epidemiological quantitative analysis with demographics, health agency operational research and economics to perform:
- Population Life Impacts Simulations: Measurement of the future potential impact of disease upon the population with respect to new disease cases, prevalence, premature death as well as potential years of life lost from disability and death;
- Labour Force Life Impacts Simulations: Measurement of the future potential impact of disease upon the labour force with respect to new disease cases, prevalence, premature death and potential years of life lost from disability and death;
- Economic Impacts of Disease Simulations: Measurement of the future potential impact of disease upon private sector disposable income impacts (wages, corporate profits, private health care costs) and public sector disposable income impacts (personal income tax, corporate income tax, consumption taxes, publicly funded health care costs).
# Types of studies
## Case series
Case-series describe the experience of a single patient or a group of patients with a similar diagnosis. They are purely descriptive and cannot be used to make inferences about the general population of patients with that disease. These types of studies, in which an astute clinician identifies an unusual feature of a disease or a patient's history, may lead to formulation of a new hypothesis. Using the data from the series, analytic studies could be done to investigate possible causal factors. These can include case control studies or prospective studies. A case control study would involve matching comparable controls without the disease to the cases in the series. A prospective study would involve following the case series over time to evaluate the disease’s natural history.
## Case control studies
Case control studies select subjects based on their disease status. The study population is comprised of individuals that are disease positive. The control group should come from the same population that gave rise to the cases. The case control study looks back through time at potential exposures both populations (cases and controls) may have encountered. A 2x2 table is constructed, displaying exposed cases (A), the exposed controls (B), unexposed cases (C) and the unexposed controls(D). The statistic generated to measure association is the odds ratio (OR), which is the ratio of the odds of exposure in the cases (A/C) to the odds of exposure in the controls (B/D). This is equal to (A*D)/(B*C).
If the OR is clearly greater than 1, then the conclusion is "those with the disease are more likely to have been exposed," whereas if it is close to 1 then the exposure and disease are not likely associated. If the OR is far less than one, then this suggests that the exposure is a protective factor in the causation of the disease.
Case control studies are usually faster and more cost effective than cohort studies, but are sensitive to bias (such as recall bias and selection bias). The main challenge is to identify the appropriate control group; the distribution of exposure among the control group should be representative of the distribution in the population that gave rise to the cases. This can be achieved by drawing a random sample from the original population at risk. This has as a consequence that the control group can contain people with the disease under study when the disease has a high attack rate in a population.
## Cohort studies
Cohort studies select subjects based on their exposure status. The study subjects should be at risk of the outcome under investigation at the beginning of the cohort study; this usually means that they should be disease free when the cohort study starts. The cohort is followed through time to assess their later outcome status. An example of a cohort study would be the investigation of a cohort of smokers and nonsmokers over time to estimate the incidence of lung cancer. The same 2x2 table is constructed as with the case control study. However, the point estimate generated is the Relative Risk (RR) , which is the incidence of disease in the exposed group (A/A+B) over the incidence in the unexposed (C/C+D).
As with the OR, a RR greater than 1 shows association, where the conclusion can be read "those with the exposure were more likely to develop disease."
Prospective studies have many benefits over case control studies. The RR is a more powerful effect measure than the OR, as the OR is just an estimation of the RR, since true incidence cannot be calculated in a case control study where subjects are selected based on disease status. Temporality can be established in a prospective study, and confounders are more easily controlled for. However, they are more costly, and there is a greater chance of losing subjects to follow-up based on the long time period over which the cohort is followed.
## Outbreak investigation
# Epidemiological methods and measures
# Criticisms of the validity of epidemiological conclusions
## Random error
Random error is the result of fluctuations around a true value because of sampling variability. Random error is just that: random. It can occur during data collection, coding, transfer, or analysis. Examples of random error include: poorly worded questions, a misunderstanding in interpreting an individual answer from a particular respondent, or a typographical error during coding. Random error effects measurement in a transient, inconsistent manner and it is impossible to correct for random error.
There is random error in all sampling procedures. This is called sampling error.
Precision in epidemiological variables is a measure of random error. Precision is also inversely related to random error, so that to reduce random error is to increase precision. Confidence intervals are computed to demonstrate the precision of relative risk estimates. The narrower the confidence interval, the more precise the relative risk estimate.
There are two basic ways to reduce random error in an epidemiological study. The first is to increase the sample size of the study. In other words, add more subjects to your study. The second is to reduce the variability in measurement in the study. This might be accomplished by using a more accurate measuring device or by increasing the number of measurements.
Note, that if we increase the sample size, increase the number of measurements, or purchase a more precise measuring tool, we are usually driving up the costs of the study. There is usually an uneasy balance between the need for adequate precision and the practical issue of study cost.
## Systematic error
A systematic error or bias occurs when there is a difference between the true value (in the population) and the observed value (in the study) from any cause other than sampling variability. An example of systematic error is if, unbeknown to you, the pulse oximeter you are using is set incorrectly and adds two points to the true value each time a measurement is taken. Because the error happens in every instance, it is systematic. Conclusions you draw based on that data will still be incorrect. But the error can be reproduced in the future (eg, by using the same mis-set instrument).
A mistake in coding the effects *all- responses for that particular question is another example of a systematic error.
The validity of a study is dependent on the degree of systematic error. Validity is usually separated into two components:
- Internal validity is dependent on the amount of error in measurements, including exposure, disease, and the associations between these variables. Good internal validity implies a lack of error in measurement and suggests that inferences may be drawn at least as they pertain to the subjects under study.
- External validity pertains to the process of generalizing the findings of the study to the population from which the sample was drawn (or even beyond that population to a more universal statement). This requires an understanding of which conditions are relevant (or irrelevant) to the generalization. Internal validity is clearly a prerequisite for external validity.
## Selection bias
Selection bias is one of three types of bias that threatens the internal validity of a study. Selection bias is an inaccurate measure of effect which results from a systematic difference in the relation between exposure and disease between those who are in the study and those who should be in the study.
If one or more of the sampled groups does not accurately represent the population they are intended to represent, then the results of that comparison may be misleading.
Selection bias can produce either an overestimation or underestimation of the effect measure. It can also produce an effect when none actually exists.
An example of selection bias is volunteer bias. Volunteers may not be representative of the true population. They may exhibit exposures or outcomes which may differ from nonvolunteers (eg volunteers tend to be healthier or they may seek out the study because they already have a problem with the disease being studied and want free treatment).
Another type of selection bias is caused by non-respondents. For example, women who have been subjected to politically motivated sexual assault may be more fearful of participating in a survey measuring incidents of mass rape than non-victims, leading researchers to underestimate the number of rapes.
To reduce selection bias, you should develop explicit (objective) definitions of exposure and/or disease. You should strive for high participation rates, for instance, by offering incentives to participants. Have a large sample size and randomly select the respondents so that you have a better chance of truly representing the population.
# Epidemiology journals
A ranked list of journals:
## General epidemiology journals
- American Journal of Epidemiology
- Epidemiologic Reviews
- Epidemiology
- International Journal of Epidemiology
- Annals of Epidemiology
- Journal of Epidemiology and Community Health
- European Journal of Epidemiology
- Emerging Themes in Epidemiology
- Epidemiologic Perspectives and Innovations
- Eurosurveillance
## Specialty epidemiology journals
- Cancer Epidemiology Biomarkers and Prevention
- Genetic Epidemiology
- Journal of Clinical Epidemiology
- Paediatric Perinatal Epidemiology
- Epidemiology and Infection
- Pharmacoepidemiology and Drug Safety
# Areas of epidemiology
## By physiology/disease area
- Infectious disease epidemiology
- Cardiovascular disease epidemiology
- Cancer epidemiology
- Neuroepidemiology
- Epidemiology of Aging
- Oral/Dental epidemiology
- Reproductive epidemiology
- Obesity/diabetes epidemiology
- Renal epidemiology
- Injury epidemiology
- Psychiatric epidemiology
- Veterinary epidemiology
- Epidemiology of zoonosis
- Respiratory Epidemiology
- Pediatric Epidemiology
## By methodological approach
- Environmental epidemiology
- Clinical epidemiology
- Conflict epidemiology
- Genetic epidemiology
- Molecular epidemiology
- Nutritional epidemiology
- Social epidemiology
- Lifecourse epidemiology
- Epi methods development / Biostatistics
- Meta-analysis
- Spatial epidemiology
- Tele-epidemiology
- Biomarker epidemiology
- Pharmacoepidemiology
- Primary care epidemiology
- Infection control and hospital epidemiology
- Public Health practice epidemiology
- Surveillance epidemiology (Clinical surveillance)
- Disease Informatics | Epidemiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Epidemiology is the study of factors affecting the health and illness of populations, and serves as the foundation and logic of interventions made in the interest of public health and preventive medicine. It is considered a cornerstone methodology of public health research, and is highly regarded in evidence-based medicine for identifying risk factors for disease and determining optimal treatment approaches to clinical practice.
The work of communicable and non-communicable disease epidemiologists ranges from outbreak investigation, to study design, data collection and analysis including the development of statistical models to test hypotheses and the 'writing-up' of results for submission to peer reviewed journals. Epidemiologists may draw on a number of other scientific disciplines such as biology in understanding disease processes and social science disciplines including sociology and philosophy in order to better understand proximate and distal risk factors.
# Etymology
Epidemiology, "the study of what is upon the people", is derived from the Greek terms epi = upon, among; demos = people, district; logos = study, word, discourse; suggesting that it applies only to human populations. But the term is widely used in studies of zoological populations (veterinary epidemiology), although the term 'epizoology' is available, and it has also been applied to studies of plant populations (botanical epidemiology).[1] It is also applied to studies of micro-organisms (microbial epidemiology).
# History of epidemiology
The Greek physician Hippocrates is sometimes said to be the "father of epidemiology". He is the first person known to have examined the relationships between the occurrence of disease and environmental influences. He coined the terms endemic (for diseases usually found in some places but not in others) and epidemic (for disease that are seen at some times but not others.[2]
One of the earliest theories on the origin of disease was that it was primarily the fault of human luxury. This was expressed by philosophers such as Plato[3] and Rousseau,[4] and social critics like Jonathan Swift [5].
In the medieval Islamic world, Muslim physicians discovered the contagious nature of infectious disease. In particular, the Persian physician Avicenna, considered a "father of modern medicine",[6] in The Canon of Medicine (1020s), discovered the contagious nature of tuberculosis and sexually transmitted disease, and the distribution of disease through water and soil,[7] stated that bodily secretion is contaminated by foul foreign earthly bodies before being infected,[8] introduced the method of quarantine as a means of limiting the spread of contagious disease,[9] the method of risk factor analysis, and the idea of a syndrome in the diagnosis of specific diseases.[10]
When the Black Death bubonic plague reached al-Andalus in the 14th century, the Arabian physician Ibn Khatima discovered that infectious diseases are caused by microorganisms which enter the human body. Another 14th century Andalusian-Arabian physician, Ibn al-Khatib (1313-1374), wrote a treatise called On the Plague, in which he stated how infectious disease can be transmitted through bodily contact and "through garments, vessels and earrings."[8]
In the middle of the 16th century, a famous Italian doctor from Florence named Girolamo Fracastoro was the first one who proposed a theory that very small, unseeable, live particles cause diseases. They were considered to be able to spread by air, multiply by themselves and to be destroyable by fire. In such a way he refuted Galen's theory of miasms (poison gas in sick people). In 1543 he wrote a book "De contagione et contagiosis morbis". At that time, based of his theory, he was the first to promote personal and environmental hygiene. This theory could not have been proven until the development of the first microscope by Anton van Leeuwenhoek in 1675.
John Graunt, a professional haberdasher and serious amateur scientist, published Natural and Political Observations ... upon the Bills of Mortality in 1662. In it, he used analysis of the mortality rolls in London before the Great Plague to present one of the first life tables and report time trends for many diseases, new and old. He provided statistical evidence for many theories on disease, and also refuted many widespread ideas on them.
Dr. John Snow is famous for the suppression of an 1854 outbreak of cholera in London's Soho district. He identified the cause of the outbreak as a public water pump on Broad Street and had the handle removed, thus ending the outbreak. (It has been questioned as to whether the epidemic was already in decline when Snow took action.) This has been perceived as a major event in the history of public health and can be regarded as the founding event of the science of epidemiology.
Other pioneers include Danish physician P. A. Schleisner, who in 1849 related his work on the prevention of the epidemic of tetanus neonatorum on the Vestmanna Islands in Iceland. Another important pioneer was Hungarian physician Ignaz Semmelweis, who in 1847 brought down infant mortality at a Vienna hospital by instituting a disinfection procedure. His findings were published in 1850, but his work was ill received by his colleagues, who discontinued the procedure. Disinfection did not become widely practiced until British surgeon Joseph Lister 'discovered' antiseptics in 1865 in light of the work of Louis Pasteur.
In the early 20th century, mathematical methods were introduced into epidemiology by Ronald Ross, Anderson Gray McKendrick and others.
Another breakthrough was the 1954 publication of the results of a British Doctors Study, led by Richard Doll and Austin Bradford Hill, which lent very strong statistical support to the suspicion that tobacco smoking was linked to lung cancer.
- History of emerging infectious diseases
# The profession of epidemiology
To date, few Universities offer epidemiology as a course of study at undergraduate level. Many epidemiologists, therefore, are physicians or hold other postgraduate degrees including a Master of Public Health (MPH), Master of Science or Epidemiology (MSc.) Other higher degrees confer the title of Doctor such as a Doctor of Public Health (DrPH), Doctor of Philosophy (PhD), Doctor of Science (ScD) or for those clinically trained, Doctor of Medicine (MD). In the United Kingdom, the title of 'doctor' is a honorary one conferred to those having attained the professional degrees of Bachelor of Medicine and Surgery (MBBS or MBChB). As public health/health protection practitioners, epidemiologists work in a number of different settings. Some epidemiologists work 'in the field', i.e., in the community, commonly in a public health/health protection service and are often at the forefront of investigating and combating disease outbreaks. Others work for non-profit organizations, universities, hospitals and larger government entities such as the Centers for Disease Control and Prevention (CDC), Health Protection Agency or the Public Health Agency of Canada.
# The practice of epidemiology
Epidemiologists employ a range of study designs from the observational to experimental and are generally categorized as descriptive, analytic (aiming to further examine known associations or hypothesized relationships), and experimental (a term often equated with clinical or community trials of treatments and other interventions). Epidemiological studies are aimed, where possible, at revealing unbiased relationships between exposures such as alcohol or smoking, biological agents, stress, or chemicals to mortality or morbidity. Identifying causal relationships between these exposures and outcomes are important aspects of epidemiology. Modern epidemiologist use disease informatics as a tool.
The term 'epidemiologic triangle' is used to describe the intersection of Host, Agent, and Environment in analyzing an outbreak.
# Epidemiology as causal inference
Although epidemiology is sometimes viewed as a collection of statistical tools used to elucidate the associations of exposures to health outcomes, a deeper understanding of this science is that of discovering causal relationships.
It is nearly impossible to say with perfect accuracy how even the most simple physical systems behave beyond the immediate future, much less the complex field of epidemiology, which draws on biology, sociology, mathematics, statistics, anthropology, psychology, and policy; "Correlation does not imply causation," is a common theme to much of the epidemiological literature. For epidemiologists, the key is in the term inference. Epidemiologists use gathered data and a broad range of biomedical and psychosocial theories in an iterative way to generate or expand theory, to test hypotheses, and to make educated, informed assertions about which relationships are causal, and about exactly how they are causal. Epidemiologists Rothman and Greenland emphasize that the "one cause - one effect" understanding is a simplistic mis-belief. Most outcomes — whether disease or death — are caused by a chain or web consisting of many component causes.
## Bradford-Hill criteria
In 1965 Austin Bradford Hill detailed criteria for assessing evidence of causation[11]. These guidelines are sometimes referred to as the Bradford-Hill criteria, but this makes it seem like it is some sort of checklist. For example, Phillips and Goodman (2004) note that they are often taught or referenced as a checklist for assessing causality, despite this not being Hill's intention [12]. Hill himself said "None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required sine qua non"[11].
- Strength: A small association does not mean that there is not a causal effect.[11]
- Consistency: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect.[11]
- Specificity: Causation is likely if a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship.[11]
- Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay).[11]
- Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence.[11]
- Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge).[11]
- Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological affect on associations" [11].
- Experiment: "Occasionally it is possible to appeal to experimental evidence" [11].
- Analogy: The effect of similar factors may be considered[11].
# Legal interpretation of epidemiological studies
In United States law, epidemiology alone cannot prove that a causal association does not exist in general. Conversely, it can be (and is in some circumstances) taken by US courts, in an individual case, to justify an inference that a causal association does exist, based upon a balance of probability. Strictly speaking, epidemiology can only go to prove that an agent could have caused but not that, in any particular case, it did cause:
"Epidemiology is concerned with the incidence of disease in populations and does not address the question of the cause of an individual’s disease. This question, sometimes referred to as specific causation, is beyond the domain of the science of epidemiology. Epidemiology has its limits at the point where an inference is made that the relationship between an agent and a disease is causal (general causation) and where the magnitude of excess risk attributed to the agent has been determined; that is, epidemiology addresses whether an agent can cause a disease, not whether an agent did cause a specific plaintiff’s disease."[13]
# Epidemiology and advocacy
As a public health discipline, epidemiologic evidence is often used to advocate both personal measures like diet change and corporate measures like removal of junk food advertising, with study findings disseminated to the general public in order to help people to make informed decisions about their health. Often the uncertainties about these findings are not communicated well; news articles often prominently report the latest result of one study with little mention of its limitations, caveats, or context. Epidemiological tools have proved effective in establishing major causes of diseases like cholera and lung cancer but have had problems with more subtle health issues, and several recent epidemiological results on medical treatments (for example, on the effects of hormone replacement therapy) have been refuted by later randomized controlled trials.[14]
# Epidemiology and population-based health management
Epidemiological practice and the results of epidemiological analysis make a significant contribution to emerging population-based health management frameworks.
Population-based health management encompasses the ability to:
- assess the health states and health needs of a target population;
- implement and evaluate interventions that are designed to improve the health of that population; and
- efficiently and effectively provide care for members of that population in a way that is consistent with the community’s cultural, policy and health resource values.
Modern population-based health management is complex, requiring a multiple set of skills (medical, political, technological, mathematical etc.) of which epidemiological practice and analysis is a core component, that is unified with management science to provide efficient and effective health care and health guidance to a population. This task requires the forward looking ability of modern risk management approaches that transform health risk factors, incidence, prevalence and mortality statistics (derived from epidemiological analysis) into management metrics that not only guide how a health system responds to current population health issues, but also how a health system can be managed to better respond to future potential population health issues.
Examples of organizations that use population-based health management that leverage the work and results of epidemiological practice include Canadian Strategy for Cancer Control, Health Canada Tobacco Control Programs, Rick Hansen Foundation, Canadian Tobacco Control Research Initiative.[15][16][17]
Each of these organizations use a population-based health management framework called Life at Risk that combines epidemiological quantitative analysis with demographics, health agency operational research and economics to perform:
- Population Life Impacts Simulations: Measurement of the future potential impact of disease upon the population with respect to new disease cases, prevalence, premature death as well as potential years of life lost from disability and death;
- Labour Force Life Impacts Simulations: Measurement of the future potential impact of disease upon the labour force with respect to new disease cases, prevalence, premature death and potential years of life lost from disability and death;
- Economic Impacts of Disease Simulations: Measurement of the future potential impact of disease upon private sector disposable income impacts (wages, corporate profits, private health care costs) and public sector disposable income impacts (personal income tax, corporate income tax, consumption taxes, publicly funded health care costs).
# Types of studies
## Case series
Case-series describe the experience of a single patient or a group of patients with a similar diagnosis. They are purely descriptive and cannot be used to make inferences about the general population of patients with that disease. These types of studies, in which an astute clinician identifies an unusual feature of a disease or a patient's history, may lead to formulation of a new hypothesis. Using the data from the series, analytic studies could be done to investigate possible causal factors. These can include case control studies or prospective studies. A case control study would involve matching comparable controls without the disease to the cases in the series. A prospective study would involve following the case series over time to evaluate the disease’s natural history.[18]
## Case control studies
Case control studies select subjects based on their disease status. The study population is comprised of individuals that are disease positive. The control group should come from the same population that gave rise to the cases. The case control study looks back through time at potential exposures both populations (cases and controls) may have encountered. A 2x2 table is constructed, displaying exposed cases (A), the exposed controls (B), unexposed cases (C) and the unexposed controls(D). The statistic generated to measure association is the odds ratio (OR), which is the ratio of the odds of exposure in the cases (A/C) to the odds of exposure in the controls (B/D). This is equal to (A*D)/(B*C).
If the OR is clearly greater than 1, then the conclusion is "those with the disease are more likely to have been exposed," whereas if it is close to 1 then the exposure and disease are not likely associated. If the OR is far less than one, then this suggests that the exposure is a protective factor in the causation of the disease.
Case control studies are usually faster and more cost effective than cohort studies, but are sensitive to bias (such as recall bias and selection bias). The main challenge is to identify the appropriate control group; the distribution of exposure among the control group should be representative of the distribution in the population that gave rise to the cases. This can be achieved by drawing a random sample from the original population at risk. This has as a consequence that the control group can contain people with the disease under study when the disease has a high attack rate in a population.
## Cohort studies
Cohort studies select subjects based on their exposure status. The study subjects should be at risk of the outcome under investigation at the beginning of the cohort study; this usually means that they should be disease free when the cohort study starts. The cohort is followed through time to assess their later outcome status. An example of a cohort study would be the investigation of a cohort of smokers and nonsmokers over time to estimate the incidence of lung cancer. The same 2x2 table is constructed as with the case control study. However, the point estimate generated is the Relative Risk (RR) [What is Relative Risk? How is it measured? How can values be interpreted? Link to statistical analysis? Explanation needed], which is the incidence of disease in the exposed group (A/A+B) over the incidence in the unexposed (C/C+D).
As with the OR, a RR greater than 1 shows association, where the conclusion can be read "those with the exposure were more likely to develop disease."
Prospective studies have many benefits over case control studies. The RR is a more powerful effect measure than the OR, as the OR is just an estimation of the RR, since true incidence cannot be calculated in a case control study where subjects are selected based on disease status. Temporality can be established in a prospective study, and confounders are more easily controlled for. However, they are more costly, and there is a greater chance of losing subjects to follow-up based on the long time period over which the cohort is followed.
## Outbreak investigation
# Epidemiological methods and measures
# Criticisms of the validity of epidemiological conclusions
## Random error
Random error is the result of fluctuations around a true value because of sampling variability. Random error is just that: random. It can occur during data collection, coding, transfer, or analysis. Examples of random error include: poorly worded questions, a misunderstanding in interpreting an individual answer from a particular respondent, or a typographical error during coding. Random error effects measurement in a transient, inconsistent manner and it is impossible to correct for random error.
There is random error in all sampling procedures. This is called sampling error.
Precision in epidemiological variables is a measure of random error. Precision is also inversely related to random error, so that to reduce random error is to increase precision. Confidence intervals are computed to demonstrate the precision of relative risk estimates. The narrower the confidence interval, the more precise the relative risk estimate.
There are two basic ways to reduce random error in an epidemiological study. The first is to increase the sample size of the study. In other words, add more subjects to your study. The second is to reduce the variability in measurement in the study. This might be accomplished by using a more accurate measuring device or by increasing the number of measurements.
Note, that if we increase the sample size, increase the number of measurements, or purchase a more precise measuring tool, we are usually driving up the costs of the study. There is usually an uneasy balance between the need for adequate precision and the practical issue of study cost.
## Systematic error
A systematic error or bias occurs when there is a difference between the true value (in the population) and the observed value (in the study) from any cause other than sampling variability. An example of systematic error is if, unbeknown to you, the pulse oximeter you are using is set incorrectly and adds two points to the true value each time a measurement is taken. Because the error happens in every instance, it is systematic. Conclusions you draw based on that data will still be incorrect. But the error can be reproduced in the future (eg, by using the same mis-set instrument).
A mistake in coding the effects *all* responses for that particular question is another example of a systematic error.
The validity of a study is dependent on the degree of systematic error. Validity is usually separated into two components:
- Internal validity is dependent on the amount of error in measurements, including exposure, disease, and the associations between these variables. Good internal validity implies a lack of error in measurement and suggests that inferences may be drawn at least as they pertain to the subjects under study.
- External validity pertains to the process of generalizing the findings of the study to the population from which the sample was drawn (or even beyond that population to a more universal statement). This requires an understanding of which conditions are relevant (or irrelevant) to the generalization. Internal validity is clearly a prerequisite for external validity.
## Selection bias
Selection bias is one of three types of bias that threatens the internal validity of a study. Selection bias is an inaccurate measure of effect which results from a systematic difference in the relation between exposure and disease between those who are in the study and those who should be in the study.
If one or more of the sampled groups does not accurately represent the population they are intended to represent, then the results of that comparison may be misleading.
Selection bias can produce either an overestimation or underestimation of the effect measure. It can also produce an effect when none actually exists.
An example of selection bias is volunteer bias. Volunteers may not be representative of the true population. They may exhibit exposures or outcomes which may differ from nonvolunteers (eg volunteers tend to be healthier or they may seek out the study because they already have a problem with the disease being studied and want free treatment).
Another type of selection bias is caused by non-respondents. For example, women who have been subjected to politically motivated sexual assault may be more fearful of participating in a survey measuring incidents of mass rape than non-victims, leading researchers to underestimate the number of rapes.
To reduce selection bias, you should develop explicit (objective) definitions of exposure and/or disease. You should strive for high participation rates, for instance, by offering incentives to participants. Have a large sample size and randomly select the respondents so that you have a better chance of truly representing the population.
# Epidemiology journals
A ranked list of journals:[19]
## General epidemiology journals
- American Journal of Epidemiology
- Epidemiologic Reviews
- Epidemiology
- International Journal of Epidemiology
- Annals of Epidemiology
- Journal of Epidemiology and Community Health
- European Journal of Epidemiology
- Emerging Themes in Epidemiology
- Epidemiologic Perspectives and Innovations
- Eurosurveillance
## Specialty epidemiology journals
- Cancer Epidemiology Biomarkers and Prevention
- Genetic Epidemiology
- Journal of Clinical Epidemiology
- Paediatric Perinatal Epidemiology
- Epidemiology and Infection
- Pharmacoepidemiology and Drug Safety
# Areas of epidemiology
## By physiology/disease area
- Infectious disease epidemiology
- Cardiovascular disease epidemiology
- Cancer epidemiology
- Neuroepidemiology
- Epidemiology of Aging
- Oral/Dental epidemiology
- Reproductive epidemiology
- Obesity/diabetes epidemiology
- Renal epidemiology
- Injury epidemiology
- Psychiatric epidemiology
- Veterinary epidemiology
- Epidemiology of zoonosis
- Respiratory Epidemiology
- Pediatric Epidemiology
## By methodological approach
- Environmental epidemiology
- Clinical epidemiology
- Conflict epidemiology
- Genetic epidemiology
- Molecular epidemiology
- Nutritional epidemiology
- Social epidemiology
- Lifecourse epidemiology
- Epi methods development / Biostatistics
- Meta-analysis
- Spatial epidemiology
- Tele-epidemiology
- Biomarker epidemiology
- Pharmacoepidemiology
- Primary care epidemiology
- Infection control and hospital epidemiology
- Public Health practice epidemiology
- Surveillance epidemiology (Clinical surveillance)
- Disease Informatics | https://www.wikidoc.org/index.php/Descriptive_epidemiology | |
3dd15c2a744beb1cd9a5f22afd37e7bbebfc0d3a | wikidoc | Desmoglein-1 | Desmoglein-1
Desmoglein-1 is a protein that in humans is encoded by the DSG1 gene. Desmoglein-1 is expressed everywhere in the skin epidermis, but mainly it is expressed in the superficial upper layers of the skin epidermis.
# Function
Desmosomes are cell-cell junctions between epithelial, myocardial and certain other cell types. Desmoglein-1 is a calcium-binding transmembrane glycoprotein component of desmosomes in vertebrate epithelial cells. Currently, four desmoglein subfamily members have been identified and all are members of the cadherin cell adhesion molecule superfamily. These desmoglein gene family members are located in a cluster on chromosome 18. The protein encoded by this gene has been identified as the autoantigen of the autoimmune skin blistering disease pemphigus foliaceus. It has been found that Desmoglein-1 is the target antigen in majority of the cases linked to IgG/IgA pemphigus, which is an autoimmune IgG/IgA antibody mediated response.
Deficiency of the Desmoglein-1 protein has been found to be associated with increased expression of the for multiple genes encoding allergy related cytokines. Desmoglein-1 is haploinsufficient and a mutation in the gene can cause the autosomal dominant mutation striate palmoplantar keratoderma. Recently, cases have arose where the homozygous loss of the Desmoglein-1 gene has resulted in a rare syndrome known as SAM syndrome - severe dermatitis, multiple allergies, and metabolic wasting.
# Interactions
Desmoglein-1 has been shown to interact with PKP3, PKP2, and PTPRT(PTPrho) | Desmoglein-1
Desmoglein-1 is a protein that in humans is encoded by the DSG1 gene.[1][2] Desmoglein-1 is expressed everywhere in the skin epidermis, but mainly it is expressed in the superficial upper layers of the skin epidermis.[3]
# Function
Desmosomes are cell-cell junctions between epithelial, myocardial and certain other cell types. Desmoglein-1 is a calcium-binding transmembrane glycoprotein component of desmosomes in vertebrate epithelial cells. Currently, four desmoglein subfamily members have been identified and all are members of the cadherin cell adhesion molecule superfamily. These desmoglein gene family members are located in a cluster on chromosome 18. The protein encoded by this gene has been identified as the autoantigen of the autoimmune skin blistering disease pemphigus foliaceus.[2] It has been found that Desmoglein-1 is the target antigen in majority of the cases linked to IgG/IgA pemphigus, which is an autoimmune IgG/IgA antibody mediated response.[4]
Deficiency of the Desmoglein-1 protein has been found to be associated with increased expression of the for multiple genes encoding allergy related cytokines.[5] Desmoglein-1 is haploinsufficient and a mutation in the gene can cause the autosomal dominant mutation striate palmoplantar keratoderma.[6] Recently, cases have arose where the homozygous loss of the Desmoglein-1 gene has resulted in a rare syndrome known as SAM syndrome - severe dermatitis, multiple allergies, and metabolic wasting.[7]
# Interactions
Desmoglein-1 has been shown to interact with PKP3,[8] PKP2,[9] and PTPRT(PTPrho)[10] | https://www.wikidoc.org/index.php/Desmoglein-1 | |
5fde9ed32b69669166fd0b256cd934da48cadea8 | wikidoc | Desmoglein-2 | Desmoglein-2
Desmoglein-2 is a protein that in humans is encoded by the DSG2 gene. Desmoglein-2 is highly expressed in epithelial cells and cardiomyocytes. Desmoglein-2 is localized to desmosome structures at regions of cell-cell contact and functions to structurally adhere adjacent cells together. In cardiac muscle, these regions are specialized regions known as intercalated discs. Mutations in desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy.
# Structure
Desmoglein-2 is a 122.2 kDa protein composed of 1118 amino acids. Desmoglein-2 is a calcium-binding transmembrane glycoprotein component of desmosomes in vertebrate cells. Currently, four desmoglein subfamily members have been identified and all are members of the cadherin cell adhesion molecule superfamily. These desmoglein gene family members are located in a cluster on chromosome 18. This second family member, desmoglein-2 is expressed in desmosome-containing tissues, such as cardiac muscle, colon, colon carcinoma, and other simple and stratified epithelial-derived cell lines. Desmoglein-2 is the only desmoglein isoform expressed in cardiomyocytes.
# Function
Desmoglein-2 is an integral component of desmosomes, which are cell-cell junctions between epithelial, myocardial, and certain other cell types. Desmogleins and desmocollins connect extracellularly via homophilic and heterophilic interactions. The cytoplasmic tails of desmosomal cadherins bind to plakoglobin and plakophilins, which bind desmoplakin. In cardiac muscle, desmoglein-2 localizes to the intercalated disc, responsible for mechanically and electrically coupling adjacent cardiomyocytes. In vitro studies in HL-1 cardiomyocytes have shown that inhibition of desmoglein-2 binding or mutation of desmoglein-2 protein (Ala517Val or Val920Gly) at cardiac intercalated discs results in a reduced strength of cell-cell contact, demonstrating that desmoglein-2 is critical for cardiomyocyte cohesion.
Studies in transgenic animals have provided insights into desmoglein-2 function. Mice harboring a mutation in DSG-2 in which desmoglein-2 lacked parts of the adhesive extracellular domains were serially examined over time. These mice exhibited white plaque-like lesions in cardiac muscle as early as 2 weeks, displaying a cardiac phenotype by 4 weeks that involved loss of viable cardiomyocytes and heavy cell calcification. Other abnormalities included near to complete dissociation of intercalated discs and inflammation, and eventual arrhythmogenic right ventricular cardiomyopathy with ventricular dilation, fibrosis and cardiac arrhythmia. Studies employing another transgenic mutant DSG2 mouse model harboring a Asn271Ser showed that this mutation caused widening of desmosomes and adherens junctions concomitant with electrophysiologic abnormalities and enhanced susceptibility to cardiac arrhythmias. These changes occurred prior to any cardiomyocyte necrosis or fibrosis. Additionally, it was demonstrated that desmoglein-2 interacts in vivo with the sodium channel protein Na(V)1.5. An additional transgenic model in which desmoglein-2 was knocked out in a cardiac-specific manner showed a loss of adhesive function at intercalated discs in adult animals, albeit normal heart development. In adulthood, 100% of transgenic mutant mice developed chamber dilation, necrosis, aseptic inflammation, fibrosis and conduction defects, as well as modified distribution of connexin-43.
# Clinical significance
Mutations in DSG2 have been identified in patients with arrhythmogenic right ventricular cardiomyopathy, along with other desmosomal proteins PKP2 and DSP. Ultrastructural analysis has identified the presence of intercalated disc remodeling in these patients. Additionally, the Val55Met mutation in DSG2 was identified as a novel risk variant for familial dilated cardiomyopathy; patients carrying this mutation exhibited shortened desmosomal structures at cardiac intercalated discs compared to non-diseased patients.
# Interactions
Desmoglein-2 has been shown to interact with:
- DSC1,
- PKP3,
- Plakoglobin, and
- SCN5A. | Desmoglein-2
Desmoglein-2 is a protein that in humans is encoded by the DSG2 gene.[1][2] Desmoglein-2 is highly expressed in epithelial cells and cardiomyocytes. Desmoglein-2 is localized to desmosome structures at regions of cell-cell contact and functions to structurally adhere adjacent cells together. In cardiac muscle, these regions are specialized regions known as intercalated discs. Mutations in desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy.
# Structure
Desmoglein-2 is a 122.2 kDa protein composed of 1118 amino acids.[3] Desmoglein-2 is a calcium-binding transmembrane glycoprotein component of desmosomes in vertebrate cells. Currently, four desmoglein subfamily members have been identified and all are members of the cadherin cell adhesion molecule superfamily. These desmoglein gene family members are located in a cluster on chromosome 18. This second family member, desmoglein-2 is expressed in desmosome-containing tissues, such as cardiac muscle, colon, colon carcinoma, and other simple and stratified epithelial-derived cell lines.[2] Desmoglein-2 is the only desmoglein isoform expressed in cardiomyocytes.
# Function
Desmoglein-2 is an integral component of desmosomes, which are cell-cell junctions between epithelial, myocardial, and certain other cell types. Desmogleins and desmocollins connect extracellularly via homophilic and heterophilic interactions. The cytoplasmic tails of desmosomal cadherins bind to plakoglobin and plakophilins, which bind desmoplakin.[4] In cardiac muscle, desmoglein-2 localizes to the intercalated disc, responsible for mechanically and electrically coupling adjacent cardiomyocytes.[5] In vitro studies in HL-1 cardiomyocytes have shown that inhibition of desmoglein-2 binding or mutation of desmoglein-2 protein (Ala517Val or Val920Gly) at cardiac intercalated discs results in a reduced strength of cell-cell contact, demonstrating that desmoglein-2 is critical for cardiomyocyte cohesion.[6]
Studies in transgenic animals have provided insights into desmoglein-2 function. Mice harboring a mutation in DSG-2 in which desmoglein-2 lacked parts of the adhesive extracellular domains were serially examined over time.[7] These mice exhibited white plaque-like lesions in cardiac muscle as early as 2 weeks, displaying a cardiac phenotype by 4 weeks that involved loss of viable cardiomyocytes and heavy cell calcification. Other abnormalities included near to complete dissociation of intercalated discs and inflammation, and eventual arrhythmogenic right ventricular cardiomyopathy with ventricular dilation, fibrosis and cardiac arrhythmia. Studies employing another transgenic mutant DSG2 mouse model harboring a Asn271Ser showed that this mutation caused widening of desmosomes and adherens junctions concomitant with electrophysiologic abnormalities and enhanced susceptibility to cardiac arrhythmias.[8] These changes occurred prior to any cardiomyocyte necrosis or fibrosis. Additionally, it was demonstrated that desmoglein-2 interacts in vivo with the sodium channel protein Na(V)1.5.[8] An additional transgenic model in which desmoglein-2 was knocked out in a cardiac-specific manner showed a loss of adhesive function at intercalated discs in adult animals, albeit normal heart development. In adulthood, 100% of transgenic mutant mice developed chamber dilation, necrosis, aseptic inflammation, fibrosis and conduction defects, as well as modified distribution of connexin-43.[9]
# Clinical significance
Mutations in DSG2 have been identified in patients with arrhythmogenic right ventricular cardiomyopathy,[10] along with other desmosomal proteins PKP2 and DSP. Ultrastructural analysis has identified the presence of intercalated disc remodeling in these patients.[11] Additionally, the Val55Met mutation in DSG2 was identified as a novel risk variant for familial dilated cardiomyopathy; patients carrying this mutation exhibited shortened desmosomal structures at cardiac intercalated discs compared to non-diseased patients.[12]
# Interactions
Desmoglein-2 has been shown to interact with:
- DSC1,[13]
- PKP3,[14]
- Plakoglobin,[15][16][17] and
- SCN5A.[8] | https://www.wikidoc.org/index.php/Desmoglein-2 | |
c2531f740a9c42a3fb564d715060ceb5bc1ea57f | wikidoc | Desmoglein-3 | Desmoglein-3
Desmoglein-3 is a protein that in humans is encoded by the DSG3 gene. In the skin epidermis Desmoglein-3 is expressed in the basal lower layers of the epidermis, and dominates in terms of expression on mucosal surfaces compared to Desmoglein-1.
# Function
Desmosomes are cell-cell junctions between epithelial, myocardial, and certain other cell types. Desmoglein 3 is a calcium-binding transmembrane glycoprotein component of desmosomes in vertebrate epithelial cells. Currently, four desmoglein subfamily members have been identified and all are members of the cadherin cell adhesion molecule superfamily. These desmoglein gene family members are located in a cluster on chromosome 18. This protein, along with Desmoglein-1, has been identified as the autoantigen of the autoimmune skin blistering disease pemphigus vulgaris. The mucosal dominant form of pemphigus vulgaris only involves antibodies against Desmoglein-3 and causes mucosal erosions, but no skin lesions. Desmoglein-3 serves as a prognostic marker of Esophageal Squamous Cell Carcinoma (ESCC), and may even be involved in the progression of ESCC.
# Pathogenicity
Pathogenicity of Desmoglein-3 antibodies comes from the existence of a tryptophan residue that could be interacting with the binding pocket that is necessary for trans-interaction of Desmoglein molecules. Such antibodies can lead to the cause of skin disorders like pemphigus vulgaris.
# Interactions
Desmoglein 3 has been shown to interact with PKP3. | Desmoglein-3
Desmoglein-3 is a protein that in humans is encoded by the DSG3 gene.[1][2] In the skin epidermis Desmoglein-3 is expressed in the basal lower layers of the epidermis, and dominates in terms of expression on mucosal surfaces compared to Desmoglein-1.[3]
# Function
Desmosomes are cell-cell junctions between epithelial, myocardial, and certain other cell types. Desmoglein 3 is a calcium-binding transmembrane glycoprotein component of desmosomes in vertebrate epithelial cells. Currently, four desmoglein subfamily members have been identified and all are members of the cadherin cell adhesion molecule superfamily. These desmoglein gene family members are located in a cluster on chromosome 18. This protein, along with Desmoglein-1, has been identified as the autoantigen of the autoimmune skin blistering disease pemphigus vulgaris.[4] The mucosal dominant form of pemphigus vulgaris only involves antibodies against Desmoglein-3 and causes mucosal erosions, but no skin lesions.[3] Desmoglein-3 serves as a prognostic marker of Esophageal Squamous Cell Carcinoma (ESCC), and may even be involved in the progression of ESCC.[5]
# Pathogenicity
Pathogenicity of Desmoglein-3 antibodies comes from the existence of a tryptophan residue that could be interacting with the binding pocket that is necessary for trans-interaction of Desmoglein molecules.[6] Such antibodies can lead to the cause of skin disorders like pemphigus vulgaris.
# Interactions
Desmoglein 3 has been shown to interact with PKP3.[7] | https://www.wikidoc.org/index.php/Desmoglein-3 | |
a6b5edb2aa7e879c5682a927b608699c34b48a9c | wikidoc | Desquamation | Desquamation
Desquamation is the shedding of the outer layers of the skin. The word comes from the Latin 'desquamare' , meaning "to scrape the scales off a fish".
For example, once the rash of measles fades, there is desquamation. Also seen in Toxic Shock Syndrome
in the eye, the epithelial basement membrane (lens capsule) completely encloses the lens, therefore desquamation of aging cells is impossible, and due to the complete absence of blood vessels or transport of metabolites in this area, there is no subsequent remodelling of these fibres, nor removal of degraded lens fibres.
Nonpathologic desquamation occurs when corneocytes, after move apically over about 14 days, are individually shed invisibly.:279 In pathologic desquamation, the stratum corneum becomes thicker (hyperkeratosis), imparting a "dry" or scaly appearance to the skin, and instead of detaching as single cells, corneocytes are shed in clusters, forming visible scales.:279 | Desquamation
Template:SignSymptom infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Desquamation is the shedding of the outer layers of the skin. The word comes from the Latin 'desquamare' , meaning "to scrape the scales off a fish".
For example, once the rash of measles fades, there is desquamation. Also seen in Toxic Shock Syndrome
in the eye, the epithelial basement membrane (lens capsule) completely encloses the lens, therefore desquamation of aging cells is impossible, and due to the complete absence of blood vessels or transport of metabolites in this area, there is no subsequent remodelling of these fibres, nor removal of degraded lens fibres.
Nonpathologic desquamation occurs when corneocytes, after move apically over about 14 days, are individually shed invisibly.[1]:279 In pathologic desquamation, the stratum corneum becomes thicker (hyperkeratosis), imparting a "dry" or scaly appearance to the skin, and instead of detaching as single cells, corneocytes are shed in clusters, forming visible scales.[1]:279 | https://www.wikidoc.org/index.php/Desquamation | |
c19ebe63215697d511dffd2c2afda761b24bbff2 | wikidoc | Detoxication | Detoxication
The major metabolites formed from most drug metabolism are detoxication products.
There are two common patterns observed:
- A drug with potent pharmacological activity is converted to a major metabolite with markedly reduced or no pharmacological activity (e.g., Pentobarbital and Hydroxypentobarbital)
- A drug is converted to a metabolite with roughly equivalent or slightly lower pharmacological activity. | Detoxication
The major metabolites formed from most drug metabolism are detoxication products.
There are two common patterns observed:
- A drug with potent pharmacological activity is converted to a major metabolite with markedly reduced or no pharmacological activity (e.g., Pentobarbital and Hydroxypentobarbital)
- A drug is converted to a metabolite with roughly equivalent or slightly lower pharmacological activity.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Detoxication | |
ac8d7c47cb38447e92842e4c2e6b266def0c0459 | wikidoc | Deuterostome | Deuterostome
# Overview
Deuterostomes (taxonomic term: Deuterostomia; from the Greek: "second mouth") are a superphylum of animals. They are a subtaxon of the Bilateria branch of the subregnum Eumetazoa, and are opposed to the protostomes. Deuterostomes are distinguished by their embryonic development; in deuterostomes, the first opening (the blastopore) becomes the anus, while in protostomes it becomes the mouth.
There are four living phyla of deuterostomes:
- Phylum Chordata (vertebrates and their kin)
- Phylum Echinodermata (starfish, sea urchins, sea cucumbers, etc.)
- Phylum Hemichordata (acorn worms and possibly graptolites)
- Phylum Xenoturbellida (2 species of worm-like animals)
The phylum Chaetognatha (arrow worms) may also belong here. Extinct groups may include the phylum Vetulicolia. Echinodermata, Hemichordata and Xenoturbellida form the clade Ambulacraria.
In both deuterostomes and protostomes, a zygote first develops into a hollow ball of cells, called a blastula. In deuterostomes, the early divisions occur parallel or perpendicular to the polar axis. This is called radial cleavage, and also occurs in certain protostomes, such as the lophophorates. Deuterostomes display indeterminate cleavage, in which the developmental fate of the cells in the developing embryo are not determined by the identity of the parent cell. Thus if the first four cells are separated, each cell is capable of forming a complete small larva, and if a cell is removed from the blastula the other cells will compensate.
In deuterostomes the mesoderm forms as evaginations of the developed gut that pinch off, forming the coelom. This is called enterocoely.
Both the Hemichordata and Chordata have gill slits, and primitive fossil echinoderms also show signs of gill slits. A hollow nerve cord is found in all chordates, even tunicates (even if it disappears in the adults). Some hemichordates also have a tubular nerve cord. In the early embryonic stage it looks like the hollow nerve cord of chordates. Because of the degenerated nervous system of echinoderms it is not possible to discern much about their ancestors in this matter, but based on different facts it is quite possible that all the present deuterostomes evolved from a common ancestor which had gill slits, a hollow nerve cord and a segmented body. It could have resembled the small group of Cambrian deuterostomes named Vetulicolia.
# Notes
- ↑ Stach, Thomas, Samuel Dupont, Olle Israelson, Geraldine Fauville, Hiroaki Nakano and Mike Thorndyke. (2005) "Immunocytological evidence supports the hypotheses that Xenoturbella bocki (Westblad 1949), phylum uncertain, is a deuterostome and that Ambulacraria is monophyletic". Organisms Diversity & Evolution. On-line at | Deuterostome
# Overview
Deuterostomes (taxonomic term: Deuterostomia; from the Greek: "second mouth") are a superphylum of animals. They are a subtaxon of the Bilateria branch of the subregnum Eumetazoa, and are opposed to the protostomes. Deuterostomes are distinguished by their embryonic development; in deuterostomes, the first opening (the blastopore) becomes the anus, while in protostomes it becomes the mouth.
There are four living phyla of deuterostomes:
- Phylum Chordata (vertebrates and their kin)
- Phylum Echinodermata (starfish, sea urchins, sea cucumbers, etc.)
- Phylum Hemichordata (acorn worms and possibly graptolites)
- Phylum Xenoturbellida (2 species of worm-like animals)
The phylum Chaetognatha (arrow worms) may also belong here. Extinct groups may include the phylum Vetulicolia. Echinodermata, Hemichordata and Xenoturbellida form the clade Ambulacraria.[1]
In both deuterostomes and protostomes, a zygote first develops into a hollow ball of cells, called a blastula. In deuterostomes, the early divisions occur parallel or perpendicular to the polar axis. This is called radial cleavage, and also occurs in certain protostomes, such as the lophophorates. Deuterostomes display indeterminate cleavage, in which the developmental fate of the cells in the developing embryo are not determined by the identity of the parent cell. Thus if the first four cells are separated, each cell is capable of forming a complete small larva, and if a cell is removed from the blastula the other cells will compensate.
In deuterostomes the mesoderm forms as evaginations of the developed gut that pinch off, forming the coelom. This is called enterocoely.
Both the Hemichordata and Chordata have gill slits, and primitive fossil echinoderms also show signs of gill slits. A hollow nerve cord is found in all chordates, even tunicates (even if it disappears in the adults). Some hemichordates also have a tubular nerve cord. In the early embryonic stage it looks like the hollow nerve cord of chordates. Because of the degenerated nervous system of echinoderms it is not possible to discern much about their ancestors in this matter, but based on different facts it is quite possible that all the present deuterostomes evolved from a common ancestor which had gill slits, a hollow nerve cord and a segmented body. It could have resembled the small group of Cambrian deuterostomes named Vetulicolia.
# Notes
- ↑ Stach, Thomas, Samuel Dupont, Olle Israelson, Geraldine Fauville, Hiroaki Nakano and Mike Thorndyke. (2005) "Immunocytological evidence supports the hypotheses that Xenoturbella bocki (Westblad 1949), phylum uncertain, is a deuterostome and that Ambulacraria is monophyletic". Organisms Diversity & Evolution. On-line at [1]
# External links
Template:Wikispecies
- UCMP-Deuterostomes
ar:ثانويات الفم
ca:Deuteròstom
cs:Druhoústí
de:Neumünder
et:Teissuused
eo:Novbuŝulo
eu:Deuterostomio
fa:پسیندهانیان
ko:후구동물
it:Deuterostomi
ka:მეორეპირიანები
lv:Otrmutnieki
hu:Újszájúak
nl:Deuterostomia
no:Deuterostomier
oc:Deuterostomia
simple:Deuterostome
sk:Druhoústovce
sr:Deuterostomia
uk:Вториннороті
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Deuterostome | |
a6e971534de8544c185c21c73853621098215641 | wikidoc | Devil's Club | Devil's Club
Devil's Club (Oplopanax horridus, Araliaceae) is a large shrub native to the Pacific Northwest coastal forests of North America. Also known as Devil's Walking Stick, it grows to 1-1.5 m tall normally; however, instances exist of it reaching in excess of 5m in rainforest gullies, with the erect stems covered in short, stout spines. The spines are also found along the upper and lower surfaces of veins of its leaves. The leaves are spirally arranged on the stems, simple, palmately lobed with 5-13 lobes, 20-40 cm across. The flowers are produced in dense umbels 10-20 cm diameter, each flower small, with five greenish-white petals. The fruit is a small red drupe 4-7 mm diameter. The species was once included in the closely related genus Fatsia as Fatsia horrida.
The brittle spines break off easily and contain a chemical that may cause dermatitis. The fruit is considered poisonous, although it (and other plant parts) have been used for medicinal purposes by several tribes in the Pacific Northwest and up into the Yukon and Alaska.
- In Sitka, Alaska, one of the most revered
members of the community is the thorny devil's club. But the plant's
popularity as a medicinal may endanger its sacred role in Tlingit culture.
NPR's Ketzel Levine reports. Morning Edition, August 11, 2004
The Tlingit have turned to devil's club for a list of ailments you wouldn't
wish on an enemy: from coughs and colds to stomach ulcers, tuberculosis and
hypoglycemia. Tribe members steep it into teas, mash it into salves, chew,
sip and steam it. It's also used to ward off evil. The plant, dubbed the
"Tlingit aspirin" has not been approved for medicinal use by the Food and
Drug Administration.
In a report for npr.org, Levine describes the devil's club characteristics
and native habitats:
Devil's club, or Oplopanax horridus, is a plant with an unmistakable
presence. It has leaves like palm fronds, spines like daggers and red fruit
that's candy for bears. It sticks its long neck out as far south as Oregon,
and to the east, has even surprised a few Michigan hikers with its cloak of
vicious thorns. But the plant is perhaps most common to the bear, deer and
salmon habitats of Alaska's Tongass National Forest.
# Habitat
This species usually grows in rich moist forest where mature specimens of Western Redcedar and Western Hemlock dominate the overstory. Other tree species that shade Devil's Club plants near the coast include Douglas-fir, Grand Fir, Pacific Silver Fir, Sitka Spruce, Mountain Hemlock, Yellow Cedar, Black Cottonwood, Bigleaf Maple, and Red Alder. Some inland populations occur under Engelmann Spruce-Subalpine Fir associations. An outlier population occurs under Balsam poplar and White Spruce at Liard Hot Springs, deep in the boreal forest zone of British Columbia near the boundary with the Northwest Territories. Far to the east, other populations occur on several islands in Lake Superior.
# Uses
The Native Americans of the region regarded it as a sacred plant, using it for both ritual and herbal medicine. One known use was for diabetes.
To prepare devil's club tea, harvest lengths of the grey prickly stalk. Caution: Plants should only be harvested in the spring before flowering and in the fall after flowers have withered. The plant is toxic when flowering. Using a knife, scrape the stalk to remove the spines and bark to expose the green layer in between the wood and the bark. This greenery is where the medicine is. (It will not harm your drink if you get pieces of the bark or the wood in it -- it will merely alter the taste.) Using the knife, cut the green layer off and let dry. Steep for two to three hours for a light tea; or, for a darker tea, for as long as 24 hours. Strong devil's club tea has been used as an emergency stimulant in Alaska. It seems to work well, but foul taste precludes recreational use. | Devil's Club
Template:Disputed
Template:Essay-entry
Devil's Club (Oplopanax horridus, Araliaceae) is a large shrub native to the Pacific Northwest coastal forests of North America. Also known as Devil's Walking Stick, it grows to 1-1.5 m tall normally; however, instances exist of it reaching in excess of 5m in rainforest gullies, with the erect stems covered in short, stout spines. The spines are also found along the upper and lower surfaces of veins of its leaves. The leaves are spirally arranged on the stems, simple, palmately lobed with 5-13 lobes, 20-40 cm across. The flowers are produced in dense umbels 10-20 cm diameter, each flower small, with five greenish-white petals. The fruit is a small red drupe 4-7 mm diameter. The species was once included in the closely related genus Fatsia as Fatsia horrida.
The brittle spines break off easily and contain a chemical that may cause dermatitis. The fruit is considered poisonous, although it (and other plant parts) have been used for medicinal purposes by several tribes in the Pacific Northwest and up into the Yukon and Alaska.
• In Sitka, Alaska, one of the most revered
members of the community is the thorny devil's club. But the plant's
popularity as a medicinal may endanger its sacred role in Tlingit culture.
NPR's Ketzel Levine reports. Morning Edition, August 11, 2004
The Tlingit have turned to devil's club for a list of ailments you wouldn't
wish on an enemy: from coughs and colds to stomach ulcers, tuberculosis and
hypoglycemia. Tribe members steep it into teas, mash it into salves, chew,
sip and steam it. It's also used to ward off evil. The plant, dubbed the
"Tlingit aspirin" has not been approved for medicinal use by the Food and
Drug Administration.
In a report for npr.org, Levine describes the devil's club characteristics
and native habitats:
Devil's club, or Oplopanax horridus, is a plant with an unmistakable
presence. It has leaves like palm fronds, spines like daggers and red fruit
that's candy for bears. It sticks its long neck out as far south as Oregon,
and to the east, has even surprised a few Michigan hikers with its cloak of
vicious thorns. But the plant is perhaps most common to the bear, deer and
salmon habitats of Alaska's Tongass National Forest.
## Habitat
This species usually grows in rich moist forest where mature specimens of Western Redcedar and Western Hemlock dominate the overstory. Other tree species that shade Devil's Club plants near the coast include Douglas-fir, Grand Fir, Pacific Silver Fir, Sitka Spruce, Mountain Hemlock, Yellow Cedar, Black Cottonwood, Bigleaf Maple, and Red Alder. Some inland populations occur under Engelmann Spruce-Subalpine Fir associations. An outlier population occurs under Balsam poplar and White Spruce at Liard Hot Springs, deep in the boreal forest zone of British Columbia near the boundary with the Northwest Territories. Far to the east, other populations occur on several islands in Lake Superior.
## Uses
The Native Americans of the region regarded it as a sacred plant, using it for both ritual and herbal medicine. One known use was for diabetes.
To prepare devil's club tea, harvest lengths of the grey prickly stalk. Caution: Plants should only be harvested in the spring before flowering and in the fall after flowers have withered. The plant is toxic when flowering. Using a knife, scrape the stalk to remove the spines and bark to expose the green layer in between the wood and the bark. This greenery is where the medicine is. (It will not harm your drink if you get pieces of the bark or the wood in it -- it will merely alter the taste.) Using the knife, cut the green layer off and let dry. Steep for two to three hours for a light tea; or, for a darker tea, for as long as 24 hours. Strong devil's club tea has been used as an emergency stimulant in Alaska. It seems to work well, but foul taste precludes recreational use. | https://www.wikidoc.org/index.php/Devil%27s_Club | |
6dfe91f73f916723d16536ed00628b061f51e75e | wikidoc | Dexpanthenol | Dexpanthenol
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Dexpanthenol is a gastrointestinal stimulant that is FDA approved for the prophylaxis of major abdominal surgery to minimize the possibility of paralytic ileus. Common adverse reactions include allergic reactions, Hypotension.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Prophylactic use immediately after major abdominal surgery to minimize the possibility of paralytic ileus. Intestinal atony causing abdominal distention; postoperative or postpartum retention of flatus, or postoperative delay in resumption of intestinal motility; paralytic ileus.
### Dosage
- Prevention of post-operative adynamic ileus: 250 mg (1 mL) or 500 mg (2 mL) intramuscularly. Repeat in 2 hours and then every 6 hours until all danger of adynamic ileus has passed.
- Treatment of adynamic ileus: 500 mg (2 mL) intramuscularly. Repeat in 2 hours and then every 6 hours as needed.
- Intravenous administration: Dexpanthenol Injection 2 mL (500 mg) may be mixed with bulk I.V. solutions such as glucose or Lactated Ringer’s and slowly infused intravenously.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dexpanthenol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dexpanthenol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dexpanthenol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dexpanthenol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dexpanthenol in pediatric patients.
# Contraindications
- There are no known contraindications to the use of Dexpanthenol Injection.
# Warnings
- There have been rare instances of allergic reactions of unknown cause during the concomitant use of Dexpanthenol Injection with drugs such as antibiotics, narcotics and barbiturates.
- Administration of Dexpanthenol Injection directly into the vein is not advised.
- Dexpanthenol Injection should not be administered within one hour of succinylcholine.
### Precautions
- If any signs of a hypersensitivity reaction appear, Dexpanthenol Injection should be discontinued. If ileus is a secondary consequence of mechanical obstruction, primary attention should be directed to the obstruction.
- The management of adynamic ileus includes the correction of any fluid and electrolyte imbalance (especially hypokalemia), anemia and hypoproteinemia, treatment of infection, avoidance where possible of drugs which are known to decrease gastrointestinal motility and decompression of the gastrointestinal tract when considerably distended by nasogastric suction or use of a long intestinal tube.
# Adverse Reactions
## Clinical Trials Experience
- There have been a few reports of allergic reactions and single reports of several other adverse events in association with the administration of dexpanthenol. A causal relationship is uncertain. One patient experienced itching, tingling, difficulty in breathing. Another patient had red patches of skin. Two patients had generalized dermatitis and one patient urticaria.
- One patient experienced temporary respiratory difficulty following administration of dexpanthenol injection 5 minutes after succinylcholine was discontinued.
- One patient experienced a noticeable but slight drop in blood pressure after administration of dexpanthenol while in the recovery room.
- One patient experienced intestinal colic one-half hour after the drug was administered.
- Two patients vomited following administration and two patients had diarrhea 10 days post-surgery and after Dexpanthenol Injection.
- One elderly patient became agitated after administration of the drug.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Dexpanthenol in the drug label.
# Drug Interactions
- The effects of succinylcholine appeared to have been prolonged in a woman administered dexpanthenol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Dexpanthenol Injection. It is also not known whether Dexpanthenol Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dexpanthenol Injection should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dexpanthenol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dexpanthenol during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dexpanthenol Injection is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Dexpanthenol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Dexpanthenol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dexpanthenol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dexpanthenol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dexpanthenol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dexpanthenol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dexpanthenol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- intramuscular
### Monitoring
There is limited information regarding Monitoring of Dexpanthenol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Dexpanthenol in the drug label.
# Overdosage
There is limited information regarding Overdose of Dexpanthenol in the drug label.
# Pharmacology
## Mechanism of Action
- Pantothenic acid is a precursor of coenzyme A, which serves as a cofactor for a variety of enzyme-catalyzed reactions involving transfer of acetyl groups. The final step in the synthesis of acetylcholine consists of the choline acetylase transfer of acetyl group from acetylcoenzyme A to choline. Acetylcholine is the neurohumoral transmitter in the parasympathetic system and as such maintains the normal functions of the intestine. Decrease in acetylcholine content would result in decreased peristalsis and in extreme cases adynamic ileus. The pharmacological mode of action of the drug is unknown.
## Structure
- Dexpanthenol is a derivative of pantothenic acid, a B complex vitamin. Dexpanthenol Injection is a sterile, nonpyrogenic, aqueous solution indicated for use as a gastrointestinal stimulant. The chemical name is D-(+)-2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethybutylamide. The structural formula is:
- Each mL contains Dexpanthenol 250 mg in Water for Injection q.s. pH (range 4 - 7) may be adjusted with Sodium Citrate and/or Citric Acid.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dexpanthenol in the drug label.
## Pharmacokinetics
- Pharmacokinetics data in humans is unavailable.
## Nonclinical Toxicology
- There have been no studies in animals to evaluate the carcinogenic, mutagenic, or impairment of fertility potential of dexpanthenol.
# Clinical Studies
There is limited information regarding Clinical Studies of Dexpanthenol in the drug label.
# How Supplied
- Dexpanthenol Injection 250 mg/mL
## Storage
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Dexpanthenol in the drug label.
# Precautions with Alcohol
- Alcohol-Dexpanthenol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DEXPANTHENOL®
# Look-Alike Drug Names
There is limited information regarding Dexpanthenol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Dexpanthenol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Dexpanthenol is a gastrointestinal stimulant that is FDA approved for the prophylaxis of major abdominal surgery to minimize the possibility of paralytic ileus. Common adverse reactions include allergic reactions, Hypotension.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Prophylactic use immediately after major abdominal surgery to minimize the possibility of paralytic ileus. Intestinal atony causing abdominal distention; postoperative or postpartum retention of flatus, or postoperative delay in resumption of intestinal motility; paralytic ileus.
### Dosage
- Prevention of post-operative adynamic ileus: 250 mg (1 mL) or 500 mg (2 mL) intramuscularly. Repeat in 2 hours and then every 6 hours until all danger of adynamic ileus has passed.
- Treatment of adynamic ileus: 500 mg (2 mL) intramuscularly. Repeat in 2 hours and then every 6 hours as needed.
- Intravenous administration: Dexpanthenol Injection 2 mL (500 mg) may be mixed with bulk I.V. solutions such as glucose or Lactated Ringer’s and slowly infused intravenously.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dexpanthenol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dexpanthenol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dexpanthenol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dexpanthenol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dexpanthenol in pediatric patients.
# Contraindications
- There are no known contraindications to the use of Dexpanthenol Injection.
# Warnings
- There have been rare instances of allergic reactions of unknown cause during the concomitant use of Dexpanthenol Injection with drugs such as antibiotics, narcotics and barbiturates.
- Administration of Dexpanthenol Injection directly into the vein is not advised.
- Dexpanthenol Injection should not be administered within one hour of succinylcholine.
### Precautions
- If any signs of a hypersensitivity reaction appear, Dexpanthenol Injection should be discontinued. If ileus is a secondary consequence of mechanical obstruction, primary attention should be directed to the obstruction.
- The management of adynamic ileus includes the correction of any fluid and electrolyte imbalance (especially hypokalemia), anemia and hypoproteinemia, treatment of infection, avoidance where possible of drugs which are known to decrease gastrointestinal motility and decompression of the gastrointestinal tract when considerably distended by nasogastric suction or use of a long intestinal tube.
# Adverse Reactions
## Clinical Trials Experience
- There have been a few reports of allergic reactions and single reports of several other adverse events in association with the administration of dexpanthenol. A causal relationship is uncertain. One patient experienced itching, tingling, difficulty in breathing. Another patient had red patches of skin. Two patients had generalized dermatitis and one patient urticaria.
- One patient experienced temporary respiratory difficulty following administration of dexpanthenol injection 5 minutes after succinylcholine was discontinued.
- One patient experienced a noticeable but slight drop in blood pressure after administration of dexpanthenol while in the recovery room.
- One patient experienced intestinal colic one-half hour after the drug was administered.
- Two patients vomited following administration and two patients had diarrhea 10 days post-surgery and after Dexpanthenol Injection.
- One elderly patient became agitated after administration of the drug.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Dexpanthenol in the drug label.
# Drug Interactions
- The effects of succinylcholine appeared to have been prolonged in a woman administered dexpanthenol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Dexpanthenol Injection. It is also not known whether Dexpanthenol Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dexpanthenol Injection should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dexpanthenol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dexpanthenol during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dexpanthenol Injection is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Dexpanthenol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Dexpanthenol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dexpanthenol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dexpanthenol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dexpanthenol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dexpanthenol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dexpanthenol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- intramuscular
### Monitoring
There is limited information regarding Monitoring of Dexpanthenol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Dexpanthenol in the drug label.
# Overdosage
There is limited information regarding Overdose of Dexpanthenol in the drug label.
# Pharmacology
## Mechanism of Action
- Pantothenic acid is a precursor of coenzyme A, which serves as a cofactor for a variety of enzyme-catalyzed reactions involving transfer of acetyl groups. The final step in the synthesis of acetylcholine consists of the choline acetylase transfer of acetyl group from acetylcoenzyme A to choline. Acetylcholine is the neurohumoral transmitter in the parasympathetic system and as such maintains the normal functions of the intestine. Decrease in acetylcholine content would result in decreased peristalsis and in extreme cases adynamic ileus. The pharmacological mode of action of the drug is unknown.
## Structure
- Dexpanthenol is a derivative of pantothenic acid, a B complex vitamin. Dexpanthenol Injection is a sterile, nonpyrogenic, aqueous solution indicated for use as a gastrointestinal stimulant. The chemical name is D-(+)-2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethybutylamide. The structural formula is:
- Each mL contains Dexpanthenol 250 mg in Water for Injection q.s. pH (range 4 - 7) may be adjusted with Sodium Citrate and/or Citric Acid.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dexpanthenol in the drug label.
## Pharmacokinetics
- Pharmacokinetics data in humans is unavailable.
## Nonclinical Toxicology
- There have been no studies in animals to evaluate the carcinogenic, mutagenic, or impairment of fertility potential of dexpanthenol.
# Clinical Studies
There is limited information regarding Clinical Studies of Dexpanthenol in the drug label.
# How Supplied
- Dexpanthenol Injection 250 mg/mL
## Storage
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Dexpanthenol in the drug label.
# Precautions with Alcohol
- Alcohol-Dexpanthenol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DEXPANTHENOL®[1]
# Look-Alike Drug Names
There is limited information regarding Dexpanthenol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dexpanthenol | |
c8563b485fbc597389458a8554b70aea27c72cee | wikidoc | Diamagnetism | Diamagnetism
Diamagnetism is a weak repulsion from a magnetic field. It is a form of magnetism that is only exhibited by a substance in the presence of an externally applied magnetic field. It results from changes in the orbital motion of electrons. Applying a magnetic field creates a magnetic force on a moving electron in the form of
F = Qv × B. This force changes the centripetal force on the electron, causing it to either speed up or slow down in its orbital motion. This changed electron speed modifies the magnetic moment of the orbital in a direction opposing the external field.
Consider two electron orbitals; one rotating clockwise and the other counterclockwise. An external magnetic field into the page will make the centripetal force on an electron rotating clockwise increase, causing it to speed up. That same field would make the centripetal force on an electron rotating counterclockwise decrease, causing it to slow down. The orbiting electrons create magnetic fields themselves, and
in both cases, the change in B due to the electron's change in velocity is in the
-pposite direction to the external B field. Since the
material originally had no net magnetic field from its
-rbiting electrons (because their orbits were aligned in
random directions), the result is that the induced B field
-pposes the applied B field, and these repel each other.
All materials, except helium, show a diamagnetic response in an applied magnetic field. In fact, diamagnetism is a very general phenomenon, because all paired electrons, including the core electrons of an atom will always make a weak diamagnetic contribution to the material's response. However, for materials which show some other form of magnetism (such as ferromagnetism or paramagnetism), the diamagnetism is completely overpowered. Substances which only, or mostly, display diamagnetic behaviour are termed diamagnetic materials, or diamagnets. Materials that are said to be diamagnetic are those which are usually considered by non-physicists as "non magnetic", and include water, DNA, most organic compounds such as petroleum and some plastics, and many metals, particularly the heavy ones with many core electrons, such as mercury, gold and bismuth.
Diamagnetic materials have a relative magnetic permeability that is less than 1, thus a magnetic susceptibility which is less than 0, and are therefore repelled by magnetic fields. However, since diamagnetism is such a weak property its effects are not observable in every-day life. For example, the magnetic susceptibility of diamagnets such as water is \ \chi_{v} = −9.05×10−6. The most strongly diamagnetic material is bismuth, \ \chi_{v} = −166×10−6, although pyrolytic graphite may have a susceptibility of \ \chi_{v} = −400×10−6 in one plane. Nevertheless these values are orders of magnitudes smaller than the magnetism exhibited by paramagnets and ferromagnets.
Superconductors may be considered to be perfect diamagnets (\ \chi_{v} = −1), since they expel all fields from their interior due to the Meissner effect.
Additionally, all conductors exhibit an effective diamagnetism when they move through a magnetic field. The Lorenz force on electrons causes them to circulate around forming eddy currents. The eddy currents then produce an induced magnetic field which opposes the applied field, resisting the conductors motion.
# History
In 1778 S. J. Brugmans was the first person to observe that bismuth and antimony were repelled by magnetic fields. However, the term "diamagnetism" was coined by Michael Faraday in September 1845, when he realized that all materials in nature possessed some form of diamagnetic response to an applied magnetic field.
# Diamagnetic levitation
Diamagnets may be levitated in stable equilibrium in a magnetic field, with no power consumption. Earnshaw's theorem seems to preclude the possibility of static magnetic levitation. However, Earnshaw's theory only applies to objects with permanent moments m, such as ferromagnets, whose magnetic energy is given by m·B. Ferromagnets are attracted to field maxima, which do not exist in free space.
Diamagnetism is an induced form of magnetism, thus the magnetic moment is proportional to the applied field B. This means that the magnetic energy of diamagnets is proportional to B², the intensity of the magnetic field. Diamagnets are also attracted to field minima, and there can be a minimum in B² in free space (in fact \nabla^2 \mathbf{B}^2\geq 0).
A thin slice of pyrolytic graphite, which is an unusually strong diamagnetic material, can be stably floated in a magnetic field, such as that from rare earth permanent magnets. This can be done with all components at room temperature, making a visually effective demonstration of diamagnetism.
The Radboud University Nijmegen, the Netherlands, has conducted experiments where water and other substances were successfully levitated. Most spectacularly, a live frog (see figure) was levitated.
Recent experiments with studying the growth of protein crystals has led to a technique that utilizes powerful magnets to allow growth in ways that counteract Earth's gravity.
A simple homemade device for demonstration can be constructed out of bismuth plates and a few permanent magnets that will levitate a permanent magnet. | Diamagnetism
Diamagnetism is a weak repulsion from a magnetic field. It is a form of magnetism that is only exhibited by a substance in the presence of an externally applied magnetic field. It results from changes in the orbital motion of electrons. Applying a magnetic field creates a magnetic force on a moving electron in the form of
F = Qv × B. This force changes the centripetal force on the electron, causing it to either speed up or slow down in its orbital motion. This changed electron speed modifies the magnetic moment of the orbital in a direction opposing the external field.
Consider two electron orbitals; one rotating clockwise and the other counterclockwise. An external magnetic field into the page will make the centripetal force on an electron rotating clockwise increase, causing it to speed up. That same field would make the centripetal force on an electron rotating counterclockwise decrease, causing it to slow down. The orbiting electrons create magnetic fields themselves, and
in both cases, the change in B due to the electron's change in velocity is in the
opposite direction to the external B field. Since the
material originally had no net magnetic field from its
orbiting electrons (because their orbits were aligned in
random directions), the result is that the induced B field
opposes the applied B field, and these repel each other.
All materials, except helium, show a diamagnetic response in an applied magnetic field. In fact, diamagnetism is a very general phenomenon, because all paired electrons, including the core electrons of an atom will always make a weak diamagnetic contribution to the material's response. However, for materials which show some other form of magnetism (such as ferromagnetism or paramagnetism), the diamagnetism is completely overpowered. Substances which only, or mostly, display diamagnetic behaviour are termed diamagnetic materials, or diamagnets. Materials that are said to be diamagnetic are those which are usually considered by non-physicists as "non magnetic", and include water, DNA, most organic compounds such as petroleum and some plastics, and many metals, particularly the heavy ones with many core electrons, such as mercury, gold and bismuth.
Diamagnetic materials have a relative magnetic permeability that is less than 1, thus a magnetic susceptibility which is less than 0, and are therefore repelled by magnetic fields. However, since diamagnetism is such a weak property its effects are not observable in every-day life. For example, the magnetic susceptibility of diamagnets such as water is <math>\ \chi_{v}</math> = −9.05×10−6. The most strongly diamagnetic material is bismuth, <math>\ \chi_{v}</math> = −166×10−6, although pyrolytic graphite may have a susceptibility of <math>\ \chi_{v}</math> = −400×10−6 in one plane. Nevertheless these values are orders of magnitudes smaller than the magnetism exhibited by paramagnets and ferromagnets.
Superconductors may be considered to be perfect diamagnets (<math>\ \chi_{v}</math> = −1), since they expel all fields from their interior due to the Meissner effect.
Additionally, all conductors exhibit an effective diamagnetism when they move through a magnetic field. The Lorenz force on electrons causes them to circulate around forming eddy currents. The eddy currents then produce an induced magnetic field which opposes the applied field, resisting the conductors motion.
# History
In 1778 S. J. Brugmans was the first person to observe that bismuth and antimony were repelled by magnetic fields. However, the term "diamagnetism" was coined by Michael Faraday in September 1845, when he realized that all materials in nature possessed some form of diamagnetic response to an applied magnetic field.
# Diamagnetic levitation
Diamagnets may be levitated in stable equilibrium in a magnetic field, with no power consumption. Earnshaw's theorem seems to preclude the possibility of static magnetic levitation. However, Earnshaw's theory only applies to objects with permanent moments m, such as ferromagnets, whose magnetic energy is given by m·B. Ferromagnets are attracted to field maxima, which do not exist in free space.
Diamagnetism is an induced form of magnetism, thus the magnetic moment is proportional to the applied field B. This means that the magnetic energy of diamagnets is proportional to B², the intensity of the magnetic field. Diamagnets are also attracted to field minima, and there can be a minimum in B² in free space (in fact <math>\nabla^2 \mathbf{B}^2\geq 0</math>).
A thin slice of pyrolytic graphite, which is an unusually strong diamagnetic material, can be stably floated in a magnetic field, such as that from rare earth permanent magnets. This can be done with all components at room temperature, making a visually effective demonstration of diamagnetism.
The Radboud University Nijmegen, the Netherlands, has conducted experiments where water and other substances were successfully levitated. Most spectacularly, a live frog (see figure) was levitated.[1]
Recent experiments with studying the growth of protein crystals has led to a technique that utilizes powerful magnets to allow growth in ways that counteract Earth's gravity.[2]
A simple homemade device for demonstration can be constructed out of bismuth plates and a few permanent magnets that will levitate a permanent magnet. [3] | https://www.wikidoc.org/index.php/Diamagnetic | |
2bd3015f4fe9899a05fc2f9bf733c1ffd16acbac | wikidoc | Diarylethene | Diarylethene
In chemistry, diarylethene is the general name of a class of compounds that have aromatic groups bonded to each end of a carbon-carbon double bond.
Under the influence of light, these compounds can generally perform two kinds of reversible isomerizations:
- E to Z isomerizations, most common for stilbenes (and azobenzenes).
- 6π electrocyclizations of the Z form, leading to an additional bond between the two aryl functionalities and a disruption of the aromatic character of these groups.
Both processes are often applied in molecular switches.
After the 6π electrocyclization of the Z form, most unsubstituted diarylethenes are prone to oxidation, leading to a re-aromatization of the π-system. The most common example is E-stilbene, which upon irradiation undergoes an E to Z isomerization, which can be followed by a 6π electrocyclization. Reaction of the product of this reaction with molecular oxygen affords phenanthrene. Although both the E-Z isomerization and the 6π electrocyclization are reversible processes, this oxidation renders the entire sequence irreversible.
# Dithienylethenes
One solution to the problem of oxidation is to replace the hydrogens ortho to the carbon-carbon double bond by groups that can not be removed during the oxidation. The most common example are the dithienylethenes, i.e. alkenes with a thiophene ring on either side. The 2-position of the thiophenes is commonly substituted with a methyl group, preventing oxidation of the ring closed form.
Following the Woodward-Hoffmann rules, the photochemical 6π cyclization takes place in a conrotatory fashion, leading to products with an anti configuration of the methyl substitutents. Because the thermal ring-opening reaction is symmetry forbidden, this type of diarylethenes is exceptionally thermally stable. As both methyl groups are attached to a stereogenic center, two enantiomers (R,R and S,S) are formed, normally as a racemic mixture.
# Applications
Typically, the open-ring isomers are colorless compounds, whereas the closed-ring isomers have colors dependent on their chemical structure, due to the extended conjugation along the molecular backbone. Therefore many diarylethenes have photochromic behavior both in solution and in solid state. Moreover, these two isomers differ from one another not only in their absorption spectra but also in various physical and chemical properties, such as their refractive indices, dielectric constants, and oxidation-reduction potentials. These properties can be readily controlled by reversible isomerization between the open- and closed-ring states using photoirradiation. The closed form has a conjugated path from one end of the molecule to the other, whereas the open form has not. This allows for the electronic communication between functional groups attached to the far ends of the diarylethene to be switched on and off using UV and visible light. | Diarylethene
In chemistry, diarylethene is the general name of a class of compounds that have aromatic groups bonded to each end of a carbon-carbon double bond.
Under the influence of light, these compounds can generally perform two kinds of reversible isomerizations:
- E to Z isomerizations, most common for stilbenes (and azobenzenes).
- 6π electrocyclizations of the Z form, leading to an additional bond between the two aryl functionalities and a disruption of the aromatic character of these groups.[1]
Both processes are often applied in molecular switches.[2][3][4]
After the 6π electrocyclization of the Z form, most unsubstituted diarylethenes are prone to oxidation, leading to a re-aromatization of the π-system. The most common example is E-stilbene, which upon irradiation undergoes an E to Z isomerization, which can be followed by a 6π electrocyclization. Reaction of the product of this reaction with molecular oxygen affords phenanthrene. Although both the E-Z isomerization and the 6π electrocyclization are reversible processes, this oxidation renders the entire sequence irreversible.[1]
# Dithienylethenes
One solution to the problem of oxidation is to replace the hydrogens ortho to the carbon-carbon double bond by groups that can not be removed during the oxidation. The most common example are the dithienylethenes, i.e. alkenes with a thiophene ring on either side. The 2-position of the thiophenes is commonly substituted with a methyl group, preventing oxidation of the ring closed form.
Following the Woodward-Hoffmann rules, the photochemical 6π cyclization takes place in a conrotatory fashion, leading to products with an anti configuration of the methyl substitutents. Because the thermal ring-opening reaction is symmetry forbidden, this type of diarylethenes is exceptionally thermally stable. As both methyl groups are attached to a stereogenic center, two enantiomers (R,R and S,S) are formed, normally as a racemic mixture.[5]
# Applications
Typically, the open-ring isomers are colorless compounds, whereas the closed-ring isomers have colors dependent on their chemical structure, due to the extended conjugation along the molecular backbone. Therefore many diarylethenes have photochromic behavior both in solution and in solid state. Moreover, these two isomers differ from one another not only in their absorption spectra but also in various physical and chemical properties, such as their refractive indices, dielectric constants, and oxidation-reduction potentials. These properties can be readily controlled by reversible isomerization between the open- and closed-ring states using photoirradiation.[5] The closed form has a conjugated path from one end of the molecule to the other, whereas the open form has not. This allows for the electronic communication between functional groups attached to the far ends of the diarylethene to be switched on and off using UV and visible light.[5][6] | https://www.wikidoc.org/index.php/Diarylethene | |
4b5bb5eb086748aceca84562a577540a39e8df52 | wikidoc | Dicoronylene | Dicoronylene
Dicoronylene is the trivial name for a very large polycyclic aromatic hydrocarbon. Its formal name is benzophenanthrochrysenocoronene (IUPAC name) or benzodicoronene (name sometimes used in Chemical Abstracts). It has 15 rings and is a brick-red solid. Its formula is (C48H20). Dicoronylene sublimes under high vacuum, 0.001 torr, abetween 250 C and 300 C.
Due to its large size and limited availability, the organic chemistry of dicoronylene is little known. Dicoronylene does undergo Diels-Alder reaction with maleic anhydride on one or both of the central bay regions on either side of the bridging ring. The double-bond part of maleic anhydroide forms two carbon-carbon bonds on the ends of the bay region, making a new six-member ring. Heating removes the anhydride as carbon dioxide gas and gives the corresponding 16-ring and 17-ring PAHs.
Dicoronylene was first observed in the solid residue produced in coal gasification. This residue contained large amounts of coronene and ovalene. After these were extracted and identified, a reddish residue remained, which was sparingly soluble in organic solvents. Elemental analysis indicated that it was most likely the condensed dimer of coronene.
Dicoronylene was later discovered to occur as a by-product of the catalytic hydrocracking used in petroleum processing. It is formed when two coronene molecules fuse. It is estimated that catalytical hydrocracking produces several hundred metric tons of dicoronylene worldwide per year, making it the most prevalent large PAH. In this process the analogous 18-ring PAH formed from coronene and ovalene (C56H22) is also formed in 1% to 20% proportions. It is purple in color.
The formation of dicoronylene in hydrocracking reactors is a serious problem because its low solubility make it precipitate in any cooler part of the reactor flow path. This causes plugging of flow lines that require periodic shutdown and removal of the reddish deposits. Dicoronylene is also a constituent of coke formed on hydrocracking catalysts, which reduces their activity.
Thermal pyrolysis of coronene shows masses of dicoronylene and the condensed trimer, tetramer, and pentamer in the mass spectrum of the black product. These larger coronene condensates are black in color.
Dicoronylene is moderately soluble in 1,2,4-trichlorobenzene and these solutions have a greenish yellow fluorescence. Unlike coronene, dicoronylene has symmetrical fluorescence excitation and emission spectra. It is virtually insoluble in most solvents.
Dicoronylene has been studied as a model for interstellar PAHs. Its large size and planarity have also shown promise as a chromatographic separation material. | Dicoronylene
Template:Chembox new
Dicoronylene is the trivial name for a very large polycyclic aromatic hydrocarbon. Its formal name is benzo[10,11]phenanthro[2',3',4',5',6':4,5,6,7]chryseno[1,2,3-bc]coronene (IUPAC name) or benzo[1,2,3-bc:4,5,6-b'c']dicoronene (name sometimes used in Chemical Abstracts). It has 15 rings and is a brick-red solid. Its formula is (C48H20).[1] Dicoronylene sublimes under high vacuum, 0.001 torr, abetween 250 C and 300 C.
Due to its large size and limited availability, the organic chemistry of dicoronylene is little known. Dicoronylene does undergo Diels-Alder reaction with maleic anhydride on one or both of the central bay regions on either side of the bridging ring. The double-bond part of maleic anhydroide forms two carbon-carbon bonds on the ends of the bay region, making a new six-member ring. Heating removes the anhydride as carbon dioxide gas and gives the corresponding 16-ring and 17-ring PAHs.
Dicoronylene was first observed in the solid residue produced in coal gasification. This residue contained large amounts of coronene and ovalene. After these were extracted and identified, a reddish residue remained, which was sparingly soluble in organic solvents. Elemental analysis indicated that it was most likely the condensed dimer of coronene.
Dicoronylene was later discovered to occur as a by-product of the catalytic hydrocracking used in petroleum processing. It is formed when two coronene molecules fuse. It is estimated that catalytical hydrocracking produces several hundred metric tons of dicoronylene worldwide per year, making it the most prevalent large PAH. In this process the analogous 18-ring PAH formed from coronene and ovalene (C56H22) is also formed in 1% to 20% proportions. It is purple in color.
The formation of dicoronylene in hydrocracking reactors is a serious problem because its low solubility make it precipitate in any cooler part of the reactor flow path. This causes plugging of flow lines that require periodic shutdown and removal of the reddish deposits. Dicoronylene is also a constituent of coke formed on hydrocracking catalysts, which reduces their activity.
Thermal pyrolysis of coronene shows masses of dicoronylene and the condensed trimer, tetramer, and pentamer in the mass spectrum of the black product. These larger coronene condensates are black in color.
Dicoronylene is moderately soluble in 1,2,4-trichlorobenzene and these solutions have a greenish yellow fluorescence. Unlike coronene, dicoronylene has symmetrical fluorescence excitation and emission spectra. It is virtually insoluble in most solvents.
Dicoronylene has been studied as a model for interstellar PAHs. Its large size and planarity have also shown promise as a chromatographic separation material. | https://www.wikidoc.org/index.php/Dicoronylene | |
743e2107a9909283e4f88e58bcfabd8645bd2fcd | wikidoc | Dictyostelid | Dictyostelid
# Overview
The dictyostelids are a group of cellular slime moulds. When food (normally bacteria) is readily available they take the form of individual amoebae, which feed and divide normally. However, when the food supply is exhausted, they aggregate to form a multicellular assembly, called a pseudoplasmodium or slug (not to be confused with the gastropod mollusc called a slug). The slug has a definite anterior and posterior, responds to light and temperature gradients, and has the ability to migrate. Under the correct circumstances the slug matures forming a fruiting body with a stalk supporting one or more balls of spores. These spores are inactive cells protected by resistant cell walls, and become new amoebae once food is available.
In Acytostelium, the fruiting body is supported by a stalk composed of cellulose, but in other dictyostelids the stalk is composed of cells, sometimes taking up the majority of the original amoebae. With a few exceptions, these cells die during stalk formation, and there is a definite correspondence between parts of the slug and parts of the fruiting body. Aggregation of amoebae generally takes place in converging streams. The amoebae move using filose pseudopods, and are attracted to chemicals produced by other amoebae. In Dictyostelium, aggregation is signalled by cAMP, but others use different chemicals. In the species Dictyostelium purpureum, the grouping is by kinship, not just by proximity.
Dictyostelium has been used as a model organism in molecular biology and genetics, and is studied as an example of cell communication, differentiation, and programmed cell death. It is also an interesting example of the evolution of cooperation and cheating (see e.g. Strassman et al., 2000, Dao et al., 2000, Brännström & Dieckmann 2005). A large body of research data concerning D.discoideum is available on-line at DictyBase.
Life cycle of Dictyostelium
# Mechanism of aggregation in Dictyostelium
The mechanism behind the aggregation of the amoebae relies on Cyclic adenosine monophosphate (cAMP) as a signal molecule. One cell, the founder of the colony, begins to secrete cAMP in response to stress. Others detect this signal, and respond in two ways:
- The amoeba moves towards the signal.
- The amoeba secretes more cAMP to boost the signal.
The effect of this is to relay the signal throughout the nearby population of amoebae and cause inward movement to the area of highest cAMP concentration.
Within an individual cell, the mechanism is as follows:
- cAMP reception at the cell membrane activates a G-protein
- G protein stimulates Adenylate cyclase
- cAMP diffuses out of cell into medium
- Internal cAMP inactivates the external cAMP receptor.
- A different g-protein stimulates Phospholipase C
- IP3 induces calcium ion release
- Calcium ions act on the cytoskeleton to induce the extension of pseudopodia.
Because the internal cAMP concentration inactivates the receptor for external cAMP, an individual cell shows oscillatory behaviour. This behaviour produces beautiful spirals seen in converging colonies and is reminiscent of the Belousov-Zhabotinsky reaction and cyclic cellular automata.
# Genome
The entire genome of Dictyostelium discoideum was published in Nature in 2005 by geneticist Ludwig Eichinger and coworkers. It contains approximately 12,500 genes on 6 chromosomes. For comparison, the human genome has 20,000-25,000 genes on 46 chromosomes. There is a high level of the nucleotides adenosine and thymidine (~77%) leading to a codon usage that favors more adenosines and thymidines in the third position. Tandem repeats of trinucleotides are abundant in Dictyostelium, which in humans cause Trinucleotide repeat disorders.
# Classification
First discovered in a North Carolina forest in 1935, Dictyostelium was at first classified under 'lower fungi.' and in subsequent years into the kingdoms Proctoctista, Fungi and Tubulomitochondrae. By the 90s most scientists accepted the current classification.
The genome of Dictyostelids is more similar to those of animals and plants than those of fungi, and many of the genes regulating development of the foetus are likely derived from a very similar organism. | Dictyostelid
# Overview
The dictyostelids are a group of cellular slime moulds. When food (normally bacteria) is readily available they take the form of individual amoebae, which feed and divide normally. However, when the food supply is exhausted, they aggregate to form a multicellular assembly, called a pseudoplasmodium or slug (not to be confused with the gastropod mollusc called a slug). The slug has a definite anterior and posterior, responds to light and temperature gradients, and has the ability to migrate. Under the correct circumstances the slug matures forming a fruiting body with a stalk supporting one or more balls of spores. These spores are inactive cells protected by resistant cell walls, and become new amoebae once food is available.
In Acytostelium, the fruiting body is supported by a stalk composed of cellulose, but in other dictyostelids the stalk is composed of cells, sometimes taking up the majority of the original amoebae. With a few exceptions, these cells die during stalk formation, and there is a definite correspondence between parts of the slug and parts of the fruiting body. Aggregation of amoebae generally takes place in converging streams. The amoebae move using filose pseudopods, and are attracted to chemicals produced by other amoebae. In Dictyostelium, aggregation is signalled by cAMP, but others use different chemicals. In the species Dictyostelium purpureum, the grouping is by kinship, not just by proximity.
Dictyostelium has been used as a model organism in molecular biology and genetics, and is studied as an example of cell communication, differentiation, and programmed cell death. It is also an interesting example of the evolution of cooperation and cheating (see e.g. Strassman et al., 2000, Dao et al., 2000, Brännström & Dieckmann 2005). A large body of research data concerning D.discoideum is available on-line at DictyBase.
Life cycle of Dictyostelium
# Mechanism of aggregation in Dictyostelium
The mechanism behind the aggregation of the amoebae relies on Cyclic adenosine monophosphate (cAMP) as a signal molecule. One cell, the founder of the colony, begins to secrete cAMP in response to stress. Others detect this signal, and respond in two ways:
- The amoeba moves towards the signal.
- The amoeba secretes more cAMP to boost the signal.
The effect of this is to relay the signal throughout the nearby population of amoebae and cause inward movement to the area of highest cAMP concentration.
Within an individual cell, the mechanism is as follows:
- cAMP reception at the cell membrane activates a G-protein
- G protein stimulates Adenylate cyclase
- cAMP diffuses out of cell into medium
- Internal cAMP inactivates the external cAMP receptor.
- A different g-protein stimulates Phospholipase C
- IP3 induces calcium ion release
- Calcium ions act on the cytoskeleton to induce the extension of pseudopodia.
Because the internal cAMP concentration inactivates the receptor for external cAMP, an individual cell shows oscillatory behaviour. This behaviour produces beautiful spirals seen in converging colonies and is reminiscent of the Belousov-Zhabotinsky reaction and cyclic cellular automata.
# Genome
The entire genome of Dictyostelium discoideum was published in Nature in 2005 by geneticist Ludwig Eichinger and coworkers. It contains approximately 12,500 genes on 6 chromosomes. For comparison, the human genome has 20,000-25,000 genes on 46 chromosomes. There is a high level of the nucleotides adenosine and thymidine (~77%) leading to a codon usage that favors more adenosines and thymidines in the third position. Tandem repeats of trinucleotides are abundant in Dictyostelium, which in humans cause Trinucleotide repeat disorders.
# Classification
First discovered in a North Carolina forest in 1935, Dictyostelium was at first classified under 'lower fungi.' and in subsequent years into the kingdoms Proctoctista, Fungi and Tubulomitochondrae. By the 90s most scientists accepted the current classification.
The genome of Dictyostelids is more similar to those of animals and plants than those of fungi, and many of the genes regulating development of the foetus are likely derived from a very similar organism. | https://www.wikidoc.org/index.php/Dictyostelid | |
ffc38b63b627bae989f2568bd10e03283717ab00 | wikidoc | Diethylamine | Diethylamine
Diethylamine is a secondary amine with the molecular structure CH3CH2NHCH2CH3. It is a flammable, strongly alkaline liquid. It is miscible with water and ethanol.
Diethylamine is manufactured from ethanol and ammonia and is obtained together with ethylamine and triethylamine. It is used as a corrosion inhibitor and in the production of rubber, resins, dyes and pharmaceuticals.
Diethylamine is a corrosive chemical and contact with skin may cause irritation or burns. | Diethylamine
Template:Chembox new
Diethylamine is a secondary amine with the molecular structure CH3CH2NHCH2CH3. It is a flammable, strongly alkaline liquid. It is miscible with water and ethanol.
Diethylamine is manufactured from ethanol and ammonia and is obtained together with ethylamine and triethylamine. It is used as a corrosion inhibitor and in the production of rubber, resins, dyes and pharmaceuticals.
Diethylamine is a corrosive chemical and contact with skin may cause irritation or burns. | https://www.wikidoc.org/index.php/Diethylamine | |
c42410fa277e96ed98fb429e6b046ff02fd43b1c | wikidoc | Dilaceration | Dilaceration
# Overview
Dilaceration is a developmental disturbance in shape of teeth. It refers to an angulation, or a sharp bend or curve, in the root or crown of a formed tooth.
# Description
The condition is thought to be due to trauma during the period in which tooth is forming. The result is that the position of the calcified portion of the tooth is changed and the remainder of the tooth is formed at an angle.
The curve or bend may occur anywhere along the length of the tooth, sometimes at the cervical portion, at other times midway along the root or even just at the apex of the root, depending upon the amount of root formed when the injury occurred.
Such an injury to a permanent tooth, resulting in dilaceration, often follows traumatic injury to the deciduous predecessor in which that tooth is driven apically into the jaw. | Dilaceration
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dilaceration is a developmental disturbance in shape of teeth. It refers to an angulation, or a sharp bend or curve, in the root or crown of a formed tooth.
# Description
The condition is thought to be due to trauma during the period in which tooth is forming. The result is that the position of the calcified portion of the tooth is changed and the remainder of the tooth is formed at an angle.
The curve or bend may occur anywhere along the length of the tooth, sometimes at the cervical portion, at other times midway along the root or even just at the apex of the root, depending upon the amount of root formed when the injury occurred.
Such an injury to a permanent tooth, resulting in dilaceration, often follows traumatic injury to the deciduous predecessor in which that tooth is driven apically into the jaw. | https://www.wikidoc.org/index.php/Dilaceration | |
992eedb5071423ddc02c4c127ca24e0d748855ba | wikidoc | Dinoprostone | Dinoprostone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Dinoprostone is a genitourinary agent that is FDA approved for the treatment of for cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor. Common adverse reactions include diarrhea, nausea, backache, headache, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dinoprostone is indicated for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor.
- The dosage of dinoprostone in the vaginal insert is 10 mg designed to be released at approximately 0.3 mg/hour over a 12 hour period. Cervidil should be removed upon onset of active labor or 12 hours after insertion.
- Dinoprostone is supplied in an individually wrapped aluminium/polyethylene package with a "tear mark" on one side of the package. The package should only be opened by tearing the aluminium package along the tear mark. The package should never be opened with scissors or other sharp objects which may compromise or cut the knitted polyester pouch that serves as the retrieval system for the polymeric slab.
- Dinoprostone must be kept frozen until use, and is administered by placing one unit transversely in the posterior fornix of the vagina immediately after removal from its foil package. The insertion of the vaginal insert does not require sterile conditions. The vaginal insert must not be used without its retrieval system. There is no need for previous warming of the product. A minimal amount of water-miscible lubricant may be used to assist insertion of dinoprostone. Care should be taken not to permit excess contact or coating with the lubricant which could prevent optimal swelling and release of dinoprostone from the vaginal insert. Patients should remain in the recumbent position for 2 hours following insertion, but thereafter may be ambulatory. If the patient is ambulatory, care should be taken to ensure the vaginal insert remains in place. If uterine hyperstimulation is encountered or if labor commences, the vaginal insert should be removed. Dinoprostone should also be removed prior to amniotomy.
- Upon removal of dinoprostone, it is essential to ensure that the slab has been removed, as it will continue delivering the active ingredient. This is accomplished by visualizing the knitted polyester retrieval system and confirming that it contains the slab. In the rare instance that the slab is not contained within the polyester retrieval system, a vaginal exam should be performed to remove the slab.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dinoprostone in adult patients.
### Non–Guideline-Supported Use
- Induction of labor.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dinoprostone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dinoprostone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dinoprostone in pediatric patients.
# Contraindications
- Dinoprostone is contraindicated in:
- Patients with known hypersensitivity to prostaglandins.
- Patients in whom there is clinical suspicion or definite evidence of fetal distress where delivery is not imminent.
- Patients with unexplained vaginal bleeding during this pregnancy.
- Patients in whom there is evidence or strong suspicion of marked cephalopelvic disproportion.
- Patients in whom oxytocic drugs are contraindicated or when prolonged contraction of the uterus may be detrimental to fetal safety or uterine integrity, such as previous cesarean section or major uterine surgery.
- Patients already receiving intravenous oxytocic drugs.
- Multipara with 6 or more previous term pregnancies.
# Warnings
- For hospital use only
- Dinoprostone should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.
- Women aged 30 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks have been shown to have an increased risk of postpartum disseminated intravascular coagulation. In addition, these factors may further increase the risk associated with labor induction.
- Therefore, in these women, use of dinoprostone should be undertaken with caution. Measures should be applied to detect as soon as possible an evolving fibrinolysisin the immediate post-partum period.
- The Clinician should be alert that use of dinoprostone may result in inadvertent disruption and subsequent embolization of antigenic tissue causing in rare circumstances the development of Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism).
# Adverse Reactions
## Clinical Trials Experience
- Dinoprostone is well tolerated. In placebo-controlled trials in which 658 women were entered and 320 received active therapy (218 without retrieval system, 102 with retrieval system), the following events were reported.
- Drug related fever, nausea, vomiting, diarrhea, and abdominal pain were noted in less than 1% of patients who received dinoprostone.
- In study 101-801 (with the retrieval system) cases of hyperstimulation reversed within 2 to 13 minutes of removal of the product. Tocolytics were required in one of the five cases.
- In cases of fetal distress, when product removal was thought advisable there was a return to normal rhythm and no neonatal sequelae.
- Five minute Apgar scores were 7 or above in 98.2% (646/658) of studied neonates whose mothers received dinoprostone. In a report of a 3 year pediatric follow-up study in 121 infants, 51 of whose mothers received dinoprostone, there were no deleterious effects on physical examination or psychomotor evaluation.
- Immune System Disorders
- Hypersensitivity.
- Blood and lymphatic system disorders.
- Disseminated Intravascular Coagulation.
- Reproductive system
- Reports of uterine rupture have been reported in association with use of dinoprostone some required a hysterectomy and some resulted in subsequent fetal or neonatal death.
- Vascular Disorders
- Hypotension
- Pregnancy, Puerperium and Perinatal Conditions
- Amniotic fluid embolism
## Postmarketing Experience
There iimited information regarding Postmarketing Experience of Dinoprostone in the drug label.
# Drug Interactions
There is limited information regarding Dinoprostone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Prostaglandin E2 has produced an increase in skeletal anomalies in rats and rabbits. No effect would be expected clinically, when used as indicated, since dinoprostone (dinoprostone) Vaginal Insert is administered after the period of organogenesis.
- Prostaglandin E2 has been shown to be embryotoxic in rats and rabbits, and any dose that produces sustained increased uterine tone could put the embryo or fetus at risk.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dinoprostone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dinoprostone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Dinoprostone with respect to nursing mothers.
### Pediatric Use
- The safety and efficacy of dinoprostone has been established in women of a reproductive age and women who are pregnant. Although safety and efficacy has not been established in pediatric patients, safety and efficacy are expected to be the same for adolescents.
### Geriatic Use
There is no FDA guidance on the use of Dinoprostone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Dinoprostone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dinoprostone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dinoprostone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dinoprostone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dinoprostone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dinoprostone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Dinoprostone in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Dinoprostone in the drug label.
# Overdosage
- dinoprostone is used as a single dosage in a single application. Overdosage is usually manifested by uterine hyperstimulation which may be accompanied by fetal distress, and is usually responsive to removal of the insert. Other treatment must be symptomatic since, to date, clinical experience with prostaglandin antagonists is insufficient.
- The use of beta-adrenergic agents should be considered in the event of undesirable increased uterine activity.
# Pharmacology
There is limited information regarding Dinoprostone Pharmacology in the drug label.
## Mechanism of Action
## Structure
- Dinoprostone vaginal insert is a thin, flat, polymeric slab which is rectangular in shape with rounded corners contained within the pouch of an off-white knitted polyester retrieval system. Each slab is buff colored, semitransparent and contains 10 mg of dinoprostone in a hydrogel insert. An integral part of the knitted polyester retrieval system is a long tape designed to aid retrieval at the end of the dosing interval or earlier if clinically indicated. The finished product is a controlled release formulation which has been found to release dinoprostone in vivo at a rate of approximately 0.3 mg/hr.
- The chemical name for dinoprostone (commonly known as prostaglandin E2 or PGE2) is 11α, 15S-dihydroxy-9-oxo-prosta-5Z,13E-dien-1-oic acid and the structural formula is represented below:
- The molecular formula is C20H32O5 and its molecular weight is 352.5. Dinoprostone occurs as a white to off-white crystalline powder. It has a melting point within the range of 65° to 69°C. Dinoprostone is soluble in ethanol and in 25% ethanol in water. - Each insert contains 10 mg of dinoprostone in 241 mg of a cross-linked polyethylene oxide/urethane polymer which is a semi-opaque, beige colored, flat rectangular slab measuring 29 mm by 9.5 mm and 0.8 mm in thickness. The insert and its retrieval system, made of polyester yarn, are non-toxic and when placed in a moist environment, absorb water, swell, and release dinoprostone.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dinoprostone in the drug label.
## Pharmacokinetics
- Dinoprostone (PGE2) is a naturally-occurring biomolecule. It is found in low concentrations in most tissues of the body and functions as a local hormone (1-3). As with any local hormone, it is very rapidly metabolized in the tissues of synthesis (the half-life estimated to be 2.5-5 minutes). The rate limiting step for inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH) (1,4). Any PGE2 that escapes local inactivation is rapidly cleared to the extent of 95% on the first pass through the pulmonary circulation (1,2).
- In pregnancy, PGE2 is secreted continuously by the fetal membranes and placenta and plays an important role in the final events leading to the initiation of labor (1,2). It is known that PGE2 stimulates the production of PGF2α which in turn sensitizes the myometrium to endogenous or exogenously administered oxytocin. Although PGE2 is capable of initiating uterine contractions and may interact with oxytocin to increase uterine contractility, the available evidence indicates that, in the concentrations found during the early part of labor, PGE2 plays an important role in cervical ripening without affecting uterine contractions (5-7). This distinction serves as the basis for considering cervical ripening and induction of labor, usually by the use of oxytocin (8-10), as two separate processes.
- PGE2 plays an important role in the complex set of biochemical and structural alterations involved in cervical ripening. Cervical ripening involves a marked relaxation of the cervical smooth muscle fibers of the uterine cervix which must be transformed from a rigid structure to a softened, yielding and dilated configuration to allow passage of the fetus through the birth canal (11-13). This process involves activation of the enzyme collagenase which is responsible for digestion of some of the structural collagen network of the cervix (1, 14). This is associated with a concomitant increase in the amount of hydrophilic glycosaminoglycan, hyaluronic acid and a decrease in dermatan sulfate (1). Failure of the cervix to undergo these natural physiologic changes, usually assessed by the method described by Bishop (15,16), prior to the onset of effective uterine contractions, results in an unfavourable outcome for successful vaginal delivery and may result in fetal compromise. It is estimated that in approximately 5% of pregnancies the cervix does not ripen normally (17). In an additional 10-11% of pregnancies, labor must be induced for medical or obstetric reasons prior to the time of cervical ripening (17).
- The delivery rate of PGE2in vivo is about 0.3 mg/hour over a period of 12 hours. The controlled release of PGE2 from the hydrogel insert is an attempt to provide sufficient quantities of PGE2 to the local receptors to satisfy hormonal requirements. In the majority of patients, these local effects are manifested by changes in the consistency, dilatation and effacement of the cervix as measured by the Bishop score. Although some patients experience uterine hyperstimulation as a result of direct PGE2- or PGF2α-, mediated sensitization of the myometrium to oxytocin, systemic effects of PGE2 are rarely encountered. The insert is fitted with a biocompatible retrieval system which facilitates removal at the conclusion of therapy or in the event of an adverse reaction.
- No correlation could be established between PGE2 release and plasma concentrations of PGEm. The relative contributions of endogenously and exogenously released PGE2 to the plasma levels of the metabolite PGEm could not be determined. Moreover, it is uncertain as to whether the measured concentrations of PGEm reflect the natural progression of PGEm concentrations in blood as birth approaches or to what extent the measured concentrations following PGE2 administration represent an increase over basal levels that might be measured in control patients.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Dinoprostone in the drug label.
# Clinical Studies
# How Supplied
- Cervidil (NDC 0456-4123-63) contains 10 mg dinoprostone. The product is wound and enclosed in an aluminium/polyethylene pack.
## Storage
- Store in a freezer: between -20°C and -10°C (-4°F and 14°F). Cervidil is packed in foil and is stable when stored in a freezer for a period of three years. Vaginal inserts exposed to high humidity will absorb moisture from the air and thereby alter the release characteristics of dinoprostone. Once used, the vaginal insert should be discarded.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Dinoprostone in the drug label.
# Precautions with Alcohol
- Alcohol-Dinoprostone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CERVIDIL®
# Look-Alike Drug Names
There is limited information regarding Dinoprostone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Dinoprostone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Dinoprostone is a genitourinary agent that is FDA approved for the treatment of for cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor. Common adverse reactions include diarrhea, nausea, backache, headache, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dinoprostone is indicated for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor.
- The dosage of dinoprostone in the vaginal insert is 10 mg designed to be released at approximately 0.3 mg/hour over a 12 hour period. Cervidil should be removed upon onset of active labor or 12 hours after insertion.
- Dinoprostone is supplied in an individually wrapped aluminium/polyethylene package with a "tear mark" on one side of the package. The package should only be opened by tearing the aluminium package along the tear mark. The package should never be opened with scissors or other sharp objects which may compromise or cut the knitted polyester pouch that serves as the retrieval system for the polymeric slab.
- Dinoprostone must be kept frozen until use, and is administered by placing one unit transversely in the posterior fornix of the vagina immediately after removal from its foil package. The insertion of the vaginal insert does not require sterile conditions. The vaginal insert must not be used without its retrieval system. There is no need for previous warming of the product. A minimal amount of water-miscible lubricant may be used to assist insertion of dinoprostone. Care should be taken not to permit excess contact or coating with the lubricant which could prevent optimal swelling and release of dinoprostone from the vaginal insert. Patients should remain in the recumbent position for 2 hours following insertion, but thereafter may be ambulatory. If the patient is ambulatory, care should be taken to ensure the vaginal insert remains in place. If uterine hyperstimulation is encountered or if labor commences, the vaginal insert should be removed. Dinoprostone should also be removed prior to amniotomy.
- Upon removal of dinoprostone, it is essential to ensure that the slab has been removed, as it will continue delivering the active ingredient. This is accomplished by visualizing the knitted polyester retrieval system and confirming that it contains the slab. In the rare instance that the slab is not contained within the polyester retrieval system, a vaginal exam should be performed to remove the slab.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dinoprostone in adult patients.
### Non–Guideline-Supported Use
- Induction of labor.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dinoprostone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dinoprostone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dinoprostone in pediatric patients.
# Contraindications
- Dinoprostone is contraindicated in:
- Patients with known hypersensitivity to prostaglandins.
- Patients in whom there is clinical suspicion or definite evidence of fetal distress where delivery is not imminent.
- Patients with unexplained vaginal bleeding during this pregnancy.
- Patients in whom there is evidence or strong suspicion of marked cephalopelvic disproportion.
- Patients in whom oxytocic drugs are contraindicated or when prolonged contraction of the uterus may be detrimental to fetal safety or uterine integrity, such as previous cesarean section or major uterine surgery.
- Patients already receiving intravenous oxytocic drugs.
- Multipara with 6 or more previous term pregnancies.
# Warnings
- For hospital use only
- Dinoprostone should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.
- Women aged 30 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks have been shown to have an increased risk of postpartum disseminated intravascular coagulation. In addition, these factors may further increase the risk associated with labor induction.
- Therefore, in these women, use of dinoprostone should be undertaken with caution. Measures should be applied to detect as soon as possible an evolving fibrinolysisin the immediate post-partum period.
- The Clinician should be alert that use of dinoprostone may result in inadvertent disruption and subsequent embolization of antigenic tissue causing in rare circumstances the development of Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism).
# Adverse Reactions
## Clinical Trials Experience
- Dinoprostone is well tolerated. In placebo-controlled trials in which 658 women were entered and 320 received active therapy (218 without retrieval system, 102 with retrieval system), the following events were reported.
- Drug related fever, nausea, vomiting, diarrhea, and abdominal pain were noted in less than 1% of patients who received dinoprostone.
- In study 101-801 (with the retrieval system) cases of hyperstimulation reversed within 2 to 13 minutes of removal of the product. Tocolytics were required in one of the five cases.
- In cases of fetal distress, when product removal was thought advisable there was a return to normal rhythm and no neonatal sequelae.
- Five minute Apgar scores were 7 or above in 98.2% (646/658) of studied neonates whose mothers received dinoprostone. In a report of a 3 year pediatric follow-up study in 121 infants, 51 of whose mothers received dinoprostone, there were no deleterious effects on physical examination or psychomotor evaluation.
- Immune System Disorders
- Hypersensitivity.
- Blood and lymphatic system disorders.
- Disseminated Intravascular Coagulation.
- Reproductive system
- Reports of uterine rupture have been reported in association with use of dinoprostone some required a hysterectomy and some resulted in subsequent fetal or neonatal death.
- Vascular Disorders
- Hypotension
- Pregnancy, Puerperium and Perinatal Conditions
- Amniotic fluid embolism
## Postmarketing Experience
There iimited information regarding Postmarketing Experience of Dinoprostone in the drug label.
# Drug Interactions
There is limited information regarding Dinoprostone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Prostaglandin E2 has produced an increase in skeletal anomalies in rats and rabbits. No effect would be expected clinically, when used as indicated, since dinoprostone (dinoprostone) Vaginal Insert is administered after the period of organogenesis.
- Prostaglandin E2 has been shown to be embryotoxic in rats and rabbits, and any dose that produces sustained increased uterine tone could put the embryo or fetus at risk.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dinoprostone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dinoprostone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Dinoprostone with respect to nursing mothers.
### Pediatric Use
- The safety and efficacy of dinoprostone has been established in women of a reproductive age and women who are pregnant. Although safety and efficacy has not been established in pediatric patients, safety and efficacy are expected to be the same for adolescents.
### Geriatic Use
There is no FDA guidance on the use of Dinoprostone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Dinoprostone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dinoprostone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dinoprostone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dinoprostone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dinoprostone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dinoprostone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Dinoprostone in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Dinoprostone in the drug label.
# Overdosage
- dinoprostone is used as a single dosage in a single application. Overdosage is usually manifested by uterine hyperstimulation which may be accompanied by fetal distress, and is usually responsive to removal of the insert. Other treatment must be symptomatic since, to date, clinical experience with prostaglandin antagonists is insufficient.
- The use of beta-adrenergic agents should be considered in the event of undesirable increased uterine activity.
# Pharmacology
There is limited information regarding Dinoprostone Pharmacology in the drug label.
## Mechanism of Action
-
## Structure
- Dinoprostone vaginal insert is a thin, flat, polymeric slab which is rectangular in shape with rounded corners contained within the pouch of an off-white knitted polyester retrieval system. Each slab is buff colored, semitransparent and contains 10 mg of dinoprostone in a hydrogel insert. An integral part of the knitted polyester retrieval system is a long tape designed to aid retrieval at the end of the dosing interval or earlier if clinically indicated. The finished product is a controlled release formulation which has been found to release dinoprostone in vivo at a rate of approximately 0.3 mg/hr.
- The chemical name for dinoprostone (commonly known as prostaglandin E2 or PGE2) is 11α, 15S-dihydroxy-9-oxo-prosta-5Z,13E-dien-1-oic acid and the structural formula is represented below:
- The molecular formula is C20H32O5 and its molecular weight is 352.5. Dinoprostone occurs as a white to off-white crystalline powder. It has a melting point within the range of 65° to 69°C. Dinoprostone is soluble in ethanol and in 25% ethanol in water. * Each insert contains 10 mg of dinoprostone in 241 mg of a cross-linked polyethylene oxide/urethane polymer which is a semi-opaque, beige colored, flat rectangular slab measuring 29 mm by 9.5 mm and 0.8 mm in thickness. The insert and its retrieval system, made of polyester yarn, are non-toxic and when placed in a moist environment, absorb water, swell, and release dinoprostone.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dinoprostone in the drug label.
## Pharmacokinetics
- Dinoprostone (PGE2) is a naturally-occurring biomolecule. It is found in low concentrations in most tissues of the body and functions as a local hormone (1-3). As with any local hormone, it is very rapidly metabolized in the tissues of synthesis (the half-life estimated to be 2.5-5 minutes). The rate limiting step for inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH) (1,4). Any PGE2 that escapes local inactivation is rapidly cleared to the extent of 95% on the first pass through the pulmonary circulation (1,2).
- In pregnancy, PGE2 is secreted continuously by the fetal membranes and placenta and plays an important role in the final events leading to the initiation of labor (1,2). It is known that PGE2 stimulates the production of PGF2α which in turn sensitizes the myometrium to endogenous or exogenously administered oxytocin. Although PGE2 is capable of initiating uterine contractions and may interact with oxytocin to increase uterine contractility, the available evidence indicates that, in the concentrations found during the early part of labor, PGE2 plays an important role in cervical ripening without affecting uterine contractions (5-7). This distinction serves as the basis for considering cervical ripening and induction of labor, usually by the use of oxytocin (8-10), as two separate processes.
- PGE2 plays an important role in the complex set of biochemical and structural alterations involved in cervical ripening. Cervical ripening involves a marked relaxation of the cervical smooth muscle fibers of the uterine cervix which must be transformed from a rigid structure to a softened, yielding and dilated configuration to allow passage of the fetus through the birth canal (11-13). This process involves activation of the enzyme collagenase which is responsible for digestion of some of the structural collagen network of the cervix (1, 14). This is associated with a concomitant increase in the amount of hydrophilic glycosaminoglycan, hyaluronic acid and a decrease in dermatan sulfate (1). Failure of the cervix to undergo these natural physiologic changes, usually assessed by the method described by Bishop (15,16), prior to the onset of effective uterine contractions, results in an unfavourable outcome for successful vaginal delivery and may result in fetal compromise. It is estimated that in approximately 5% of pregnancies the cervix does not ripen normally (17). In an additional 10-11% of pregnancies, labor must be induced for medical or obstetric reasons prior to the time of cervical ripening (17).
- The delivery rate of PGE2in vivo is about 0.3 mg/hour over a period of 12 hours. The controlled release of PGE2 from the hydrogel insert is an attempt to provide sufficient quantities of PGE2 to the local receptors to satisfy hormonal requirements. In the majority of patients, these local effects are manifested by changes in the consistency, dilatation and effacement of the cervix as measured by the Bishop score. Although some patients experience uterine hyperstimulation as a result of direct PGE2- or PGF2α-, mediated sensitization of the myometrium to oxytocin, systemic effects of PGE2 are rarely encountered. The insert is fitted with a biocompatible retrieval system which facilitates removal at the conclusion of therapy or in the event of an adverse reaction.
- No correlation could be established between PGE2 release and plasma concentrations of PGEm. The relative contributions of endogenously and exogenously released PGE2 to the plasma levels of the metabolite PGEm could not be determined. Moreover, it is uncertain as to whether the measured concentrations of PGEm reflect the natural progression of PGEm concentrations in blood as birth approaches or to what extent the measured concentrations following PGE2 administration represent an increase over basal levels that might be measured in control patients.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Dinoprostone in the drug label.
# Clinical Studies
# How Supplied
- Cervidil (NDC 0456-4123-63) contains 10 mg dinoprostone. The product is wound and enclosed in an aluminium/polyethylene pack.
## Storage
- Store in a freezer: between -20°C and -10°C (-4°F and 14°F). Cervidil is packed in foil and is stable when stored in a freezer for a period of three years. Vaginal inserts exposed to high humidity will absorb moisture from the air and thereby alter the release characteristics of dinoprostone. Once used, the vaginal insert should be discarded.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Dinoprostone in the drug label.
# Precautions with Alcohol
- Alcohol-Dinoprostone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CERVIDIL®[1]
# Look-Alike Drug Names
There is limited information regarding Dinoprostone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dinoprostone | |
8b61f3930aded0e153b9ee48e780b6596ffcaa59 | wikidoc | Disaccharide | Disaccharide
A disaccharide is a sugar (a carbohydrate) composed of two monosaccharides.
'Disaccharide' is one of the four chemical groupings of carbohydrates (monosaccharide, disaccharide, oligosaccharide, and polysaccharide).
# Formation
It is formed when two sugars are joined together and a molecule of water is removed. For example; milk sugar (lactose) is made from glucose and galactose whereas cane sugar (sucrose) is made from glucose and fructose.
The two monosaccharides are bonded via a dehydration reaction (also called a condensation reaction or dehydration synthesis) that leads to the loss of a molecule of water and formation of a glycosidic bond.
# Properties
The glycosidic bond can be formed between any hydroxyl group on the component monosaccharide. So, even if both component sugars are the same (e.g., glucose), different bond combinations (regiochemistry) and stereochemistry (alpha- or beta-) result in disaccharides that are diastereoisomers with different chemical and physical properties.
Depending on the monosaccharide constituents, disaccharides are sometimes crystalline, sometimes water-soluble, and sometimes sweet-tasting and sticky-feeling.
# Common disaccharides
Maltose and cellobiose are hydrolysis products of the polysaccharides, starch and cellulose, respectively.
Less common disaccharides include: Gentiobiose, that consists of two glucose monomers with an β(1→6) linkage; Isomaltose, that consists of two glucose monomers with an α(1→6) linkage; Kojibiose, that consists of two glucose monomers with an α(1→2) linkage ; Laminaribiose, that consists of two glucose monomers with a β(1→3) linkage; Mannobiose, that consists of two mannose monomers with either an α(1→2), α(1→3), α(1→4), or an α(1→6) linkage; Melibiose, that consists of a glucose monomer and a galactose monomer with an α(1→6) linkage; Nigerose, that consists of two glucose monomers with an α(1→3) linkage; Rutinose, that consists of a rhamnose monomer and a glucose monomer with an α(1→6) linkage; and Xylobiose, that consists of two xylopyranose monomers with a β(1→4) linkage. | Disaccharide
A disaccharide is a sugar (a carbohydrate) composed of two monosaccharides.[1]
'Disaccharide' is one of the four chemical groupings of carbohydrates (monosaccharide, disaccharide, oligosaccharide, and polysaccharide).
# Formation
It is formed when two sugars are joined together and a molecule of water is removed. For example; milk sugar (lactose) is made from glucose and galactose whereas cane sugar (sucrose) is made from glucose and fructose.
The two monosaccharides are bonded via a dehydration reaction (also called a condensation reaction or dehydration synthesis) that leads to the loss of a molecule of water and formation of a glycosidic bond.
# Properties
The glycosidic bond can be formed between any hydroxyl group on the component monosaccharide. So, even if both component sugars are the same (e.g., glucose), different bond combinations (regiochemistry) and stereochemistry (alpha- or beta-) result in disaccharides that are diastereoisomers with different chemical and physical properties.
Depending on the monosaccharide constituents, disaccharides are sometimes crystalline, sometimes water-soluble, and sometimes sweet-tasting and sticky-feeling.
# Common disaccharides
Maltose and cellobiose are hydrolysis products of the polysaccharides, starch and cellulose, respectively.
Less common disaccharides include: Gentiobiose, that consists of two glucose monomers with an β(1→6) linkage; Isomaltose, that consists of two glucose monomers with an α(1→6) linkage; Kojibiose, that consists of two glucose monomers with an α(1→2) linkage [2]; Laminaribiose, that consists of two glucose monomers with a β(1→3) linkage; Mannobiose, that consists of two mannose monomers with either an α(1→2), α(1→3), α(1→4), or an α(1→6) linkage; Melibiose, that consists of a glucose monomer and a galactose monomer with an α(1→6) linkage; Nigerose, that consists of two glucose monomers with an α(1→3) linkage; Rutinose, that consists of a rhamnose monomer and a glucose monomer with an α(1→6) linkage; and Xylobiose, that consists of two xylopyranose monomers with a β(1→4) linkage. | https://www.wikidoc.org/index.php/Disaccharide | |
dbbf415756c51865439053e4dc6af19e4a30cf3f | wikidoc | Disinfectant | Disinfectant
Disinfectants are antimicrobial agents that are applied to non-living objects to destroy microorganisms, the process of which is known as disinfection. Disinfectants should generally be distinguished from antibiotics that destroy microorganisms within the body, and from antiseptics, which destroy microorganisms on living tissue. Sanitisers are high level disinfectants that kill over 99.9% of a target microorganism in applicable situations. Very few disinfectants and sanitisers can sterilise (the complete elimination of all microorganisms), and those that can depend entirely on their mode of application. Bacterial endospores are most resistant to disinfectants, however some viruses and bacteria also possess some tolerance.
# Properties
A perfect disinfectant would offer complete sterilisation, without harming other forms of life, be inexpensive, and non-corrosive. Unfortunately ideal disinfectants do not exist. Most disinfectants are also, by their very nature, potentially harmful (even toxic) to humans or animals. They should be treated with appropriate care. Most come with safety instructions printed on the packaging, which should be read in full before using the disinfectant. Most modern household disinfectants contain Bitrex, an exceptionally bitter substance designed to discourage ingestion, as an added safety measure. Those that are used indoors should never be mixed with other cleaning products as chemical reactions can occur. They are frequently used in hospitals, dental surgeries, kitchens and bathrooms to kill infectious organisms.
The choice of the disinfectant to be used depends on the particular situation. Some disinfectants have a wide spectrum (kill nearly all microorganisms), whilst others kill a smaller range of disease-causing organisms but are preferred for other properties (they may be non-corrosive, non-toxic, or inexpensive).
The disinfecting properties of sunlight (ultra-violet) are powerful. Rather than total reliance on chemicals, basic hygiene - a pillar of food safety - is important in the fight against bacteria since they generally prefer a warm-moist-dark environment. There are arguments for creating or maintaining conditions which are not conducive to bacterial survival and multiplication, rather than attempting to kill them with chemicals. Bacteria have a very rapid multiplication rate, which enables them to evolve rapidly. Should some bacteria survive a chemical attack, they give rise to the next generation. Thus they are able to develop resistance to hostile chemicals. For this reason, some question the wisdom of impregnating cloths, cutting boards and worktops in the home with bactericidal chemicals. Hygiene is important in prevention of foodborne illness.
# Types of disinfectants
## Alcohols
Alcohols, usually ethanol or isopropanol, are wiped over benches and skin and allowed to evaporate for quick disinfection. They have wide microbiocidal activity, are non corrosive, but can be a fire hazard. They also have limited residual activity due to evaporation, which results in brief contact times, and have a limited activity in the presence of organic material. Alcohols are more effective combined with purified water—70% isopropyl alcohol or 62% ethyl alcohol is more effective than 95% alcohol. Alcohol is not effective against fungal or bacterial spores.
## Aldehydes
Aldehydes, such as Glutaraldehyde, have a wide microbiocidal activity and are sporocidal and fungicidal. They are partly inactivated by organic matter and have slight residual activity.
## Halogens
- Chloramine is used in drinking water treatment instead of chlorine because it produces fewer disinfection byproducts.
- Chlorine is used to disinfect swimming pools, and is added in small quantities to drinking water to reduce waterborne diseases.
- Hypochlorites (Sodium hypochlorite), often in the form of common household bleach, are used in the home to disinfect drains, and toilets. Other hypochlorites such as calcium hypochlorite are also used, especially as a swimming pool additive. Hypochlorites yield an aqueous solution of hypochlorous acid that is the true disinfectant. Hypobromite solutions are also sometimes used.
- Iodine is usually dissolved in an organic solvent or as Lugol's iodine solution. It is used in the poultry industry. It is added to the birds' drinking water. Although no longer recommended because it increases scar tissue formation and increases healing time, tincture of iodine has also been used as an antiseptic for skin cuts and scrapes.
- Chloramine-T is antibacterial even after the chlorine has been spent.
## Oxidizing agents
Oxidizing agents act by oxidising the cell membrane of microorganisms, which results in a loss of structure and leads to cell lysis and death.
- Chlorine dioxide is used as an advanced disinfectant for drinking water to reduce waterborne diseases. In certain parts of the world, it has largely replaced chlorine because it forms fewer byproducts. Sodium chlorite, sodium chlorate, and potassium chlorate are used as precursors for generating chlorine dioxide.
- Hydrogen peroxide is used in hospitals to disinfect surfaces. It is sometimes mixed with colloidal silver. It is often preferred because it causes far fewer allergic reactions than alternative disinfectants. Also used in the food packaging industry to disinfect foil containers. A 3% solution is also used as an antiseptic. When hydrogen peroxide comes into contact with the catalase enzyme in cells it is broken down into water and a hydroxyl free radical. It is the damage caused by the oxygen free radical that kills bacteria. However, recent studies have shown hydrogen peroxide to be toxic to growing cells as well as bacteria; its use as an antiseptic is no longer recommended.
- Ozone is a gas that can be added to water for sanitation.
- Acidic Electrolyzed Water is a strong oxidising solution made from the electrolysis of ordinary tap water in the presence of a specific amount of salt, generally sodium chloride. Anolyte has a typical pH range of 3.5 to 8.5 and an Oxidation-Reduction Potential (ORP) of +600 to +1200 mV. The most powerful anolyte disinfecting solution is that produced at a controlled 5.0 to 6.3 pH where the predominant oxchlorine species is hypochlorous acid. This environmentally-responsible disinfectant is highly efficacious against bacteria, fungus, mold, spores and other micro-organisms, in very short contact times. It may be applied as liquid, fog or ice.
- Peracetic acid is a disinfectant produced by reacting hydrogen peroxide with acetic acid. It is broadly effective against microorganisms and is not deactivated by catalase and peroxidase, the enzymes which break down hydrogen peroxide. It also breaks down to food safe and environmentally friendly residues (acetic acid and hydrogen peroxide), and therefore can be used in non-rinse applications. It can be used over a wide temperature range (0-40°C), wide pH range (3.0-7.5), in clean-in-place (CIP) processes, in hard water conditions, and is not affected by protein residues.
- Potassium permanganate (KMnO4) is a red crystalline powder that colours everything it touches, and is used to disinfect aquariums. It is also used widely in community swimming pools to disinfect ones feet before entering the pool. Typically, a large shallow basin of KMnO4/water solution is kept near the pool ladder. Participants are required to step in the basin and then go into the pool. Additionally, it is widely used to disinfect community water ponds and wells in tropical countries, as well as to disinfect the mouth before pulling out teeth. It can be applied to wounds in dilute solution; potassium permanganate is a very useful disinfectant.
- Potassium peroxymonosulfate, the principal ingredient in Virkon, is a wide-spectrum disinfectant used in labs. Virkon kills bacteria, viruses, and fungi. It is used as a 1% solution in water, and keeps for one week once it is made up. It is expensive, but very effective, its pink colour fades as it is used up so it is possible to see at a glance if it is still fresh.
## Phenolics
Phenolics are active ingredients in some household disinfectants. They are also found in some mouthwashes and in disinfectant soap and handwashes.
- Phenol is probably the oldest known disinfectant as it was first used by Lister, when it was called carbolic acid. It is rather corrosive to the skin and sometimes toxic to sensitive people.
- O-phenylphenol is often used instead of Phenol, since it is somewhat less corrosive.
- Chloroxylenol is the principal ingredient in Dettol, a household disinfectant and antiseptic.
- Hexachlorophene is a phenolic that was once used as a germicidal additive to some household products but was banned due to suspected harmful effects.
- Thymol, derived from the herb thyme, is the active ingredient in the only 100% botanical disinfectant with an EPA registration (#74771-1), Benefect. Registered as "broad spectrum," or hospital-grade, it is also the only disinfectant with a green certification, Environmental Choice.
## Quaternary ammonium compounds
Quaternary ammonium compounds (Quats), such as benzalkonium chloride, are a large group of related compounds. Some have been used as low level disinfectants. They are effective against bacteria, but not against some species of Pseudomonas bacteria or bacterial spores. Quats are biocides which also kill algae and are used as an additive in large-scale industrial water systems to minimize undesired biological growth. Quaternary ammonium compounds can also be effective disinfectants against enveloped viruses.
## Other
The biguanide polymer polyaminopropyl biguanide is specifically bactericidal at very low concentrations (10 mg/l). It has an unique method of action: the polymer strands are incorporated into the bacterial cell wall, which disrupts the membrane and reduces its permeability, which has an lethal effect to bacteria. It is also known to bind to bacterial DNA, alter its transcription, and cause lethal DNA damage. It has very low toxicity to higher organisms such as human cells, which have more complex and protective membranes.
High-intensity shortwave ultraviolet light can be used for disinfecting smooth surfaces such as dental tools, but not porous materials that are opaque to the light such as wood or foam. Ultraviolet light fixtures are often present in microbiology labs, and are activated only when there are no occupants in a room (e.g., at night).
# Relative effectiveness of disinfectants
One way to compare disinfectants is to compare how well they do against a known disinfectant and rate them accordingly. Phenol is the standard, and the corresponding rating system is called the "Phenol coefficient". The disinfectant to be tested is compared with phenol on a standard microbe (usually Salmonella typhi or Staphylococcus aureus). Disinfectants that are more effective than phenol have a coefficient > 1. Those that are less effective have a coefficient < 1.
# Home disinfectants
By far the most cost-effective home disinfectant is the commonly used chlorine bleach (a 5% solution of Sodium hypochlorite) which is effective against most common pathogens, including such difficult organisms tuberculosis (mycobacterium tuberculosis), hepatitis B and C, fungi, and antibiotic-resistant strains of staphylococcus and enterococcus. It even has some disinfectant action against parasitic organisms . Positives are that it kills the widest range of pathogens of any inexpensive disinfectant; it is extremely powerful against viruses and bacteria at room temperature; it is commonly available and inexpensive; and it breaks down quickly into harmless components (primarily table salt and oxygen). Negatives are that it is caustic to the skin and eyes, especially at higher concentrations; like many common disinfectants, it degrades in the presence of organic substances; it has a strong odor; it is not effective against giardia lamblia and cryptosporidium; and extreme caution must be taken not to combine it with ammonia or any acid (such as vinegar as this may cause noxious gases to be formed). The best practice is not to add anything to household bleach except water. Dilute bleach can be tolerated on the skin for a period of time by most persons, as witnessed by the long exposure to extremely dilute "chlorine" (actually sodium or calcium hypochlorite) many children get in swimming pools.
To use chlorine bleach effectively, the surface or item to be disinfected must be clean. In the bathroom, special caution must be taken to wipe up urine. A 1 to 20 solution in water is effective simply by being wiped on and left to dry. The user should wear rubber gloves and, in tight airless spaces, goggles. If parasitic organisms are suspected, it should be applied at 1 to 1 concentration, or even undiluted; extreme caution must be taken to avoid contact with eyes and mucous membranes. Protective goggles and good ventilation are mandatory when applying concentrated bleach.
Where one does not want to risk the corrosive effects of bleach, alcohol-based disinfectants are reasonably inexpensive and quite safe. The great drawback to them is their rapid evaporation; sometimes effective disinfection can be obtained only by immersing an object in the alcohol. | Disinfectant
Disinfectants are antimicrobial agents that are applied to non-living objects to destroy microorganisms, the process of which is known as disinfection. Disinfectants should generally be distinguished from antibiotics that destroy microorganisms within the body, and from antiseptics, which destroy microorganisms on living tissue. Sanitisers are high level disinfectants that kill over 99.9% of a target microorganism in applicable situations. Very few disinfectants and sanitisers can sterilise (the complete elimination of all microorganisms), and those that can depend entirely on their mode of application. Bacterial endospores are most resistant to disinfectants, however some viruses and bacteria also possess some tolerance.
# Properties
A perfect disinfectant would offer complete sterilisation, without harming other forms of life, be inexpensive, and non-corrosive. Unfortunately ideal disinfectants do not exist. Most disinfectants are also, by their very nature, potentially harmful (even toxic) to humans or animals. They should be treated with appropriate care. Most come with safety instructions printed on the packaging, which should be read in full before using the disinfectant. Most modern household disinfectants contain Bitrex, an exceptionally bitter substance designed to discourage ingestion, as an added safety measure. Those that are used indoors should never be mixed with other cleaning products as chemical reactions can occur. They are frequently used in hospitals, dental surgeries, kitchens and bathrooms to kill infectious organisms.
The choice of the disinfectant to be used depends on the particular situation. Some disinfectants have a wide spectrum (kill nearly all microorganisms), whilst others kill a smaller range of disease-causing organisms but are preferred for other properties (they may be non-corrosive, non-toxic, or inexpensive).
The disinfecting properties of sunlight (ultra-violet) are powerful. Rather than total reliance on chemicals, basic hygiene - a pillar of food safety - is important in the fight against bacteria since they generally prefer a warm-moist-dark environment. There are arguments for creating or maintaining conditions which are not conducive to bacterial survival and multiplication, rather than attempting to kill them with chemicals. Bacteria have a very rapid multiplication rate, which enables them to evolve rapidly. Should some bacteria survive a chemical attack, they give rise to the next generation. Thus they are able to develop resistance to hostile chemicals. For this reason, some question the wisdom of impregnating cloths, cutting boards and worktops in the home with bactericidal chemicals. Hygiene is important in prevention of foodborne illness.
# Types of disinfectants
## Alcohols
Alcohols, usually ethanol or isopropanol, are wiped over benches and skin and allowed to evaporate for quick disinfection. They have wide microbiocidal activity, are non corrosive, but can be a fire hazard. They also have limited residual activity due to evaporation, which results in brief contact times, and have a limited activity in the presence of organic material. Alcohols are more effective combined with purified water—70% isopropyl alcohol or 62% ethyl alcohol is more effective than 95% alcohol. Alcohol is not effective against fungal or bacterial spores.
## Aldehydes
Aldehydes, such as Glutaraldehyde, have a wide microbiocidal activity and are sporocidal and fungicidal. They are partly inactivated by organic matter and have slight residual activity.
## Halogens
- Chloramine is used in drinking water treatment instead of chlorine because it produces fewer disinfection byproducts.
- Chlorine is used to disinfect swimming pools, and is added in small quantities to drinking water to reduce waterborne diseases.
- Hypochlorites (Sodium hypochlorite), often in the form of common household bleach, are used in the home to disinfect drains, and toilets. Other hypochlorites such as calcium hypochlorite are also used, especially as a swimming pool additive. Hypochlorites yield an aqueous solution of hypochlorous acid that is the true disinfectant. Hypobromite solutions are also sometimes used.
- Iodine is usually dissolved in an organic solvent or as Lugol's iodine solution. It is used in the poultry industry. It is added to the birds' drinking water. Although no longer recommended because it increases scar tissue formation and increases healing time, tincture of iodine has also been used as an antiseptic for skin cuts and scrapes.
- Chloramine-T is antibacterial even after the chlorine has been spent.
## Oxidizing agents
Oxidizing agents act by oxidising the cell membrane of microorganisms, which results in a loss of structure and leads to cell lysis and death.
- Chlorine dioxide is used as an advanced disinfectant for drinking water to reduce waterborne diseases. In certain parts of the world, it has largely replaced chlorine because it forms fewer byproducts. Sodium chlorite, sodium chlorate, and potassium chlorate are used as precursors for generating chlorine dioxide.
- Hydrogen peroxide is used in hospitals to disinfect surfaces. It is sometimes mixed with colloidal silver. It is often preferred because it causes far fewer allergic reactions than alternative disinfectants. Also used in the food packaging industry to disinfect foil containers. A 3% solution is also used as an antiseptic. When hydrogen peroxide comes into contact with the catalase enzyme in cells it is broken down into water and a hydroxyl free radical. It is the damage caused by the oxygen free radical that kills bacteria. However, recent studies have shown hydrogen peroxide to be toxic to growing cells as well as bacteria; its use as an antiseptic is no longer recommended.
- Ozone is a gas that can be added to water for sanitation.
- Acidic Electrolyzed Water is a strong oxidising solution made from the electrolysis of ordinary tap water in the presence of a specific amount of salt, generally sodium chloride. Anolyte has a typical pH range of 3.5 to 8.5 and an Oxidation-Reduction Potential (ORP) of +600 to +1200 mV. The most powerful anolyte disinfecting solution is that produced at a controlled 5.0 to 6.3 pH where the predominant oxchlorine species is hypochlorous acid. This environmentally-responsible disinfectant is highly efficacious against bacteria, fungus, mold, spores and other micro-organisms, in very short contact times. It may be applied as liquid, fog or ice.
- Peracetic acid is a disinfectant produced by reacting hydrogen peroxide with acetic acid. It is broadly effective against microorganisms and is not deactivated by catalase and peroxidase, the enzymes which break down hydrogen peroxide. It also breaks down to food safe and environmentally friendly residues (acetic acid and hydrogen peroxide), and therefore can be used in non-rinse applications. It can be used over a wide temperature range (0-40°C), wide pH range (3.0-7.5), in clean-in-place (CIP) processes, in hard water conditions, and is not affected by protein residues.
- Potassium permanganate (KMnO4) is a red crystalline powder that colours everything it touches, and is used to disinfect aquariums. It is also used widely in community swimming pools to disinfect ones feet before entering the pool. Typically, a large shallow basin of KMnO4/water solution is kept near the pool ladder. Participants are required to step in the basin and then go into the pool. Additionally, it is widely used to disinfect community water ponds and wells in tropical countries, as well as to disinfect the mouth before pulling out teeth. It can be applied to wounds in dilute solution; potassium permanganate is a very useful disinfectant.
- Potassium peroxymonosulfate, the principal ingredient in Virkon, is a wide-spectrum disinfectant used in labs. Virkon kills bacteria, viruses, and fungi. It is used as a 1% solution in water, and keeps for one week once it is made up. It is expensive, but very effective, its pink colour fades as it is used up so it is possible to see at a glance if it is still fresh.
## Phenolics
Phenolics are active ingredients in some household disinfectants. They are also found in some mouthwashes and in disinfectant soap and handwashes.
- Phenol is probably the oldest known disinfectant as it was first used by Lister, when it was called carbolic acid. It is rather corrosive to the skin and sometimes toxic to sensitive people.
- O-phenylphenol is often used instead of Phenol, since it is somewhat less corrosive.
- Chloroxylenol is the principal ingredient in Dettol, a household disinfectant and antiseptic.
- Hexachlorophene is a phenolic that was once used as a germicidal additive to some household products but was banned due to suspected harmful effects.
- Thymol, derived from the herb thyme, is the active ingredient in the only 100% botanical disinfectant with an EPA registration (#74771-1), Benefect. Registered as "broad spectrum," or hospital-grade, it is also the only disinfectant with a green certification, Environmental Choice.
## Quaternary ammonium compounds
Quaternary ammonium compounds (Quats), such as benzalkonium chloride, are a large group of related compounds. Some have been used as low level disinfectants. They are effective against bacteria, but not against some species of Pseudomonas bacteria or bacterial spores. Quats are biocides which also kill algae and are used as an additive in large-scale industrial water systems to minimize undesired biological growth. Quaternary ammonium compounds can also be effective disinfectants against enveloped viruses.
## Other
The biguanide polymer polyaminopropyl biguanide is specifically bactericidal at very low concentrations (10 mg/l). It has an unique method of action: the polymer strands are incorporated into the bacterial cell wall, which disrupts the membrane and reduces its permeability, which has an lethal effect to bacteria. It is also known to bind to bacterial DNA, alter its transcription, and cause lethal DNA damage.[1] It has very low toxicity to higher organisms such as human cells, which have more complex and protective membranes.
High-intensity shortwave ultraviolet light can be used for disinfecting smooth surfaces such as dental tools, but not porous materials that are opaque to the light such as wood or foam. Ultraviolet light fixtures are often present in microbiology labs, and are activated only when there are no occupants in a room (e.g., at night).
# Relative effectiveness of disinfectants
One way to compare disinfectants is to compare how well they do against a known disinfectant and rate them accordingly. Phenol is the standard, and the corresponding rating system is called the "Phenol coefficient". The disinfectant to be tested is compared with phenol on a standard microbe (usually Salmonella typhi or Staphylococcus aureus). Disinfectants that are more effective than phenol have a coefficient > 1. Those that are less effective have a coefficient < 1.
# Home disinfectants
By far the most cost-effective home disinfectant is the commonly used chlorine bleach (a 5% solution of Sodium hypochlorite) which is effective against most common pathogens, including such difficult organisms tuberculosis (mycobacterium tuberculosis), hepatitis B and C, fungi, and antibiotic-resistant strains of staphylococcus and enterococcus. It even has some disinfectant action against parasitic organisms [2]. Positives are that it kills the widest range of pathogens of any inexpensive disinfectant; it is extremely powerful against viruses and bacteria at room temperature; it is commonly available and inexpensive; and it breaks down quickly into harmless components (primarily table salt and oxygen). Negatives are that it is caustic to the skin and eyes, especially at higher concentrations; like many common disinfectants, it degrades in the presence of organic substances; it has a strong odor; it is not effective against giardia lamblia and cryptosporidium; and extreme caution must be taken not to combine it with ammonia or any acid (such as vinegar as this may cause noxious gases to be formed). The best practice is not to add anything to household bleach except water. Dilute bleach can be tolerated on the skin for a period of time by most persons, as witnessed by the long exposure to extremely dilute "chlorine" (actually sodium or calcium hypochlorite) many children get in swimming pools.
To use chlorine bleach effectively, the surface or item to be disinfected must be clean. In the bathroom, special caution must be taken to wipe up urine. A 1 to 20 solution in water is effective simply by being wiped on and left to dry. The user should wear rubber gloves and, in tight airless spaces, goggles. If parasitic organisms are suspected, it should be applied at 1 to 1 concentration, or even undiluted; extreme caution must be taken to avoid contact with eyes and mucous membranes. Protective goggles and good ventilation are mandatory when applying concentrated bleach.
Where one does not want to risk the corrosive effects of bleach, alcohol-based disinfectants are reasonably inexpensive and quite safe. The great drawback to them is their rapid evaporation; sometimes effective disinfection can be obtained only by immersing an object in the alcohol. | https://www.wikidoc.org/index.php/Disinfectant | |
b7312b6da8c2b52c523704f6bf7d6af10af660d3 | wikidoc | Disopyramide | Disopyramide
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# Black Box Warning
# Overview
Disopyramide is a antiarrhythmic Group IA , cardiovascular agent that is FDA approved for the treatment of ventricular arrhythmias such as sustained ventricular tachycardia, that, in the judgment of the physician, are life-threatening. There is a Black Box Warning for this drug as shown here. Common adverse reactions include negative inotropic effect on myocardium, constipation, nausea, xerostomia, muscle weakness, blurred vision, delay when starting to pass urine, urinary retention, generalized aches and pains, malaise and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
The dosage of disopyramide phosphate must be individualized for each patient on the basis of response and tolerance. The usual adult dosage of disopyramide phosphate is 400 to 800 mg per day given in divided doses. The recommended dosage for most adults is 600 mg/day given in divided doses (150 mg every 6 hours). For patients whose body weight is less than 110 pounds (50 kg), the recommended dosage is 400 mg/day given in divided doses (100 mg every 6 hours). In the event of increased anticholinergic side effects, plasma levels of disopyramide should be monitored and the dose of the drug adjusted accordingly. A reduction of the dose by one third, from the recommended 600 mg/day to 400 mg/day, would be reasonable, without changing the dosing interval.
For patients with cardiomyopathy or possible cardiac decompensation, a loading dose, as discussed below, should not be given, and initial dosage should be limited to 100 mg every 6 to 8 hours. Subsequent dosage adjustments should be made gradually, with close monitoring for the possible development of hypotension and/or congestive heart failure.
For patients with moderate renal insufficiency (creatinine clearance greater than 40 mL/min) or hepatic insufficiency, the recommended dosage is 400 mg/day given in divided doses (100 mg every 6 hours).
For patients with severe renal insufficiency (Ccr 40 mL/min or less), the recommended dosage regimen is 100 mg at intervals shown in the table below, with or without an initial loading dose of 150 mg.
For patients in whom rapid control of ventricular arrhythmia is essential, an initial loading dose of 300 mg of disopyramide phosphate (200 mg for patients whose body weight is less than 110 pounds) is recommended, followed by the appropriate maintenance dosage. Therapeutic effects are usually attained 30 minutes to 3 hours after administration of a 300 mg loading dose. If there is no response or evidence of toxicity within 6 hours of the loading dose, 200 mg of disopyramide phosphate every 6 hours may be prescribed instead of the usual 150 mg. If there is no response to this dosage within 48 hours, either disopyramide phosphate should then be discontinued or the physician should consider hospitalizing the patient for careful monitoring while subsequent disopyramide phosphate doses of 250 mg or 300 mg every 6 hours are given. A limited number of patients with severe refractory ventricular tachycardia have tolerated daily doses of disopyramide phosphate up to 1600 mg per day (400 mg every 6 hours), resulting in disopyramide plasma levels up to 9 mcg/mL. If such treatment is warranted, it is essential that patients be hospitalized for close evaluation and continuous monitoring.
The following dosage schedule based on theoretical considerations rather than experimental data is suggested for transferring patients with normal renal function from either quinidine sulfate or procainamide therapy (Type 1 antiarrhythmic agents) to disopyramide phosphate therapy:
- Disopyramide phosphate should be started using the regular maintenance schedule without a loading dose 6 to 12 hours after the last dose of quinidine sulfate or 3 to 6 hours after the last dose of procainamide.
- In patients in whom withdrawal of quinidine sulfate or procainamide is likely to produce life-threatening arrhythmias, the physician should consider hospitalization of the patient.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
### Atrial Fibrillation=
- Developed by: AHA/ACC
- Class of Recommendation: Class IIb
- Strength of Evidence: Level of Evidence C
- Dosing Information
- Immediate release tablets: 100-200 mg four times a day.
- Extended release tablets: 200-400 mg bid.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Disopyramide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Controlled clinical studies have not been conducted in pediatric patients; however, the following suggested dosage table is based on published clinical experience.
Total daily dosage should be divided and equal doses administered orally every 6 hours or at intervals according to individual patient needs. Disopyramide plasma levels and therapeutic response must be monitored closely. Patients should be hospitalized during the initial treatment period, and dose titration should start at the lower end of the ranges provided below.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Disopyramide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Disopyramide in pediatric patients.
# Contraindications
- Cardiogenic shock
- Preexisting second-degree AV block or third-degree AV block (if no pacemaker is present)
- Congenital Q-T prolongation
- Hypersensitivity to the drug
# Warnings
### Negative Inotropic Properties=
Disopyramide phosphate may cause or worsen congestive heart failure or produce severe hypotension as a consequence of its negative inotropic properties. Hypotension has been observed primarily in patients with primary cardiomyopathy or inadequately compensated congestive heart failure. Disopyramide phosphate should not be used in patients with uncompensated or marginally compensated congestive heart failure or hypotension unless the congestive heart failure or hypotension is secondary to cardiac arrhythmia. Patients with a history of heart failure may be treated with Disopyramide phosphate, but careful attention must be given to the maintenance of cardiac function, including optimal digitalization. If hypotension occurs or congestive heart failure worsens, disopyramide phosphate should be discontinued and, if necessary, restarted at a lower dosage only after adequate cardiac compensation has been established.
Although it is unusual, significant widening (greater than 25%) of the QRS complex may occur during Disopyramide phosphate administration; in such cases disopyramide phosphate should be discontinued.
As with other Type 1 antiarrhythmic drugs, prolongation of the Q-T interval (corrected) and worsening of the arrhythmia, including ventricular tachycardia and ventricular fibrillation, may occur. Patients who have evidenced prolongation of the Q-T interval in response to quinidine may be at particular risk. As with other Type 1A antiarrhythmics, disopyramide phosphate has been associated with torsade de pointes.
If a Q-T prolongation of greater than 25% is observed and if ectopy continues, the patient should be monitored closely, and consideration given to discontinuing disopyramide phosphate.
In rare instances significant lowering of blood-glucose values has been reported during disopyramide phosphate administration. The physician should be alert to this possibility, especially in patients with congestive heart failure, chronic malnutrition, hepatic, renal or other diseases, or drugs (e.g., beta blockers, alcohol) which could compromise preservation of the normal glucoregulatory mechanisms in the absence of food. In these patients, the blood-glucose levels should be carefully followed.
The concomitant use of disopyramide phosphate with other Type 1A antiarrhythmic agents (such as quinidine or procainamide), Type 1C antiarrhythmics (such as encainide, flecainide or propafenone), and/or propranolol should be reserved for patients with life-threatening arrhythmias who are demonstrably unresponsive to single-agent antiarrhythmic therapy. Such use may produce serious negative inotropic effects, or may excessively prolong conduction. This should be considered particularly in patients with any degree of cardiac decompensation or those with a prior history thereof. Patients receiving more than one antiarrhythmic drug must be carefully monitored.
If first-degree heart block develops in a patient receiving disopyramide phosphate, the dosage should be reduced. If the block persists despite reduction of dosage, continuation of the drug must depend upon weighing the benefit being obtained against the risk of higher degrees of heart block. Development of second-degree AV block or third-degree AV block or unifascicular, bifascicular, or trifascicular block requires discontinuation of disopyramide phosphate therapy, unless the ventricular rate is adequately controlled by a temporary or implanted ventricular pacemaker.
Because of its anticholinergic activity, disopyramide phosphate should not be used in patients with glaucoma, myasthenia gravis or urinary retention unless adequate overriding measures are taken; these consist of the topical application of potent miotics (e.g., pilocarpine) for patients with glaucoma, and catheter drainage or operative relief for patients with urinary retention. Urinary retention may occur in patients of either sex as a consequence of disopyramide phosphate administration, but males with benign prostatic hypertrophy are at particular risk. In patients with a family history of glaucoma, intraocular pressure should be measured before initiating disopyramide phosphate therapy. Disopyramide phosphate should be used with special care in patients with myasthenia gravis since its anticholinergic properties could precipitate a myasthenic crisis in such patients.
## Precautions
### General
Patients with atrial flutter or atrial fibrillation should be digitalized prior to disopyramide phosphate administration to ensure that drug-induced enhancement of AV conduction does not result in an increase of ventricular rate beyond physiologically acceptable limits.
Care should be taken when prescribing disopyramide phosphate for patients with sick sinus syndrome (bradycardia-tachycardia syndrome), Wolff-Parkinson-White syndrome (WPW), or bundle branch block. The effect of disopyramide phosphate in these conditions is uncertain at present.
Patients with myocarditis or other cardiomyopathy may develop significant hypotension in response to the usual dosage of disopyramide phosphate, probably due to cardiodepressant mechanisms. Therefore, a loading dose of disopyramide phosphate should not be given to such patients, and initial dosage and subsequent dosage adjustments should be made under close supervision.
# Adverse Reactions
## Clinical Trials Experience
The adverse reactions which were reported in disopyramide phosphate clinical trials encompass observations in 1,500 patients, including 90 patients studied for at least 4 years. The most serious adverse reactions are hypotension and congestive heart failure. The most common adverse reactions, which are dose dependent, are associated with the anticholinergic properties of the drug. These may be transitory, but may be persistent or can be severe. Urinary retention is the most serious anticholinergic effect.
- Anticholinergic: Dry mouth, urinary hesitancy, constipation.
- Anticholinergic: Blurred vision, dry nose/eyes/throat.
- Genitourinary: Urinary retention, urinary frequency and urinary urgency.
- Gastrointestinal: Nausea, abdominal pain/bloating/gas.
- General: Dizziness, fatigue/muscle weakness, headache, malaise, aches/pains.
- Genitourinary: Impotence.
- Cardiovascular: Hypotension with or without congestive heart failure, increased congestive heart failure, cardiac conduction disturbances]], edema/weight gain, shortness of breath, syncope, chest pain.
- Gastrointestinal: Anorexia, diarrhea, vomiting.
- Dermatologic: Generalized rash/dermatoses, itching.
- Central nervous system: Nervousness.
- Other: Hypokalemia, elevated cholesterol/triglycerides
- Depression.
- Insomnia.
- Dysuria.
- Numbness/tingling.
- Elevated liver enzymes.
- AV block.
- Elevated BUN.
- Elevated creatinine.
- Decreased hemoglobin/hematocrit.
- Hypoglycemia.
- Reversible cholestatic jaundice.
- Fever.
- Thrombocytopenia.
- Reversible agranulocytosis.
- Gynecomastia.
- Some cases of SLE (systmic lupus erythematosus) symptoms have been reported; most cases occurred in patients who had been switched to disopyramide from procainamide following the development of SLE symptoms.
- Rarely, acute psychosis has been reported following disopyramide phosphate therapy, with prompt return to normal mental status when therapy was stopped.
## Postmarketing Experience
There is limited information regarding Disopyramide Postmarketing Experience in the drug label.
# Drug Interactions
- If phenytoin or other hepatic enzyme inducers are taken concurrently with disopyramide phosphate, lower plasma levels of disopyramide may occur. Monitoring of disopyramide plasma levels is recommended in such concurrent use to avoid ineffective therapy.
- Other antiarrhythmic drugs (e.g., quinidine, procainamide, lidocaine, propranolol) have occasionally been used concurrently with disopyramide phosphate. Excessive widening of the QRS complex and/or prolongation of the Q-T interval may occur in these situations. In healthy subjects, no significant drug-drug interaction was observed when disopyramide phosphate was coadministered with either propranolol or diazepam. Concomitant administration of Disopyramide Phosphate and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels.
- Disopyramide Phosphate does not increase serum digoxin levels.
- Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
- Although potent inhibitors of cytochrome P450 3A4 (e.g., ketoconazole) have not been studied clinically, in vitro studies have shown that erythromycin and oleandomycin inhibit the metabolism of disopyramide. Cases of life-threatening interactions have been reported for disopyramide when given with clarithromycin and erythromycin indicating that coadministration of disopyramide with inhibitors of cytochrome P450 3A4 could result in potentially fatal interaction.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
### Teratogenic Effeects=
Disopyramide Phosphate was associated with decreased numbers of implantation sites and decreased growth and survival of pups when administered to pregnant rats at 250 mg/kg/day (20 or more times the usual daily human dose of 12 mg/kg, assuming a patient weight of at least 50 kg), a level at which weight gain and food consumption of dams were also reduced. Increased resorption rates were reported in rabbits at 60 mg/kg/day (5 or more times the usual daily human dose). Effects on implantation, pup growth, and survival were not evaluated in rabbits. There are no adequate and well-controlled studies in pregnant women. Disopyramide Phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Disopyramide phosphate has been reported to stimulate contractions of the pregnant uterus. Disopyramide has been found in human fetal blood.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Disopyramide in women who are pregnant.
### Labor and Delivery
It is not known whether the use of disopyramide phosphate during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention.
### Nursing Mothers
Studies in rats have shown that the concentration of disopyramide and its metabolites is between one and three times greater in milk than it is in plasma. Following oral administration, disopyramide has been detected in human milk at a concentration not exceeding that in plasma. Because of the potential for serious adverse reactions in nursing infants from disopyramide phosphate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Clinical studies of disopyramide phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Because of its anticholinergic activity, disopyramide phosphate should not be used in patients with glaucoma, urinary retention, or benign prostatic hypertrophy (medical conditions commonly associated with the elderly) unless adequate overriding measures are taken (see WARNINGS: Anticholinergic Activity). In the event of increased anticholinergic side effects, plasma levels of disopyramide should be monitored and the dose of the drug adjusted accordingly. A reduction of the dose by one third, from the recommended 600 mg/day to 400 mg/day, would be reasonable, without changing the dosing interval. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Disopyramide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Disopyramide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Disopyramide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Disopyramide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Disopyramide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Disopyramide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
For patients with cardiomyopathy or possible cardiac decompensation, a loading dose, as discussed below, should not be given, and initial dosage should be limited to 100 mg every 6 to 8 hours. Subsequent dosage adjustments should be made gradually, with close monitoring for the possible development of hypotension and/or congestive heart failure
# IV Compatibility
There is limited information regarding the compatibility of Disopyramide and IV administrations.
# Overdosage
### Symptoms=
- Deliberate or accidental overdosage of oral disopyramide may be followed by apnea, loss of consciousness, cardiac arrhythmias, and loss of spontaneous respiration. Death has occurred following overdosage.
- Toxic plasma levels of disopyramide produce excessive widening of the QRS complex and Q-T interval, worsening of congestive heart failure, hypotension, varying kinds and degrees of conduction disturbance, bradycardia, and finally asystole. Obvious anticholinergic effects are also observed.
- The approximate oral LD50 of disopyramide phosphate is 580 and 700 mg/kg for rats and mice, respectively.
- Experience indicates that prompt and vigorous treatment of overdosage is necessary, even in the absence of symptoms. Such treatment may be life-saving. No specific antidote for disopyramide phosphate has been identified. Treatment should be symptomatic and may include induction of emesis or gastric lavage, administration of a cathartic followed by activated charcoal by mouth or stomach tube, intravenous administration of isoproterenol and dopamine, insertion of an intra-aortic balloon forcounterpulsation, and mechanical ventilation. Hemodialysis or, preferably, hemoperfusion with charcoal may be employed to lower serum concentration of the drug.
- The electrocardiogram should be monitored, and supportive therapy with cardiac glycosides and diuretics should be given as required.
- If progressive AV block should develop, endocardial pacing should be implemented. In case of any impaired renal function, measures to increase the glomerular filtration rate may reduce the toxicity (disopyramide is excreted primarily by the kidney).
- The anticholinergic effects can be reversed with neostigmine at the discretion of the physician.
- Altering the urinary pH in humans does not affect the plasma half-life or the amount of disopyramide excreted in the urine.
# Pharmacology
There is limited information regarding Disopyramide Pharmacology in the drug label.
## Mechanism of Action
Disopyramide phosphate is a Type 1 antiarrhythmic drug (i.e., similar to procainamide and quinidine). In animal studies, disopyramide phosphate decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells, decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors.
## Structure
Disopyramide Phosphate is an antiarrhythmic drug available for oral administration in capsules containing 100 mg or 150 mg of disopyramide base, present as the phosphate. The base content of the phosphate salt is 77.6%. The structural formula of Disopyramide Phosphate is:
C21H29N3O·H3PO4 M.W. 437.47
α--α-phenyl-2-pyridineacetamide phosphate
Disopyramide Phosphate is freely soluble in water, and the free base (pKa 10.4) has an aqueous solubility of 1 mg/mL. The chloroform:water partition coefficient of the base is 3.1 at pH 7.2.
Disopyramide Phosphate is a racemic mixture of d- and l-isomers. This drug is not chemically related to other antiarrhythmic drugs.
Inactive Ingredients: Capsules: Lactose Monohydrate, Magnesium Stearate and Sodium Starch Glycolate.
Capsule Print and Shell Constituents: Black Iron Oxide, D&C Red #28, D&C Red #33, D&C Yellow #10, D&C Yellow #10 Aluminum Lake, FD&C Blue #1, FD&C Blue #1 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, Gelatin, Propylene Glycol, Shellac, Sodium Lauryl Sulfate, Sorbitan Monolaurate and Titanium Dioxide.
## Pharmacodynamics
### Electrophysiology=
In man, disopyramide phosphate at therapeutic plasma levels shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the effective refractory period of the AV node. Little effect has been shown on AV-nodal and His-Purkinje conduction times or QRS duration. However, prolongation of conduction in accessory pathways occurs.
At recommended oral doses, disopyramide phosphate rarely produces significant alterations of blood pressure in patients without congestive heart failure. With intravenous disopyramide phosphate, either increases in systolic/diastolic or decreases in systolic blood pressure have been reported, depending on the infusion rate and the patient population. Intravenous disopyramide phosphate may cause cardiac depression with an approximate mean 10% reduction of cardiac output, which is more pronounced in patients with cardiac dysfunction.
The in vitro anticholinergic activity of disopyramide phosphate is approximately 0.06% that of atropine; however, the usual dose for disopyramide phosphate is 150 mg every 6 hours compared to 0.4 to 0.6 mg for atropine.
## Pharmacokinetics
Following oral administration of disopyramide phosphate, disopyramide phosphate is rapidly and almost completely absorbed, and peak plasma levels are usually attained within 2 hours. The usual therapeutic plasma levels of disopyramide base are 2 to 4 mcg/mL, and at these concentrations protein binding varies from 50% to 65%. Because of concentration-dependent protein binding, it is difficult to predict the concentration of the free drug when total drug is measured.
The mean plasma half-life of disopyramide in healthy humans is 6.7 hours (range of 4 to 10 hours). In six patients with impaired renal function (creatinine clearance less than 40 mL/min), disopyramide half-life values were 8 to 18 hours.
After the oral administration of 200 mg of disopyramide to 10 cardiac patients with borderline to moderate heart failure, the time to peak serum concentration of 2.3 ± 1.5 hours (mean ± SD) was increased, and the mean peak serum concentration of 4.8 ± 1.6 mcg/mL was higher than in healthy volunteers. After intravenous administration in these same patients, the mean elimination half-life was 9.7 ± 4.2 hours (range in healthy volunteers of 4.4 to 7.8 hours). In a second study of the oral administration of disopyramide to 7 patients with heart disease, including left ventricular dysfunction, the mean plasma half-life was slightly prolonged to 7.8 ± 1.9 hours (range of 5 to 9.5 hours).
In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite, and 10% as the other metabolites. The plasma concentration of the major metabolite is approximately one tenth that of disopyramide. Altering the urinary pH in man does not affect the plasma half-life of disopyramide.
## Nonclinical Toxicology
Eighteen months of Disopyramide Phosphate administration to rats, at oral doses up to 400 mg/kg/day (about 30 times the usual daily human dose of 600 mg/day, assuming a patient weight of at least 50 kg), revealed no evidence of carcinogenic potential. An evaluation of mutagenic potential by Ames test was negative. Disopyramide Phosphate, at doses up to 250 mg/kg/day, did not adversely affect fertility of rats.
Pregnancy
# Clinical Studies
There is limited information regarding Clinical Studies of Disopyramide in the drug label.
# How Supplied
Disopyramide Phosphate is supplied as:
- 100 mg - hard gelatin capsule with a light-blue body imprinted "93-3127" and a scarlet cap imprinted "93-3127", containing 100 mg of disopyramide base present as the phosphate, in bottles of 100.
- 150 mg - hard gelatin capsule with a scarlet body imprinted "93-3129" and a buff cap imprinted "93-3129", containing 150 mg of disopyramide base present as the phosphate, in bottles of 100.
## Storage
Store at 20º to 25º (68º to77ºF).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Disopyramide in the drug label.
# Precautions with Alcohol
In rare instances significant lowering of blood-glucose values has been reported during disopyramide phosphate administration. The physician should be alert to this possibility, especially in patients with congestive heart failure, chronic malnutrition, hepatic, renal or other diseases, or drugs (e.g., beta blockers, alcohol) which could compromise preservation of the normal glucoregulatory mechanisms in the absence of food. In these patients, the blood-glucose levels should be carefully followed.
# Brand Names
- Norpace
- Norpace CR
# Look-Alike Drug Names
- Disopyramide - Desipramine
# Drug Shortage Status
# Price | Disopyramide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]; Adeel Jamil, M.D. [3]
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# Black Box Warning
# Overview
Disopyramide is a antiarrhythmic Group IA , cardiovascular agent that is FDA approved for the treatment of ventricular arrhythmias such as sustained ventricular tachycardia, that, in the judgment of the physician, are life-threatening. There is a Black Box Warning for this drug as shown here. Common adverse reactions include negative inotropic effect on myocardium, constipation, nausea, xerostomia, muscle weakness, blurred vision, delay when starting to pass urine, urinary retention, generalized aches and pains, malaise and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
The dosage of disopyramide phosphate must be individualized for each patient on the basis of response and tolerance. The usual adult dosage of disopyramide phosphate is 400 to 800 mg per day given in divided doses. The recommended dosage for most adults is 600 mg/day given in divided doses (150 mg every 6 hours). For patients whose body weight is less than 110 pounds (50 kg), the recommended dosage is 400 mg/day given in divided doses (100 mg every 6 hours). In the event of increased anticholinergic side effects, plasma levels of disopyramide should be monitored and the dose of the drug adjusted accordingly. A reduction of the dose by one third, from the recommended 600 mg/day to 400 mg/day, would be reasonable, without changing the dosing interval.
For patients with cardiomyopathy or possible cardiac decompensation, a loading dose, as discussed below, should not be given, and initial dosage should be limited to 100 mg every 6 to 8 hours. Subsequent dosage adjustments should be made gradually, with close monitoring for the possible development of hypotension and/or congestive heart failure.
For patients with moderate renal insufficiency (creatinine clearance greater than 40 mL/min) or hepatic insufficiency, the recommended dosage is 400 mg/day given in divided doses (100 mg every 6 hours).
For patients with severe renal insufficiency (Ccr 40 mL/min or less), the recommended dosage regimen is 100 mg at intervals shown in the table below, with or without an initial loading dose of 150 mg.
For patients in whom rapid control of ventricular arrhythmia is essential, an initial loading dose of 300 mg of disopyramide phosphate (200 mg for patients whose body weight is less than 110 pounds) is recommended, followed by the appropriate maintenance dosage. Therapeutic effects are usually attained 30 minutes to 3 hours after administration of a 300 mg loading dose. If there is no response or evidence of toxicity within 6 hours of the loading dose, 200 mg of disopyramide phosphate every 6 hours may be prescribed instead of the usual 150 mg. If there is no response to this dosage within 48 hours, either disopyramide phosphate should then be discontinued or the physician should consider hospitalizing the patient for careful monitoring while subsequent disopyramide phosphate doses of 250 mg or 300 mg every 6 hours are given. A limited number of patients with severe refractory ventricular tachycardia have tolerated daily doses of disopyramide phosphate up to 1600 mg per day (400 mg every 6 hours), resulting in disopyramide plasma levels up to 9 mcg/mL. If such treatment is warranted, it is essential that patients be hospitalized for close evaluation and continuous monitoring.
The following dosage schedule based on theoretical considerations rather than experimental data is suggested for transferring patients with normal renal function from either quinidine sulfate or procainamide therapy (Type 1 antiarrhythmic agents) to disopyramide phosphate therapy:
- Disopyramide phosphate should be started using the regular maintenance schedule without a loading dose 6 to 12 hours after the last dose of quinidine sulfate or 3 to 6 hours after the last dose of procainamide.
- In patients in whom withdrawal of quinidine sulfate or procainamide is likely to produce life-threatening arrhythmias, the physician should consider hospitalization of the patient.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
### Atrial Fibrillation=
- Developed by: AHA/ACC[1]
- Class of Recommendation: Class IIb
- Strength of Evidence: Level of Evidence C
- Dosing Information
- Immediate release tablets: 100-200 mg four times a day.
- Extended release tablets: 200-400 mg bid.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Disopyramide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Controlled clinical studies have not been conducted in pediatric patients; however, the following suggested dosage table is based on published clinical experience.
Total daily dosage should be divided and equal doses administered orally every 6 hours or at intervals according to individual patient needs. Disopyramide plasma levels and therapeutic response must be monitored closely. Patients should be hospitalized during the initial treatment period, and dose titration should start at the lower end of the ranges provided below.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Disopyramide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Disopyramide in pediatric patients.
# Contraindications
- Cardiogenic shock
- Preexisting second-degree AV block or third-degree AV block (if no pacemaker is present)
- Congenital Q-T prolongation
- Hypersensitivity to the drug
# Warnings
### Negative Inotropic Properties=
Disopyramide phosphate may cause or worsen congestive heart failure or produce severe hypotension as a consequence of its negative inotropic properties. Hypotension has been observed primarily in patients with primary cardiomyopathy or inadequately compensated congestive heart failure. Disopyramide phosphate should not be used in patients with uncompensated or marginally compensated congestive heart failure or hypotension unless the congestive heart failure or hypotension is secondary to cardiac arrhythmia. Patients with a history of heart failure may be treated with Disopyramide phosphate, but careful attention must be given to the maintenance of cardiac function, including optimal digitalization. If hypotension occurs or congestive heart failure worsens, disopyramide phosphate should be discontinued and, if necessary, restarted at a lower dosage only after adequate cardiac compensation has been established.
Although it is unusual, significant widening (greater than 25%) of the QRS complex may occur during Disopyramide phosphate administration; in such cases disopyramide phosphate should be discontinued.
As with other Type 1 antiarrhythmic drugs, prolongation of the Q-T interval (corrected) and worsening of the arrhythmia, including ventricular tachycardia and ventricular fibrillation, may occur. Patients who have evidenced prolongation of the Q-T interval in response to quinidine may be at particular risk. As with other Type 1A antiarrhythmics, disopyramide phosphate has been associated with torsade de pointes.
If a Q-T prolongation of greater than 25% is observed and if ectopy continues, the patient should be monitored closely, and consideration given to discontinuing disopyramide phosphate.
In rare instances significant lowering of blood-glucose values has been reported during disopyramide phosphate administration. The physician should be alert to this possibility, especially in patients with congestive heart failure, chronic malnutrition, hepatic, renal or other diseases, or drugs (e.g., beta blockers, alcohol) which could compromise preservation of the normal glucoregulatory mechanisms in the absence of food. In these patients, the blood-glucose levels should be carefully followed.
The concomitant use of disopyramide phosphate with other Type 1A antiarrhythmic agents (such as quinidine or procainamide), Type 1C antiarrhythmics (such as encainide, flecainide or propafenone), and/or propranolol should be reserved for patients with life-threatening arrhythmias who are demonstrably unresponsive to single-agent antiarrhythmic therapy. Such use may produce serious negative inotropic effects, or may excessively prolong conduction. This should be considered particularly in patients with any degree of cardiac decompensation or those with a prior history thereof. Patients receiving more than one antiarrhythmic drug must be carefully monitored.
If first-degree heart block develops in a patient receiving disopyramide phosphate, the dosage should be reduced. If the block persists despite reduction of dosage, continuation of the drug must depend upon weighing the benefit being obtained against the risk of higher degrees of heart block. Development of second-degree AV block or third-degree AV block or unifascicular, bifascicular, or trifascicular block requires discontinuation of disopyramide phosphate therapy, unless the ventricular rate is adequately controlled by a temporary or implanted ventricular pacemaker.
Because of its anticholinergic activity, disopyramide phosphate should not be used in patients with glaucoma, myasthenia gravis or urinary retention unless adequate overriding measures are taken; these consist of the topical application of potent miotics (e.g., pilocarpine) for patients with glaucoma, and catheter drainage or operative relief for patients with urinary retention. Urinary retention may occur in patients of either sex as a consequence of disopyramide phosphate administration, but males with benign prostatic hypertrophy are at particular risk. In patients with a family history of glaucoma, intraocular pressure should be measured before initiating disopyramide phosphate therapy. Disopyramide phosphate should be used with special care in patients with myasthenia gravis since its anticholinergic properties could precipitate a myasthenic crisis in such patients.
## Precautions
### General
Patients with atrial flutter or atrial fibrillation should be digitalized prior to disopyramide phosphate administration to ensure that drug-induced enhancement of AV conduction does not result in an increase of ventricular rate beyond physiologically acceptable limits.
Care should be taken when prescribing disopyramide phosphate for patients with sick sinus syndrome (bradycardia-tachycardia syndrome), Wolff-Parkinson-White syndrome (WPW), or bundle branch block. The effect of disopyramide phosphate in these conditions is uncertain at present.
Patients with myocarditis or other cardiomyopathy may develop significant hypotension in response to the usual dosage of disopyramide phosphate, probably due to cardiodepressant mechanisms. Therefore, a loading dose of disopyramide phosphate should not be given to such patients, and initial dosage and subsequent dosage adjustments should be made under close supervision.
# Adverse Reactions
## Clinical Trials Experience
The adverse reactions which were reported in disopyramide phosphate clinical trials encompass observations in 1,500 patients, including 90 patients studied for at least 4 years. The most serious adverse reactions are hypotension and congestive heart failure. The most common adverse reactions, which are dose dependent, are associated with the anticholinergic properties of the drug. These may be transitory, but may be persistent or can be severe. Urinary retention is the most serious anticholinergic effect.
- Anticholinergic: Dry mouth, urinary hesitancy, constipation.
- Anticholinergic: Blurred vision, dry nose/eyes/throat.
- Genitourinary: Urinary retention, urinary frequency and urinary urgency.
- Gastrointestinal: Nausea, abdominal pain/bloating/gas.
- General: Dizziness, fatigue/muscle weakness, headache, malaise, aches/pains.
- Genitourinary: Impotence.
- Cardiovascular: Hypotension with or without congestive heart failure, increased congestive heart failure, cardiac conduction disturbances]], edema/weight gain, shortness of breath, syncope, chest pain.
- Gastrointestinal: Anorexia, diarrhea, vomiting.
- Dermatologic: Generalized rash/dermatoses, itching.
- Central nervous system: Nervousness.
- Other: Hypokalemia, elevated cholesterol/triglycerides
- Depression.
- Insomnia.
- Dysuria.
- Numbness/tingling.
- Elevated liver enzymes.
- AV block.
- Elevated BUN.
- Elevated creatinine.
- Decreased hemoglobin/hematocrit.
- Hypoglycemia.
- Reversible cholestatic jaundice.
- Fever.
- Thrombocytopenia.
- Reversible agranulocytosis.
- Gynecomastia.
- Some cases of SLE (systmic lupus erythematosus) symptoms have been reported; most cases occurred in patients who had been switched to disopyramide from procainamide following the development of SLE symptoms.
- Rarely, acute psychosis has been reported following disopyramide phosphate therapy, with prompt return to normal mental status when therapy was stopped.
## Postmarketing Experience
There is limited information regarding Disopyramide Postmarketing Experience in the drug label.
# Drug Interactions
- If phenytoin or other hepatic enzyme inducers are taken concurrently with disopyramide phosphate, lower plasma levels of disopyramide may occur. Monitoring of disopyramide plasma levels is recommended in such concurrent use to avoid ineffective therapy.
- Other antiarrhythmic drugs (e.g., quinidine, procainamide, lidocaine, propranolol) have occasionally been used concurrently with disopyramide phosphate. Excessive widening of the QRS complex and/or prolongation of the Q-T interval may occur in these situations. In healthy subjects, no significant drug-drug interaction was observed when disopyramide phosphate was coadministered with either propranolol or diazepam. Concomitant administration of Disopyramide Phosphate and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels.
- Disopyramide Phosphate does not increase serum digoxin levels.
- Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
- Although potent inhibitors of cytochrome P450 3A4 (e.g., ketoconazole) have not been studied clinically, in vitro studies have shown that erythromycin and oleandomycin inhibit the metabolism of disopyramide. Cases of life-threatening interactions have been reported for disopyramide when given with clarithromycin and erythromycin indicating that coadministration of disopyramide with inhibitors of cytochrome P450 3A4 could result in potentially fatal interaction.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
### Teratogenic Effeects=
Disopyramide Phosphate was associated with decreased numbers of implantation sites and decreased growth and survival of pups when administered to pregnant rats at 250 mg/kg/day (20 or more times the usual daily human dose of 12 mg/kg, assuming a patient weight of at least 50 kg), a level at which weight gain and food consumption of dams were also reduced. Increased resorption rates were reported in rabbits at 60 mg/kg/day (5 or more times the usual daily human dose). Effects on implantation, pup growth, and survival were not evaluated in rabbits. There are no adequate and well-controlled studies in pregnant women. Disopyramide Phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Disopyramide phosphate has been reported to stimulate contractions of the pregnant uterus. Disopyramide has been found in human fetal blood.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Disopyramide in women who are pregnant.
### Labor and Delivery
It is not known whether the use of disopyramide phosphate during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention.
### Nursing Mothers
Studies in rats have shown that the concentration of disopyramide and its metabolites is between one and three times greater in milk than it is in plasma. Following oral administration, disopyramide has been detected in human milk at a concentration not exceeding that in plasma. Because of the potential for serious adverse reactions in nursing infants from disopyramide phosphate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Clinical studies of disopyramide phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Because of its anticholinergic activity, disopyramide phosphate should not be used in patients with glaucoma, urinary retention, or benign prostatic hypertrophy (medical conditions commonly associated with the elderly) unless adequate overriding measures are taken (see WARNINGS: Anticholinergic Activity). In the event of increased anticholinergic side effects, plasma levels of disopyramide should be monitored and the dose of the drug adjusted accordingly. A reduction of the dose by one third, from the recommended 600 mg/day to 400 mg/day, would be reasonable, without changing the dosing interval. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Disopyramide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Disopyramide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Disopyramide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Disopyramide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Disopyramide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Disopyramide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
For patients with cardiomyopathy or possible cardiac decompensation, a loading dose, as discussed below, should not be given, and initial dosage should be limited to 100 mg every 6 to 8 hours. Subsequent dosage adjustments should be made gradually, with close monitoring for the possible development of hypotension and/or congestive heart failure
# IV Compatibility
There is limited information regarding the compatibility of Disopyramide and IV administrations.
# Overdosage
### Symptoms=
- Deliberate or accidental overdosage of oral disopyramide may be followed by apnea, loss of consciousness, cardiac arrhythmias, and loss of spontaneous respiration. Death has occurred following overdosage.
- Toxic plasma levels of disopyramide produce excessive widening of the QRS complex and Q-T interval, worsening of congestive heart failure, hypotension, varying kinds and degrees of conduction disturbance, bradycardia, and finally asystole. Obvious anticholinergic effects are also observed.
- The approximate oral LD50 of disopyramide phosphate is 580 and 700 mg/kg for rats and mice, respectively.
- Experience indicates that prompt and vigorous treatment of overdosage is necessary, even in the absence of symptoms. Such treatment may be life-saving. No specific antidote for disopyramide phosphate has been identified. Treatment should be symptomatic and may include induction of emesis or gastric lavage, administration of a cathartic followed by activated charcoal by mouth or stomach tube, intravenous administration of isoproterenol and dopamine, insertion of an intra-aortic balloon forcounterpulsation, and mechanical ventilation. Hemodialysis or, preferably, hemoperfusion with charcoal may be employed to lower serum concentration of the drug.
- The electrocardiogram should be monitored, and supportive therapy with cardiac glycosides and diuretics should be given as required.
- If progressive AV block should develop, endocardial pacing should be implemented. In case of any impaired renal function, measures to increase the glomerular filtration rate may reduce the toxicity (disopyramide is excreted primarily by the kidney).
- The anticholinergic effects can be reversed with neostigmine at the discretion of the physician.
- Altering the urinary pH in humans does not affect the plasma half-life or the amount of disopyramide excreted in the urine.
# Pharmacology
There is limited information regarding Disopyramide Pharmacology in the drug label.
## Mechanism of Action
Disopyramide phosphate is a Type 1 antiarrhythmic drug (i.e., similar to procainamide and quinidine). In animal studies, disopyramide phosphate decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells, decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors.
## Structure
Disopyramide Phosphate is an antiarrhythmic drug available for oral administration in capsules containing 100 mg or 150 mg of disopyramide base, present as the phosphate. The base content of the phosphate salt is 77.6%. The structural formula of Disopyramide Phosphate is:
C21H29N3O·H3PO4 M.W. 437.47
α-[2-(diisopropylamino) ethyl]-α-phenyl-2-pyridineacetamide phosphate
Disopyramide Phosphate is freely soluble in water, and the free base (pKa 10.4) has an aqueous solubility of 1 mg/mL. The chloroform:water partition coefficient of the base is 3.1 at pH 7.2.
Disopyramide Phosphate is a racemic mixture of d- and l-isomers. This drug is not chemically related to other antiarrhythmic drugs.
Inactive Ingredients: Capsules: Lactose Monohydrate, Magnesium Stearate and Sodium Starch Glycolate.
Capsule Print and Shell Constituents: Black Iron Oxide, D&C Red #28, D&C Red #33, D&C Yellow #10, D&C Yellow #10 Aluminum Lake, FD&C Blue #1, FD&C Blue #1 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, Gelatin, Propylene Glycol, Shellac, Sodium Lauryl Sulfate, Sorbitan Monolaurate and Titanium Dioxide.
## Pharmacodynamics
### Electrophysiology=
In man, disopyramide phosphate at therapeutic plasma levels shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the effective refractory period of the AV node. Little effect has been shown on AV-nodal and His-Purkinje conduction times or QRS duration. However, prolongation of conduction in accessory pathways occurs.
At recommended oral doses, disopyramide phosphate rarely produces significant alterations of blood pressure in patients without congestive heart failure. With intravenous disopyramide phosphate, either increases in systolic/diastolic or decreases in systolic blood pressure have been reported, depending on the infusion rate and the patient population. Intravenous disopyramide phosphate may cause cardiac depression with an approximate mean 10% reduction of cardiac output, which is more pronounced in patients with cardiac dysfunction.
The in vitro anticholinergic activity of disopyramide phosphate is approximately 0.06% that of atropine; however, the usual dose for disopyramide phosphate is 150 mg every 6 hours compared to 0.4 to 0.6 mg for atropine.
## Pharmacokinetics
Following oral administration of disopyramide phosphate, disopyramide phosphate is rapidly and almost completely absorbed, and peak plasma levels are usually attained within 2 hours. The usual therapeutic plasma levels of disopyramide base are 2 to 4 mcg/mL, and at these concentrations protein binding varies from 50% to 65%. Because of concentration-dependent protein binding, it is difficult to predict the concentration of the free drug when total drug is measured.
The mean plasma half-life of disopyramide in healthy humans is 6.7 hours (range of 4 to 10 hours). In six patients with impaired renal function (creatinine clearance less than 40 mL/min), disopyramide half-life values were 8 to 18 hours.
After the oral administration of 200 mg of disopyramide to 10 cardiac patients with borderline to moderate heart failure, the time to peak serum concentration of 2.3 ± 1.5 hours (mean ± SD) was increased, and the mean peak serum concentration of 4.8 ± 1.6 mcg/mL was higher than in healthy volunteers. After intravenous administration in these same patients, the mean elimination half-life was 9.7 ± 4.2 hours (range in healthy volunteers of 4.4 to 7.8 hours). In a second study of the oral administration of disopyramide to 7 patients with heart disease, including left ventricular dysfunction, the mean plasma half-life was slightly prolonged to 7.8 ± 1.9 hours (range of 5 to 9.5 hours).
In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite, and 10% as the other metabolites. The plasma concentration of the major metabolite is approximately one tenth that of disopyramide. Altering the urinary pH in man does not affect the plasma half-life of disopyramide.
## Nonclinical Toxicology
Eighteen months of Disopyramide Phosphate administration to rats, at oral doses up to 400 mg/kg/day (about 30 times the usual daily human dose of 600 mg/day, assuming a patient weight of at least 50 kg), revealed no evidence of carcinogenic potential. An evaluation of mutagenic potential by Ames test was negative. Disopyramide Phosphate, at doses up to 250 mg/kg/day, did not adversely affect fertility of rats.
Pregnancy
# Clinical Studies
There is limited information regarding Clinical Studies of Disopyramide in the drug label.
# How Supplied
Disopyramide Phosphate is supplied as:
- 100 mg - hard gelatin capsule with a light-blue body imprinted "93-3127" and a scarlet cap imprinted "93-3127", containing 100 mg of disopyramide base present as the phosphate, in bottles of 100.
- 150 mg - hard gelatin capsule with a scarlet body imprinted "93-3129" and a buff cap imprinted "93-3129", containing 150 mg of disopyramide base present as the phosphate, in bottles of 100.
## Storage
Store at 20º to 25º (68º to77ºF).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Disopyramide in the drug label.
# Precautions with Alcohol
In rare instances significant lowering of blood-glucose values has been reported during disopyramide phosphate administration. The physician should be alert to this possibility, especially in patients with congestive heart failure, chronic malnutrition, hepatic, renal or other diseases, or drugs (e.g., beta blockers, alcohol) which could compromise preservation of the normal glucoregulatory mechanisms in the absence of food. In these patients, the blood-glucose levels should be carefully followed.
# Brand Names
- Norpace
- Norpace CR
# Look-Alike Drug Names
- Disopyramide - Desipramine
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Disopyramide | |
5208e1046161af6cda4c74a87f604c9531b919a7 | wikidoc | Distillation | Distillation
Distillation is a method of separating chemical substances based on differences in their volatilities in a boiling liquid mixture. Distillation usually forms part of a larger chemical process, and is thus referred to as a unit operation.
Commercially, distillation has a number of uses. It is used to separate crude oil into more fractions for specific uses such as transport, power generation and heating. Water is distilled to remove impurities, such as salt from sea water. Air is distilled to separate its components - notably oxygen, nitrogen and argon - for industrial use. Distillation of fermented solutions has been used since ancient times to produce distilled beverages with a higher alcohol content.
# History
Early forms of distillation were known to Babylonian alchemists in Mesopotamia (in what is now Iraq) from at least the 2nd millennium BC. Distillation was later known to Greek alchemists from the 1st century AD, and the later development of large-scale distillation apparatus occurred in response to demands for spirits. Hypathia of Alexandria is credited with having invented an early distillation apparatus, and the first exact description of apparatus for distillation is given by Zosimos of Alexandria in the fourth century.
In the 8th century, alchemists in the Middle East produced distillation processes to purify chemical substances for industrial purposes such as isolating natural esters (perfumes) and producing pure alcohol. The first among them was the Persian Jabir ibn Hayyan (Geber) circa 800 AD, who is credited with the invention of numerous chemical apparatus and processes that are still in use today. In particular, his alembic was the first still with retorts which could fully purify chemicals, a precursor to the pot still, and its design has served as inspiration for modern micro-scale distillation apparatus such as the Hickman stillhead. Petroleum was first distilled by another Persian, al-Razi (Rhazes) in the 9th century, for producing kerosene, while steam distillation was invented by Avicenna in the early 11th century, for producing essential oils.
In 1500, German alchemist Hieronymus Braunschweig published Liber de arte destillandi (The Book of the Art of Distillation) the first book on the subject, followed in 1512 by a much expanded version.
In 1651, John French published The Art of Distillation the first major English compendium of practice, though it has been claimed that much of it derives from Braunschweig's work. This includes diagrams with people in them showing the industrial rather than bench scale of the operation.
As alchemy evolved into the science of chemistry, vessels called retorts became used for distillations. Both alembics and retorts are forms of glassware with long necks pointing to the side at a downward angle which acted as air-cooled condensers to condense the distillate and let it drip downward for collection.
Later, copper alembics were invented. Riveted joints were often kept tight by using various mixtures, for instance a dough made of rye flour. These alembics often featured a cooling system around the beak, using cold water for instance, which made the condensation of alcohol more efficient. These were called pot stills.
Today, the retorts and pot stills have been largely supplanted by more efficient distillation methods in most industrial processes. However, the pot still is still widely used for the elaboration of some fine alcohols such as cognac, Scotch whisky and some vodkas. Pot stills made of various materials (wood, clay, stainless steel) are also used by bootleggers in various countries. Small pot stills are also sold for the domestic production of flower water or essential oils.
In the early 19th century the basics of modern techniques including pre-heating and reflux were developed, particularly by the French, then in 1830 a British Patent was issued to Aeneas Coffey for a whiskey distillation column, which worked continuously and may be regarded as the archetype of modern petrochemical units. In 1877, Ernest Solvay was granted a U.S. Patent for a tray column for ammonia distillation and the same and subsequent years saw developments of this theme for oil and spirits.
With the emergence of chemical engineering as a discipline at the end of the 19th century, scientific rather than empirical methods could be applied. The developing petroleum industry in the early 20th century provided the impetus for the development of accurate design methods such as the McCabe-Thiele method and the Fenske equation.
# Applications of distillation
The application of distillation can roughly be divided in four groups: laboratory scale, industrial distillation, distillation of herbs for perfumery and medicinals (herbal distillate) and food processing. The latter two are distinct from the former two, in that in the distillation is not used as a true purification method, but more to transfer all volatiles from the source materials to the distillate.
The main difference between laboratory scale distillation and industrial distillation is that laboratory scale distillation is often performed batch-wise, whereas industrial distillation often occurs continuously. In batch distillation, the composition of the source material, the vapors of the distilling compounds and the distillate change during the distillation. In batch distillation, a still is charged (supplied) with a batch of feed mixture, which is then separated into its component fractions which are collected sequentially from most volatile to less volatile, with the bottoms (remaining least or non-volatile fraction) removed at the end. The still can then be recharged and the process repeated.
In continuous distillation, the source materials, vapors and distillate are kept at a constant composition by carefully replenishing the source material and removing fractions from both vapor and liquid in the system. This results in a better control of the separation process.
# Idealized distillation model
The boiling point of a liquid is the temperature at which the vapor pressure of the liquid equals the pressure surrounding the liquid. The normal boiling point of a liquid is the special case at which the vapor pressure of the liquid equals the ambient atmospheric pressure. A liquid in a container at a pressure below atmospheric pressure will boil at temperature lower than the normal boiling point, and a liquid in a container at a pressure higher than atmospheric pressure will boil at a temperature higher than the normal boiling point. In other words, all liquids have an infinite number of boiling points.
It is a common misconception that in a liquid mixture at a given pressure, each component boils at the boiling point corresponding to the given pressure and the vapors of each component will collect separately and purely. This, however, does not occur even in an idealized system. Idealized models of distillation are essentially governed by Raoult's law and Dalton's law.
Raoult's law assumes that a component contributes to the total vapor pressure of the mixture in proportion to its percentage of the mixture and its vapor pressure when pure. If one component changes another component's vapor pressure, or if the volatility of a component is dependent on its percentage in the mixture, the law will fail.
Dalton's law states that the total vapor pressure is the sum of the vapor pressures of each individual component in the mixture. When a multi-component liquid is heated, the vapor pressure of each component will rise, thus causing the total vapor pressure to rise. When the total vapor pressure reaches the pressure surrounding the liquid, boiling occurs and liquid turns to gas throughout the bulk of the liquid. Note that a given mixture has one boiling point at a given pressure, when the components are mutually soluble.
The idealized model is accurate in the case of chemically similar liquids, such as benzene and toluene. In other cases, severe deviations from Raoult's law and Dalton's law are observed, most famously in the mixture of ethanol and water. These compounds, when heated together, form an azeotrope, in which the boiling temperature of the mixture is lower than the boiling temperature of each separate liquid. Virtually all liquids, when mixed and heated, will display azeotropic behaviour. Although there are computational methods that can be used to estimate the behavior of a mixture of arbitrary components, the only way to obtain accurate vapor-liquid equilibrium data is by measurement.
It is not possible to completely purify a mixture of components by distillation, as this would require each component in the mixture to have a zero partial pressure. If ultra-pure products are the goal, then further chemical separation must be applied.
## Batch distillation
Heating an ideal mixture of two volatile substances A and B (with A having the higher volatility, or lower boiling point) in a batch distillation setup (such as in an apparatus depicted in the opening figure) until the mixture is boiling results in a vapor above the liquid which contains a mixture of A and B. The ratio between A and B in the vapor will be different from the ratio in the liquid: the ratio in the liquid will be determined by how the original mixture was prepared, while the ratio in the vapor will be enriched in the more volatile compound, A (due to Raoult's Law, see above). The vapor goes through the condenser and is removed from the system. This in turn means that the ratio of compounds in the remaining liquid is now different from the initial ratio (i.e. more enriched in B than the starting liquid).
The result is that the ratio in the liquid mixture is changing, becoming richer in component B. This causes the boiling point of the mixture to rise, which in turn results in a rise in the temperature in the vapor, which results in a changing ratio of A : B in the gas phase (as distillation continues, there is an increasing proportion of B in the gas phase). This results in a slowly changing ratio A : B in the distillate.
If the difference in vapor pressure between the two components A and B is large (generally expressed as the difference in boiling points), the mixture in the beginning of the distillation is highly enriched in component A, and when component A has distilled off, the boiling liquid is enriched in component B.
## Continuous distillation
Continuous distillation is an ongoing distillation in which a liquid mixture is continuously (without interruption) fed into the process and separated fractions are removed continuously as output streams as time passes during the operation. Continuous distillation produces at least two output fractions, including at least one volatile distillate fraction, which has boiled and been separately captured as a vapor condensed to a liquid. There is always a bottoms (or residue) fraction, which is the least volatile residue that has not been separately captured as a condensed vapor.
## General improvements
Both batch and continuous distillations can be improved by making use of a fractionating column on top of the distillation flask. The column improves separation by providing a larger surface area for the vapor and condensate to come into contact. This helps it remain at equilibrium for as long as possible. The column can even consist of small subsystems ('trays' or 'dishes') which all contain an enriched, boiling liquid mixture, all with their own vapor-liquid equilibrium.
There are differences between laboratory-scale and industrial-scale fractionating columns, but the principles are the same. Examples of laboratory-scale fractionating columns (in increasing efficacy) include:
- Air condenser
- Vigreux column (usually laboratory scale only)
- Packed column (packed with glass beads, metal pieces, or other chemically inert material)
- Spinning band distillation system
# Laboratory scale distillation
Laboratory scale distillations are almost exclusively run as batch distillations. The device used in distillation, sometimes referred to as a still, consists at a minimum of a reboiler or pot in which the source material is heated, a condenser in which the heated vapour is cooled back to the liquid state, and a receiver in which the concentrated or purified liquid, called the distillate, is collected. Several laboratory scale techniques for distillation exist (see also distillation types).
## Simple distillation
In simple distillation, all the hot vapors produced are immediately channeled into a condenser which cools and condenses the vapors. Therefore, the distillate will not be pure - its composition will be identical to the composition of the vapors at the given temperature and pressure, and can be computed from Raoult's law.
As a result, simple distillation is usually used only to separate liquids whose boiling points differ greatly (rule of thumb is 25 °C), or to separate liquids from involatile solids or oils. For these cases, the vapor pressures of the components are usually sufficiently different that Raoult's law may be neglected due to the insignificant contribution of the less volatile component. In this case, the distillate may be sufficiently pure for its intended purpose.
## Fractional distillation
For many cases, the boiling points of the components in the mixture will be sufficiently close that Raoult's law must be taken into consideration. Therefore, fractional distillation must be used in order to separate the components well by repeated vaporization-condensation cycles within a packed fractionating column.
As the solution to be purified is heated, its vapors rise to the fractionating column. As it rises, it cools, condensing on the condenser walls and the surfaces of the packing material. Here, the condensate continues to be heated by the rising hot vapors; it vaporizes once more. However, the composition of the fresh vapors are determined once again by Raoult's law. Each vaporization-condensation cycle (called a theoretical plate) will yield a purer solution of the more volatile component. In reality, each cycle at a given temperature does not occur at exactly the same position in the fractionating column; theoretical plate is thus a concept rather than an accurate description.
More theoretical plates lead to better separations. A spinning band distillation system uses a spinning band of Teflon or metal to force the rising vapors into close contact with the descending condensate, increasing the number of theoretical plates.
## Steam distillation
Like vacuum distillation, steam distillation is a method for distilling compounds which are heat-sensitive. This process involves using bubbling steam through a heated mixture of the raw material. By Raoult's law, some of the target compound will vaporize (in accordance with its partial pressure). The vapor mixture is cooled and condensed, usually yielding a layer of oil and a layer of water.
Steam distillation of various aromatic herbs and flowers can result in two products; an essential oil as well as a watery herbal distillate. The essential oils are often used in perfumery and aromatherapy while the watery distillates have many applications in aromatherapy, food processing and skin care.
## Vacuum distillation
Some compounds have very high boiling points. To boil such compounds, it is often better to lower the pressure at which such compounds are boiled instead of increasing the temperature. Once the pressure is lowered to the vapor pressure of the compound (at the given temperature), boiling and the rest of the distillation process can commence. This technique is referred to as vacuum distillation and it is commonly found in the laboratory in the form of the rotary evaporator.
This technique is also very useful for compounds which boil beyond their decomposition temperature at atmospheric pressure and which would therefore be decomposed by any attempt to boil them under atmospheric pressure.
## Air-sensitive vacuum distillation
Some compounds have high boiling points as well as being air sensitive. A simple vacuum distillation system as exemplified above can be used, whereby the vacuum is replaced with an inert gas after the distillation is complete. However, this is a less satisfactory system if one desires to collect fractions under a reduced pressure. To do this a "pig" adaptor can be added to the end of the condenser, or for better results or for very air sensitive compounds a Perkin triangle apparatus can be used.
The Perkin triangle, has means via a series of glass or Teflon taps to allows fractions to be isolated from the rest of the still, without the main body of the distillation being removed from either the vacuum or heat source, and thus can remain in a state of reflux. To do this, the sample is first isolated from the vacuum by means of the taps, the vacuum over the sample is then replaced with an inert gas (such as nitrogen or argon) and can then be stoppered and removed. A fresh collection vessel can then be added to the system, evacuated and linked back into the distillation system via the taps to collect a second fraction, and so on, until all fractions have been collected.
## Short path distillation
Short path distillation is a distillation technique that involves the distillate traveling a short distance, often only a few centimeters. A classic example would be a distillation involving the distillate traveling from one glass bulb to another, without the need for a condenser separating the two chambers. This technique is often used for compounds which are unstable at high temperatures. The Advantage is that the heating temperature can be considerably lower (at this reduced pressure) than the boiling point of the liquid at standard pressure, and that the distillate only has to travel a short distance before condensing. A Kugelrohr apparatus can be used for Short path distillation.
## Other types
- In rotary evaporation a vacuum distillation apparatus is used to remove bulk solvents from a sample. Typically the vacuum is generated by a water aspirator or a membrane pump.
- In a kugelrohr a short path distillation apparatus is typically used (generally in combination with a (high) vacuum) to distill high boiling (> 300 °C) compounds. The apparatus consists of an oven in which the compound to be distilled is placed, a receiving portion which is outside of the oven, and a means of rotating the sample. The vacuum is normally generated by using a high vacuum pump.
- The process of reactive distillation involves using the reaction vessel as the still. In this process, the product is usually significantly lower-boiling than its reactants. As the product is formed from the reactants, it is vaporized and removed from the reaction mixture. This technique is an example of a continuous vs. a batch process; advantages include less downtime to charge the reaction vessel with starting material, and less workup.
- Destructive distillation involves the strong heating of solids (often organic material) in the absence of oxygen (to prevent combustion) to evaporate various high-boiling liquids, as well as thermolysis products. The gases evolved are cooled and condensed as in normal distillation. The destructive distillation of wood to give methanol is the root of its common name - wood alcohol.
- Pervaporation is a method for the separation of mixtures of liquids by partial vaporization through a non-porous membrane.
- Dry distillation, despite its name, is not truly distillation, but rather a chemical reaction known as pyrolysis in which solid substances are heated in a strongly reducing atmosphere and any volatile fractions are collected.
- Extractive distillation is defined as distillation in the presence of a miscible, high boiling, relatively non-volatile component, the solvent, that forms no azeotrope with the other components in the mixture.
- Flash evaporation (or partial evaporation) is the partial vaporization that occurs when a saturated liquid stream undergoes a reduction in pressure by passing through a throttling valve or other throttling device. This process is one of the simplest unit operations.
- Freeze distillation is an analogous method of purification using freezing instead of evaporation. It is not truly distillation, and does not produce products equivalent to distillation. This process is used in the production of ice beer and ice wine to increase ethanol and sugar content, respectively.
- Codistillation is distillation which is performed on mixtures in which the two compounds are not miscible.
# Azeotropic distillation
Interactions between the components of the solution create properties unique to the solution, as most processes entail nonideal mixtures, where Raoult's law does not hold. Such interactions can result in a constant-boiling azeotrope which behaves as if it were a pure compound (i.e., boils at a single temperature instead of a range). At an azeotrope, the solution contains the given component in the same proportion as the vapor, so that evaporation does not change the purity, and distillation does not effect separation. For example, ethyl alcohol and water form an azeotrope of 95% at 78.2 °C.
If the azeotrope is not considered sufficiently pure for use, there exist some techniques to break the azeotrope to give a pure distillate. This set of techniques are known as azeotropic distillation. Some techniques achieve this by "jumping" over the azeotropic composition (by adding an additional component to create a new azeotrope, or by varying the pressure). Others work by chemically or physically remove or sequester the impurity. For example, to purify ethanol beyond 95%, a drying agent or a desiccant such as potassium carbonate can be added to convert the soluble water into insoluble water of crystallization. Molecular sieves are often used for this purpose as well.
Immiscible liquids, such as water and toluene, easily form azeotropes. Commonly, these azeotropes are referred to as a low boiling azeotrope because the boiling point of the azeotrope is lower than the boiling point of either pure component. The temperature and composition of the azeotrope is easily predicted from the vapor pressure of the pure components, without use of Raoult's law. The azeotrope is easily broken in a distillation set-up by using a liquid-liquid separator ( a decanter ) to separate the two liquid layers that are condensed overhead. Only one of the two liquid layers is refluxed to the distillation set-up.
High boiling azeotropes, such as a 20 weight percent mixture of hydrochloric acid in water also exist. As implied by the name, the boiling point of the azeotrope is greater than the boiling point of either pure component.
To break azeotropic distillations and cross distillation boundaries, such as in the DeRosier Problem, it is necessary to increase the composition of the light key in the distillate.
## Breaking an azeotrope with unidirectional pressure manipulation
A vacuum distillation can be used to "break" an azeotropic mixture. Varying the temperature of the vapour generating flask when distilling an azeotrope from cold to the solutions boiling point does not produce a continuously sliding ratio of product to contaminate in the distillate. The two separate boiling points still remain, they merely overlap; these can be thought of as required activation energies for the release of a particular vapour. By exposing an azeotrope to a vacuum, it's possible to bias the boiling point of one away from the other by exploiting the difference between each components vapour pressure. When the bias is great enough, the two boiling points no longer overlap and so the azeotropic band disappears.
This method is not without drawbacks. As an example, exposing a solution of water and ethanol to a 70 torr vacuum will allow for absolute ethanol to be distilled. However, due to the low pressure atmosphere, the ethanol vapour requires a significantly cooler condenser surface to liquefy, going from 78.3 °C at atmospheric pressure to 24.5 °C at 70 torr; failure to provide such results in the vapours passing through the condenser and into the vacuum source. This can also affect the efficiency of the condenser, as the liquefying temperature drops towards the minimum the condensing equipment can cool to, the thermal gradient across the liquefying surfaces reduces and, so with it, the rate at which heat can be extracted from the vapour.
Conversely, increasing a distillation pressure can also break an azeotrope, but will bring with it the possibility of thermal decomposition, for organic compounds in particular, and may be more beneficial to high temperature tolerant distillations, such as those of the metallic salts.
## Pressure-swing Distillation
This method of distillation can be used to separate azeotropic mixtures and relies on a principle similar to vacuum distillation, that being the manipulation of boiling points by altering the pressure of the atmosphere to which a solution is exposed.
It might be chosen over pure vacuum distillation of an azeotrope if that solution, for instance, had such a low liquefying point at the pressure required to break the azeotrope that the equipment was unable to provide for it, allowing the product to stream out of the condenser and into the vacuum source. Here, rather than manipulate just one boiling point, one or more are altered, one after the other; with the number of pressure alternations being determined by the number of components in the feed solution considered to be contaminants. This could be beneficial to a purification as it is likely to create less extreme thermal requirements. Simply, instead of swinging distillation pressure in one direction alone in an attempt to break the azeotrope in one step, the break is performed in two or more steps with pressure swung in two directions to create an operating band centered around more accessible temperatures; perhaps going from a negative pressure to atmospheric and on to a positive pressure. In essence, pressure-swing distillation is an attempt to reduce extreme conditions by dispersing the manipulation load across the equipment generating the distillation environment.
If a continuous feed is desired, or the distillation pressures required are extreme enough to warrant specialised design, each step may require a physically separate column. If only a batch run is required and the same column can perform under all the required pressures, this single column may suffice; with the vapour generating flask being emptied after the first distillation, the first distillate run back to the start and the distillation rerun under the second pressure conditions, and so on.
Selection of which component the distillate should be biased towards may be made based on the energy required to evaporate it from the feed solution.
Pressure-swing distillation is employed during the purification of ethyl acetate after its catalytic synthesis from ethanol.
# Industrial distillation
Large scale industrial distillation applications include both batch and continuous fractional, vacuum, azeotropic, extractive, and steam distillation. The most widely used industrial applications of continuous, steady-state fractional distillation are in petroleum refineries, petrochemical and chemical plants and natural gas processing plants.
Industrial distillation is typically performed in large, vertical cylindrical columns known as distillation towers or distillation columns with diameters ranging from about 65 centimeters to 16 meters and heights ranging from about 6 meters to 90 meters or more. When the process feed has a diverse composition, as in distilling crude oil, liquid outlets at intervals up the column allow for the withdrawal of different fractions or products having different boiling points or boiling ranges. The "lightest" products (those with the lowest boiling point) exit from the top of the columns and the "heaviest" products (those with the highest boiling point) exit from the bottom of the column and are often called the bottoms.
Large-scale industrial towers use reflux to achieve a more complete separation of products. Reflux refers to the portion of the condensed overhead liquid product from a distillation or fractionation tower that is returned to the upper part of the tower as shown in the schematic diagram of a typical, large-scale industrial distillation tower. Inside the tower, the downflowing reflux liquid provides cooling and condensation of the upflowing vapors thereby increasing the efficacy of the distillation tower. The more reflux is provided for a given number of theoretical plates, the better is the tower's separation of lower boiling materials from higher boiling materials. Alternatively, the more reflux is provided for a given desired separation, the fewer theoretical plates are required.
Such industrial fractionating towers are also used in air separation, producing liquid oxygen, liquid nitrogen, and high purity argon. Distillation of chlorosilanes also enables the production of high-purity silicon for use as a semiconductor.
Design and operation of a distillation tower depends on the feed and desired products. Given a simple, binary component feed, analytical methods such as the McCabe-Thiele method or the Fenske equation can be used. For a multi-component feed, simulation models are used both for design and operation. Moreover, the efficiencies of the vapor-liquid contact devices (referred to as "plates" or "trays") used in distillation towers are typically lower than that of a theoretical 100% efficient equilibrium stage. Hence, a distillation tower needs more trays than the number of theoretical vapor-liquid equilibrium stages.
In industrial uses, sometimes a packing material is used in the column instead of trays, especially when low pressure drops across the column are required, as when operating under vacuum.
This packing material can either be random dumped packing (1-3" wide) such as Raschig rings or structured sheet metal. Liquids tend to wet the surface of the packing and the vapors pass across this wetted surface, where mass transfer takes place. Unlike conventional tray distillation in which every tray represents a separate point of vapor-liquid equilibrium, the vapor-liquid equilibrium curve in a packed column is continuous. However, when modeling packed columns, it is useful to compute a number of "theoretical stages" to denote the separation efficiency of the packed column with respect to more traditional trays. Differently shaped packings have different surface areas and void space between packings. Both of these factors affect packing performance.
Another factor in addition to the packing shape and surface area that affects the performance of random or structured packing is the liquid and vapor distribution entering the packed bed. The number of theoretical stages required to make a given separation is calculated using a specific vapor to liquid ratio. If the liquid and vapor are not evenly distributed across the superficial tower area as it enters the packed bed, the liquid to vapor ratio will not be correct in the packed bed and the required separation will not be achieved. The packing will appear to not be working properly. The height equivalent of a theoretical plate (HETP) will be greater than expected. The problem is not the packing itself but the mal-distribution of the fluids entering the packed bed. Liquid mal-distribution is more frequently the problem than vapor. The design of the liquid distributors used to introduce the feed and reflux to a packed bed is critical to making the packing perform to it maximum efficiency. Methods of evaluating the effectiveness of a liquid distributor to evenly distribute the liquid entering a packed bed can be found in references. Considerable work as been done on this topic by Fractionation Research, Inc. (commonly known as FRI).
# Distillation in food processing
## Distilled beverages
Carbohydrate-containing plant materials are allowed to ferment, producing a dilute solution of ethanol in the process. Spirits such as whiskey and rum are prepared by distilling these dilute solutions of ethanol. Other components than ethanol are collected in the condensate, including water, esters, and other alcohols which account for the flavor of the beverage. | Distillation
Distillation is a method of separating chemical substances based on differences in their volatilities in a boiling liquid mixture. Distillation usually forms part of a larger chemical process, and is thus referred to as a unit operation.
Commercially, distillation has a number of uses. It is used to separate crude oil into more fractions for specific uses such as transport, power generation and heating. Water is distilled to remove impurities, such as salt from sea water. Air is distilled to separate its components - notably oxygen, nitrogen and argon - for industrial use. Distillation of fermented solutions has been used since ancient times to produce distilled beverages with a higher alcohol content.
# History
Early forms of distillation were known to Babylonian alchemists in Mesopotamia (in what is now Iraq) from at least the 2nd millennium BC.[1] Distillation was later known to Greek alchemists from the 1st century AD,[2][3][4] and the later development of large-scale distillation apparatus occurred in response to demands for spirits.[2] Hypathia of Alexandria is credited with having invented an early distillation apparatus,[5] and the first exact description of apparatus for distillation is given by Zosimos of Alexandria in the fourth century.[4]
In the 8th century, alchemists in the Middle East produced distillation processes to purify chemical substances for industrial purposes such as isolating natural esters (perfumes) and producing pure alcohol.[6] The first among them was the Persian Jabir ibn Hayyan (Geber) circa 800 AD, who is credited with the invention of numerous chemical apparatus and processes that are still in use today. In particular, his alembic was the first still with retorts which could fully purify chemicals, a precursor to the pot still, and its design has served as inspiration for modern micro-scale distillation apparatus such as the Hickman stillhead.[7] Petroleum was first distilled by another Persian, al-Razi (Rhazes) in the 9th century, for producing kerosene,[8] while steam distillation was invented by Avicenna in the early 11th century, for producing essential oils.[9]
In 1500, German alchemist Hieronymus Braunschweig published Liber de arte destillandi (The Book of the Art of Distillation)[1] the first book on the subject, followed in 1512 by a much expanded version.
In 1651, John French published The Art of Distillation the first major English compendium of practice, though it has been claimed[10] that much of it derives from Braunschweig's work. This includes diagrams with people in them showing the industrial rather than bench scale of the operation.
As alchemy evolved into the science of chemistry, vessels called retorts became used for distillations. Both alembics and retorts are forms of glassware with long necks pointing to the side at a downward angle which acted as air-cooled condensers to condense the distillate and let it drip downward for collection.
Later, copper alembics were invented. Riveted joints were often kept tight by using various mixtures, for instance a dough made of rye flour.[11] These alembics often featured a cooling system around the beak, using cold water for instance, which made the condensation of alcohol more efficient. These were called pot stills.
Today, the retorts and pot stills have been largely supplanted by more efficient distillation methods in most industrial processes. However, the pot still is still widely used for the elaboration of some fine alcohols such as cognac, Scotch whisky and some vodkas. Pot stills made of various materials (wood, clay, stainless steel) are also used by bootleggers in various countries. Small pot stills are also sold for the domestic production[12] of flower water or essential oils.
In the early 19th century the basics of modern techniques including pre-heating and reflux were developed, particularly by the French[13], then in 1830 a British Patent was issued to Aeneas Coffey for a whiskey distillation column[14], which worked continuously and may be regarded as the archetype of modern petrochemical units. In 1877, Ernest Solvay was granted a U.S. Patent for a tray column for ammonia distillation[15] and the same and subsequent years saw developments of this theme for oil and spirits.
With the emergence of chemical engineering as a discipline at the end of the 19th century, scientific rather than empirical methods could be applied. The developing petroleum industry in the early 20th century provided the impetus for the development of accurate design methods such as the McCabe-Thiele method and the Fenske equation.
# Applications of distillation
The application of distillation can roughly be divided in four groups: laboratory scale, industrial distillation, distillation of herbs for perfumery and medicinals (herbal distillate) and food processing. The latter two are distinct from the former two, in that in the distillation is not used as a true purification method, but more to transfer all volatiles from the source materials to the distillate.
The main difference between laboratory scale distillation and industrial distillation is that laboratory scale distillation is often performed batch-wise, whereas industrial distillation often occurs continuously. In batch distillation, the composition of the source material, the vapors of the distilling compounds and the distillate change during the distillation. In batch distillation, a still is charged (supplied) with a batch of feed mixture, which is then separated into its component fractions which are collected sequentially from most volatile to less volatile, with the bottoms (remaining least or non-volatile fraction) removed at the end. The still can then be recharged and the process repeated.
In continuous distillation, the source materials, vapors and distillate are kept at a constant composition by carefully replenishing the source material and removing fractions from both vapor and liquid in the system. This results in a better control of the separation process.
# Idealized distillation model
The boiling point of a liquid is the temperature at which the vapor pressure of the liquid equals the pressure surrounding the liquid. The normal boiling point of a liquid is the special case at which the vapor pressure of the liquid equals the ambient atmospheric pressure. A liquid in a container at a pressure below atmospheric pressure will boil at temperature lower than the normal boiling point, and a liquid in a container at a pressure higher than atmospheric pressure will boil at a temperature higher than the normal boiling point. In other words, all liquids have an infinite number of boiling points.
It is a common misconception that in a liquid mixture at a given pressure, each component boils at the boiling point corresponding to the given pressure and the vapors of each component will collect separately and purely. This, however, does not occur even in an idealized system. Idealized models of distillation are essentially governed by Raoult's law and Dalton's law.
Raoult's law assumes that a component contributes to the total vapor pressure of the mixture in proportion to its percentage of the mixture and its vapor pressure when pure. If one component changes another component's vapor pressure, or if the volatility of a component is dependent on its percentage in the mixture, the law will fail.
Dalton's law states that the total vapor pressure is the sum of the vapor pressures of each individual component in the mixture. When a multi-component liquid is heated, the vapor pressure of each component will rise, thus causing the total vapor pressure to rise. When the total vapor pressure reaches the pressure surrounding the liquid, boiling occurs and liquid turns to gas throughout the bulk of the liquid. Note that a given mixture has one boiling point at a given pressure, when the components are mutually soluble.
The idealized model is accurate in the case of chemically similar liquids, such as benzene and toluene. In other cases, severe deviations from Raoult's law and Dalton's law are observed, most famously in the mixture of ethanol and water. These compounds, when heated together, form an azeotrope, in which the boiling temperature of the mixture is lower than the boiling temperature of each separate liquid. Virtually all liquids, when mixed and heated, will display azeotropic behaviour. Although there are computational methods that can be used to estimate the behavior of a mixture of arbitrary components, the only way to obtain accurate vapor-liquid equilibrium data is by measurement.
It is not possible to completely purify a mixture of components by distillation, as this would require each component in the mixture to have a zero partial pressure. If ultra-pure products are the goal, then further chemical separation must be applied.
## Batch distillation
Heating an ideal mixture of two volatile substances A and B (with A having the higher volatility, or lower boiling point) in a batch distillation setup (such as in an apparatus depicted in the opening figure) until the mixture is boiling results in a vapor above the liquid which contains a mixture of A and B. The ratio between A and B in the vapor will be different from the ratio in the liquid: the ratio in the liquid will be determined by how the original mixture was prepared, while the ratio in the vapor will be enriched in the more volatile compound, A (due to Raoult's Law, see above). The vapor goes through the condenser and is removed from the system. This in turn means that the ratio of compounds in the remaining liquid is now different from the initial ratio (i.e. more enriched in B than the starting liquid).
The result is that the ratio in the liquid mixture is changing, becoming richer in component B. This causes the boiling point of the mixture to rise, which in turn results in a rise in the temperature in the vapor, which results in a changing ratio of A : B in the gas phase (as distillation continues, there is an increasing proportion of B in the gas phase). This results in a slowly changing ratio A : B in the distillate.
If the difference in vapor pressure between the two components A and B is large (generally expressed as the difference in boiling points), the mixture in the beginning of the distillation is highly enriched in component A, and when component A has distilled off, the boiling liquid is enriched in component B.
## Continuous distillation
Continuous distillation is an ongoing distillation in which a liquid mixture is continuously (without interruption) fed into the process and separated fractions are removed continuously as output streams as time passes during the operation. Continuous distillation produces at least two output fractions, including at least one volatile distillate fraction, which has boiled and been separately captured as a vapor condensed to a liquid. There is always a bottoms (or residue) fraction, which is the least volatile residue that has not been separately captured as a condensed vapor.
## General improvements
Both batch and continuous distillations can be improved by making use of a fractionating column on top of the distillation flask. The column improves separation by providing a larger surface area for the vapor and condensate to come into contact. This helps it remain at equilibrium for as long as possible. The column can even consist of small subsystems ('trays' or 'dishes') which all contain an enriched, boiling liquid mixture, all with their own vapor-liquid equilibrium.
There are differences between laboratory-scale and industrial-scale fractionating columns, but the principles are the same. Examples of laboratory-scale fractionating columns (in increasing efficacy) include:
- Air condenser
- Vigreux column (usually laboratory scale only)
- Packed column (packed with glass beads, metal pieces, or other chemically inert material)
- Spinning band distillation system
# Laboratory scale distillation
Laboratory scale distillations are almost exclusively run as batch distillations. The device used in distillation, sometimes referred to as a still, consists at a minimum of a reboiler or pot in which the source material is heated, a condenser in which the heated vapour is cooled back to the liquid state, and a receiver in which the concentrated or purified liquid, called the distillate, is collected. Several laboratory scale techniques for distillation exist (see also distillation types).
## Simple distillation
In simple distillation, all the hot vapors produced are immediately channeled into a condenser which cools and condenses the vapors. Therefore, the distillate will not be pure - its composition will be identical to the composition of the vapors at the given temperature and pressure, and can be computed from Raoult's law.
As a result, simple distillation is usually used only to separate liquids whose boiling points differ greatly (rule of thumb is 25 °C),[16] or to separate liquids from involatile solids or oils. For these cases, the vapor pressures of the components are usually sufficiently different that Raoult's law may be neglected due to the insignificant contribution of the less volatile component. In this case, the distillate may be sufficiently pure for its intended purpose.
## Fractional distillation
For many cases, the boiling points of the components in the mixture will be sufficiently close that Raoult's law must be taken into consideration. Therefore, fractional distillation must be used in order to separate the components well by repeated vaporization-condensation cycles within a packed fractionating column.
As the solution to be purified is heated, its vapors rise to the fractionating column. As it rises, it cools, condensing on the condenser walls and the surfaces of the packing material. Here, the condensate continues to be heated by the rising hot vapors; it vaporizes once more. However, the composition of the fresh vapors are determined once again by Raoult's law. Each vaporization-condensation cycle (called a theoretical plate) will yield a purer solution of the more volatile component.[17] In reality, each cycle at a given temperature does not occur at exactly the same position in the fractionating column; theoretical plate is thus a concept rather than an accurate description.
More theoretical plates lead to better separations. A spinning band distillation system uses a spinning band of Teflon or metal to force the rising vapors into close contact with the descending condensate, increasing the number of theoretical plates.[18]
## Steam distillation
Like vacuum distillation, steam distillation is a method for distilling compounds which are heat-sensitive. This process involves using bubbling steam through a heated mixture of the raw material. By Raoult's law, some of the target compound will vaporize (in accordance with its partial pressure). The vapor mixture is cooled and condensed, usually yielding a layer of oil and a layer of water.
Steam distillation of various aromatic herbs and flowers can result in two products; an essential oil as well as a watery herbal distillate. The essential oils are often used in perfumery and aromatherapy while the watery distillates have many applications in aromatherapy, food processing and skin care.
## Vacuum distillation
Some compounds have very high boiling points. To boil such compounds, it is often better to lower the pressure at which such compounds are boiled instead of increasing the temperature. Once the pressure is lowered to the vapor pressure of the compound (at the given temperature), boiling and the rest of the distillation process can commence. This technique is referred to as vacuum distillation and it is commonly found in the laboratory in the form of the rotary evaporator.
This technique is also very useful for compounds which boil beyond their decomposition temperature at atmospheric pressure and which would therefore be decomposed by any attempt to boil them under atmospheric pressure.
## Air-sensitive vacuum distillation
Some compounds have high boiling points as well as being air sensitive. A simple vacuum distillation system as exemplified above can be used, whereby the vacuum is replaced with an inert gas after the distillation is complete. However, this is a less satisfactory system if one desires to collect fractions under a reduced pressure. To do this a "pig" adaptor can be added to the end of the condenser, or for better results or for very air sensitive compounds a Perkin triangle apparatus can be used.
The Perkin triangle, has means via a series of glass or Teflon taps to allows fractions to be isolated from the rest of the still, without the main body of the distillation being removed from either the vacuum or heat source, and thus can remain in a state of reflux. To do this, the sample is first isolated from the vacuum by means of the taps, the vacuum over the sample is then replaced with an inert gas (such as nitrogen or argon) and can then be stoppered and removed. A fresh collection vessel can then be added to the system, evacuated and linked back into the distillation system via the taps to collect a second fraction, and so on, until all fractions have been collected.
## Short path distillation
Short path distillation is a distillation technique that involves the distillate traveling a short distance, often only a few centimeters. A classic example would be a distillation involving the distillate traveling from one glass bulb to another, without the need for a condenser separating the two chambers. This technique is often used for compounds which are unstable at high temperatures. The Advantage is that the heating temperature can be considerably lower (at this reduced pressure) than the boiling point of the liquid at standard pressure, and that the distillate only has to travel a short distance before condensing. A Kugelrohr apparatus can be used for Short path distillation.
## Other types
- In rotary evaporation a vacuum distillation apparatus is used to remove bulk solvents from a sample. Typically the vacuum is generated by a water aspirator or a membrane pump.
- In a kugelrohr a short path distillation apparatus is typically used (generally in combination with a (high) vacuum) to distill high boiling (> 300 °C) compounds. The apparatus consists of an oven in which the compound to be distilled is placed, a receiving portion which is outside of the oven, and a means of rotating the sample. The vacuum is normally generated by using a high vacuum pump.
- The process of reactive distillation involves using the reaction vessel as the still. In this process, the product is usually significantly lower-boiling than its reactants. As the product is formed from the reactants, it is vaporized and removed from the reaction mixture. This technique is an example of a continuous vs. a batch process; advantages include less downtime to charge the reaction vessel with starting material, and less workup.
- Destructive distillation involves the strong heating of solids (often organic material) in the absence of oxygen (to prevent combustion) to evaporate various high-boiling liquids, as well as thermolysis products. The gases evolved are cooled and condensed as in normal distillation. The destructive distillation of wood to give methanol is the root of its common name - wood alcohol.
- Pervaporation is a method for the separation of mixtures of liquids by partial vaporization through a non-porous membrane.
- Dry distillation, despite its name, is not truly distillation, but rather a chemical reaction known as pyrolysis in which solid substances are heated in a strongly reducing atmosphere and any volatile fractions are collected.
- Extractive distillation is defined as distillation in the presence of a miscible, high boiling, relatively non-volatile component, the solvent, that forms no azeotrope with the other components in the mixture.
- Flash evaporation (or partial evaporation) is the partial vaporization that occurs when a saturated liquid stream undergoes a reduction in pressure by passing through a throttling valve or other throttling device. This process is one of the simplest unit operations.
- Freeze distillation is an analogous method of purification using freezing instead of evaporation. It is not truly distillation, and does not produce products equivalent to distillation. This process is used in the production of ice beer and ice wine to increase ethanol and sugar content, respectively.
- Codistillation is distillation which is performed on mixtures in which the two compounds are not miscible.
# Azeotropic distillation
Interactions between the components of the solution create properties unique to the solution, as most processes entail nonideal mixtures, where Raoult's law does not hold. Such interactions can result in a constant-boiling azeotrope which behaves as if it were a pure compound (i.e., boils at a single temperature instead of a range). At an azeotrope, the solution contains the given component in the same proportion as the vapor, so that evaporation does not change the purity, and distillation does not effect separation. For example, ethyl alcohol and water form an azeotrope of 95% at 78.2 °C.
If the azeotrope is not considered sufficiently pure for use, there exist some techniques to break the azeotrope to give a pure distillate. This set of techniques are known as azeotropic distillation. Some techniques achieve this by "jumping" over the azeotropic composition (by adding an additional component to create a new azeotrope, or by varying the pressure). Others work by chemically or physically remove or sequester the impurity. For example, to purify ethanol beyond 95%, a drying agent or a desiccant such as potassium carbonate can be added to convert the soluble water into insoluble water of crystallization. Molecular sieves are often used for this purpose as well.
Immiscible liquids, such as water and toluene, easily form azeotropes. Commonly, these azeotropes are referred to as a low boiling azeotrope because the boiling point of the azeotrope is lower than the boiling point of either pure component. The temperature and composition of the azeotrope is easily predicted from the vapor pressure of the pure components, without use of Raoult's law. The azeotrope is easily broken in a distillation set-up by using a liquid-liquid separator ( a decanter ) to separate the two liquid layers that are condensed overhead. Only one of the two liquid layers is refluxed to the distillation set-up.
High boiling azeotropes, such as a 20 weight percent mixture of hydrochloric acid in water also exist. As implied by the name, the boiling point of the azeotrope is greater than the boiling point of either pure component.
To break azeotropic distillations and cross distillation boundaries, such as in the DeRosier Problem, it is necessary to increase the composition of the light key in the distillate.
## Breaking an azeotrope with unidirectional pressure manipulation
A vacuum distillation can be used to "break" an azeotropic mixture. Varying the temperature of the vapour generating flask when distilling an azeotrope from cold to the solutions boiling point does not produce a continuously sliding ratio of product to contaminate in the distillate. The two separate boiling points still remain, they merely overlap; these can be thought of as required activation energies for the release of a particular vapour. By exposing an azeotrope to a vacuum, it's possible to bias the boiling point of one away from the other by exploiting the difference between each components vapour pressure. When the bias is great enough, the two boiling points no longer overlap and so the azeotropic band disappears.
This method is not without drawbacks. As an example, exposing a solution of water and ethanol to a 70 torr vacuum will allow for absolute ethanol to be distilled. However, due to the low pressure atmosphere, the ethanol vapour requires a significantly cooler condenser surface to liquefy, going from 78.3 °C at atmospheric pressure to 24.5 °C at 70 torr; failure to provide such results in the vapours passing through the condenser and into the vacuum source. This can also affect the efficiency of the condenser, as the liquefying temperature drops towards the minimum the condensing equipment can cool to, the thermal gradient across the liquefying surfaces reduces and, so with it, the rate at which heat can be extracted from the vapour.
Conversely, increasing a distillation pressure can also break an azeotrope, but will bring with it the possibility of thermal decomposition, for organic compounds in particular, and may be more beneficial to high temperature tolerant distillations, such as those of the metallic salts.
## Pressure-swing Distillation
This method of distillation can be used to separate azeotropic mixtures and relies on a principle similar to vacuum distillation, that being the manipulation of boiling points by altering the pressure of the atmosphere to which a solution is exposed.
It might be chosen over pure vacuum distillation of an azeotrope if that solution, for instance, had such a low liquefying point at the pressure required to break the azeotrope that the equipment was unable to provide for it, allowing the product to stream out of the condenser and into the vacuum source. Here, rather than manipulate just one boiling point, one or more are altered, one after the other; with the number of pressure alternations being determined by the number of components in the feed solution considered to be contaminants. This could be beneficial to a purification as it is likely to create less extreme thermal requirements. Simply, instead of swinging distillation pressure in one direction alone in an attempt to break the azeotrope in one step, the break is performed in two or more steps with pressure swung in two directions to create an operating band centered around more accessible temperatures; perhaps going from a negative pressure to atmospheric and on to a positive pressure. In essence, pressure-swing distillation is an attempt to reduce extreme conditions by dispersing the manipulation load across the equipment generating the distillation environment.
If a continuous feed is desired, or the distillation pressures required are extreme enough to warrant specialised design, each step may require a physically separate column. If only a batch run is required and the same column can perform under all the required pressures, this single column may suffice; with the vapour generating flask being emptied after the first distillation, the first distillate run back to the start and the distillation rerun under the second pressure conditions, and so on.
Selection of which component the distillate should be biased towards may be made based on the energy required to evaporate it from the feed solution.
Pressure-swing distillation is employed during the purification of ethyl acetate after its catalytic synthesis from ethanol.
# Industrial distillation
Large scale industrial distillation applications include both batch and continuous fractional, vacuum, azeotropic, extractive, and steam distillation. The most widely used industrial applications of continuous, steady-state fractional distillation are in petroleum refineries, petrochemical and chemical plants and natural gas processing plants.
Industrial distillation[19][20] is typically performed in large, vertical cylindrical columns known as distillation towers or distillation columns with diameters ranging from about 65 centimeters to 16 meters and heights ranging from about 6 meters to 90 meters or more. When the process feed has a diverse composition, as in distilling crude oil, liquid outlets at intervals up the column allow for the withdrawal of different fractions or products having different boiling points or boiling ranges. The "lightest" products (those with the lowest boiling point) exit from the top of the columns and the "heaviest" products (those with the highest boiling point) exit from the bottom of the column and are often called the bottoms.
Large-scale industrial towers use reflux to achieve a more complete separation of products. Reflux refers to the portion of the condensed overhead liquid product from a distillation or fractionation tower that is returned to the upper part of the tower as shown in the schematic diagram of a typical, large-scale industrial distillation tower. Inside the tower, the downflowing reflux liquid provides cooling and condensation of the upflowing vapors thereby increasing the efficacy of the distillation tower. The more reflux is provided for a given number of theoretical plates, the better is the tower's separation of lower boiling materials from higher boiling materials. Alternatively, the more reflux is provided for a given desired separation, the fewer theoretical plates are required.
Such industrial fractionating towers are also used in air separation, producing liquid oxygen, liquid nitrogen, and high purity argon. Distillation of chlorosilanes also enables the production of high-purity silicon for use as a semiconductor.
Design and operation of a distillation tower depends on the feed and desired products. Given a simple, binary component feed, analytical methods such as the McCabe-Thiele method[20][21] or the Fenske equation[20] can be used. For a multi-component feed, simulation models are used both for design and operation. Moreover, the efficiencies of the vapor-liquid contact devices (referred to as "plates" or "trays") used in distillation towers are typically lower than that of a theoretical 100% efficient equilibrium stage. Hence, a distillation tower needs more trays than the number of theoretical vapor-liquid equilibrium stages.
In industrial uses, sometimes a packing material is used in the column instead of trays, especially when low pressure drops across the column are required, as when operating under vacuum.
This packing material can either be random dumped packing (1-3" wide) such as Raschig rings or structured sheet metal. Liquids tend to wet the surface of the packing and the vapors pass across this wetted surface, where mass transfer takes place. Unlike conventional tray distillation in which every tray represents a separate point of vapor-liquid equilibrium, the vapor-liquid equilibrium curve in a packed column is continuous. However, when modeling packed columns, it is useful to compute a number of "theoretical stages" to denote the separation efficiency of the packed column with respect to more traditional trays. Differently shaped packings have different surface areas and void space between packings. Both of these factors affect packing performance.
Another factor in addition to the packing shape and surface area that affects the performance of random or structured packing is the liquid and vapor distribution entering the packed bed. The number of theoretical stages required to make a given separation is calculated using a specific vapor to liquid ratio. If the liquid and vapor are not evenly distributed across the superficial tower area as it enters the packed bed, the liquid to vapor ratio will not be correct in the packed bed and the required separation will not be achieved. The packing will appear to not be working properly. The height equivalent of a theoretical plate (HETP) will be greater than expected. The problem is not the packing itself but the mal-distribution of the fluids entering the packed bed. Liquid mal-distribution is more frequently the problem than vapor. The design of the liquid distributors used to introduce the feed and reflux to a packed bed is critical to making the packing perform to it maximum efficiency. Methods of evaluating the effectiveness of a liquid distributor to evenly distribute the liquid entering a packed bed can be found in references.[23][24] Considerable work as been done on this topic by Fractionation Research, Inc. (commonly known as FRI).[25]
# Distillation in food processing
## Distilled beverages
Carbohydrate-containing plant materials are allowed to ferment, producing a dilute solution of ethanol in the process. Spirits such as whiskey and rum are prepared by distilling these dilute solutions of ethanol. Other components than ethanol are collected in the condensate, including water, esters, and other alcohols which account for the flavor of the beverage. | https://www.wikidoc.org/index.php/Distillation | |
6323409d91826f952c83a3a40e698e37e9d03c12 | wikidoc | Dodecahedron | Dodecahedron
A dodecahedron is any polyhedron with twelve faces, but usually a regular dodecahedron is meant: a Platonic solid composed of twelve regular pentagonal faces, with three meeting at each vertex. It has twenty (20) vertices and thirty (30) edges. Its dual polyhedron is the icosahedron. To the ancient Greeks, the dodecahedron was a symbol of the universe. If one were to make every one of the Platonic solids with edges of the same length, the dodecahedron would be the largest.
# Area and volume
The area A and the volume V of a regular dodecahedron of edge length a are:
# Cartesian coordinates
The following Cartesian coordinates define the vertices of a dodecahedron centered at the origin:
where φ = (1+√5)/2 is the golden ratio (also written τ). The side length is 2/φ = √5−1. The containing sphere has a radius of √3.
The dihedral angle of a dodecahedron is 2arctan(φ) or approximately 116.565 degrees.
# Geometric relations
The regular dodecahedron is the third in an infinite set of truncated trapezohedra which can be constructed by truncating the two axial vertices of a pentagonal trapezohedron.
The stellations of the dodecahedron make up three of the four Kepler-Poinsot polyhedra.
A rectified dodecahedron forms an icosidodecahedron.
The regular dodecahedron has 120 symmetries, forming the group A_5\times Z_2.
## Vertex arrangement
The dodecahedron shares its vertex arrangement with four nonconvex uniform polyhedrons and three uniform compounds.
Five cubes fit within, with their edges as diagonals of the dodecahedron's faces, and together these make up the regular polyhedral compound of five cubes. Since two tetrahedra can fit on alternate cube vertices, five and ten tetrahedra can also fit in a dodecahedron.
## Icosahedron vs dodecahedron
When a dodecahedron is inscribed in a sphere, it occupies more of the sphere's volume (66.49%) than an icosahedron inscribed in the same sphere (60.54%).
A regular dodecahedron with edge length 1 has more than three and a half times the volume of an icosahedron with the same length edges (7.663... compared with 2.181...).
# Other dodecahedra
The term dodecahedron is also used for other polyhedra with twelve faces, most notably the rhombic dodecahedron which is dual to the cuboctahedron (an Archimedean solid) and occurs in nature as a crystal form. The Platonic solid dodecahedron can be called a pentagonal dodecahedron or a regular dodecahedron to distinguish it. The pyritohedron is an irregular pentagonal dodecahedron.
Other dodecahedra include:
- Uniform polyhedra:
Pentagonal antiprism - 10 equilateral triangles, 2 pentagons
Decagonal prism - 10 squares, 2 decagons
- Pentagonal antiprism - 10 equilateral triangles, 2 pentagons
- Decagonal prism - 10 squares, 2 decagons
- Johnson solids (regular faced):
Pentagonal cupola - 5 triangles, 5 squares, 1 pentagon, 1 decagon
Snub disphenoid - 12 triangles
Elongated square dipyramid - 8 triangles and 4 squares
Metabidiminished icosahedron - 10 triangles and 2 pentagons
- Pentagonal cupola - 5 triangles, 5 squares, 1 pentagon, 1 decagon
- Snub disphenoid - 12 triangles
- Elongated square dipyramid - 8 triangles and 4 squares
- Metabidiminished icosahedron - 10 triangles and 2 pentagons
- Congruent nonregular faced: (face-transitive)
Hexagonal bipyramid - 12 isosceles triangles, dual of hexagonal prism
Hexagonal trapezohedron - 12 kites, dual of hexagonal antiprism
Triakis tetrahedron - 12 isosceles triangles, dual of truncated tetrahedron
Rhombic dodecahedron (mentioned above) - 12 rhombi, dual of cuboctahedron
- Hexagonal bipyramid - 12 isosceles triangles, dual of hexagonal prism
- Hexagonal trapezohedron - 12 kites, dual of hexagonal antiprism
- Triakis tetrahedron - 12 isosceles triangles, dual of truncated tetrahedron
- Rhombic dodecahedron (mentioned above) - 12 rhombi, dual of cuboctahedron
- Other nonregular faced:
Hendecagonal pyramid - 11 isosceles triangles and 1 hendecagon
Trapezo-rhombic dodecahedron - 6 rhombi, 6 trapezoids - dual of Triangular orthobicupola
Rhombo-hexagonal dodecahedron or Elongated Dodecahedron - 8 rhombi and 4 equilateral hexagons.
- Hendecagonal pyramid - 11 isosceles triangles and 1 hendecagon
- Trapezo-rhombic dodecahedron - 6 rhombi, 6 trapezoids - dual of Triangular orthobicupola
- Rhombo-hexagonal dodecahedron or Elongated Dodecahedron - 8 rhombi and 4 equilateral hexagons.
# Regular dodecahedra in the arts, sciences, and popular culture
Small, hollow bronze Roman dodecahedra dating from the 3rd century A.D. have been found in various places in Europe. Their purpose is not certain.
A dodecahedron sits on the table in M. C. Escher's lithograph print "Reptiles" (1943), and a stellated dodecahedron is used in his "Gravitation". In Salvador Dalí's painting of The Sacrament of the Last Supper (1955), the room is a hollow dodecahedron.
One of the characters in The Phantom Tollbooth, a children's novel from 1961, is named Dodecahedron and is a man with 12 faces.
The Dodecahedron was the mysterious power source for an underground city in the Doctor Who episode "Meglos" (1980).
In "Blood Feud", an episode of The Simpsons, Lisa attempts to teach Maggie the word dodecahedron.
In Carl Sagan's novel Contact, the transport device constructed to the plans transmitted by the alien intelligence is dodecahedral.
"Dodecaheedron" (misspelled, possibly intentionally, with an extra "e") is the title of a song by Aphex Twin.
Plato in the dialogue Timaeus c.360 B.C associated platonic solids with the four classical elements. Aristotle added a fifth element, aithêr (aether in Latin, "ether" in English) and postulated that the heavens were made of this element, but he had no interest in matching it with Plato's fifth solid.
In 2003, an apparent periodicity in the cosmic microwave background led to the suggestion, by Jean-Pierre Luminet of the Observatoire de Paris and colleagues, that the shape of the Universe is a finite dodecahedron, attached to itself by each pair of opposite faces to form a Poincaré homology sphere. ("Is the universe a dodecahedron?", article at PhysicsWeb.) During the following year, astronomers searched for more evidence to support this hypothesis but found none.
The 20 vertices and 30 edges of a dodecahedron form the map for an early computer game, Hunt the Wumpus. In the seminal 1980s computer game Elite, the more advanced "Dodec" class space stations took the form of dodecahedra. The save points in the Castlevania games, Castlevania: Symphony of the Night (for the PSX) and Castlevania: Harmony of Dissonance (GBA) are shaped like dodecahedrons. In the Nintendo 64 game Paper Mario, the mountains in the background of Toad Town are dodecahedra. ( Image of background)
The regular dodecahedron is often used in role-playing games as a twelve-sided die ("d12" for short), one of the more common polyhedral dice.
Desk calendars are occasionally made in the shape of a dodecahedron, usually from a die-cut folded card, with one month on each face. | Dodecahedron
Template:Reg polyhedra db
A dodecahedron is any polyhedron with twelve faces, but usually a regular dodecahedron is meant: a Platonic solid composed of twelve regular pentagonal faces, with three meeting at each vertex. It has twenty (20) vertices and thirty (30) edges. Its dual polyhedron is the icosahedron. To the ancient Greeks, the dodecahedron was a symbol of the universe. If one were to make every one of the Platonic solids with edges of the same length, the dodecahedron would be the largest.
# Area and volume
The area A and the volume V of a regular dodecahedron of edge length a are:
# Cartesian coordinates
The following Cartesian coordinates define the vertices of a dodecahedron centered at the origin:
where φ = (1+√5)/2 is the golden ratio (also written τ). The side length is 2/φ = √5−1. The containing sphere has a radius of √3.
The dihedral angle of a dodecahedron is 2arctan(φ) or approximately 116.565 degrees.
# Geometric relations
The regular dodecahedron is the third in an infinite set of truncated trapezohedra which can be constructed by truncating the two axial vertices of a pentagonal trapezohedron.
The stellations of the dodecahedron make up three of the four Kepler-Poinsot polyhedra.
A rectified dodecahedron forms an icosidodecahedron.
The regular dodecahedron has 120 symmetries, forming the group <math>A_5\times Z_2</math>.
## Vertex arrangement
The dodecahedron shares its vertex arrangement with four nonconvex uniform polyhedrons and three uniform compounds.
Five cubes fit within, with their edges as diagonals of the dodecahedron's faces, and together these make up the regular polyhedral compound of five cubes. Since two tetrahedra can fit on alternate cube vertices, five and ten tetrahedra can also fit in a dodecahedron.
## Icosahedron vs dodecahedron
When a dodecahedron is inscribed in a sphere, it occupies more of the sphere's volume (66.49%) than an icosahedron inscribed in the same sphere (60.54%).
A regular dodecahedron with edge length 1 has more than three and a half times the volume of an icosahedron with the same length edges (7.663... compared with 2.181...).
# Other dodecahedra
The term dodecahedron is also used for other polyhedra with twelve faces, most notably the rhombic dodecahedron which is dual to the cuboctahedron (an Archimedean solid) and occurs in nature as a crystal form. The Platonic solid dodecahedron can be called a pentagonal dodecahedron or a regular dodecahedron to distinguish it. The pyritohedron is an irregular pentagonal dodecahedron.
Other dodecahedra include:
- Uniform polyhedra:
Pentagonal antiprism - 10 equilateral triangles, 2 pentagons
Decagonal prism - 10 squares, 2 decagons
- Pentagonal antiprism - 10 equilateral triangles, 2 pentagons
- Decagonal prism - 10 squares, 2 decagons
- Johnson solids (regular faced):
Pentagonal cupola - 5 triangles, 5 squares, 1 pentagon, 1 decagon
Snub disphenoid - 12 triangles
Elongated square dipyramid - 8 triangles and 4 squares
Metabidiminished icosahedron - 10 triangles and 2 pentagons
- Pentagonal cupola - 5 triangles, 5 squares, 1 pentagon, 1 decagon
- Snub disphenoid - 12 triangles
- Elongated square dipyramid - 8 triangles and 4 squares
- Metabidiminished icosahedron - 10 triangles and 2 pentagons
- Congruent nonregular faced: (face-transitive)
Hexagonal bipyramid - 12 isosceles triangles, dual of hexagonal prism
Hexagonal trapezohedron - 12 kites, dual of hexagonal antiprism
Triakis tetrahedron - 12 isosceles triangles, dual of truncated tetrahedron
Rhombic dodecahedron (mentioned above) - 12 rhombi, dual of cuboctahedron
- Hexagonal bipyramid - 12 isosceles triangles, dual of hexagonal prism
- Hexagonal trapezohedron - 12 kites, dual of hexagonal antiprism
- Triakis tetrahedron - 12 isosceles triangles, dual of truncated tetrahedron
- Rhombic dodecahedron (mentioned above) - 12 rhombi, dual of cuboctahedron
- Other nonregular faced:
Hendecagonal pyramid - 11 isosceles triangles and 1 hendecagon
Trapezo-rhombic dodecahedron - 6 rhombi, 6 trapezoids - dual of Triangular orthobicupola
Rhombo-hexagonal dodecahedron or Elongated Dodecahedron - 8 rhombi and 4 equilateral hexagons.
- Hendecagonal pyramid - 11 isosceles triangles and 1 hendecagon
- Trapezo-rhombic dodecahedron - 6 rhombi, 6 trapezoids - dual of Triangular orthobicupola
- Rhombo-hexagonal dodecahedron or Elongated Dodecahedron - 8 rhombi and 4 equilateral hexagons.
# Regular dodecahedra in the arts, sciences, and popular culture
Small, hollow bronze Roman dodecahedra dating from the 3rd century A.D. have been found in various places in Europe. Their purpose is not certain.
A dodecahedron sits on the table in M. C. Escher's lithograph print "Reptiles" (1943), and a stellated dodecahedron is used in his "Gravitation". In Salvador Dalí's painting of The Sacrament of the Last Supper (1955), the room is a hollow dodecahedron.
One of the characters in The Phantom Tollbooth, a children's novel from 1961, is named Dodecahedron and is a man with 12 faces.
The Dodecahedron was the mysterious power source for an underground city in the Doctor Who episode "Meglos" (1980).
In "Blood Feud", an episode of The Simpsons, Lisa attempts to teach Maggie the word dodecahedron.
In Carl Sagan's novel Contact, the transport device constructed to the plans transmitted by the alien intelligence is dodecahedral.
"Dodecaheedron" (misspelled, possibly intentionally, with an extra "e") is the title of a song by Aphex Twin.
Plato in the dialogue Timaeus c.360 B.C associated platonic solids with the four classical elements. Aristotle added a fifth element, aithêr (aether in Latin, "ether" in English) and postulated that the heavens were made of this element, but he had no interest in matching it with Plato's fifth solid.
In 2003, an apparent periodicity in the cosmic microwave background led to the suggestion, by Jean-Pierre Luminet of the Observatoire de Paris and colleagues, that the shape of the Universe is a finite dodecahedron, attached to itself by each pair of opposite faces to form a Poincaré homology sphere. ("Is the universe a dodecahedron?", article at PhysicsWeb.) During the following year, astronomers searched for more evidence to support this hypothesis but found none.
The 20 vertices and 30 edges of a dodecahedron form the map for an early computer game, Hunt the Wumpus. In the seminal 1980s computer game Elite, the more advanced "Dodec" class space stations took the form of dodecahedra. The save points in the Castlevania games, Castlevania: Symphony of the Night (for the PSX) and Castlevania: Harmony of Dissonance (GBA) are shaped like dodecahedrons. In the Nintendo 64 game Paper Mario, the mountains in the background of Toad Town are dodecahedra. ([1] Image of background)
The regular dodecahedron is often used in role-playing games as a twelve-sided die ("d12" for short), one of the more common polyhedral dice.
Desk calendars are occasionally made in the shape of a dodecahedron, usually from a die-cut folded card, with one month on each face. | https://www.wikidoc.org/index.php/Dodecahedron | |
65cd1e79ef1f9b1ef71aca8fd2612ff9704504bc | wikidoc | Dog spinning | Dog spinning
Dog spinning (Template:Lang-bg, trichane na kuche(ta)) is a ritual formerly practiced in a village in southeastern Bulgaria.
In dog spinning, a dog is suspended above water on a rope. This rope is then 'wound' by being twisted repeatedly in a given direction (clockwise or anticlockwise), before being released so that the suspended dog rotates rapidly around in the opposite direction (respectively, anticlockwise or clockwise). The ancient ritual of pagan origin was done in order to prevent rabies.
The first known reference to this practice in English is in a press release issued by the UK Green Party, issued on July 29 2005.
It includes a statement from Green Party MEP Dr Caroline Lucas, vice-president of the RSPCA and the European Parliament's cross-party Animal Welfare Intergroup. Dr Lucas criticised it as being cruel to dogs, saying "Dog-spinning is a barbaric practice and must not be allowed to continue into the 21st century."
Swedish newspaper Aftonbladet reported the practice in March 2005.
It used to place in March every year, only in the village of Brodilovo. The practice of the ritual was banned by the mayor of Tsarevo in 2006 after complaints by Bulgarian animal welfare organizations. | Dog spinning
Dog spinning (Template:Lang-bg, trichane na kuche(ta)) is a ritual formerly practiced in a village in southeastern Bulgaria.
In dog spinning, a dog is suspended above water on a rope. This rope is then 'wound' by being twisted repeatedly in a given direction (clockwise or anticlockwise), before being released so that the suspended dog rotates rapidly around in the opposite direction (respectively, anticlockwise or clockwise). The ancient ritual of pagan origin was done in order to prevent rabies.[1]
The first known reference to this practice in English is in a press release issued by the UK Green Party, issued on July 29 2005.
It includes a statement from Green Party MEP Dr Caroline Lucas, vice-president of the RSPCA and the European Parliament's cross-party Animal Welfare Intergroup. Dr Lucas criticised it as being cruel to dogs, saying "Dog-spinning is a barbaric practice and must not be allowed to continue into the 21st century."
Swedish newspaper Aftonbladet reported the practice in March 2005. [2] [3]
It used to place in March every year, only in the village of Brodilovo. [4] The practice of the ritual was banned by the mayor of Tsarevo in 2006[5] after complaints by Bulgarian animal welfare organizations.[6] | https://www.wikidoc.org/index.php/Dog_spinning | |
09dc45d5f54e83be11494fbd08c161cc8e0e54a8 | wikidoc | Dolutegravir | Dolutegravir
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Dolutegravir is a antiviral that is FDA approved for the treatment of HIV-1 infection. Common adverse reactions include hyperglycemia, increased serum lipase level, headache, insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dolutegravir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dolutegravir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended dose of Dolutegravir in pediatric patients aged 12 years and older and weighing at least 40 kg is 50 mg administered orally once daily.
- If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin are coadministered, the recommended dose of Dolutegravir is 50 mg twice daily.
- Safety and efficacy of Dolutegravir have not been established in pediatric patients younger than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dolutegravir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dolutegravir in pediatric patients.
# Contraindications
Dolutegravir is contraindicated in patients:
- With previous hypersensitivity reaction to dolutegravir
- Receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events.
# Warnings
- Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving Dolutegravir in Phase 3 clinical trials. Discontinue Dolutegravir and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with Dolutegravir or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Dolutegravir is contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir.
- Patients with underlying hepatitis B or hepatitis C may be at increased risk for worsening or development of transaminase elevations with use of Dolutegravir In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with Dolutegravir are recommended in patients with underlying hepatic disease such as hepatitis B or hepatitis C.
- Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Dolutegravir During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia PCP, or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
# Adverse Reactions
## Clinical Trials Experience
### Treatment in Adult Subjects
- The safety assessment of Dolutegravir in HIV‑1‑infected treatment-naïve subjects is based on the analyses of 96-week data from 2 international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and 48-week data from the international, multicenter, open-label FLAMINGO (ING114915) trial.
- In SPRING-2, 822 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine or emtricitabine/tenofovir TRUVADA®). There were 808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms.
- In SINGLE, 833 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir once daily. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving Dolutegravir 50 mg once daily + EPZICOM and 12% in subjects receiving once daily.
- Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 2. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
- In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving Dolutegravir and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for Dolutegravir and , respectively. These events were not treatment limiting.
- In a multicenter, open-label trial (FLAMINGO), 243 subjects received Dolutegravir 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 48 weeks, the rates of adverse events leading to discontinuation were 2% in subjects receiving Dolutegravir and 4% in subjects receiving darunavir/ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE.
- Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV‑1‑infected, antiretroviral treatment-experienced adults were randomized and received either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving Dolutegravir 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen.
- The only treatment-emergent ADR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving Dolutegravir 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen.
- Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Dolutegravir 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48.
- Treatment-emergent ADRs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials.
The following ADRs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving Dolutegravir in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship.
- Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, vomiting.
- General Disorders: Fatigue.
- Hepatobiliary Disorders: Hepatitis.
- Musculoskeletal Disorders: Myositis.
- Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness.
- Renal and Urinary Disorders: Renal impairment.
Skin and Subcutaneous Tissue Disorders: Pruritus.
- Treatment-naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
- Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials.
- The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% ) being the most frequently reported.
- In Phase 3 trials, subjects with hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that observed in subjects without hepatitis B or hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or hepatitis C co-infected compared with HIV mono-infected subjects receiving Dolutegravir were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or hepatitis C at the start of therapy with Dolutegravir, particularly in the setting where anti-hepatitis therapy was withdrawn.
- Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 48 to 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects.
### Clinical Trials Experience in Pediatric Subjects
- IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV‑1‑infected pediatric subjects aged 6 weeks to less than 18 years, of which 23 treatment-experienced, INSTI-naïve subjects aged 12 to less than 18 years were enrolled.
- The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported in at least 1 subject were rash (n = 1), abdominal pain (n = 1), and diarrhea (n = 1). No Grade 3 or 4 ADRs were reported. The Grade 3 laboratory abnormalities were elevated total bilirubin and lipase reported in 1 subject each. No Grade 4 laboratory abnormalities were reported. The changes in mean serum creatinine were similar to those observed in adults.
## Postmarketing Experience
There is limited information regarding Dolutegravir Postmarketing Experience in the drug label.
# Drug Interactions
### Effect of Dolutegravir on the Pharmacokinetics of Other Agents
- In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 µM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 µM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin). In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 µM) and OAT3 (IC50 = 1.97 µM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.
- In vitro, dolutegravir did not inhibit (IC50 greater than 50 μM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.
- In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, boceprevir, and telaprevir.
### Effect of Other Agents on the Pharmacokinetics of Dolutegravir
- Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration.
- Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, telaprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.
### Established and Other Potentially Significant Drug Interactions
- Table 5 provides clinical recommendations as a result of drug interactions with Dolutegravir These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir was shown to cross the placenta in animal studies, this drug should be used during pregnancy only if clearly needed.
- To monitor maternal-fetal outcomes of pregnant women with HIV exposed to Dolutegravir and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- Reproduction studies have been performed in rats and rabbits at doses up to 27 times the human dose of 50 mg twice daily and have revealed no evidence of impaired fertility or harm to the fetus due to Dolutegravir.
- Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 27 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity.
- Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.4 times the 50‑mg twice-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg per kg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dolutegravir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dolutegravir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV‑1‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human milk.
- Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, instruct mothers not to breastfeed.
### Pediatric Use
- Safety and efficacy of Dolutegravir have not been established in pediatric patients younger than 12 years, weighing less than 40 kg, or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).
- The safety, virologic, and immunologic responses in subjects who received Dolutegravir were evaluated in 23 treatment-experienced, INSTI-naïve, HIV‑1–infected subjects aged 12 to less than 18 years in an open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Pharmacokinetic parameters, evaluated in 9 subjects weighing at least 40 kg receiving 50 mg daily and 1 subject (weighing 37 kg) receiving 35 mg once daily, were similar to adults receiving 50 mg once daily. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults.
### Geriatic Use
- Clinical trials of Dolutegravir did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Dolutegravir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Dolutegravir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dolutegravir with respect to specific racial populations.
### Renal Impairment
- Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to Dolutegravir or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients on dialysis.
### Hepatic Impairment
- No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, Dolutegravir is not recommended for use in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dolutegravir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dolutegravir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Dolutegravir Administration in the drug label.
### Monitoring
There is limited information regarding Dolutegravir Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Dolutegravir and IV administrations.
# Overdosage
- There is no known specific treatment for overdose with Dolutegravir If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
# Pharmacology
## Mechanism of Action
- Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.
## Structure
- The empirical formula is C20H18F2N3NaO5 and the molecular weight is 441.36 g per mol. It has the following structural formula:
## Pharmacodynamics
- In a randomized, dose-ranging trial, HIV‑1‑infected subjects treated with dolutegravir monotherapy demonstrated rapid and dose-dependent antiviral activity with mean declines from baseline to Day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50-mg group.
- In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.
- The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3‑arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.
## Pharmacokinetics
- The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV‑1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV‑1–infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV‑1–infected subjects (Table 6) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. Dolutegravir was administered without regard to food in these trials.
Table 6. Dolutegravir Steady-state Pharmacokinetic Parameter Estimates in HIV‑1–Infected Adults
Parameter
- Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5.
- Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P‑gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.
- Dolutegravir may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67%; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.
- Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.
- Cerebrospinal Fluid (CSF): In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per mL (range: 3.74 ng per mL to 18.3 ng per mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established.
- Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose).
- Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses.
- Polymorphisms in Drug‑metabolizing Enzymes: In a meta-analysis of healthy subject trials, subjects with UGT1A1 (n = 7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n = 41).
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14-fold higher than those in humans at the recommended dose of 50 mg twice daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10-fold and 15-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg twice daily.
- Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.
- In a study conducted in rats, there were no effects on mating or fertility with dolutegravir up to 1,000 mg per kg per day. This dose is associated with an exposure that is approximately 24 times higher than the exposure in humans at the recommended dose of 50 mg twice daily.
# Clinical Studies
The efficacy of Dolutegravir is based on analyses of data from 3 trials, SPRING-2 (ING113086), SINGLE (ING114467), and FLAMINGO (ING114915), in treatment-naïve, HIV‑1‑infected subjects (n = 2,125); one trial, SAILING (ING111762), in treatment-experienced, INSTI-naïve HIV‑1‑infected subjects (n = 715); and from VIKING-3 (ING112574) trial in INSTI-experienced HIV‑1‑infected subjects (n = 183). The use of Dolutegravir in pediatric patients aged 12 years and older is based on evaluation of safety, pharmacokinetics, and efficacy through 24 weeks in a multicenter, open-label trial in subjects (n = 23) without INSTI resistance.
### Adult Subjects
- In SPRING-2, 822 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual NRTI treatment (either abacavir sulfate and lamivudine EPZICOM or emtricitabine/tenofovir TRUVADA). There were 808 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 36 years, 13% female, 15% non-white, 11% had hepatitis B and/or hepatitis C virus co-infection, 2% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, 48% had CD4+ cell count less than 350 cells per mm3, and 39% received EPZICOM; these characteristics were similar between treatment groups.
- In SINGLE, 833 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir. At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups.
Week 96 outcomes for SPRING-2 and SINGLE are provided in Table 12. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
- Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen. The median change in CD4+ cell counts from baseline were 276 cells per mm3 in the group receiving Dolutegravir and 264 cells per mm3 for the raltegravir group at 96 weeks.
- There was no treatment-emergent resistance to dolutegravir or to the NRTI background.
- Treatment differences were maintained across baseline characteristics including CD4+ cell count, age, gender, and race.
- The adjusted mean changes in CD4+ cell counts from baseline were 325 cells per mm3 in the group receiving Dolutegravir + EPZICOM and 281 cells per mm3 for the group at 96 weeks. The adjusted difference between treatment arms and 95% CI was 44.0 cells per mm3 (14.3 cells per mm3, 73.6 cells per mm3) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, baseline CD4+ cell count, and multiplicity).
- There was no treatment-emergent resistance to dolutegravir, abacavir, or lamivudine.
- In FLAMINGO, 485 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily (n = 243) or darunavir + ritonavir 800 mg/100 mg once daily (n = 242), both in combination with investigator-selected NRTI background regimen (either fixed-dose abacavir and lamivudine or fixed-dose emtricitabine/tenofovir disoproxil fumarate ). There were 484 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years, 15% female, 28% non-white, 10% had hepatitis B and/or C virus co-infection, 3% were CDC Class C (AIDS), 25% had HIV‑1 RNA greater than 100,000 copies per mL, and 35% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. Overall response rates by Snapshot algorithm through Week 48 were 90% for Dolutegravir and 83% for darunavir/ritonavir. The adjusted difference in proportion and 95% CI was 7.1% (0.9%, 13.2%). No treatment-emergent primary resistance substitutions were observed in either treatment group.
Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects
- In the international, multicenter, double-blind trial (SAILING), 719 HIV‑1‑ infected, antiretroviral treatment-experienced adults were randomized and received either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least 1 fully active agent. There were 715 subjects included in the efficacy and safety analyses. At baseline, the median age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or hepatitis C virus co-infection, 46% were CDC Class C (AIDS), 20% had HIV-1 RNA greater than 100,000 copies per mL, and 72% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline. Week 48 outcomes for SAILING are shown in Table 13.
### Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects
- VIKING-3 examined the effect of Dolutegravir 50 mg twice daily over 7 days of functional monotherapy, followed by optimized background therapy (OBT) with continued treatment of Dolutegravir 50 mg twice daily.
- In the multicenter, open-label, single-arm VIKING-3 trial, 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Dolutegravir 50 mg twice daily with the current failing background regimen for 7 days, then received Dolutegravir with OBT from Day 8. A total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening). At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis B and/or hepatitis C virus co-infection. Median baseline CD4+ cell count was 140 cells per mm3, median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C. Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had greater than or equal to 2 NRTI, 75% greater than or equal to 1 NNRTI, and 71% greater than or equal to 2 PI major substitutions; 62% had non-R5 virus.
- Mean reduction from baseline in HIV-1 RNA at Day 8 (primary endpoint) was 1.4 log10 (95% CI: 1.3 log10, 1.5 log10). Response at Week 48 was affected by baseline INSTI substitutions.
- After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. Week 48 virologic outcomes for VIKING-3 are shown in Table 14.
# How Supplied
- Dolutegravir Tablets, 50 mg, are yellow, round, film-coated, biconvex tablets debossed with SV 572 on one side and 50 on the other side.
- Bottle of 30 tablets with child-resistant closure NDC 49702-228-13.
## Storage
- Store at 25°C (77°F); excursions permitted 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Dolutegravir Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Dolutegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tivicay
# Look-Alike Drug Names
There is limited information regarding Dolutegravir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Dolutegravir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Dolutegravir is a antiviral that is FDA approved for the treatment of HIV-1 infection. Common adverse reactions include hyperglycemia, increased serum lipase level, headache, insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dolutegravir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dolutegravir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended dose of Dolutegravir in pediatric patients aged 12 years and older and weighing at least 40 kg is 50 mg administered orally once daily.
- If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin are coadministered, the recommended dose of Dolutegravir is 50 mg twice daily.
- Safety and efficacy of Dolutegravir have not been established in pediatric patients younger than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dolutegravir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dolutegravir in pediatric patients.
# Contraindications
Dolutegravir is contraindicated in patients:
- With previous hypersensitivity reaction to dolutegravir
- Receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events.
# Warnings
- Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving Dolutegravir in Phase 3 clinical trials. Discontinue Dolutegravir and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with Dolutegravir or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Dolutegravir is contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir.
- Patients with underlying hepatitis B or hepatitis C may be at increased risk for worsening or development of transaminase elevations with use of Dolutegravir In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with Dolutegravir are recommended in patients with underlying hepatic disease such as hepatitis B or hepatitis C.
- Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Dolutegravir During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia PCP, or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
# Adverse Reactions
## Clinical Trials Experience
### Treatment in Adult Subjects
- The safety assessment of Dolutegravir in HIV‑1‑infected treatment-naïve subjects is based on the analyses of 96-week data from 2 international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and 48-week data from the international, multicenter, open-label FLAMINGO (ING114915) trial.
- In SPRING-2, 822 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM®] or emtricitabine/tenofovir TRUVADA®). There were 808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms.
- In SINGLE, 833 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir once daily. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving Dolutegravir 50 mg once daily + EPZICOM and 12% in subjects receiving once daily.
- Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 2. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
- In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving Dolutegravir and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for Dolutegravir and , respectively. These events were not treatment limiting.
- In a multicenter, open-label trial (FLAMINGO), 243 subjects received Dolutegravir 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 48 weeks, the rates of adverse events leading to discontinuation were 2% in subjects receiving Dolutegravir and 4% in subjects receiving darunavir/ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE.
- Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV‑1‑infected, antiretroviral treatment-experienced adults were randomized and received either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving Dolutegravir 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen.
- The only treatment-emergent ADR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving Dolutegravir 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen.
- Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Dolutegravir 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48.
- Treatment-emergent ADRs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials.
The following ADRs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving Dolutegravir in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship.
- Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, vomiting.
- General Disorders: Fatigue.
- Hepatobiliary Disorders: Hepatitis.
- Musculoskeletal Disorders: Myositis.
- Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness.
- Renal and Urinary Disorders: Renal impairment.
Skin and Subcutaneous Tissue Disorders: Pruritus.
- Treatment-naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
- Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials.
- The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported.
- In Phase 3 trials, subjects with hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that observed in subjects without hepatitis B or hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or hepatitis C co-infected compared with HIV mono-infected subjects receiving Dolutegravir were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or hepatitis C at the start of therapy with Dolutegravir, particularly in the setting where anti-hepatitis therapy was withdrawn.
- Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 48 to 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects.
### Clinical Trials Experience in Pediatric Subjects
- IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV‑1‑infected pediatric subjects aged 6 weeks to less than 18 years, of which 23 treatment-experienced, INSTI-naïve subjects aged 12 to less than 18 years were enrolled.
- The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported in at least 1 subject were rash (n = 1), abdominal pain (n = 1), and diarrhea (n = 1). No Grade 3 or 4 ADRs were reported. The Grade 3 laboratory abnormalities were elevated total bilirubin and lipase reported in 1 subject each. No Grade 4 laboratory abnormalities were reported. The changes in mean serum creatinine were similar to those observed in adults.
## Postmarketing Experience
There is limited information regarding Dolutegravir Postmarketing Experience in the drug label.
# Drug Interactions
### Effect of Dolutegravir on the Pharmacokinetics of Other Agents
- In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 µM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 µM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin). In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 µM) and OAT3 (IC50 = 1.97 µM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.
- In vitro, dolutegravir did not inhibit (IC50 greater than 50 μM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.
- In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, boceprevir, and telaprevir.
### Effect of Other Agents on the Pharmacokinetics of Dolutegravir
- Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration.
- Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, telaprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.
### Established and Other Potentially Significant Drug Interactions
- Table 5 provides clinical recommendations as a result of drug interactions with Dolutegravir These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir was shown to cross the placenta in animal studies, this drug should be used during pregnancy only if clearly needed.
- To monitor maternal-fetal outcomes of pregnant women with HIV exposed to Dolutegravir and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- Reproduction studies have been performed in rats and rabbits at doses up to 27 times the human dose of 50 mg twice daily and have revealed no evidence of impaired fertility or harm to the fetus due to Dolutegravir.
- Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 27 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity.
- Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.4 times the 50‑mg twice-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg per kg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dolutegravir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dolutegravir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV‑1‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human milk.
- Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, instruct mothers not to breastfeed.
### Pediatric Use
- Safety and efficacy of Dolutegravir have not been established in pediatric patients younger than 12 years, weighing less than 40 kg, or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).
- The safety, virologic, and immunologic responses in subjects who received Dolutegravir were evaluated in 23 treatment-experienced, INSTI-naïve, HIV‑1–infected subjects aged 12 to less than 18 years in an open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Pharmacokinetic parameters, evaluated in 9 subjects weighing at least 40 kg receiving 50 mg daily and 1 subject (weighing 37 kg) receiving 35 mg once daily, were similar to adults receiving 50 mg once daily. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults.
### Geriatic Use
- Clinical trials of Dolutegravir did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Dolutegravir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Dolutegravir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dolutegravir with respect to specific racial populations.
### Renal Impairment
- Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to Dolutegravir or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients on dialysis.
### Hepatic Impairment
- No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, Dolutegravir is not recommended for use in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dolutegravir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dolutegravir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Dolutegravir Administration in the drug label.
### Monitoring
There is limited information regarding Dolutegravir Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Dolutegravir and IV administrations.
# Overdosage
- There is no known specific treatment for overdose with Dolutegravir If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
# Pharmacology
## Mechanism of Action
- Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.
## Structure
- The empirical formula is C20H18F2N3NaO5 and the molecular weight is 441.36 g per mol. It has the following structural formula:
## Pharmacodynamics
- In a randomized, dose-ranging trial, HIV‑1‑infected subjects treated with dolutegravir monotherapy demonstrated rapid and dose-dependent antiviral activity with mean declines from baseline to Day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50-mg group.
- In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.
- The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3‑arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.
## Pharmacokinetics
- The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV‑1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV‑1–infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV‑1–infected subjects (Table 6) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. Dolutegravir was administered without regard to food in these trials.
Table 6. Dolutegravir Steady-state Pharmacokinetic Parameter Estimates in HIV‑1–Infected Adults
Parameter
- Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5.
- Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P‑gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.
- Dolutegravir may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67%; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.
- Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.
- Cerebrospinal Fluid (CSF): In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per mL (range: 3.74 ng per mL to 18.3 ng per mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established.
- Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [14C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose).
- Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses.
- Polymorphisms in Drug‑metabolizing Enzymes: In a meta-analysis of healthy subject trials, subjects with UGT1A1 (n = 7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n = 41).
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14-fold higher than those in humans at the recommended dose of 50 mg twice daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10-fold and 15-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg twice daily.
- Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.
- In a study conducted in rats, there were no effects on mating or fertility with dolutegravir up to 1,000 mg per kg per day. This dose is associated with an exposure that is approximately 24 times higher than the exposure in humans at the recommended dose of 50 mg twice daily.
# Clinical Studies
The efficacy of Dolutegravir is based on analyses of data from 3 trials, SPRING-2 (ING113086), SINGLE (ING114467), and FLAMINGO (ING114915), in treatment-naïve, HIV‑1‑infected subjects (n = 2,125); one trial, SAILING (ING111762), in treatment-experienced, INSTI-naïve HIV‑1‑infected subjects (n = 715); and from VIKING-3 (ING112574) trial in INSTI-experienced HIV‑1‑infected subjects (n = 183). The use of Dolutegravir in pediatric patients aged 12 years and older is based on evaluation of safety, pharmacokinetics, and efficacy through 24 weeks in a multicenter, open-label trial in subjects (n = 23) without INSTI resistance.
### Adult Subjects
- In SPRING-2, 822 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual NRTI treatment (either abacavir sulfate and lamivudine EPZICOM or emtricitabine/tenofovir TRUVADA). There were 808 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 36 years, 13% female, 15% non-white, 11% had hepatitis B and/or hepatitis C virus co-infection, 2% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, 48% had CD4+ cell count less than 350 cells per mm3, and 39% received EPZICOM; these characteristics were similar between treatment groups.
- In SINGLE, 833 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir. At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups.
Week 96 outcomes for SPRING-2 and SINGLE are provided in Table 12. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
- Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen. The median change in CD4+ cell counts from baseline were 276 cells per mm3 in the group receiving Dolutegravir and 264 cells per mm3 for the raltegravir group at 96 weeks.
- There was no treatment-emergent resistance to dolutegravir or to the NRTI background.
- Treatment differences were maintained across baseline characteristics including CD4+ cell count, age, gender, and race.
- The adjusted mean changes in CD4+ cell counts from baseline were 325 cells per mm3 in the group receiving Dolutegravir + EPZICOM and 281 cells per mm3 for the group at 96 weeks. The adjusted difference between treatment arms and 95% CI was 44.0 cells per mm3 (14.3 cells per mm3, 73.6 cells per mm3) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, baseline CD4+ cell count, and multiplicity).
- There was no treatment-emergent resistance to dolutegravir, abacavir, or lamivudine.
- In FLAMINGO, 485 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily (n = 243) or darunavir + ritonavir 800 mg/100 mg once daily (n = 242), both in combination with investigator-selected NRTI background regimen (either fixed-dose abacavir and lamivudine [EPZICOM] or fixed-dose emtricitabine/tenofovir disoproxil fumarate [TRUVADA]). There were 484 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years, 15% female, 28% non-white, 10% had hepatitis B and/or C virus co-infection, 3% were CDC Class C (AIDS), 25% had HIV‑1 RNA greater than 100,000 copies per mL, and 35% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. Overall response rates by Snapshot algorithm through Week 48 were 90% for Dolutegravir and 83% for darunavir/ritonavir. The adjusted difference in proportion and 95% CI was 7.1% (0.9%, 13.2%). No treatment-emergent primary resistance substitutions were observed in either treatment group.
Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects
- In the international, multicenter, double-blind trial (SAILING), 719 HIV‑1‑ infected, antiretroviral treatment-experienced adults were randomized and received either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least 1 fully active agent. There were 715 subjects included in the efficacy and safety analyses. At baseline, the median age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or hepatitis C virus co-infection, 46% were CDC Class C (AIDS), 20% had HIV-1 RNA greater than 100,000 copies per mL, and 72% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline. Week 48 outcomes for SAILING are shown in Table 13.
### Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects
- VIKING-3 examined the effect of Dolutegravir 50 mg twice daily over 7 days of functional monotherapy, followed by optimized background therapy (OBT) with continued treatment of Dolutegravir 50 mg twice daily.
- In the multicenter, open-label, single-arm VIKING-3 trial, 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Dolutegravir 50 mg twice daily with the current failing background regimen for 7 days, then received Dolutegravir with OBT from Day 8. A total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening). At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis B and/or hepatitis C virus co-infection. Median baseline CD4+ cell count was 140 cells per mm3, median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C. Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had greater than or equal to 2 NRTI, 75% greater than or equal to 1 NNRTI, and 71% greater than or equal to 2 PI major substitutions; 62% had non-R5 virus.
- Mean reduction from baseline in HIV-1 RNA at Day 8 (primary endpoint) was 1.4 log10 (95% CI: 1.3 log10, 1.5 log10). Response at Week 48 was affected by baseline INSTI substitutions.
- After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. Week 48 virologic outcomes for VIKING-3 are shown in Table 14.
# How Supplied
- Dolutegravir Tablets, 50 mg, are yellow, round, film-coated, biconvex tablets debossed with SV 572 on one side and 50 on the other side.
- Bottle of 30 tablets with child-resistant closure NDC 49702-228-13.
## Storage
- Store at 25°C (77°F); excursions permitted 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Dolutegravir Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Dolutegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tivicay
# Look-Alike Drug Names
There is limited information regarding Dolutegravir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dolutegravir | |
6cbe2acde5284c5403558a5d4fe93fea5449951d | wikidoc | Dopaminergic | Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes which regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase (AAAD) or DOPA decarboxylase (DDC), monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Lastly, any endogenous or exogenous chemical substance which acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids which enhance dopamine release indirectly in the reward pathways, and amphetamines, which enhance dopamine release directly by binding to, and inhibiting VMAT2.
# Supplements and drugs
A complete list of dopaminergic substances used as supplements and drugs includes:
- Dopamine (DA; Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc) itself, which is used in the treatment of severe hypotension, circulatory shock, and cardiac arrest as a vasopressor or antihypotensive agent.
- Precursors including L-phenylalanine (PHE), L-tyrosine (TYR), and L-DOPA (Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc; also found in Mucuna pruriens (Velvet Bean)), which are all used as dietary supplements, and the latter of which is also used in the treatment of Parkinson's disease (PD).
- Cofactors including ferrous iron (Fe2+), tetrahydrobiopterin (THB, BH4), vitamin B3 (niacin, niacinamide) → NADPH, vitamin B6 (pyridoxine, pyridoxamine, pyridoxal → pyridoxal phosphate (PLP), vitamin B9 (folic acid) → tetrahydrofolic acid (THFA, H4FA), vitamin C (ascorbic acid), and zinc (Zn2+), which are used as dietary supplements.
- Dopamine receptor agonists such as apomorphine (Apokyn, Uprima), bromocriptine (Parolodel), cabergoline (Dostinex), dihydrexidine (LS-186,899), dopamine (Intropin, Revivan), fenoldopam (Corlopam), piribedil (Trivastal), lisuride (Dopergin), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), and rotigotine (Neupro), which are used in the treatment of Parkinson's disease (PD), restless legs syndrome (RLS), hyperprolactinemia (HPA), and sexual dysfunction (SD), as well as are being investigated in the treatment of depression and anxiety as antidepressants and anxiolytics, respectively.
- Dopamine receptor antagonists including typical antipsychotics such as chlorpromazine (Thorazine), fluphenazine (Prolixin), haloperidol (Haldol), loxapine (Loxitane), molindone (Moban), perphenazine (Trilafon), pimozide (Orap), thioridazine (Mellaril), thiothixene (Navane), and trifluoperazine (Stelazine), the atypical antipsychotics such as amisulpride (Solian), clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), sulpiride (Dogmatil), and ziprasidone (Geodon), and antiemetics like domperidone, metoclopramide (Reglan), and prochlorperazine (Compazine), among others, which are used in the treatment of schizophrenia (SCZ) and bipolar disorder (BD) as antipsychotics, and nausea and vomiting.
- Dopamine reuptake inhibitors (DRIs) or dopamine transporter (DAT) inhibitors such as methylphenidate (Ritalin, Focalin, Concerta), bupropion (Wellbutrin, Zyban), amineptine (Survector, Maneon, Directin), and nomifensine (Merital, Alival), as well as cocaine ("Coke", "Crack", etc), methylenedioxypyrovalerone (MDPV; "Sonic"), ketamine (K; Ketalar, Ketanest, Ketaset; "Special-K", "Kit Kat", etc), and phencyclidine (PCP; Sernyl; "Angel Dust", "Rocket Fuel", etc), among others, which are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy as psychostimulants, obesity as anorectics, depression and anxiety as antidepressants and anxiolytics, respectively, drug addiction as anticraving agents, and sexual dysfunction, as well as illicit street drugs.
- Dopamine releasing agents (DRAs) such as amphetamine (Adderall, Dexedrine; "Speed"), lisdexamfetamine (Vyvanse), methamphetamine (Desoxyn; "Meth", "Crank", "Crystal", etc), methylenedioxymethamphetamine (MDMA; "Ecstasy", "E", "X", "XTC", etc), phenmetrazine (Preludin; "Prellies"), pemoline (Cylert), 4-methylaminorex (4-MAR; "Ice", "Euphoria", etc), and benzylpiperazine (BZP; "Bennies", "A2", "Sunrise", "Frenzy", etc), among many others, which, like DRIs, are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy as psychostimulants, obesity as anorectics, depression and anxiety as antidepressants and anxiolytics, respectively, drug addiction as anticraving agents, and sexual dysfunction, as well as illicit street drugs.
- Dopamine activity enhancers such as BPAP and PPAP, which are currently only research chemicals, but are being investigated for clinical development in the treatment of a number of medical disorders.
- Vesicular monoamine transporter 2 (VMAT2) inhibitors such as reserpine (Serpasil), tetrabenazine (Nitoman, Xenazine), and deserpidine (Harmonyl), which are used as sympatholytics or antihypertensives, and in the past as antipsychotics.
- Monoamine oxidase (MAO) inhibitors (MAOIs) including nonselective agents such as phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan), MAOA selective agents like moclobemide (Aurorix, Manerix), and MAOB selective agents such as selegiline (Eldepryl, Zelapar, Emsam), rasagiline (Azilect), and pargyline (Eutonyl), as well as the harmala alkaloids like harmine, harmaline, tetrahydroharmine, harmalol, harman, and norharman, which are found to varying degrees in Nicotiana tabacum (Tobacco; also cigarettes, cigars, chew, hookah, etc), Banisteriopsis caapi (Ayahausca, Caapi, Yage), Peganum harmala (Harmal, Syrian Rue), Passiflora incarnata (Passion Flower), and Tribulus terrestris (Puncture Vine), among others, which are used in the treatment of depression and anxiety as antidepressants and anxiolytics, respectively, in the treatment of Parkinson's disease (PD) and dementia, and for the recreational purpose of boosting the effects of certain drugs like phenethylamine (PEA) and psychedelics like dimethyltryptamine (DMT) via inhibiting their metabolism.
- Catechol O-methyl transferase (COMT) inhibitors such as entacapone (Comtan, Stalevo) and tolcapone (Tasmar), which are used in the treatment of Parkinson's disease (PD).
- Dopamine β-hydroxylase (DBH) inhibitors like disulfiram (Antabuse), which is used in the treatment of drug addiction as an anticraving agent.
- Phenylalanine hydroxylase (PAH) inhibitors like 3,4-dihydroxystyrene (DHS) which is currently only a research chemical with no suitable therapeutic indications, likely on account of the fact that such drugs would induce the potentially highly dangerous hyperphenylalaninemia (HPA) and/or phenylketonuria (PKU).
- Tyrosine hydroxylase (TH) inhibitors like metirosine (Demser), which is used in the treatment of pheochromocytoma (PCC) as a sympatholytic or antihypertensive agent.
- Aromatic L-amino acid decarboxylase (AAAD) or DOPA decarboxylase (DDC) inhibitors including benserazide (Prolopa, Madopar, etc), carbidopa (Lodosyn, Atamet, Parcopa, Sinemet, Stalevo, etc), and methyldopa (Aldomet, Aldoril, Dopamet, Dopegyt, etc), which are used in the treatment of Parkinson's disease (PD) in augmentation of L-DOPA ((Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc)) to block the peripheral conversion of dopamine thereby inhibiting undesirable side effects, and as sympatholytic or antihypertensive agents.
- Others such as hyperforin and adhyperforin (both found in Hypericum perforatum (St. John's Wort (SJW))), L-theanine (found in Camellia sinensis (Tea Plant, also known as Black, White, Oolong, Pu-erh, or Green Tea)), and S-adenosyl-L-methionine (SAMe), which are all dietary supplements used mainly for the remedification of depression and anxiety as antidepressants and anxiolytics, respectively. | Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine.[1] For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes which regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase (AAAD) or DOPA decarboxylase (DDC), monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Lastly, any endogenous or exogenous chemical substance which acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids which enhance dopamine release indirectly in the reward pathways, and amphetamines, which enhance dopamine release directly by binding to, and inhibiting VMAT2.
# Supplements and drugs
A complete list of dopaminergic substances used as supplements and drugs includes:
- Dopamine (DA; Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc) itself, which is used in the treatment of severe hypotension, circulatory shock, and cardiac arrest as a vasopressor or antihypotensive agent.
- Precursors including L-phenylalanine (PHE), L-tyrosine (TYR), and L-DOPA (Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc; also found in Mucuna pruriens (Velvet Bean)), which are all used as dietary supplements, and the latter of which is also used in the treatment of Parkinson's disease (PD).
- Cofactors including ferrous iron (Fe2+), tetrahydrobiopterin (THB, BH4), vitamin B3 (niacin, niacinamide) → NADPH, vitamin B6 (pyridoxine, pyridoxamine, pyridoxal → pyridoxal phosphate (PLP), vitamin B9 (folic acid) → tetrahydrofolic acid (THFA, H4FA), vitamin C (ascorbic acid), and zinc (Zn2+), which are used as dietary supplements.
- Dopamine receptor agonists such as apomorphine (Apokyn, Uprima), bromocriptine (Parolodel), cabergoline (Dostinex), dihydrexidine (LS-186,899), dopamine (Intropin, Revivan), fenoldopam (Corlopam), piribedil (Trivastal), lisuride (Dopergin), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), and rotigotine (Neupro), which are used in the treatment of Parkinson's disease (PD), restless legs syndrome (RLS), hyperprolactinemia (HPA), and sexual dysfunction (SD), as well as are being investigated in the treatment of depression and anxiety as antidepressants and anxiolytics, respectively.
- Dopamine receptor antagonists including typical antipsychotics such as chlorpromazine (Thorazine), fluphenazine (Prolixin), haloperidol (Haldol), loxapine (Loxitane), molindone (Moban), perphenazine (Trilafon), pimozide (Orap), thioridazine (Mellaril), thiothixene (Navane), and trifluoperazine (Stelazine), the atypical antipsychotics such as amisulpride (Solian), clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), sulpiride (Dogmatil), and ziprasidone (Geodon), and antiemetics like domperidone, metoclopramide (Reglan), and prochlorperazine (Compazine), among others, which are used in the treatment of schizophrenia (SCZ) and bipolar disorder (BD) as antipsychotics, and nausea and vomiting.
- Dopamine reuptake inhibitors (DRIs) or dopamine transporter (DAT) inhibitors such as methylphenidate (Ritalin, Focalin, Concerta), bupropion (Wellbutrin, Zyban), amineptine (Survector, Maneon, Directin), and nomifensine (Merital, Alival), as well as cocaine ("Coke", "Crack", etc), methylenedioxypyrovalerone (MDPV; "Sonic"), ketamine (K; Ketalar, Ketanest, Ketaset; "Special-K", "Kit Kat", etc), and phencyclidine (PCP; Sernyl; "Angel Dust", "Rocket Fuel", etc), among others, which are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy as psychostimulants, obesity as anorectics, depression and anxiety as antidepressants and anxiolytics, respectively, drug addiction as anticraving agents, and sexual dysfunction, as well as illicit street drugs.
- Dopamine releasing agents (DRAs) such as amphetamine (Adderall, Dexedrine; "Speed"), lisdexamfetamine (Vyvanse), methamphetamine (Desoxyn; "Meth", "Crank", "Crystal", etc), methylenedioxymethamphetamine (MDMA; "Ecstasy", "E", "X", "XTC", etc), phenmetrazine (Preludin; "Prellies"), pemoline (Cylert), 4-methylaminorex (4-MAR; "Ice", "Euphoria", etc), and benzylpiperazine (BZP; "Bennies", "A2", "Sunrise", "Frenzy", etc), among many others, which, like DRIs, are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy as psychostimulants, obesity as anorectics, depression and anxiety as antidepressants and anxiolytics, respectively, drug addiction as anticraving agents, and sexual dysfunction, as well as illicit street drugs.
- Dopamine activity enhancers such as BPAP and PPAP, which are currently only research chemicals, but are being investigated for clinical development in the treatment of a number of medical disorders.
- Vesicular monoamine transporter 2 (VMAT2) inhibitors such as reserpine (Serpasil), tetrabenazine (Nitoman, Xenazine), and deserpidine (Harmonyl), which are used as sympatholytics or antihypertensives, and in the past as antipsychotics.
- Monoamine oxidase (MAO) inhibitors (MAOIs) including nonselective agents such as phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan), MAOA selective agents like moclobemide (Aurorix, Manerix), and MAOB selective agents such as selegiline (Eldepryl, Zelapar, Emsam), rasagiline (Azilect), and pargyline (Eutonyl), as well as the harmala alkaloids like harmine, harmaline, tetrahydroharmine, harmalol, harman, and norharman, which are found to varying degrees in Nicotiana tabacum (Tobacco; also cigarettes, cigars, chew, hookah, etc), Banisteriopsis caapi (Ayahausca, Caapi, Yage), Peganum harmala (Harmal, Syrian Rue), Passiflora incarnata (Passion Flower), and Tribulus terrestris (Puncture Vine), among others, which are used in the treatment of depression and anxiety as antidepressants and anxiolytics, respectively, in the treatment of Parkinson's disease (PD) and dementia, and for the recreational purpose of boosting the effects of certain drugs like phenethylamine (PEA) and psychedelics like dimethyltryptamine (DMT) via inhibiting their metabolism.
- Catechol O-methyl transferase (COMT) inhibitors such as entacapone (Comtan, Stalevo) and tolcapone (Tasmar), which are used in the treatment of Parkinson's disease (PD).
- Dopamine β-hydroxylase (DBH) inhibitors like disulfiram (Antabuse), which is used in the treatment of drug addiction as an anticraving agent.
- Phenylalanine hydroxylase (PAH) inhibitors like 3,4-dihydroxystyrene (DHS) which is currently only a research chemical with no suitable therapeutic indications, likely on account of the fact that such drugs would induce the potentially highly dangerous hyperphenylalaninemia (HPA) and/or phenylketonuria (PKU).
- Tyrosine hydroxylase (TH) inhibitors like metirosine (Demser), which is used in the treatment of pheochromocytoma (PCC) as a sympatholytic or antihypertensive agent.
- Aromatic L-amino acid decarboxylase (AAAD) or DOPA decarboxylase (DDC) inhibitors including benserazide (Prolopa, Madopar, etc), carbidopa (Lodosyn, Atamet, Parcopa, Sinemet, Stalevo, etc), and methyldopa (Aldomet, Aldoril, Dopamet, Dopegyt, etc), which are used in the treatment of Parkinson's disease (PD) in augmentation of L-DOPA ((Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc)) to block the peripheral conversion of dopamine thereby inhibiting undesirable side effects, and as sympatholytic or antihypertensive agents.
- Others such as hyperforin and adhyperforin (both found in Hypericum perforatum (St. John's Wort (SJW))), L-theanine (found in Camellia sinensis (Tea Plant, also known as Black, White, Oolong, Pu-erh, or Green Tea)), and S-adenosyl-L-methionine (SAMe), which are all dietary supplements used mainly for the remedification of depression and anxiety as antidepressants and anxiolytics, respectively. | https://www.wikidoc.org/index.php/Dopaminergic | |
5de780260d4565cfde28548e65a134affaef8e0b | wikidoc | Dor Yeshorim | Dor Yeshorim
Dor Yeshorim (Hebrew: "upright generation", cf. Psalms 112:2) is an organization that offers genetic screening to members of the worldwide Jewish community. Its objective is to minimize, and eventually eliminate, the incidence of genetic disorders common to Jewish people, such as Tay-Sachs disease.
Dor Yeshorim is based in Brooklyn, New York, but has offices in Israel and various other countries. It announces testing sessions in community newspapers and Orthodox Jewish high schools as well as on its website.
# Background
In both the Ashkenazi and Sephardi Jewish communities, there is an increased rate of a number of genetic disorders such as Tay-Sachs disease, an autosomal recessive disorder that goes unnoticed in carriers but is fatal within the first few years of life in homozygotes.
Orthodox Judaism generally frowns on selective abortion. Although preimplantation genetic diagnosis (PGD) is often approved by Halakha, it is a difficult and costly process. By avoiding the marriage between "carriers", the incidence of the disorders decreases without having to resort to such methods.
# Policy
Dor Yeshorim screens only for recessive traits that give rise to lethal or severely debilitating disorders, providing prophylactic, rather than diagnostic services. They do not screen for disorders arising from dominant gene mutations, as these cannot be prevented by informed mate selection.
# Methods
Dor Yeshorim advocates anonymous testing. Individuals are tested during large sessions in Jewish schools and processed anonymously with only a PIN linking the sample with the candidate.
At present, testing is offered for the following disorders:
- Tay-Sachs disease
- Familial dysautonomia
- Cystic fibrosis
- Canavan disease
- Glycogen storage disease (type 1)
- Fanconi anemia (type C)
- Bloom syndrome
- Niemann-Pick disease
- Mucolipidosis (type IV)
- Gaucher's disease (only by request)
When two members of the system contemplate marriage, they contact the organization and enter both their PINs. When both carry a gene for the same disorder, the risk of affected offspring is 25%, and it is considered advisable to discontinue the plans. In the context of shidduchim, the "carriership check" is often run within the first three dates, to avoid disappointments and heartbreak. Ideally, it should be checked prior to the first date, as there are no charges applied to any particular query; however, there is a strange hesitation to contact the organization until the couple are considering further dates.
# History
Dor Yeshorim was started in the 1980s by Rabbi Joseph Ekstein, who lost four children to Tay-Sachs disease between 1965 and 1983. In a 2006 interview, Ekstein revealed that while four of his first five children died of Tay-Sachs disease, none of his children born subsequent to the founding of Dor Yeshorim suffered the condition. The same interview quotes a New York neurologist who credits the near-total disappearance of the condition from the community to Dor Yeshorim's involvement. In 2005 Dor Yeshorim created a new program for the collection and storing of Umbilical Cord Blood. Called Kehila Cord, this program operates in the USA and in Israel.
# Criticism
The system has received criticism from both within as well as outside the community. The largely Eastern-European Orthodox community of Antwerp, for example, uses alternative methods of testing because of misgivings about the procedure.
Another criticism that is being leveled against the method used by Dor Yeshorim is its resemblance to eugenics. However, the program is not intended to affect allele frequency, but rather the occurrence of homozygosity.
Additionally they only test for recessive disorders that require two carriers, and thus are only concerned with eliminating the incidence of active cases of the disease. The testing has no impact on the incidence of heterozygous carriers, and they will not test for disorders that manifest with solely one carrier. (See Policy section above.) | Dor Yeshorim
Dor Yeshorim (Hebrew: "upright generation", cf. Psalms 112:2) is an organization that offers genetic screening to members of the worldwide Jewish community. Its objective is to minimize, and eventually eliminate, the incidence of genetic disorders common to Jewish people, such as Tay-Sachs disease.
Dor Yeshorim is based in Brooklyn, New York, but has offices in Israel and various other countries. It announces testing sessions in community newspapers and Orthodox Jewish high schools as well as on its website.
# Background
In both the Ashkenazi and Sephardi Jewish communities, there is an increased rate of a number of genetic disorders such as Tay-Sachs disease, an autosomal recessive disorder that goes unnoticed in carriers but is fatal within the first few years of life in homozygotes.
Orthodox Judaism generally frowns on selective abortion. Although preimplantation genetic diagnosis (PGD) is often approved by Halakha, it is a difficult and costly process. By avoiding the marriage between "carriers", the incidence of the disorders decreases without having to resort to such methods.
# Policy
Dor Yeshorim screens only for recessive traits that give rise to lethal or severely debilitating disorders, providing prophylactic, rather than diagnostic services. They do not screen for disorders arising from dominant gene mutations, as these cannot be prevented by informed mate selection.
# Methods
Dor Yeshorim advocates anonymous testing. Individuals are tested during large sessions in Jewish schools and processed anonymously with only a PIN linking the sample with the candidate.
At present, testing is offered for the following disorders:
- Tay-Sachs disease
- Familial dysautonomia
- Cystic fibrosis
- Canavan disease
- Glycogen storage disease (type 1)
- Fanconi anemia (type C)
- Bloom syndrome
- Niemann-Pick disease
- Mucolipidosis (type IV)
- Gaucher's disease (only by request)
When two members of the system contemplate marriage, they contact the organization and enter both their PINs. When both carry a gene for the same disorder, the risk of affected offspring is 25%, and it is considered advisable to discontinue the plans. In the context of shidduchim, the "carriership check" is often run within the first three dates, to avoid disappointments and heartbreak. Ideally, it should be checked prior to the first date, as there are no charges applied to any particular query; however, there is a strange hesitation to contact the organization until the couple are considering further dates.
# History
Dor Yeshorim was started in the 1980s by Rabbi Joseph Ekstein, who lost four children to Tay-Sachs disease between 1965 and 1983[1]. In a 2006 interview, Ekstein revealed[2] that while four of his first five children died of Tay-Sachs disease, none of his children born subsequent to the founding of Dor Yeshorim suffered the condition. The same interview quotes a New York neurologist who credits the near-total disappearance of the condition from the community to Dor Yeshorim's involvement[2]. In 2005 Dor Yeshorim created a new program for the collection and storing of Umbilical Cord Blood. Called Kehila Cord, this program operates in the USA and in Israel.
# Criticism
The system has received criticism from both within as well as outside the community. The largely Eastern-European Orthodox community of Antwerp, for example, uses alternative methods of testing because of misgivings about the procedure.
Another criticism that is being leveled against the method used by Dor Yeshorim is its resemblance to eugenics[3]. However, the program is not intended to affect allele frequency, but rather the occurrence of homozygosity.
Additionally they only test for recessive disorders that require two carriers, and thus are only concerned with eliminating the incidence of active cases of the disease. The testing has no impact on the incidence of heterozygous carriers, and they will not test for disorders that manifest with solely one carrier. (See Policy section above.) | https://www.wikidoc.org/index.php/Dor_Yeshorim | |
ea1cc174b8f5225bb9d09fd7a99cd1cb80617641 | wikidoc | Dornase alfa | Dornase alfa
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# Overview
Dornase alfa is a Mucolytic enzyme that is FDA approved for the treatment of cystic fibrosis (CF) patients. Common adverse reactions include voice alteration, pharyngitis, rash, laryngitis, chest pain, conjunctivitis, rhinitis, decrease in FVC of ≥10%, fever, and dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- PULMOZYME® (dornase alfa) is indicated for daily administration in conjunction with standard therapies for the management of cystic fibrosis (CF) patients to improve pulmonary function.
- In CF patients with an FVC ≥ 40% of predicted, daily administration of PULMOZYME has also been shown to reduce the risk of respiratory tract infections requiring parenteral antibiotics.
### Recommended Dosage
- The recommended dosage for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended jet nebulizer/compressor system or eRapid™ Nebulizer System.
- Some patients may benefit from twice daily administration
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dornase alfa in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dornase alfa in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dornase alfa in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dornase alfa in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dornase alfa in pediatric patients.
# Contraindications
- PULMOZYME is contraindicated in patients with known hypersensitivity to dornase alfa, Chinese Hamster Ovary cell products, or any component of the product.
# Warnings
- None
### Precautions
- None
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data described below reflect exposure to PULMOZYME in 902 patients, with exposures ranging from 2 weeks of daily administration up to once or twice daily administration for six months. PULMOZYME was studied in both placebo-controlled and uncontrolled trials (n=804 and n=98). The population of patients in placebo-controlled trials was with FVC ≥ 40% of predicted (n=643) or with more advanced pulmonary disease, FVC < 40% of predicted (n=161). The population in the uncontrolled trial included 98 pediatric patients with CF ranging from 3 months to 10 years of age. More than half of the patients received PULMOZYME 2.5 mg by inhalation once a day (n=581), while the rest of patients (n=321) received PULMOZYME 2.5 mg by inhalation twice a day.
- Trial 1: Trial 1 was a randomized, placebo-controlled clinical trial in patients with FVC ≥ 40% of predicted. In this trial, over 600 patients received PULMOZYME once or twice daily for six months. The most common adverse reaction (risk difference ≥5%) was voice alteration. The proportion of most adverse events was similar for patients on PULMOZYME and on placebo, probably reflecting the sequelae of the underlying lung disease. In most cases reactions that were increased were mild, transient in nature, and did not require alterations in dosing. Few patients experienced adverse reactions resulting in permanent discontinuation from PULMOZYME, and the proportion of discontinuations were similar for placebo (2%) and PULMOZYME (3%). Adverse reactions occurring in a higher proportion (greater than 3%) of PULMOZYME treated patients than in placebo-treated patients are listed in Table 2.
- Trial 2: Trial 2 was a randomized, placebo-controlled trial in patients with more advanced pulmonary disease (FVC < 40% of predicted) who were treated for 12 weeks. In this trial, the safety profile of PULMOZYME was similar to that reported in patients with less advanced pulmonary disease (FVC ≥ 40% of predicted). Adverse reactions that were reported in this trial with a higher proportion (greater than 3%) in the PULMOZYME treated patients are listed in Table 2.
- Mortality rates observed in controlled trials were similar for the placebo and PULMOZYME treated patients. Causes of death were consistent with progression of cystic fibrosis and included apnea, cardiac arrest, cardiopulmonary arrest, cor pulmonale, heart failure, massive hemoptysis, pneumonia, pneumothorax, and respiratory failure.
- Trial 3: The safety of PULMOZYME, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 98 pediatric patients with cystic fibrosis 3 months to 10 years of age (65 aged 3 months to < 5 years, 33 aged 5 to ≤ 10 years). The PARI BABY™ reusable nebulizer (which uses a facemask instead of a mouthpiece) was utilized in patients unable to demonstrate the ability to inhale or exhale orally throughout the entire treatment period (54/65, 83% of the younger and 2/33, 6% of the older patients). Overall, the nature of adverse reactions was similar to that seen in the placebo-controlled trials. The number of patients reporting cough was higher in the younger age group as compared to the older age group (29/65, 45% compared to 10/33, 30%) as was the number reporting moderate to severe cough (24/65, 37% as compared to 6/33, 18%). The number of patients reporting rhinitis was higher in the younger age group as compared to the older age group (23/65, 35% compared to 9/33, 27%) as was the number reporting rash (4/65, 6% as compared to 0/33).
- There have been no reports of anaphylaxis attributed to the administration of PULMOZYME. Urticaria, mild to moderate, and mild skin rash have been observed and have been transient. Within all of the studies, a small percentage (average of 2-4%) of patients treated with PULMOZYME developed serum antibodies to PULMOZYME. None of these patients developed anaphylaxis, and the clinical significance of serum antibodies to PULMOZYME is unknown.
## Postmarketing Experience
- Postmarketing spontaneous reports and prospectively collected safety data from observational studies confirm the safety profile to be as described in clinical trials
# Drug Interactions
- Available data indicate there are no clinically important drug-drug interactions with PULMOZYME.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no adequate and well-controlled studies with PULMOZYME in pregnant women. However, animal reproduction studies have been conducted with dornase alfa. In these studies, no evidence of fetal harm was observed in rats and rabbits at doses of dornase alfa up to approximately 600 times the maximum recommended human dose (MRHD).
- The background risk of major birth defects and miscarriage for the cystic fibrosis population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
- Reproductive studies have been performed in rats and rabbits at intravenous doses of dornase alfa up to 10 mg/kg/day (approximately 600 times the MRHD in adults). In a combined embryo-fetal development and pre- and post-natal development study, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed when dornase alfa was administered to dams throughout organogenesis (Gestation days 6 to 17). Dornase alfa did not elicit adverse effects on fetal or neonatal growth when administered to dams throughout most of gestation and delivery (Gestation days 6 to 25) and nursing (Post-partum days 6 to 21).
- A pharmacokinetic study in Cynomolgus monkeys found no detectable levels of dornase alfa in fetal blood or amniotic fluid on gestation day 150 (end of gestation) from mothers that were administered an intravenous bolus dose (0.1 mg/kg) followed by an intravenous infusion dose (0.080 mg/kg) over a 6-hour period during pregnancy.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dornase alfa in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dornase alfa during labor and delivery.
### Nursing Mothers
Risk Summary
- It is not known whether PULMOZYME is present in human milk. In a pharmacokinetic study in Cynomolgus monkeys, levels of dornase alfa detected in milk were less than 0.1% of the maternal serum concentration at 24 hours after dosing on post-partum day 14. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PULMOZYME and any potential adverse effects on the breastfed child from PULMOZYME or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of PULMOZYME have been established in pediatric patients 5 years of age and older. The safety of PULMOZYME, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 65 patients with cystic fibrosis aged 3 months to < 5 years. While clinical trial data are limited in pediatric patients younger than 5 years of age, the use of PULMOZYME should be considered for pediatric CF patients who may experience potential benefit in pulmonary function or who may be at risk of respiratory tract infection.
### Geriatic Use
- Cystic fibrosis is primarily a disease of children and young adults. Clinical studies of PULMOZYME did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Dornase alfa with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dornase alfa with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dornase alfa in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dornase alfa in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dornase alfa in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dornase alfa in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer PULMOZYME via the eRapid Nebulizer System or via a jet nebulizer connected to an air compressor with an adequate air flow and equipped with a mouthpiece or suitable face mask (see Table 1). No data are currently available to support the administration of PULMOZYME with other nebulizer systems.
- Do not dilute or mix PULMOZYME with other drugs in the nebulizer. Mixing of PULMOZYME with other drugs could lead to adverse physicochemical and/or functional changes in PULMOZYME or the admixed compound.
- The patient should follow the manufacturer's instructions on the use and maintenance of the equipment, including cleaning and disinfection procedures.
- When PULMOZYME is administered with the eRapid Nebulizer System, advise patients to replace the handset after 90 uses, regardless of whether the EasyCare cleaning aid is used. Since delivery data are not available for PULMOZYME administered with the eRapid handset beyond 90 administrations, delivery of the appropriate therapeutic dose of PULMOZYME cannot be assured beyond 90 administrations. The eRapid Nebulizer System should only be used by adults and children who can use a mouthpiece, and not by younger children who need a mask to take PULMOZYME.
- Store PULMOZYME ampules in their protective foil pouch under refrigeration and protected from light. Refrigerate ampules during transport and do not expose to room temperatures for a total time of 24 hours.
- Each PULMOZYME ampule should be squeezed prior to use in order to check for leaks. Discard ampules if the solution is cloudy or discolored. Once opened, the entire contents of the ampule must be used or discarded.
### DOSAGE FORMS AND STRENGTHS
- Inhalation Solution: 2.5 mg/2.5 mL in single-use ampules.
### Monitoring
There is limited information regarding Monitoring of Dornase alfa in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Dornase alfa in the drug label.
# Overdosage
- Single-dose inhalation studies in rats and monkeys at doses up to 180-times higher than doses routinely used in clinical studies are well tolerated. Single dose oral administration of PULMOZYME in doses up to 200 mg/kg are also well tolerated by rats.
- Cystic fibrosis patients have received up to 20 mg BID for up to 6 days and 10 mg BID intermittently (2 weeks on/2 weeks off drug) for 168 days. These doses were well tolerated.
# Pharmacology
## Mechanism of Action
- PULMOZYME is recombinant human deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA. In preclinical in vitro studies, PULMOZYME hydrolyzes the DNA in sputum of CF patients and reduces sputum viscoelasticity. In CF patients, retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbations of infection. Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating leukocytes that accumulate in response to infection.
## Structure
- PULMOZYME is a recombinant human deoxyribonuclease I (rhDNase) an enzyme which selectively cleaves DNA. The protein is produced by genetically engineered Chinese Hamster Ovary (CHO) cells containing DNA encoding for the native human protein, deoxyribonuclease I (DNase). Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin, 100–200 mg/L. However, the presence of the antibiotic is not detectable in the final product. The product is purified by tangential flow filtration and column chromatography. The purified glycoprotein contains 260 amino acids with an approximate molecular weight of 37,000 daltons. The primary amino acid sequence is identical to that of the native human enzyme.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dornase alfa in the drug label.
## Pharmacokinetics
- When 2.5 mg PULMOZYME was administered by inhalation to eighteen CF patients, mean sputum concentrations of 3 µg/mL DNase were measurable within 15 minutes. Mean sputum concentrations declined to an average of 0.6 µg/mL two hours following inhalation. Inhalation of up to 10 mg TID of PULMOZYME by 4 CF patients for six consecutive days, did not result in a significant elevation of serum concentrations of DNase above normal endogenous levels. After administration of up to 2.5 mg of PULMOZYME twice daily for six months to 321 CF patients, no accumulation of serum DNase was noted. Dornase alfa is expected to be metabolized by proteases present in biological fluids. A human intravenous dose study suggested an elimination half-life of 3-4 hours for dornase alpha.
- PULMOZYME, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to ≤ 10 years, and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the first dose. BAL DNase concentrations were detectable in all patients but showed a broad range, from 0.007 to 1.8 µg/mL. Over an average of 14 days of exposure, serum DNase concentrations (mean ± s.d.) increased by 1.1 ± 1.6 ng/mL for the 3 months to < 5 year age group and by 0.8 ± 1.2 ng/mL for the 5 to ≤ 10 year age group. The relationship between BAL or serum DNase concentration and adverse experiences and clinical outcomes is unknown.
## Nonclinical Toxicology
- PULMOZYME produced no treatment-related increases in the incidence of tumors in a lifetime study in Sprague Dawley rats that were administered inhaled doses up to 0.246 mg/kg/day (approximately 30 times the MRHD in adults). There was no increase in the development of benign or malignant neoplasms and no occurrence of unusual tumor types in rats after lifetime exposure.
- PULMOZYME tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo mouse bone marrow micronucleus assay. No evidence of impairment of fertility was observed in male and female rats that received intravenous doses up to 10 mg/kg/day (approximately 600 times the MRHD in adults).
# Clinical Studies
- PULMOZYME has been evaluated in a randomized, placebo-controlled trial of clinically stable cystic fibrosis patients, 5 years of age and older, with baseline forced vital capacity (FVC) greater than or equal to 40% of predicted and receiving standard therapies for cystic fibrosis. Patients were treated with placebo (325 patients), 2.5 mg of PULMOZYME once a day (322 patients), or 2.5 mg of PULMOZYME twice a day (321 patients) for six months administered via a Hudson T Up-draft II® nebulizer with a Pulmo-Aide® compressor.
- Both doses of PULMOZYME resulted in significant reductions in the number of patients experiencing respiratory tract infections requiring use of parenteral antibiotics compared with the placebo group. Administration of PULMOZYME reduced the relative risk of developing a respiratory tract infection by 27% and 29% for the 2.5 mg daily dose and the 2.5 mg twice daily dose, respectively (see Table 3). The data suggest that the effects of PULMOZYME on respiratory tract infections in older patients ( > 21 years) may be smaller than in younger patients, and that twice daily dosing may be required in the older patients. Patients with baseline FVC > 85% may also benefit from twice a day dosing (see Table 3). The reduced risk of respiratory infection observed in PULMOZYME treated patients did not directly correlate with improvement in FEV1 during the initial two weeks of therapy.
- Within 8 days of the start of treatment with PULMOZYME, mean FEV1 increased 7.9% in those treated once a day and 9.0% in those treated twice a day compared to the baseline values. The overall mean FEV1 during long-term therapy increased 5.8% from baseline at the 2.5 mg daily dose level and 5.6% from baseline at the 2.5 mg twice daily dose level. Placebo recipients did not show significant mean changes in pulmonary function testing (see Figure 1).
- For patients 5 years of age or older, with baseline FVC greater than or equal to 40%, administration of PULMOZYME decreased the incidence of occurrence of first respiratory tract infection requiring parenteral antibiotics, and improved mean FEV1, regardless of age or baseline FVC.
- PULMOZYME has also been evaluated in a second randomized, placebo-controlled trial in clinically stable patients with baseline FVC < 40% of predicted. Patients were enrolled and treated with placebo (162 patients) or PULMOZYME 2.5 mg QD (158 patients) for twelve weeks. In patients who received PULMOZYME, there was an increase in mean change (as percent of baseline) compared to placebo in FEV1 (9.4% vs. 2.1%, p < 0.001) and in FVC (12.4% vs. 7.3%, p < 0.01). PULMOZYME did not significantly reduce the risk of developing a respiratory tract infection requiring parenteral antibiotics (54% of PULMOZYME patients vs. 55% of placebo patients had experienced a respiratory tract infection by 12 weeks, relative risk = .93, p = 0.62).
- The effect of PULMOZYME on exercise tolerance has not been established in adult and pediatric patients.
- Clinical trials have indicated that PULMOZYME therapy can be continued or initiated during an acute respiratory exacerbation.
- Short-term dose ranging studies demonstrated that doses in excess of 2.5 mg BID did not provide further improvement in FEV1. Patients who have received drug on a cyclical regimen (i.e., administration of PULMOZYME 10 mg BID for 14 days, followed by a 14 day wash out period) showed rapid improvement in FEV1 with the initiation of each cycle and a return to baseline with each PULMOZYME withdrawal.
# How Supplied
- PULMOZYME is supplied in:
## Storage
- Store PULMOZYME under refrigeration (2°C to 8°C/36°F to 46°F) in their protective foil to protect from light. Do not use beyond the expiration date stamped on the ampule. Store unused ampules in their protective foil pouch under refrigeration. Refrigerate PULMOZYME during transport and do not expose to room temperatures for a total time of 24 hours.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 30 Ampule Carton
NDC 50242-100-40
DORNASE ALFA
PULMOZYME®
INHALATION SOLUTION
KEEP REFRIGERATED
Genentech, Inc.
A Member of the Roche Group
1 DNA Way, South San Francisco, CA 94080-4990
US License No.: 1048
### Ingredients and Appearance
# Patient Counseling Information
- Advise patients to read the FDA-approved Patient Labeling (Instructions for Use)
- Instruct patients on the proper techniques to store and handle PULMOZYME. PULMOZYME must be stored in the refrigerator at 2 to 8°C (36 to 46°F) and protected from light. It should be kept refrigerated during transport and should not be exposed to room temperatures for a total time of 24 hours.
- Advise patients to squeeze each ampule prior to use in order to check for leaks. The solution should be discarded if it is cloudy or discolored. Once opened, the entire contents of the ampule must be used or discarded.
- Instruct patients in the proper use and maintenance of the jet nebulizer/compressor system or eRapid Nebulizer System used in PULMOZYME delivery.
- Instruct patients not to dilute or mix PULMOZYME with other drugs in the nebulizer. Mixing of PULMOZYME with other drugs could lead to adverse physicochemical and/or functional changes in PULMOZYME or the admixed compound.
- Instruct patients and caregivers to read and follow the directions in both the PULMOZYME Instructions for Use and in the Manufacturer's eRapid Nebulizer System Instruction Booklet.
- Instruct patients and caregivers to clean the handset, including the medication reservoir, medicine cap, aerosol head, and mouthpiece, after each use. Instruct patients and caregivers to disinfect the handset, including the medication reservoir, medicine cap, aerosol head, and mouthpiece, after each day of use.
- Instruct patients to replace the handset after 90 uses, regardless of whether the EasyCare cleaning aid is used. Since delivery data are not available for PULMOZYME administered with the eRapid handset beyond 90 administrations, delivery of the appropriate therapeutic dose of PULMOZYME cannot be assured beyond 90 administrations.
### Instructions for Use
PULMOZYME® (PULL-muh-zyme)
(dornase alfa)
Inhalation Solution
Instructions for Use with Jet Nebulizers and Compressors
- See the other side of this Instructions for Use for information on use of Pulmozyme with the ultrasonic eRapid™ Nebulizer System
- Read this Instructions for Use before you start taking Pulmozyme and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
- A nebulizer and a compressor are used together to give a dose of Pulmozyme. A nebulizer changes the Pulmozyme liquid medicine into a fine mist you inhale by breathing through a mouthpiece. A compressor gives the nebulizer power and makes the nebulizer work.
- Pulmozyme should only be used with the approved nebulizers and compressors listed below, or with the eRapid Nebulizer System (see other side).
- Do not use any other inhaled medicines in the nebulizer at the same time. Keep all other inhaled medication systems completely separate from Pulmozyme.
- Do not use a mask. Use the mouthpiece provided with each nebulizer kit.
- If your child cannot breathe in or breathe out by mouth, you may use the PARI BABY™ reusable nebulizer, but you should discuss it with your doctor first. The PARI BABY™ nebulizer is the same as the PARI LC Plus Jet system, except the mouthpiece is replaced by a tight fitting face mask connected to an elbow piece.
- Follow the steps on this side of the sheet to administer Pulmozyme using the following jet nebulizer systems.
### Instructions for Use
PULMOZYME® (PULL-muh-zyme)
(dornase alfa)
Inhalation Solution
Instructions for Use with the eRapid™ Nebulizer System
- See the other side of this Instructions for Use for information on use with Jet Nebulizers and Compressors
- Read this Instructions for Use before you start taking Pulmozyme and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
- This information does not take the place of the Manufacturer's eRapid Nebulizer System Instruction Booklet. This information is needed to show you the right way to use the eRapid Nebulizer System.
- The eRapid Nebulizer System changes the Pulmozyme liquid medicine into a fine mist you inhale by breathing through a mouthpiece.
- Do not use any other inhaled medicines in the nebulizer at the same time. Keep all other inhaled medication systems completely separate from Pulmozyme.
- The eRapid Nebulizer System should only be used by adults and children who can use a mouthpiece, and not by younger children who need a mask to take Pulmozyme.
- Follow the instructions on this side of the sheet to give Pulmozyme using the eRapid Nebulizer System.
- Supplies you will need to give a dose of Pulmozyme (See Figure A):
- This Instructions for Use has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Dornase alfa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PULMOZYME®
# Look-Alike Drug Names
There is limited information regarding Dornase alfa Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Dornase alfa
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Overview
Dornase alfa is a Mucolytic enzyme that is FDA approved for the treatment of cystic fibrosis (CF) patients. Common adverse reactions include voice alteration, pharyngitis, rash, laryngitis, chest pain, conjunctivitis, rhinitis, decrease in FVC of ≥10%, fever, and dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- PULMOZYME® (dornase alfa) is indicated for daily administration in conjunction with standard therapies for the management of cystic fibrosis (CF) patients to improve pulmonary function.
- In CF patients with an FVC ≥ 40% of predicted, daily administration of PULMOZYME has also been shown to reduce the risk of respiratory tract infections requiring parenteral antibiotics.
### Recommended Dosage
- The recommended dosage for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended jet nebulizer/compressor system or eRapid™ Nebulizer System.
- Some patients may benefit from twice daily administration
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dornase alfa in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dornase alfa in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dornase alfa in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dornase alfa in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dornase alfa in pediatric patients.
# Contraindications
- PULMOZYME is contraindicated in patients with known hypersensitivity to dornase alfa, Chinese Hamster Ovary cell products, or any component of the product.
# Warnings
- None
### Precautions
- None
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data described below reflect exposure to PULMOZYME in 902 patients, with exposures ranging from 2 weeks of daily administration up to once or twice daily administration for six months. PULMOZYME was studied in both placebo-controlled and uncontrolled trials (n=804 and n=98). The population of patients in placebo-controlled trials was with FVC ≥ 40% of predicted (n=643) or with more advanced pulmonary disease, FVC < 40% of predicted (n=161). The population in the uncontrolled trial included 98 pediatric patients with CF ranging from 3 months to 10 years of age. More than half of the patients received PULMOZYME 2.5 mg by inhalation once a day (n=581), while the rest of patients (n=321) received PULMOZYME 2.5 mg by inhalation twice a day.
- Trial 1: Trial 1 was a randomized, placebo-controlled clinical trial in patients with FVC ≥ 40% of predicted. In this trial, over 600 patients received PULMOZYME once or twice daily for six months. The most common adverse reaction (risk difference ≥5%) was voice alteration. The proportion of most adverse events was similar for patients on PULMOZYME and on placebo, probably reflecting the sequelae of the underlying lung disease. In most cases reactions that were increased were mild, transient in nature, and did not require alterations in dosing. Few patients experienced adverse reactions resulting in permanent discontinuation from PULMOZYME, and the proportion of discontinuations were similar for placebo (2%) and PULMOZYME (3%). Adverse reactions occurring in a higher proportion (greater than 3%) of PULMOZYME treated patients than in placebo-treated patients are listed in Table 2.
- Trial 2: Trial 2 was a randomized, placebo-controlled trial in patients with more advanced pulmonary disease (FVC < 40% of predicted) who were treated for 12 weeks. In this trial, the safety profile of PULMOZYME was similar to that reported in patients with less advanced pulmonary disease (FVC ≥ 40% of predicted). Adverse reactions that were reported in this trial with a higher proportion (greater than 3%) in the PULMOZYME treated patients are listed in Table 2.
- Mortality rates observed in controlled trials were similar for the placebo and PULMOZYME treated patients. Causes of death were consistent with progression of cystic fibrosis and included apnea, cardiac arrest, cardiopulmonary arrest, cor pulmonale, heart failure, massive hemoptysis, pneumonia, pneumothorax, and respiratory failure.
- Trial 3: The safety of PULMOZYME, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 98 pediatric patients with cystic fibrosis 3 months to 10 years of age (65 aged 3 months to < 5 years, 33 aged 5 to ≤ 10 years). The PARI BABY™ reusable nebulizer (which uses a facemask instead of a mouthpiece) was utilized in patients unable to demonstrate the ability to inhale or exhale orally throughout the entire treatment period (54/65, 83% of the younger and 2/33, 6% of the older patients). Overall, the nature of adverse reactions was similar to that seen in the placebo-controlled trials. The number of patients reporting cough was higher in the younger age group as compared to the older age group (29/65, 45% compared to 10/33, 30%) as was the number reporting moderate to severe cough (24/65, 37% as compared to 6/33, 18%). The number of patients reporting rhinitis was higher in the younger age group as compared to the older age group (23/65, 35% compared to 9/33, 27%) as was the number reporting rash (4/65, 6% as compared to 0/33).
- There have been no reports of anaphylaxis attributed to the administration of PULMOZYME. Urticaria, mild to moderate, and mild skin rash have been observed and have been transient. Within all of the studies, a small percentage (average of 2-4%) of patients treated with PULMOZYME developed serum antibodies to PULMOZYME. None of these patients developed anaphylaxis, and the clinical significance of serum antibodies to PULMOZYME is unknown.
## Postmarketing Experience
- Postmarketing spontaneous reports and prospectively collected safety data from observational studies confirm the safety profile to be as described in clinical trials
# Drug Interactions
- Available data indicate there are no clinically important drug-drug interactions with PULMOZYME.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no adequate and well-controlled studies with PULMOZYME in pregnant women. However, animal reproduction studies have been conducted with dornase alfa. In these studies, no evidence of fetal harm was observed in rats and rabbits at doses of dornase alfa up to approximately 600 times the maximum recommended human dose (MRHD).
- The background risk of major birth defects and miscarriage for the cystic fibrosis population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
- Reproductive studies have been performed in rats and rabbits at intravenous doses of dornase alfa up to 10 mg/kg/day (approximately 600 times the MRHD in adults). In a combined embryo-fetal development and pre- and post-natal development study, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed when dornase alfa was administered to dams throughout organogenesis (Gestation days 6 to 17). Dornase alfa did not elicit adverse effects on fetal or neonatal growth when administered to dams throughout most of gestation and delivery (Gestation days 6 to 25) and nursing (Post-partum days 6 to 21).
- A pharmacokinetic study in Cynomolgus monkeys found no detectable levels of dornase alfa in fetal blood or amniotic fluid on gestation day 150 (end of gestation) from mothers that were administered an intravenous bolus dose (0.1 mg/kg) followed by an intravenous infusion dose (0.080 mg/kg) over a 6-hour period during pregnancy.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dornase alfa in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dornase alfa during labor and delivery.
### Nursing Mothers
Risk Summary
- It is not known whether PULMOZYME is present in human milk. In a pharmacokinetic study in Cynomolgus monkeys, levels of dornase alfa detected in milk were less than 0.1% of the maternal serum concentration at 24 hours after dosing [intravenous bolus dose (0.1 mg/kg) of dornase alfa followed by an intravenous infusion (0.080 mg/kg/hr) over a 6-hour period] on post-partum day 14. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PULMOZYME and any potential adverse effects on the breastfed child from PULMOZYME or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of PULMOZYME have been established in pediatric patients 5 years of age and older. The safety of PULMOZYME, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 65 patients with cystic fibrosis aged 3 months to < 5 years. While clinical trial data are limited in pediatric patients younger than 5 years of age, the use of PULMOZYME should be considered for pediatric CF patients who may experience potential benefit in pulmonary function or who may be at risk of respiratory tract infection.
### Geriatic Use
- Cystic fibrosis is primarily a disease of children and young adults. Clinical studies of PULMOZYME did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Dornase alfa with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dornase alfa with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dornase alfa in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dornase alfa in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dornase alfa in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dornase alfa in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer PULMOZYME via the eRapid Nebulizer System or via a jet nebulizer connected to an air compressor with an adequate air flow and equipped with a mouthpiece or suitable face mask (see Table 1). No data are currently available to support the administration of PULMOZYME with other nebulizer systems.
- Do not dilute or mix PULMOZYME with other drugs in the nebulizer. Mixing of PULMOZYME with other drugs could lead to adverse physicochemical and/or functional changes in PULMOZYME or the admixed compound.
- The patient should follow the manufacturer's instructions on the use and maintenance of the equipment, including cleaning and disinfection procedures.
- When PULMOZYME is administered with the eRapid Nebulizer System, advise patients to replace the handset after 90 uses, regardless of whether the EasyCare cleaning aid is used. Since delivery data are not available for PULMOZYME administered with the eRapid handset beyond 90 administrations, delivery of the appropriate therapeutic dose of PULMOZYME cannot be assured beyond 90 administrations. The eRapid Nebulizer System should only be used by adults and children who can use a mouthpiece, and not by younger children who need a mask to take PULMOZYME.
- Store PULMOZYME ampules in their protective foil pouch under refrigeration and protected from light. Refrigerate ampules during transport and do not expose to room temperatures for a total time of 24 hours.
- Each PULMOZYME ampule should be squeezed prior to use in order to check for leaks. Discard ampules if the solution is cloudy or discolored. Once opened, the entire contents of the ampule must be used or discarded.
### DOSAGE FORMS AND STRENGTHS
- Inhalation Solution: 2.5 mg/2.5 mL in single-use ampules.
### Monitoring
There is limited information regarding Monitoring of Dornase alfa in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Dornase alfa in the drug label.
# Overdosage
- Single-dose inhalation studies in rats and monkeys at doses up to 180-times higher than doses routinely used in clinical studies are well tolerated. Single dose oral administration of PULMOZYME in doses up to 200 mg/kg are also well tolerated by rats.
- Cystic fibrosis patients have received up to 20 mg BID for up to 6 days and 10 mg BID intermittently (2 weeks on/2 weeks off drug) for 168 days. These doses were well tolerated.
# Pharmacology
## Mechanism of Action
- PULMOZYME is recombinant human deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA. In preclinical in vitro studies, PULMOZYME hydrolyzes the DNA in sputum of CF patients and reduces sputum viscoelasticity. In CF patients, retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbations of infection. Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating leukocytes that accumulate in response to infection.
## Structure
- PULMOZYME is a recombinant human deoxyribonuclease I (rhDNase) an enzyme which selectively cleaves DNA. The protein is produced by genetically engineered Chinese Hamster Ovary (CHO) cells containing DNA encoding for the native human protein, deoxyribonuclease I (DNase). Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin, 100–200 mg/L. However, the presence of the antibiotic is not detectable in the final product. The product is purified by tangential flow filtration and column chromatography. The purified glycoprotein contains 260 amino acids with an approximate molecular weight of 37,000 daltons. The primary amino acid sequence is identical to that of the native human enzyme.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dornase alfa in the drug label.
## Pharmacokinetics
- When 2.5 mg PULMOZYME was administered by inhalation to eighteen CF patients, mean sputum concentrations of 3 µg/mL DNase were measurable within 15 minutes. Mean sputum concentrations declined to an average of 0.6 µg/mL two hours following inhalation. Inhalation of up to 10 mg TID of PULMOZYME by 4 CF patients for six consecutive days, did not result in a significant elevation of serum concentrations of DNase above normal endogenous levels. After administration of up to 2.5 mg of PULMOZYME twice daily for six months to 321 CF patients, no accumulation of serum DNase was noted. Dornase alfa is expected to be metabolized by proteases present in biological fluids. A human intravenous dose study suggested an elimination half-life of 3-4 hours for dornase alpha.
- PULMOZYME, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to ≤ 10 years, and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the first dose. BAL DNase concentrations were detectable in all patients but showed a broad range, from 0.007 to 1.8 µg/mL. Over an average of 14 days of exposure, serum DNase concentrations (mean ± s.d.) increased by 1.1 ± 1.6 ng/mL for the 3 months to < 5 year age group and by 0.8 ± 1.2 ng/mL for the 5 to ≤ 10 year age group. The relationship between BAL or serum DNase concentration and adverse experiences and clinical outcomes is unknown.
## Nonclinical Toxicology
- PULMOZYME produced no treatment-related increases in the incidence of tumors in a lifetime study in Sprague Dawley rats that were administered inhaled doses up to 0.246 mg/kg/day (approximately 30 times the MRHD in adults). There was no increase in the development of benign or malignant neoplasms and no occurrence of unusual tumor types in rats after lifetime exposure.
- PULMOZYME tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo mouse bone marrow micronucleus assay. No evidence of impairment of fertility was observed in male and female rats that received intravenous doses up to 10 mg/kg/day (approximately 600 times the MRHD in adults).
# Clinical Studies
- PULMOZYME has been evaluated in a randomized, placebo-controlled trial of clinically stable cystic fibrosis patients, 5 years of age and older, with baseline forced vital capacity (FVC) greater than or equal to 40% of predicted and receiving standard therapies for cystic fibrosis. Patients were treated with placebo (325 patients), 2.5 mg of PULMOZYME once a day (322 patients), or 2.5 mg of PULMOZYME twice a day (321 patients) for six months administered via a Hudson T Up-draft II® nebulizer with a Pulmo-Aide® compressor.
- Both doses of PULMOZYME resulted in significant reductions in the number of patients experiencing respiratory tract infections requiring use of parenteral antibiotics compared with the placebo group. Administration of PULMOZYME reduced the relative risk of developing a respiratory tract infection by 27% and 29% for the 2.5 mg daily dose and the 2.5 mg twice daily dose, respectively (see Table 3). The data suggest that the effects of PULMOZYME on respiratory tract infections in older patients ( > 21 years) may be smaller than in younger patients, and that twice daily dosing may be required in the older patients. Patients with baseline FVC > 85% may also benefit from twice a day dosing (see Table 3). The reduced risk of respiratory infection observed in PULMOZYME treated patients did not directly correlate with improvement in FEV1 during the initial two weeks of therapy.
- Within 8 days of the start of treatment with PULMOZYME, mean FEV1 increased 7.9% in those treated once a day and 9.0% in those treated twice a day compared to the baseline values. The overall mean FEV1 during long-term therapy increased 5.8% from baseline at the 2.5 mg daily dose level and 5.6% from baseline at the 2.5 mg twice daily dose level. Placebo recipients did not show significant mean changes in pulmonary function testing (see Figure 1).
- For patients 5 years of age or older, with baseline FVC greater than or equal to 40%, administration of PULMOZYME decreased the incidence of occurrence of first respiratory tract infection requiring parenteral antibiotics, and improved mean FEV1, regardless of age or baseline FVC.
- PULMOZYME has also been evaluated in a second randomized, placebo-controlled trial in clinically stable patients with baseline FVC < 40% of predicted. Patients were enrolled and treated with placebo (162 patients) or PULMOZYME 2.5 mg QD (158 patients) for twelve weeks. In patients who received PULMOZYME, there was an increase in mean change (as percent of baseline) compared to placebo in FEV1 (9.4% vs. 2.1%, p < 0.001) and in FVC (12.4% vs. 7.3%, p < 0.01). PULMOZYME did not significantly reduce the risk of developing a respiratory tract infection requiring parenteral antibiotics (54% of PULMOZYME patients vs. 55% of placebo patients had experienced a respiratory tract infection by 12 weeks, relative risk = .93, p = 0.62).
- The effect of PULMOZYME on exercise tolerance has not been established in adult and pediatric patients.
- Clinical trials have indicated that PULMOZYME therapy can be continued or initiated during an acute respiratory exacerbation.
- Short-term dose ranging studies demonstrated that doses in excess of 2.5 mg BID did not provide further improvement in FEV1. Patients who have received drug on a cyclical regimen (i.e., administration of PULMOZYME 10 mg BID for 14 days, followed by a 14 day wash out period) showed rapid improvement in FEV1 with the initiation of each cycle and a return to baseline with each PULMOZYME withdrawal.
# How Supplied
- PULMOZYME is supplied in:
## Storage
- Store PULMOZYME under refrigeration (2°C to 8°C/36°F to 46°F) in their protective foil to protect from light. Do not use beyond the expiration date stamped on the ampule. Store unused ampules in their protective foil pouch under refrigeration. Refrigerate PULMOZYME during transport and do not expose to room temperatures for a total time of 24 hours.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 30 Ampule Carton
NDC 50242-100-40
DORNASE ALFA
PULMOZYME®
INHALATION SOLUTION
KEEP REFRIGERATED
Genentech, Inc.
A Member of the Roche Group
1 DNA Way, South San Francisco, CA 94080-4990
US License No.: 1048
### Ingredients and Appearance
# Patient Counseling Information
- Advise patients to read the FDA-approved Patient Labeling (Instructions for Use)
- Instruct patients on the proper techniques to store and handle PULMOZYME. PULMOZYME must be stored in the refrigerator at 2 to 8°C (36 to 46°F) and protected from light. It should be kept refrigerated during transport and should not be exposed to room temperatures for a total time of 24 hours.
- Advise patients to squeeze each ampule prior to use in order to check for leaks. The solution should be discarded if it is cloudy or discolored. Once opened, the entire contents of the ampule must be used or discarded.
- Instruct patients in the proper use and maintenance of the jet nebulizer/compressor system or eRapid Nebulizer System used in PULMOZYME delivery.
- Instruct patients not to dilute or mix PULMOZYME with other drugs in the nebulizer. Mixing of PULMOZYME with other drugs could lead to adverse physicochemical and/or functional changes in PULMOZYME or the admixed compound.
- Instruct patients and caregivers to read and follow the directions in both the PULMOZYME Instructions for Use and in the Manufacturer's eRapid Nebulizer System Instruction Booklet.
- Instruct patients and caregivers to clean the handset, including the medication reservoir, medicine cap, aerosol head, and mouthpiece, after each use. Instruct patients and caregivers to disinfect the handset, including the medication reservoir, medicine cap, aerosol head, and mouthpiece, after each day of use.
- Instruct patients to replace the handset after 90 uses, regardless of whether the EasyCare cleaning aid is used. Since delivery data are not available for PULMOZYME administered with the eRapid handset beyond 90 administrations, delivery of the appropriate therapeutic dose of PULMOZYME cannot be assured beyond 90 administrations.
### Instructions for Use
PULMOZYME® (PULL-muh-zyme)
(dornase alfa)
Inhalation Solution
Instructions for Use with Jet Nebulizers and Compressors
- See the other side of this Instructions for Use for information on use of Pulmozyme with the ultrasonic eRapid™ Nebulizer System
- Read this Instructions for Use before you start taking Pulmozyme and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
- A nebulizer and a compressor are used together to give a dose of Pulmozyme. A nebulizer changes the Pulmozyme liquid medicine into a fine mist you inhale by breathing through a mouthpiece. A compressor gives the nebulizer power and makes the nebulizer work.
- Pulmozyme should only be used with the approved nebulizers and compressors listed below, or with the eRapid Nebulizer System (see other side).
- Do not use any other inhaled medicines in the nebulizer at the same time. Keep all other inhaled medication systems completely separate from Pulmozyme.
- Do not use a mask. Use the mouthpiece provided with each nebulizer kit.
- If your child cannot breathe in or breathe out by mouth, you may use the PARI BABY™ reusable nebulizer, but you should discuss it with your doctor first. The PARI BABY™ nebulizer is the same as the PARI LC Plus Jet system, except the mouthpiece is replaced by a tight fitting face mask connected to an elbow piece.
- Follow the steps on this side of the sheet to administer Pulmozyme using the following jet nebulizer systems.
### Instructions for Use
PULMOZYME® (PULL-muh-zyme)
(dornase alfa)
Inhalation Solution
Instructions for Use with the eRapid™ Nebulizer System
- See the other side of this Instructions for Use for information on use with Jet Nebulizers and Compressors
- Read this Instructions for Use before you start taking Pulmozyme and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
- This information does not take the place of the Manufacturer's eRapid Nebulizer System Instruction Booklet. This information is needed to show you the right way to use the eRapid Nebulizer System.
- The eRapid Nebulizer System changes the Pulmozyme liquid medicine into a fine mist you inhale by breathing through a mouthpiece.
- Do not use any other inhaled medicines in the nebulizer at the same time. Keep all other inhaled medication systems completely separate from Pulmozyme.
- The eRapid Nebulizer System should only be used by adults and children who can use a mouthpiece, and not by younger children who need a mask to take Pulmozyme.
- Follow the instructions on this side of the sheet to give Pulmozyme using the eRapid Nebulizer System.
- Supplies you will need to give a dose of Pulmozyme (See Figure A):
- This Instructions for Use has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Dornase alfa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PULMOZYME®[1]
# Look-Alike Drug Names
There is limited information regarding Dornase alfa Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dornase_alfa | |
f423ba6a3ffc28c34f1836f0ac1b3cafaf2d4cd1 | wikidoc | Dorsal aorta | Dorsal aorta
Each primitive aorta receives anteriorly a vein—the vitelline vein—from the yolk-sac, and is prolonged backward on the lateral aspect of the notochord under the name of the dorsal aorta.
The dorsal aortæ give branches to the yolk-sac, and are continued backward through the body-stalk as the umbilical arteries to the villi of the chorion.
The two dorsal aortae combine to become the descending aorta in later development. | Dorsal aorta
Template:Infobox Embryology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Each primitive aorta receives anteriorly a vein—the vitelline vein—from the yolk-sac, and is prolonged backward on the lateral aspect of the notochord under the name of the dorsal aorta.
The dorsal aortæ give branches to the yolk-sac, and are continued backward through the body-stalk as the umbilical arteries to the villi of the chorion.
The two dorsal aortae combine to become the descending aorta in later development.
# External links
- Template:EmbryologyUNSW
- Template:EmbryologyUNC
Template:Development of circulatory system
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dorsal_aorta | |
f285f90aeddae28ba3600264c1e469dcde0b39e6 | wikidoc | Dose Profile | Dose Profile
# Overview
In External Beam Radiotherapy, transverse and longitudinal dose measurements are taken by a radiation detector in order to characterise the radiation beams from medical linear accelerators. Typically, an ionisation chamber and water phantom are used to create these radiation dose profiles. Water is used due to its tissue equivalence.
Central Axis Dose profile for 15MV photon beam incident on water phantom. Here the linear accelerator collimation projects a 1x1 cm2 field at isocentre i.e. 100 cm SSD
Tranverse dose measurements are performed in the x (crossplane) or y (inplane) directions perpendicular to the radiation beam, and at a given depth (z) in the phantom. These are known dose profiles.
Dose measurements taken along the z direction create radiation dose distribution known as a depth-dose curve. | Dose Profile
# Overview
In External Beam Radiotherapy, transverse and longitudinal dose measurements are taken by a radiation detector in order to characterise the radiation beams from medical linear accelerators. Typically, an ionisation chamber and water phantom are used to create these radiation dose profiles. Water is used due to its tissue equivalence.
Central Axis Dose profile for 15MV photon beam incident on water phantom. Here the linear accelerator collimation projects a 1x1 cm2 field at isocentre i.e. 100 cm SSD
Tranverse dose measurements are performed in the x (crossplane) or y (inplane) directions perpendicular to the radiation beam, and at a given depth (z) in the phantom. These are known dose profiles.
Dose measurements taken along the z direction create radiation dose distribution known as a depth-dose curve. | https://www.wikidoc.org/index.php/Dose_Profile | |
1090d374fa9073e1acf577a504224704dded94a7 | wikidoc | Dose dumping | Dose dumping
Dose dumping is a phenomenon of drug metabolism in which environmental factors can cause the premature and exaggerated release of a drug. This can greatly increase the concentration of a drug in the body and thereby produce adverse effects or even drug-induced toxicity.
Dose dumping is most commonly seen in drugs taken by mouth and digested in the gastrointestinal tract. Around the same time patients take their medication, they can also ingest other substances like fatty meals or alcohol that increase drug delivery. The substances may act on the drug's capsule to speed up drug release, or they may stimulate the body's absorptive surfaces to increase the rate of drug uptake.
In general, drug companies try to avoid drugs with significant dose dumping effects. Such drugs are prone to problems and are often pulled from the market. Such was the case with the pain medication Palladone due to its dose-dumping effects when taken with alcohol. | Dose dumping
Dose dumping is a phenomenon of drug metabolism in which environmental factors can cause the premature and exaggerated release of a drug. This can greatly increase the concentration of a drug in the body and thereby produce adverse effects or even drug-induced toxicity.[1]
Dose dumping is most commonly seen in drugs taken by mouth and digested in the gastrointestinal tract. Around the same time patients take their medication, they can also ingest other substances like fatty meals or alcohol that increase drug delivery. The substances may act on the drug's capsule to speed up drug release, or they may stimulate the body's absorptive surfaces to increase the rate of drug uptake.
In general, drug companies try to avoid drugs with significant dose dumping effects. Such drugs are prone to problems and are often pulled from the market. Such was the case with the pain medication Palladone due to its dose-dumping effects when taken with alcohol.[2] | https://www.wikidoc.org/index.php/Dose_dumping | |
f50b7c4720cd8cfa452d923dbdc61a6904f5cf4c | wikidoc | Doublecortin | Doublecortin
Neuronal migration protein doublecortin, also known as doublin or lissencephalin-X is a protein that in humans is encoded by the DCX gene.
# Function
Doublecortin (DCX) is a microtubule-associated protein expressed by neuronal precursor cells and immature neurons in embryonic and adult cortical structures. Neuronal precursor cells begin to express DCX while actively dividing, and their neuronal daughter cells continue to express DCX for 2–3 weeks as the cells mature into neurons. Downregulation of DCX begins after 2 weeks, and occurs at the same time that these cells begin to express NeuN, a marker for mature neurons.
Due to the nearly exclusive expression of DCX in developing neurons, this protein has been used increasingly as a marker for neurogenesis. Indeed, levels of DCX expression increase in response to exercise, and that increase occurs in parallel with increased BrdU labelling (which is currently a "gold standard" in measuring neurogenesis).
Doublecortin was found to bind to the microtubule cytoskeleton. In vivo and in vitro assays show that Doublecortin stabilises microtubules and causes bundling. Doublecortin is a basic protein with an iso-electric point of 10, typical of microtubule-binding proteins.
# Knock out mouse
In mice where the Doublecortin gene has been knocked out, cortical layers are still correctly formed. However, the hippocampi of these mice show disorganisation in the CA3 region. The normally single layer of pyramidal cells in mutants is seen as a double layer. These mice also have different behavior than their wild type littermates and are epileptic.
# Structure
The detailed sequence analysis of Doublecortin and Doublecortin-like proteins allowed the identification of a tandem repeat of evolutionarily conserved Doublecortin (DC) domains. These domains are found in the N terminus of proteins and consists of tandemly repeated copies of an around 80 amino acids region. It has been suggested that the first DC domain of Doublecortin binds tubulin and enhances microtubule polymerisation.
Doublecortin has been shown to influence the structure of microtubules. Microtubule nucleated in vitro in the presence of Doublecortin have almost exclusively 13 protofilaments, whereas microtubule nucleated without Doublecortin are present in a range of different sizes.
# Interactions
Doublecortin has been shown to interact with PAFAH1B1.
# Clinical significance
Doublecortin is mutated in X-linked lissencephaly and the double cortex syndrome, and the clinical manifestations are sex-linked. In males, X-linked lissencephaly produces a smooth brain due to lack of migration of immature neurons, which normally promote folding of the brain surface. Double cortex syndrome is characterized by abnormal migration of neural tissue during development which results in two bands of misplaced neurons within the subcortical white, generating two cortices, giving the name to the syndrome; this finding generally occurs in females. The mutation was discovered by Joseph Gleeson and Christopher A. Walsh in Boston. | Doublecortin
Neuronal migration protein doublecortin, also known as doublin or lissencephalin-X is a protein that in humans is encoded by the DCX gene.[1]
# Function
Doublecortin (DCX) is a microtubule-associated protein expressed by neuronal precursor cells and immature neurons in embryonic and adult cortical structures. Neuronal precursor cells begin to express DCX while actively dividing, and their neuronal daughter cells continue to express DCX for 2–3 weeks as the cells mature into neurons. Downregulation of DCX begins after 2 weeks, and occurs at the same time that these cells begin to express NeuN, a marker for mature neurons.[3]
Due to the nearly exclusive expression of DCX in developing neurons, this protein has been used increasingly as a marker for neurogenesis. Indeed, levels of DCX expression increase in response to exercise,[4] and that increase occurs in parallel with increased BrdU labelling (which is currently a "gold standard" in measuring neurogenesis).
Doublecortin was found to bind to the microtubule cytoskeleton. In vivo and in vitro assays show that Doublecortin stabilises microtubules and causes bundling.[5] Doublecortin is a basic protein with an iso-electric point of 10, typical of microtubule-binding proteins.
# Knock out mouse
In mice where the Doublecortin gene has been knocked out, cortical layers are still correctly formed. However, the hippocampi of these mice show disorganisation in the CA3 region. The normally single layer of pyramidal cells in mutants is seen as a double layer. These mice also have different behavior than their wild type littermates and are epileptic.[6]
# Structure
The detailed sequence analysis of Doublecortin and Doublecortin-like proteins allowed the identification of a tandem repeat of evolutionarily conserved Doublecortin (DC) domains. These domains are found in the N terminus of proteins and consists of tandemly repeated copies of an around 80 amino acids region. It has been suggested that the first DC domain of Doublecortin binds tubulin and enhances microtubule polymerisation.[7]
Doublecortin has been shown to influence the structure of microtubules. Microtubule nucleated in vitro in the presence of Doublecortin have almost exclusively 13 protofilaments, whereas microtubule nucleated without Doublecortin are present in a range of different sizes.
# Interactions
Doublecortin has been shown to interact with PAFAH1B1.[8]
# Clinical significance
Doublecortin is mutated in X-linked lissencephaly and the double cortex syndrome, and the clinical manifestations are sex-linked. In males, X-linked lissencephaly produces a smooth brain due to lack of migration of immature neurons, which normally promote folding of the brain surface. Double cortex syndrome is characterized by abnormal migration of neural tissue during development which results in two bands of misplaced neurons within the subcortical white, generating two cortices, giving the name to the syndrome; this finding generally occurs in females.[9] The mutation was discovered by Joseph Gleeson and Christopher A. Walsh in Boston.[10][11] | https://www.wikidoc.org/index.php/Doublecortin | |
2983613714373833b1beddc26737274e606e7d41 | wikidoc | Dowell Myers | Dowell Myers
Dowell Myers is a professor of urban planning and demography in the School of Policy, Planning, and Development, at the University of Southern California (USC). He directs the school’s Population Dynamics Research Group, whose recent projects have been funded by the National Institute of Health, the Haynes Foundation, Fannie Mae Foundation, and the Ford Foundation.
He leads the ongoing California Demographic Futures research project at USC. Recent applications have focused on the upward mobility of immigrants to the US and Southern California, trajectories into homeownership in the United States, changing transportation behavior, education and labor force trends, and projections for the future of the California population.
He is a well-known specialist in demographic trends and their relation to all areas of policy and planning. In 2000 he was a member of the Census Advisory Committee of Professional Associations (Population Association of America) for the United States Census Bureau and is the author of the most widely referenced text on census analysis, Analysis with Local Census Data: Portraits of Change (Academic Press, 1992).
In March 2007, the Russell Sage Foundation published his newest book, Immigrants and Boomers: Forging a New Social Contract for the Future of America. In fall 2006, Dowell Myers was recipient of the Haynes Award for Research Impact that was issued on the occasion of the Haynes Foundation’s 80th anniversary.
His undergraduate degree in anthropology from Columbia University was followed by a Master of Planning degree from the University of California, Berkeley. His Ph.D. is in urban planning from MIT and he also studied demography and sociology at Harvard University.
Dowell Myers has recently testified before the House Committee on the Judiciary about the reform of U.S. immigration policy.
# Published works
## Books
- The Future of America. New York: Russell Sage Foundation. February 2007.
- Analysis with Local Census Data: Portraits of Change, New York: Academic Press, 1992; 15 chapters and 3 appendices.
# Notes
- ↑ California Demographic Futures research project
- ↑ Staff (2002) "Homeownership rates get boost from minorities, baby boomers" Multi-Housing News 37(3): p.8
- ↑ Appendix D, Minutes of the Census Advistory Committee, p. 59
- ↑ Myers's bio
- ↑ Written testimony of Dowell Myers to the House Committee on the Judiciary | Dowell Myers
Dowell Myers is a professor of urban planning and demography in the School of Policy, Planning, and Development, at the University of Southern California (USC). He directs the school’s Population Dynamics Research Group, whose recent projects have been funded by the National Institute of Health, the Haynes Foundation, Fannie Mae Foundation, and the Ford Foundation.
He leads the ongoing California Demographic Futures research project at USC[1]. Recent applications have focused on the upward mobility of immigrants to the US and Southern California, trajectories into homeownership in the United States[2], changing transportation behavior, education and labor force trends, and projections for the future of the California population.
He is a well-known specialist in demographic trends and their relation to all areas of policy and planning[citation needed]. In 2000 he was a member of the Census Advisory Committee of Professional Associations (Population Association of America) for the United States Census Bureau[3] and is the author of the most widely referenced text on census analysis, Analysis with Local Census Data: Portraits of Change (Academic Press, 1992)[citation needed].
In March 2007, the Russell Sage Foundation published his newest book, Immigrants and Boomers: Forging a New Social Contract for the Future of America. In fall 2006, Dowell Myers was recipient of the Haynes Award for Research Impact that was issued on the occasion of the Haynes Foundation’s 80th anniversary.
His undergraduate degree in anthropology from Columbia University was followed by a Master of Planning degree from the University of California, Berkeley. His Ph.D. is in urban planning from MIT and he also studied demography and sociology at Harvard University.[4]
Dowell Myers has recently testified before the House Committee on the Judiciary about the reform of U.S. immigration policy. [5]
# Published works
## Books
- The Future of America. New York: Russell Sage Foundation. February 2007.
- Analysis with Local Census Data: Portraits of Change, New York: Academic Press, 1992; 15 chapters and 3 appendices.
- (editor), Housing Demography: Linking Demographic Structure and Housing Markets, Madison, WI: University of Wisconsin Press, 1990.
# Notes
- ↑ California Demographic Futures research project
- ↑ Staff (2002) "Homeownership rates get boost from minorities, baby boomers" Multi-Housing News 37(3): p.8
- ↑ Appendix D, Minutes of the Census Advistory Committee, p. 59
- ↑ Myers's bio
- ↑ Written testimony of Dowell Myers to the House Committee on the Judiciary
# External links
- Dowell Myers's Homepage
- The School of Policy, Planning, and Development at the University of Southern California
- Population Dynamics Research Group of the School of Policy, Planning, and Development at the University of Southern California
- California Housing Futures Project
- Where Millions Entered U.S., a Debate on Letting in More, March 31, 2007 New York Times | https://www.wikidoc.org/index.php/Dowell_Myers | |
a5e067f8aae827ea4c3418513b8e120bf6b50586 | wikidoc | Drospirenone | Drospirenone
Drospirenone is a synthetic progestin that is an analog to spironolactone. Its molecular weight is 366.5 and its molecular formula is C24H30O3.
# Properties and uses
The compound is part of certain birth control formulations. Drospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has anti-mineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and is not androgenic. With its activities similar to spironolactone it may lead to less water retention and breast tenderness and improved skin appearance (less acne).
Drospirenone is taken orally with about 76% bioavailability. It is not bound by sex hormone binding globulin or corticosteroid binding globulin, but by other serum proteins. Metabolites have not been shown to be biologically active, show up in urine and feces, and are essentially completely excreted within 10 days.
The compound is part of certain newer oral contraceptive formulations:
- Yasmin® contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet. It is indicated for the prevention of pregnancy in women who elect an oral contraceptive.
- Yaz® contains 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is given for 24/4 days with the same indications.
It has also been formulated in medication to manage menopausal symptoms using 0.5 mg drsp and 1 mg estradiol per day by oral application. This medication was introduced in the USA in 2007 as Angeliq®.
Drospirenone, which can potentially cause hyperkalemia in high-risk patients, is comparable to a 25mg dose of spironolactone.
The medication is contraindicated in patients with hepatic dysfunction, renal insufficiency, adrenal insufficiency, or in whom the use of oral contraceptives is contraindicated, such as smokers and patients with a history of DVT, stroke, or other blood clots. Because of the anti-mineralocorticoid effects care needs to be exercised when other drugs that may increase potassium levels are taken. Such medications include ACE inhibitors, angiotensin-II receptor agonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs. | Drospirenone
Drospirenone is a synthetic progestin that is an analog to spironolactone. Its molecular weight is 366.5 and its molecular formula is C24H30O3.
# Properties and uses
The compound is part of certain birth control formulations. Drospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has anti-mineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and is not androgenic. With its activities similar to spironolactone it may lead to less water retention and breast tenderness and improved skin appearance (less acne).
Drospirenone is taken orally with about 76% bioavailability. It is not bound by sex hormone binding globulin or corticosteroid binding globulin, but by other serum proteins. Metabolites have not been shown to be biologically active, show up in urine and feces, and are essentially completely excreted within 10 days.
The compound is part of certain newer oral contraceptive formulations:
- Yasmin® contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet. It is indicated for the prevention of pregnancy in women who elect an oral contraceptive.
- Yaz® contains 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is given for 24/4 days with the same indications.
It has also been formulated in medication to manage menopausal symptoms using 0.5 mg drsp and 1 mg estradiol per day by oral application. This medication was introduced in the USA in 2007 as Angeliq®.
Drospirenone, which can potentially cause hyperkalemia in high-risk patients, is comparable to a 25mg dose of spironolactone.
The medication is contraindicated in patients with hepatic dysfunction, renal insufficiency, adrenal insufficiency, or in whom the use of oral contraceptives is contraindicated, such as smokers and patients with a history of DVT, stroke, or other blood clots. Because of the anti-mineralocorticoid effects care needs to be exercised when other drugs that may increase potassium levels are taken. Such medications include ACE inhibitors, angiotensin-II receptor agonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs. | https://www.wikidoc.org/index.php/Drospirenone | |
eb09ee08bce8117141477eef0ca729828285a20c | wikidoc | Drug project | Drug project
# WikiDoc Drug Project — Mission Statement
- Thank you for your interest in the WikiDoc Drug Project!
- WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature.
- The content provided herein is not intended to supplant but supplement clinical judgment.
- Please let us know if there is specific or more detailed information you would like to see included. We welcome your comments by email. | Drug project
# WikiDoc Drug Project — Mission Statement
- Thank you for your interest in the WikiDoc Drug Project!
- WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature.
- The content provided herein is not intended to supplant but supplement clinical judgment.
- Please let us know if there is specific or more detailed information you would like to see included. We welcome your comments by email. | https://www.wikidoc.org/index.php/Drug_Project | |
af8d20a81b05a9c8497cfc2a0cd72012f23d3c88 | wikidoc | Drug holiday | Drug holiday
A drug holiday (sometimes also called a drug vacation, medication vacation or structured treatment interruption) is when a medicated patient stops taking a drug for a period of time, from a few days to several months.
Planned drug holidays are used in several fields of medicine. They are perhaps best known in HIV therapy, after a study showed that stopping medication may stimulate the immune system to attack the virus.
# As a treatment for HIV
HIV selectively targets activated helper T-cells. Thus, over time, this means that HIV will tend to selectively destroy those helper T-cells most capable of fighting the HIV infection off, effectively desensitizing the immune system to the infection. The purpose of a structured treatment interruption in to create a short interval in which the virus becomes common enough to stimulate reproduction of T-cells capable of fighting the virus.
A 2006 HIV literature review noted that "two studies suggested that so-called drug holidays were of no benefit and might actually harm patients, while a third study suggested that the idea might still have value and should be revisited."
# Other uses
Another reason for drug holidays is to permit a drug to regain effectiveness after a period of continuous use, and to reduce the tolerance effect that may require increased dosages.
In addition to drug holidays that are intended for therapeutic effect, they are sometimes used to reduce drug side effects so that patients may enjoy a more normal life for a period of time such as a weekend or holiday, or engage in a particular activity. For example, it is common for patients using SSRI anti-depressant therapies to take a drug holiday to reduce or avoid side effects associated with sexual dysfunction. | Drug holiday
A drug holiday (sometimes also called a drug vacation, medication vacation or structured treatment interruption) is when a medicated patient stops taking a drug for a period of time, from a few days to several months.
Planned drug holidays are used in several fields of medicine. They are perhaps best known in HIV therapy, after a study showed that stopping medication may stimulate the immune system to attack the virus.
[1]
# As a treatment for HIV
HIV selectively targets activated helper T-cells. Thus, over time, this means that HIV will tend to selectively destroy those helper T-cells most capable of fighting the HIV infection off, effectively desensitizing the immune system to the infection. The purpose of a structured treatment interruption in to create a short interval in which the virus becomes common enough to stimulate reproduction of T-cells capable of fighting the virus.
A 2006 HIV literature review noted that "two studies suggested that so-called drug holidays were of no benefit and might actually harm patients, while a third study suggested that the idea might still have value and should be revisited."
[2]
# Other uses
Another reason for drug holidays is to permit a drug to regain effectiveness after a period of continuous use, and to reduce the tolerance effect that may require increased dosages.
In addition to drug holidays that are intended for therapeutic effect, they are sometimes used to reduce drug side effects so that patients may enjoy a more normal life for a period of time such as a weekend or holiday, or engage in a particular activity. For example, it is common for patients using SSRI anti-depressant therapies to take a drug holiday to reduce or avoid side effects associated with sexual dysfunction.
[3] | https://www.wikidoc.org/index.php/Drug_holiday | |
28e12d34b87640c53bf9c0245c2fe4c109c5f681 | wikidoc | Intoxication | Intoxication
Intoxication is the state of being affected by one or more psychoactive drugs. It can also refer to the effects caused by the ingestion of poison or by the overconsumption of normally harmless substances.
Some types of intoxication:
- Drunkenness (alcohol intoxication)
- Caffeine intoxication
- Cannabis intoxication
- Heroin intoxication
- Water intoxication
Intoxication can cause a state of mind that remains once the person is no longer intoxicated that can be used as a legal defense:
- Settled insanity
Drug intoxication must be differentiated from other causes of headache,seizures and loss of consciousness.
bs:Intoksikacija
da:Rus
de:Rausch
ko:음주
it:Intossicazione
nl:High (toestand)
qu:Hampiwan musphay
simple:Intoxication
fi:Päihtymys
sv:Förgiftning
- ↑ Carbonnelle E (2009). "". Med Mal Infect. 39 (7–8): 581–605. doi:10.1016/j.medmal.2009.02.017. PMID 19398286..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Morgenstern LB, Frankowski RF (1999). "Brain tumor masquerading as stroke". J Neurooncol. 44 (1): 47–52. PMID 10582668.
- ↑ Weston CL, Glantz MJ, Connor JR (2011). "Detection of cancer cells in the cerebrospinal fluid: current methods and future directions". Fluids Barriers CNS. 8 (1): 14. doi:10.1186/2045-8118-8-14. PMC 3059292. PMID 21371327.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 4.0 4.1 Birenbaum D, Bancroft LW, Felsberg GJ (2011). "Imaging in acute stroke". West J Emerg Med. 12 (1): 67–76. PMC 3088377. PMID 21694755.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 5.0 5.1 DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF; et al. (2011). "ACR Appropriateness Criteria® on cerebrovascular disease". J Am Coll Radiol. 8 (8): 532–8. doi:10.1016/j.jacr.2011.05.010. PMID 21807345.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Lee MC, Heaney LM, Jacobson RL, Klassen AC (1975). "Cerebrospinal fluid in cerebral hemorrhage and infarction". Stroke. 6 (6): 638–41. PMID 1198628.CS1 maint: Multiple names: authors list (link)
- ↑ Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–9. doi:10.1016/j.jns.2012.03.003. PMID 22482824.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430.
- ↑ Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. doi:10.1097/OLQ.0b013e31824ee574. PMC 3746559. PMID 22421697.
- ↑ Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH; et al. (1994). "Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group". Arch Neurol. 51 (1): 61–6. PMID 8274111.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Manford M (2001). "Assessment and investigation of possible epileptic seizures". J Neurol Neurosurg Psychiatry. 70 Suppl 2: II3–8. PMC 1765557. PMID 11385043. | Intoxication
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Intoxication is the state of being affected by one or more psychoactive drugs. It can also refer to the effects caused by the ingestion of poison or by the overconsumption of normally harmless substances.
Some types of intoxication:
- Drunkenness (alcohol intoxication)
- Caffeine intoxication
- Cannabis intoxication
- Heroin intoxication
- Water intoxication
Intoxication can cause a state of mind that remains once the person is no longer intoxicated that can be used as a legal defense:
- Settled insanity
Drug intoxication must be differentiated from other causes of headache,seizures and loss of consciousness.
bs:Intoksikacija
da:Rus
de:Rausch
ko:음주
it:Intossicazione
nl:High (toestand)
qu:Hampiwan musphay
simple:Intoxication
fi:Päihtymys
sv:Förgiftning
Template:WikiDoc Sources
- ↑ Carbonnelle E (2009). "[Laboratory diagnosis of bacterial meningitis: usefulness of various tests for the determination of the etiological agent]". Med Mal Infect. 39 (7–8): 581–605. doi:10.1016/j.medmal.2009.02.017. PMID 19398286..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Morgenstern LB, Frankowski RF (1999). "Brain tumor masquerading as stroke". J Neurooncol. 44 (1): 47–52. PMID 10582668.
- ↑ Weston CL, Glantz MJ, Connor JR (2011). "Detection of cancer cells in the cerebrospinal fluid: current methods and future directions". Fluids Barriers CNS. 8 (1): 14. doi:10.1186/2045-8118-8-14. PMC 3059292. PMID 21371327.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 4.0 4.1 Birenbaum D, Bancroft LW, Felsberg GJ (2011). "Imaging in acute stroke". West J Emerg Med. 12 (1): 67–76. PMC 3088377. PMID 21694755.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 5.0 5.1 DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF; et al. (2011). "ACR Appropriateness Criteria® on cerebrovascular disease". J Am Coll Radiol. 8 (8): 532–8. doi:10.1016/j.jacr.2011.05.010. PMID 21807345.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Lee MC, Heaney LM, Jacobson RL, Klassen AC (1975). "Cerebrospinal fluid in cerebral hemorrhage and infarction". Stroke. 6 (6): 638–41. PMID 1198628.CS1 maint: Multiple names: authors list (link)
- ↑ Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–9. doi:10.1016/j.jns.2012.03.003. PMID 22482824.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430.
- ↑ Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. doi:10.1097/OLQ.0b013e31824ee574. PMC 3746559. PMID 22421697.
- ↑ Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH; et al. (1994). "Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group". Arch Neurol. 51 (1): 61–6. PMID 8274111.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Manford M (2001). "Assessment and investigation of possible epileptic seizures". J Neurol Neurosurg Psychiatry. 70 Suppl 2: II3–8. PMC 1765557. PMID 11385043. | https://www.wikidoc.org/index.php/Drug_intoxication | |
cdba25e190f6b08877771702e61e58e78e59b8d9 | wikidoc | Dry needling | Dry needling
Dry needling is a term for acupuncture when the acupuncture is performed by practitioners and therapists who have limited or little formal training in acupuncture. The term "dry needling" is purported to describe the technique of using acupuncture needles on trigger points to release tight muscles. This is part of traditional acupuncture therapy, and always has been.
Practitioners and therapists who attempt to draw a distinction between acupuncture and "dry needling" are demonstrating their lack of knowledge of the full range of acupuncture techniques, which has always included the use of "ashi points", or trigger points in the release of tight or knotted muscles.
The confusion perhaps arises when the distinction is made between "injection therapy", where substances are injected into acupuncture points, and "dry needling". Dry needling means using acupuncture needles and not a syringe. So, the distinction is between "injection therapy", which is not strictly speaking "acupuncture", and acupuncture. | Dry needling
Dry needling is a term for acupuncture when the acupuncture is performed by practitioners and therapists who have limited or little formal training in acupuncture. The term "dry needling" is purported to describe the technique of using acupuncture needles on trigger points to release tight muscles. This is part of traditional acupuncture therapy, and always has been.
Practitioners and therapists who attempt to draw a distinction between acupuncture and "dry needling" are demonstrating their lack of knowledge of the full range of acupuncture techniques, which has always included the use of "ashi points", or trigger points in the release of tight or knotted muscles.
The confusion perhaps arises when the distinction is made between "injection therapy", where substances are injected into acupuncture points, and "dry needling". Dry needling means using acupuncture needles and not a syringe. So, the distinction is between "injection therapy", which is not strictly speaking "acupuncture", and acupuncture. | https://www.wikidoc.org/index.php/Dry_needling | |
51cb9aec69b155300324555bdeaec4ba312db818 | wikidoc | Vas deferens | Vas deferens
# Overview
The vas deferens (plural: vasa deferentia), also called ductus deferens, (Latin: "carrying-away vessel") is part of the male anatomy of some species, including humans.
# Structure
There are two such ducts; they are muscular tubes (surrounded by smooth muscle) connecting the left and right epididymis to the ejaculatory ducts in order to move sperm. Each tube is about 30 centimeters long (in humans).
They are part of the spermatic cords.
# Function in ejaculation
During ejaculation the smooth muscle in the walls of the ductus deferens or vas deferens contracts reflexively, thus propelling the sperm forward. This is also known as peristalsis. The sperm is transferred from the vas deferens into the urethra, collecting secretions from the male accessory sex glands such as the seminal vesicles, prostate gland and the bulbourethral glands, which form the bulk of semen.
# Significance in contraception
The procedure of deferentectomy, popularly known as a vasectomy, is a method of contraception in which the vasa deferentia (Latin plural) are permanently cut, though in some cases it can be reversed. A modern variation, which is also popularly known as a vasectomy even though it does not include cutting the vas, involves injecting an obstructive material into the ductus to block the flow of sperm.
Investigational attempts for male contraception have focused on the vas with the use of the intra vas device and reversible inhibition of sperm under guidance (RISUG).
# Blood supply
The vas deferens is supplied by an accompanying artery (artery of vas deferens). This artery normally arises from the superior vesical artery, itself a branch of the internal iliac artery.
# Additional images
- Male reproductive system.
- Coronal section of pelvis, showing arrangement of fasciæ. Viewed from behind.
- The relations of the femoral and abdominal inguinal rings, seen from within the abdomen. Right side.
- The spermatic cord in the inguinal canal.
- Fundus of the bladder with the vesiculæ seminales.
- Vertical section of bladder, penis, and urethra.
- Prostate with seminal vesicles and seminal ducts, viewed from in front and above.
- Prostate
- Microscopic cross section. | Vas deferens
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The vas deferens (plural: vasa deferentia), also called ductus deferens, (Latin: "carrying-away vessel") is part of the male anatomy of some species, including humans.
# Structure
There are two such ducts; they are muscular tubes (surrounded by smooth muscle) connecting the left and right epididymis to the ejaculatory ducts in order to move sperm. Each tube is about 30 centimeters long (in humans).
They are part of the spermatic cords.
# Function in ejaculation
During ejaculation the smooth muscle in the walls of the ductus deferens or vas deferens contracts reflexively, thus propelling the sperm forward. This is also known as peristalsis. The sperm is transferred from the vas deferens into the urethra, collecting secretions from the male accessory sex glands such as the seminal vesicles, prostate gland and the bulbourethral glands, which form the bulk of semen.
# Significance in contraception
The procedure of deferentectomy, popularly known as a vasectomy, is a method of contraception in which the vasa deferentia (Latin plural) are permanently cut, though in some cases it can be reversed. A modern variation, which is also popularly known as a vasectomy even though it does not include cutting the vas, involves injecting an obstructive material into the ductus to block the flow of sperm.
Investigational attempts for male contraception have focused on the vas with the use of the intra vas device and reversible inhibition of sperm under guidance (RISUG).
# Blood supply
The vas deferens is supplied by an accompanying artery (artery of vas deferens). This artery normally arises from the superior vesical artery, itself a branch of the internal iliac artery.
# Additional images
- Male reproductive system.
- Coronal section of pelvis, showing arrangement of fasciæ. Viewed from behind.
- The relations of the femoral and abdominal inguinal rings, seen from within the abdomen. Right side.
- The spermatic cord in the inguinal canal.
- Fundus of the bladder with the vesiculæ seminales.
- Vertical section of bladder, penis, and urethra.
- Prostate with seminal vesicles and seminal ducts, viewed from in front and above.
- Prostate
- Microscopic cross section. | https://www.wikidoc.org/index.php/Ductus_deferens |
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