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864778ce1262c8b0df683218f68d27d111f0e298 | wikidoc | Life history | Life history
The term life history has been given many meanings in several scientific fields. It can refer to a variety of methods and techniques that are used for conducting qualitative interviews, especially in the fields of sociology and anthropology.
# Biology
In biology the life history of an organism refers to the reproductive cycle of animals and plants. Some use the term "alternation of generations" when referring to algae, however as there are in many cases, especially the Rhodophyta, three stages the term "alternation" is not appropriate.
# Medicine
In medicine, a life history may refer to a general health assessment or standard medical history. In seeking to identify certain health patterns, the interviewer may conduct a thorough interview. This form of interview can be utilized to find various kinds of sources for effects on the body and general health.
# Psychology
Life history theory is an analytic method of sociobiology for understanding reproductive behaviors in animals and people.
# Ethnography
In sociological and anthropological research, a life history refers to the overall picture of the informant's or interviewee's life. The purpose of the interview is to be able to describe what it is like to be this particular person, that is, the one being interviewed.
## Background
The method was first used when interviewing indigenous peoples of the Americas. The subjects were native American leaders. One interviewed them, and the subjects were asked to describe their lives as such, what it was like to be that particular person. The purpose of the interview was to capture a living picture of a disappearing (as such) people/way of life.
Later the method was used to interview criminals and prostitutes in Chicago. The subjects were asked to tell about their lives. The interviewers also looked at social- and police-records, and the society in general in which the subject lived. The result was a report in which one could read about (i) Chicago at that particular time; (ii) how the subject viewed his own life (i.e. `how it was like to be this particular person') and (iii) how society looked upon the subject what the consequence of this was for that particular person -- i.e. `social work'/-help, incarceration etc.
## Technique
In both cases, the one doing the interview should be careful not to ask "yes or no"-questions, but to get the subject to tell "the story of his or her life", in his or her own words. It is common practice to begin the interview with the subject's early childhood and to proceed chronologically to the present.
# Bibliography
- Molles, Manuel C., Jr. (1999). Ecology: Concepts and Applications (International Edition ed.). Dubuque: The McGraw-Hill Companies, Inc. pp. 510pp. doi:QH541.M65 Check |doi= value (help). ISBN 0-07-042716-X.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}
- Smith, Robert Leo (2002). Elements of Ecology (Fourth Edition ed.). Singapore: Addison-Wesley Publishing Company, Inc. pp. 567pp. ISBN 981-4119-31-8. Unknown parameter |coauthors= ignored (help)CS1 maint: Extra text (link) | Life history
The term life history has been given many meanings in several scientific fields. It can refer to a variety of methods and techniques that are used for conducting qualitative interviews, especially in the fields of sociology and anthropology.
# Biology
In biology the life history of an organism refers to the reproductive cycle of animals and plants.[1] Some use the term "alternation of generations" when referring to algae, however as there are in many cases, especially the Rhodophyta, three stages the term "alternation" is not appropriate.
# Medicine
In medicine, a life history may refer to a general health assessment or standard medical history. In seeking to identify certain health patterns, the interviewer may conduct a thorough interview. This form of interview can be utilized to find various kinds of sources for effects on the body and general health.
# Psychology
Life history theory is an analytic method of sociobiology for understanding reproductive behaviors in animals and people.
# Ethnography
In sociological and anthropological research, a life history refers to the overall picture of the informant's or interviewee's life. The purpose of the interview is to be able to describe what it is like to be this particular person, that is, the one being interviewed.
## Background
The method was first used when interviewing indigenous peoples of the Americas. The subjects were native American leaders. One interviewed them, and the subjects were asked to describe their lives as such, what it was like to be that particular person. The purpose of the interview was to capture a living picture of a disappearing (as such) people/way of life.
Later the method was used to interview criminals and prostitutes in Chicago. The subjects were asked to tell about their lives. The interviewers also looked at social- and police-records, and the society in general in which the subject lived. The result was a report in which one could read about (i) Chicago at that particular time; (ii) how the subject viewed his own life (i.e. `how it was like to be this particular person') and (iii) how society looked upon the subject what the consequence of this was for that particular person -- i.e. `social work'/-help, incarceration etc.
## Technique
In both cases, the one doing the interview should be careful not to ask "yes or no"-questions, but to get the subject to tell "the story of his or her life", in his or her own words. It is common practice to begin the interview with the subject's early childhood and to proceed chronologically to the present.
# Bibliography
- Molles, Manuel C., Jr. (1999). Ecology: Concepts and Applications (International Edition ed.). Dubuque: The McGraw-Hill Companies, Inc. pp. 510pp. doi:QH541.M65 Check |doi= value (help). ISBN 0-07-042716-X.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}
- Smith, Robert Leo (2002). Elements of Ecology (Fourth Edition ed.). Singapore: Addison-Wesley Publishing Company, Inc. pp. 567pp. ISBN 981-4119-31-8. Unknown parameter |coauthors= ignored (help)CS1 maint: Extra text (link) | https://www.wikidoc.org/index.php/Life_history | |
9f4e0ef7851cd4985756188b57cde1a483c38815 | wikidoc | Likert scale | Likert scale
A Likert scale (pronounced 'lick-urt') is a type of psychometric response scale often used in questionnaires, and is the most widely used scale in survey research. When responding to a Likert questionnaire item, respondents specify their level of agreement to a statement. The scale is named after Rensis Likert, who published a report describing its use (Likert, 1932).
# Sample Question presented using a five-point Likert Scale
A typical test item in a Likert scale is a statement. The respondent is asked to indicate his or her degree of agreement with the statement or any kind of subjective or objective evaluation of the statement. Traditionally a five-point scale is used, however many psychometricians advocate using a seven or nine point scale.
Ice cream is good for breakfast
- Strongly disagree
- Disagree
- Neither agree nor disagree
- Agree
- Strongly agree
Likert scaling is a bipolar scaling method, measuring either positive or negative response to a statement. Sometimes a four-point scale is used; this is a forced choice method since the middle option of "Neither agree nor disagree" is not available. Likert scales may be subject to distortion from several causes. Respondents may avoid using extreme response categories (central tendency bias); agree with statements as presented (acquiescence bias); or try to portray themselves or their organization in a more favorable light (social desirability bias).
# Scoring and analysis
After the questionnaire is completed, each item may be analyzed separately or in some cases item responses may be summed to create a score for a group of items. Hence, Likert scales are often called summative scales.
Responses to a single Likert item are normally treated as ordinal data, because, especially when using only five levels, one cannot assume that respondents perceive the difference between adjacent levels as equidistant. When treated as ordinal data, Likert responses can be collated into bar charts, central tendency summarised by the median or the mode (but not the mean), dispersion summarised by the range across quartiles (but not the standard deviation), or analyzed using non-parametric tests, e.g. Chi-square test, Mann-Whitney test, Wilcoxon signed-rank test, or Kruskal-Wallis test.
Responses to several Likert questions may be summed, providing that all questions use the same Likert scale and that the scale is a defendable approximation to an interval scale, in which case they may be treated as interval data measuring a latent variable. If the summed responses fulfils these assumptions, parametric statistical tests such as the analysis of variance can be applied. These can be applied only when the components are more than 5.
Data from Likert scales are sometimes reduced to the nominal level by combining all agree and disagree responses into two categories of "accept" and "reject". The Chi-Square, Cochran Q, or McNemar-Test are common statistical procedures used after this transformation.
Consensus based assessment (CBA) can be used to create an objective standard for Likert scales in domains where no generally accepted standard or objective standard exists. Consensus based assessment (CBA) can be used to refine or even validate generally accepted standards.
# Level of measurement
The five response categories represent an Interval level of measurement.
# Rasch model
Likert scale data can, in principle, be used as a basis for obtaining interval level estimates on a continuum by applying the polytomous Rasch model, when data can be obtained that fit this model. In addition, the polytomous Rasch model permits testing of the hypothesis that the statements reflect increasing levels of an attitude or trait, as intended. For example, application of the model often indicates that the neutral category does not represent a level of attitude or trait between the disagree and agree categories.
# Pronunciation
If one were to rely on standard American English phonology to determine the pronunciation of the word 'Likert,' it would be pronounced 'like-urt,' with a long "i" sound. However, Rensis Likert, the developer of the scale pronounced his name 'lick-urt' with a short "i" sound (Babbie, 2005; Meyers, Guarino, & Gamst, 2005). It has been claimed that Likert's name "is among the most mispronounced in field" (Latham, 2006, p. 15). Because of this distinction, although many people use the long "i" variant, those who attempt to stay true to Dr. Likert's pronunciation use the short "i" pronunciation. | Likert scale
A Likert scale (pronounced 'lick-urt') is a type of psychometric response scale often used in questionnaires, and is the most widely used scale in survey research. When responding to a Likert questionnaire item, respondents specify their level of agreement to a statement. The scale is named after Rensis Likert, who published a report describing its use (Likert, 1932).
# Sample Question presented using a five-point Likert Scale
A typical test item in a Likert scale is a statement. The respondent is asked to indicate his or her degree of agreement with the statement or any kind of subjective or objective evaluation of the statement. Traditionally a five-point scale is used, however many psychometricians advocate using a seven or nine point scale.
Ice cream is good for breakfast
- Strongly disagree
- Disagree
- Neither agree nor disagree
- Agree
- Strongly agree
Likert scaling is a bipolar scaling method, measuring either positive or negative response to a statement. Sometimes a four-point scale is used; this is a forced choice method since the middle option of "Neither agree nor disagree" is not available. Likert scales may be subject to distortion from several causes. Respondents may avoid using extreme response categories (central tendency bias); agree with statements as presented (acquiescence bias); or try to portray themselves or their organization in a more favorable light (social desirability bias).
# Scoring and analysis
After the questionnaire is completed, each item may be analyzed separately or in some cases item responses may be summed to create a score for a group of items. Hence, Likert scales are often called summative scales.
Responses to a single Likert item are normally treated as ordinal data, because, especially when using only five levels, one cannot assume that respondents perceive the difference between adjacent levels as equidistant. When treated as ordinal data, Likert responses can be collated into bar charts, central tendency summarised by the median or the mode (but not the mean), dispersion summarised by the range across quartiles (but not the standard deviation), or analyzed using non-parametric tests, e.g. Chi-square test, Mann-Whitney test, Wilcoxon signed-rank test, or Kruskal-Wallis test.[1]
Responses to several Likert questions may be summed, providing that all questions use the same Likert scale and that the scale is a defendable approximation to an interval scale, in which case they may be treated as interval data measuring a latent variable. If the summed responses fulfils these assumptions, parametric statistical tests such as the analysis of variance can be applied. These can be applied only when the components are more than 5.
Data from Likert scales are sometimes reduced to the nominal level by combining all agree and disagree responses into two categories of "accept" and "reject". The Chi-Square, Cochran Q, or McNemar-Test are common statistical procedures used after this transformation.
Consensus based assessment (CBA) can be used to create an objective standard for Likert scales in domains where no generally accepted standard or objective standard exists. Consensus based assessment (CBA) can be used to refine or even validate generally accepted standards.
# Level of measurement
The five response categories represent an Interval level of measurement.
# Rasch model
Likert scale data can, in principle, be used as a basis for obtaining interval level estimates on a continuum by applying the polytomous Rasch model, when data can be obtained that fit this model. In addition, the polytomous Rasch model permits testing of the hypothesis that the statements reflect increasing levels of an attitude or trait, as intended. For example, application of the model often indicates that the neutral category does not represent a level of attitude or trait between the disagree and agree categories.
# Pronunciation
If one were to rely on standard American English phonology to determine the pronunciation of the word 'Likert,' it would be pronounced 'like-urt,' with a long "i" sound. However, Rensis Likert, the developer of the scale pronounced his name 'lick-urt' with a short "i" sound (Babbie, 2005; Meyers, Guarino, & Gamst, 2005). It has been claimed that Likert's name "is among the most mispronounced in [the] field" (Latham, 2006, p. 15). Because of this distinction, although many people use the long "i" variant, those who attempt to stay true to Dr. Likert's pronunciation use the short "i" pronunciation. | https://www.wikidoc.org/index.php/Likert_scale | |
55e95c69a886c386479c63c9912d8956765f6a46 | wikidoc | Lincosamides | Lincosamides
Lincosamides (eg. lincomycin, clindamycin) are a class of drugs which bind to the 23s portion of the 50S subunit of bacterial ribosomes and inhibit early elongation of peptide chain by inhibiting transpeptidase reaction. In this sense they have a similar action to macrolides.
# History and uses
The first lincosamide to be discovered was lincomycin, which is a true antibiotic (one occurring naturally rather than being synthetic), from "Streptomyces lincolnensis".
Lincomycin has been superseeded by clindamycin, which exhibits improved antibacterial activity. Clindamycin also exhibits some activity against parasitic protozoa, and has been used in toxoplasmosis and malaria.
They are normally used to treat staphylococci and streptococci, and have proved useful in treating Bacteroides fragili and some other anaerobes.
# Resistance
Target bacteria may alter the drug's binding site (similar to resistance found in macrolides and streptogramins). The resistance mechanism is methylation of the 23s binding site. If this occurs then the bacteria are resistant to both the macrolides and the lincosamides. Also, enzymatic inactivation of clindamycin has been described (rare).
# Formulation
The lincosamides, as the hydrochloride salt, are bitter to taste, so for oral formulation they are given as the palmitate esters, or formulated in capsules. Clindamycin is given intravenously as clindamycin phosphate, which is then converted into active clindamycin wihin the body.
# Pharmacodynamics
These are bacteriostatic drugs and antagonists of macrolides and streptogramins.
# Further reading
- Van Bambeke F. Mechanisms of action. In Armstrong D, Cohen J. Infectious diseases. Mosby, London, 1999, pp7/1.1-7/1.14
de:Lincosamid | Lincosamides
Lincosamides (eg. lincomycin, clindamycin) are a class of drugs which bind to the 23s portion of the 50S subunit of bacterial ribosomes and inhibit early elongation of peptide chain by inhibiting transpeptidase reaction. In this sense they have a similar action to macrolides.
# History and uses
The first lincosamide to be discovered was lincomycin, which is a true antibiotic (one occurring naturally rather than being synthetic), from "Streptomyces lincolnensis".
Lincomycin has been superseeded by clindamycin, which exhibits improved antibacterial activity. Clindamycin also exhibits some activity against parasitic protozoa, and has been used in toxoplasmosis and malaria.
They are normally used to treat staphylococci and streptococci, and have proved useful in treating Bacteroides fragili and some other anaerobes.
# Resistance
Target bacteria may alter the drug's binding site (similar to resistance found in macrolides and streptogramins). The resistance mechanism is methylation of the 23s binding site. If this occurs then the bacteria are resistant to both the macrolides and the lincosamides. Also, enzymatic inactivation of clindamycin has been described (rare).
# Formulation
The lincosamides, as the hydrochloride salt, are bitter to taste, so for oral formulation they are given as the palmitate esters, or formulated in capsules. Clindamycin is given intravenously as clindamycin phosphate, which is then converted into active clindamycin wihin the body.
# Pharmacodynamics
These are bacteriostatic drugs and antagonists of macrolides and streptogramins.
# Further reading
- Van Bambeke F. Mechanisms of action. In Armstrong D, Cohen J. Infectious diseases. Mosby, London, 1999, pp7/1.1-7/1.14
de:Lincosamid
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Lincosamides | |
7ac832312811ebacd4c25dfea9f0a703cd109e4b | wikidoc | Lipid rescue | Lipid rescue
Lipid Rescue is a term that has been coined to describe the use of intravenous lipid emulsion to treat severe local anaesthetic toxicity.
To date, Intralipid, a commonly available intravenous lipid emulsion is the only such emulsion to be shown to be effective in this way.
This is supported by animal evidence
and human case reports of successful use in this way. In the UK, efforts have been made to publicise this use more widely | Lipid rescue
Lipid Rescue is a term that has been coined to describe the use of intravenous lipid emulsion to treat severe local anaesthetic toxicity.
To date, Intralipid, a commonly available intravenous lipid emulsion is the only such emulsion to be shown to be effective in this way.
This is supported by animal evidence [1]
[2] and human case reports of successful use in this way.[3][4] In the UK, efforts have been made to publicise this use more widely[5] | https://www.wikidoc.org/index.php/Lipid_rescue | |
20215e8cc029b60de2e49c2b635acab5328d36c7 | wikidoc | Lipoxygenase | Lipoxygenase
Lipoxygenases (EC 1.13.11.-) are a family of iron-containing enzymes that catalyse the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene structure. It catalyses the following reaction:
Lipoxygenases are found in plants, animals and fungi. Products of lipoxygenases are involved in diverse cell functions.
# Biological function and classification
These enzymes are most common in plants where they may be involved in a number of diverse aspects of plant physiology including growth and development, pest resistance, and senescence or responses to wounding. In mammals a number of lipoxygenases isozymes are involved in the metabolism of prostaglandins and leukotrienes. Sequence data is available for the following lipoxygenases:
- Plant lipoxygenases (EC 1.13.11.12InterPro: IPR001246). Plants express a variety of cytosolic isozymes as well as what seems to be a chloroplast isozyme.
- Mammalian arachidonate 5-lipoxygenase (EC 1.13.11.34InterPro: IPR001885).
- Mammalian arachidonate 12-lipoxygenase (EC 1.13.11.31InterPro: IPR001885).
- Mammalian erythroid cell-specific 15-lipoxygenase (EC 1.13.11.33InterPro: IPR001885).
# 3D structure
The crystal structures of soybean and rabbit lipoxygenases are known. The protein consists of a small N-terminal PLAT domain and a major C-terminal catalytic domain (see Pfam link in this article), which contains the active site. In both plant and mammalian enzymes, the N-terminal domain contains an eight-stranded antiparallel β-barrel, but in the soybean lipoxygenases this domain is significantly larger than in the rabbit enzyme. The plant lipoxygenases can be enzymatically cleaved into two fragments which stay tightly associated while the enzyme remains active; separation of the two domains leads to loss of catalytic activity. The C-terminal (catalytic) domain consists of 18-22 helices and one (in rabbit enzyme) or two (in soybean enzymes) antiparallel β-sheets at the opposite end from the N-terminal β-barrel.
# Active site
The iron atom in lipoxygenases is bound by four ligands, three of which are histidine residues. Six histidines are conserved in all lipoxygenase sequences, five of them are found clustered in a stretch of 40 amino acids. This region contains two of the three zinc-ligands; the other histidines have been shown to be important for the activity of lipoxygenases.
The two long central helices cross at the active site; both helices include internal stretches of π-helix that provide three histidine (His) ligands to the active site iron. Two cavities in the major domain of soybean lipoxygenase-1 (cavities I and II) extend from the surface to the active site. The funnel-shaped cavity I may function as a dioxygen channel; the long narrow cavity II is presumably a substrate pocket. The more compact mammalian enzyme contains only one boot-shaped cavity (cavity II). In soybean lipoxygenase-3 there is a third cavity which runs from the iron site to the interface of the β-barrel and catalytic domains. Cavity III, the iron site and cavity II form a continuous passage throughout the protein molecule.
The active site iron is coordinated by Nε of three conserved His residues and one oxygen of the C-terminal carboxyl group. In addition, in soybean enzymes the side chain oxygen of asparagine is weakly associated with the iron. In rabbit lipoxygenase, this Asn residue is replaced with His which coordinates the iron via Nδ atom. Thus, the coordination number of iron is either five or six, with a hydroxyl or water ligand to a hexacoordinate iron.
# Biochemical classification
Soybean Lipoxygenase 1 exhibits the largest H/D kinetic isotope effect (KIE) on kcat (kH/kD) (81 near room temperature) so far reported for a biological system. | Lipoxygenase
Lipoxygenases (EC 1.13.11.-) are a family of iron-containing enzymes that catalyse the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene structure. It catalyses the following reaction:
Lipoxygenases are found in plants, animals and fungi. Products of lipoxygenases are involved in diverse cell functions.
# Biological function and classification
These enzymes are most common in plants where they may be involved in a number of diverse aspects of plant physiology including growth and development, pest resistance, and senescence or responses to wounding[1]. In mammals a number of lipoxygenases isozymes are involved in the metabolism of prostaglandins and leukotrienes[2]. Sequence data is available for the following lipoxygenases:
- Plant lipoxygenases (EC 1.13.11.12InterPro: IPR001246). Plants express a variety of cytosolic isozymes as well as what seems to be a chloroplast isozyme[3].
- Mammalian arachidonate 5-lipoxygenase (EC 1.13.11.34InterPro: IPR001885).
- Mammalian arachidonate 12-lipoxygenase (EC 1.13.11.31InterPro: IPR001885).
- Mammalian erythroid cell-specific 15-lipoxygenase (EC 1.13.11.33InterPro: IPR001885).
# 3D structure
The crystal structures of soybean and rabbit lipoxygenases are known. The protein consists of a small N-terminal PLAT domain and a major C-terminal catalytic domain (see Pfam link in this article), which contains the active site. In both plant and mammalian enzymes, the N-terminal domain contains an eight-stranded antiparallel β-barrel, but in the soybean lipoxygenases this domain is significantly larger than in the rabbit enzyme. The plant lipoxygenases can be enzymatically cleaved into two fragments which stay tightly associated while the enzyme remains active; separation of the two domains leads to loss of catalytic activity. The C-terminal (catalytic) domain consists of 18-22 helices and one (in rabbit enzyme) or two (in soybean enzymes) antiparallel β-sheets at the opposite end from the N-terminal β-barrel.
# Active site
The iron atom in lipoxygenases is bound by four ligands, three of which are histidine residues[4]. Six histidines are conserved in all lipoxygenase sequences, five of them are found clustered in a stretch of 40 amino acids. This region contains two of the three zinc-ligands; the other histidines have been shown[5] to be important for the activity of lipoxygenases.
The two long central helices cross at the active site; both helices include internal stretches of π-helix that provide three histidine (His) ligands to the active site iron. Two cavities in the major domain of soybean lipoxygenase-1 (cavities I and II) extend from the surface to the active site. The funnel-shaped cavity I may function as a dioxygen channel; the long narrow cavity II is presumably a substrate pocket. The more compact mammalian enzyme contains only one boot-shaped cavity (cavity II). In soybean lipoxygenase-3 there is a third cavity which runs from the iron site to the interface of the β-barrel and catalytic domains. Cavity III, the iron site and cavity II form a continuous passage throughout the protein molecule.
The active site iron is coordinated by Nε of three conserved His residues and one oxygen of the C-terminal carboxyl group. In addition, in soybean enzymes the side chain oxygen of asparagine is weakly associated with the iron. In rabbit lipoxygenase, this Asn residue is replaced with His which coordinates the iron via Nδ atom. Thus, the coordination number of iron is either five or six, with a hydroxyl or water ligand to a hexacoordinate iron.
# Biochemical classification
Soybean Lipoxygenase 1 exhibits the largest H/D kinetic isotope effect (KIE) on kcat (kH/kD) (81 near room temperature) so far reported for a biological system. | https://www.wikidoc.org/index.php/Lipooxygenase | |
690366090621b3d7ad9f6fb7d28b00f01e2149ca | wikidoc | Lixisenatide | Lixisenatide
# Overview
Lixisenatide (intended trade name Lyxumia) is a once-daily injectable GLP-1 receptor agonist discovered by Zealand Pharma A/S of Denmark and licensed and developed by Sanofi. As of September 2010 it is in clinical trials for diabetes. Lixisenatide was accepted for review by the US FDA on February 19, 2013, and approved by the European Commission on February 1, 2013. On September 12, 2013, Sanofi delayed the approval process in the US, citing internal data from a cardiovascular risk study. The drug will likely be resubmitted for approval in 2015.
GLP-1 is a naturally-occurring peptide that is released within minutes of eating a meal. It is known to suppress glucagon secretion from pancreatic alpha cells and stimulate insulin secretion by pancreatic beta cells. GLP-1 receptor agonists are in development as an add-on treatment for type 2 diabetes and their use is endorsed by the European Association for the Study of Diabetes, the American Diabetes Association, the American Association of Clinical Endocrinologists and the American College of Endocrinology.
The GetGoal phase III clinical program will provide data for lixisenatide in adults with type 2 diabetes treated with various oral anti-diabetic agents or insulin. With ten trials in the program, GetGoal started in May 2008 and has enrolled more than 4,300 patients. To date, GetGoal-X, GetGoal-L, GetGoal-L Asia, GetGoal-Mono, GetGoal-S and GetGoal-F1 have reported positive top-line results supporting efficacy and safety for lixisenatide.
# Chemistry
Lixisenatixe has been described as "des-38-proline-exendin-4 (Heloderma suspectum)-(1–39)-peptidylpenta-L-lysyl-L-lysinamide", meaning it is derived from the first 39 amino acids in the sequence of the peptide exendin-4, found in the Gila monster (Heloderma suspectum), omitting proline at position 38 and adding six lysine residues. Its complete sequence is: | Lixisenatide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lixisenatide (intended trade name Lyxumia) is a once-daily injectable GLP-1 receptor agonist discovered by Zealand Pharma A/S of Denmark and licensed and developed by Sanofi.[1] As of September 2010[update] it is in clinical trials for diabetes.[2] Lixisenatide was accepted for review by the US FDA on February 19, 2013, and approved by the European Commission on February 1, 2013.[3] On September 12, 2013, Sanofi delayed the approval process in the US, citing internal data from a cardiovascular risk study. The drug will likely be resubmitted for approval in 2015.
GLP-1 is a naturally-occurring peptide that is released within minutes of eating a meal. It is known to suppress glucagon secretion from pancreatic alpha cells and stimulate insulin secretion by pancreatic beta cells. GLP-1 receptor agonists are in development as an add-on treatment for type 2 diabetes and their use is endorsed by the European Association for the Study of Diabetes, the American Diabetes Association, the American Association of Clinical Endocrinologists and the American College of Endocrinology.
The GetGoal phase III clinical program will provide data for lixisenatide in adults with type 2 diabetes treated with various oral anti-diabetic agents or insulin. With ten trials in the program, GetGoal started in May 2008 and has enrolled more than 4,300 patients. To date, GetGoal-X, GetGoal-L, GetGoal-L Asia, GetGoal-Mono, GetGoal-S and GetGoal-F1 have reported positive top-line results supporting efficacy and safety for lixisenatide.
# Chemistry
Lixisenatixe has been described as "des-38-proline-exendin-4 (Heloderma suspectum)-(1–39)-peptidylpenta-L-lysyl-L-lysinamide", meaning it is derived from the first 39 amino acids in the sequence of the peptide exendin-4, found in the Gila monster (Heloderma suspectum), omitting proline at position 38 and adding six lysine residues. Its complete sequence is:[4] | https://www.wikidoc.org/index.php/Lixisenatide | |
94c6353bd353a7c7b20bb4e2f377ce992c9274ea | wikidoc | Lopressor IV | Lopressor IV
For information about metoprolol, click here.
# Disclaimer
# Overview
Lopressor IV is a Beta-adrenergic agonist drug that is FDA approved for the treatment of Hypertension, AMI, Angina. Adverse reactions include Here are some adverse reactions.
# Adult Indications and Dosage
# Pediatric Indications and Dosage
# Contraindications
# Warnings
# Adverse Reactions
# Drug Interactions
# Use in Specific Populations
# Routes and Preparations
# IV Compatibility
# Overdosage
# Pharmacology
# Clinical Studies
# How Supplied
# Images
# Patient Information
## Patient Information from FDA
## Patient Information from NLM
# Look-Alike Drug Names
# Price
# Drug Shortage
# Black Box Warning
Below is the code to be placed on the Black Box Warning Microchapter:
__NOTOC__
# Adult Indications and Dosage
Below is the code to be placed on the Adult Indications and Dosage Microchapeter:
__NOTOC__
===FDA-Labeled Indications and Dosage (Adult)===
Adults can use it for this
===Off-Label Use and Dosage (Adult)===
XXX
# Pediatric Indications and Dosage
Below is the code to be placed on the Adult Indications and Dosage Microchapeter:
__NOTOC__
===FDA-Labeled Indications and Dosage (Pediatric)===
Kids use it for this
===Off-Label Use and Dosage (Pediatric)===
# Contraindications
Below is the code to be placed in the Contraindication Microchapter:
__NOTOC__
===Contraindications===
Don't use it when
# Warnings
Below is the code to be placed on the Warnings and Precautions Microchapter:
__NOTOC__
===Warnings===
WARNING
# Adverse Reactions
Below is the code to be placed on the Adverse Reaction Microchapter:
__NOTOC__
===Clinical Trials Experience===
We found in a phase 2 study
===Postmarketing Experience===
That a phase 4 study showed this
# Drug Interactions
Below is the code to be placed on the Drug Interaction Microchapter:
__NOTOC__
===Drug Interactions===
the drug has the following known interactions
# Use in Specific Populations
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__NOTOC__
===Pregnancy===
There is no FDA guidance on usage of {{BASEPAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{BASEPAGENAME}} in women who are pregnant.
===Labor and Delivery===
Or in labor or Delivery
===Nursing Mothers===
There is no FDA guidance on the use of {{BASEPAGENAME}} in women who are nursing.
===Pediatric Use===
Or a child
===Geriatic Use===
There is no FDA guidance on the use of {{BASEPAGENAME}} in geriatric settings.
===Gender===
Or a male
===Race===
There is no FDA guidance on the use of {BASEPAGENAME}} with respect to specific racial populations.
===Renal Impairment===
-r have bad kidneys
===Hepatic Impairment===
-r have been drinking too much
===Females of Reproductive Potential and Males===
There is no FDA guidance on the use of {{BASEPAGENAME}} in women of reproductive potentials and males.
===Immunocompromised Patients===
-r are very very sick
# Routes and Preparations
Below is the code to be placed on the Routes and Preparations Microchapter:
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===Routes===
You can take this drug
===Preparations===
this way
# IV compatibility
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__NOTOC__
===IV compatibility===
Don't mix the IV
# Overdose
Below is the code to be placed on the Overdose Microchapter:
__NOTOC__
'''Please contact the National Poison Help hotline (1-800-222-1222) immediately if there is suspicion of drug poisoning or overdose.'''
===Overdose===
# Pharmacology
Below is the code to be placed on the Pharmacology Microchapter:
__NOTOC__
===Mechanism of Action===
It works like this
===Structure===
It has this shape
===Pharmacodynamics===
And does this
===Pharmacokinetics===
This quickly
===Nonclinical Toxicology===
And is kind of toxic
# Clinical Studies
Below is the code to be placed on the Clinical Studies Microchapter:
__NOTOC__
===Clinical Studies===
We studied it again here
# How Supplied
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===How Supplied===
The package looks like
# Images
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===Drug Images===
This is a placeholder
===Package and Label Display Panel===
This is a placeholder
# Patient Information
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==Patient Information==
===Patient Information from the FDA===
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===Patient Information from the National Library of Medicine===
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# Price
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# Drug Shortage
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===Drug Shortage===
This is a placeholder | Lopressor IV
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2]
For information about metoprolol, click here.
# Disclaimer
# Overview
Lopressor IV is a Beta-adrenergic agonist drug that is FDA approved for the treatment of Hypertension, AMI, Angina. Adverse reactions include Here are some adverse reactions.
# Adult Indications and Dosage
# Pediatric Indications and Dosage
# Contraindications
# Warnings
# Adverse Reactions
# Drug Interactions
# Use in Specific Populations
# Routes and Preparations
# IV Compatibility
# Overdosage
# Pharmacology
# Clinical Studies
# How Supplied
# Images
# Patient Information
## Patient Information from FDA
## Patient Information from NLM
# Look-Alike Drug Names
# Price
# Drug Shortage
# Black Box Warning
Below is the code to be placed on the Black Box Warning Microchapter:
__NOTOC__
# Adult Indications and Dosage
Below is the code to be placed on the Adult Indications and Dosage Microchapeter:
__NOTOC__
===FDA-Labeled Indications and Dosage (Adult)===
Adults can use it for this
===Off-Label Use and Dosage (Adult)===
XXX
# Pediatric Indications and Dosage
Below is the code to be placed on the Adult Indications and Dosage Microchapeter:
__NOTOC__
===FDA-Labeled Indications and Dosage (Pediatric)===
Kids use it for this
===Off-Label Use and Dosage (Pediatric)===
# Contraindications
Below is the code to be placed in the Contraindication Microchapter:
__NOTOC__
===Contraindications===
Don't use it when
# Warnings
Below is the code to be placed on the Warnings and Precautions Microchapter:
__NOTOC__
===Warnings===
WARNING
# Adverse Reactions
Below is the code to be placed on the Adverse Reaction Microchapter:
__NOTOC__
===Clinical Trials Experience===
We found in a phase 2 study
===Postmarketing Experience===
That a phase 4 study showed this
# Drug Interactions
Below is the code to be placed on the Drug Interaction Microchapter:
__NOTOC__
===Drug Interactions===
the drug has the following known interactions
# Use in Specific Populations
Below is the code to be placed on the Drug Interaction Microchapter:
__NOTOC__
===Pregnancy===
: '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]'''
There is no FDA guidance on usage of {{BASEPAGENAME}} in women who are pregnant.
:'''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{BASEPAGENAME}} in women who are pregnant.
===Labor and Delivery===
Or in labor or Delivery
===Nursing Mothers===
There is no FDA guidance on the use of {{BASEPAGENAME}} in women who are nursing.
===Pediatric Use===
Or a child
===Geriatic Use===
There is no FDA guidance on the use of {{BASEPAGENAME}} in geriatric settings.
===Gender===
Or a male
===Race===
There is no FDA guidance on the use of {BASEPAGENAME}} with respect to specific racial populations.
===Renal Impairment===
or have bad kidneys
===Hepatic Impairment===
or have been drinking too much
===Females of Reproductive Potential and Males===
There is no FDA guidance on the use of {{BASEPAGENAME}} in women of reproductive potentials and males.
===Immunocompromised Patients===
or are very very sick
# Routes and Preparations
Below is the code to be placed on the Routes and Preparations Microchapter:
__NOTOC__
===Routes===
You can take this drug
===Preparations===
this way
# IV compatibility
Below is the code to be placed on the IV compatibility Microchapter:
__NOTOC__
===IV compatibility===
Don't mix the IV
# Overdose
Below is the code to be placed on the Overdose Microchapter:
__NOTOC__
'''Please contact the National Poison Help hotline (1-800-222-1222) immediately if there is suspicion of drug poisoning or overdose.'''
===Overdose===
# Pharmacology
Below is the code to be placed on the Pharmacology Microchapter:
__NOTOC__
===Mechanism of Action===
It works like this
===Structure===
It has this shape
===Pharmacodynamics===
And does this
===Pharmacokinetics===
This quickly
===Nonclinical Toxicology===
And is kind of toxic
# Clinical Studies
Below is the code to be placed on the Clinical Studies Microchapter:
__NOTOC__
===Clinical Studies===
We studied it again here
# How Supplied
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===How Supplied===
The package looks like
# Images
Below is the code to be placed on the Image Microchapter:
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===Drug Images===
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===Package and Label Display Panel===
This is a placeholder
# Patient Information
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==Patient Information==
===Patient Information from the FDA===
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# Price
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# Drug Shortage
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This is a placeholder | https://www.wikidoc.org/index.php/Lopressor_IV | |
e7f8ae6e89c2059dbb0c63b52111f7a51e0cf60c | wikidoc | Lormetazepam | Lormetazepam
# Overview
Lormetazepam is available as a generic or available under the following trade or brand names (Noctamid, Ergocalm, Loramet, Dilamet, Sedaben, Stilaze, Nocton, Pronoctan, Noctamide, Loretam, Minias, Aldosomnil) and is also sometimes known as methyllorazepam, is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.
Lormetazepam is not approved for sale in the United States or Canada, though it is licensed it the UK as 0.5 and 1 mg tablets for short term treatment (2-4 weeks) of severe or disabling insomnia. It is the most expensive hypnotic benzodiazepine on the UK market - costing upwards of £15 (trade price) for a 28 day supply of the 1mg variant. Recently however, prices have stabilised towards the £3 region. It's bioavailability was found to be 80%.
# Mechanism of Action
Lormetazepam and other benzodiazepine drugs act as positive modulators at the GABAa-benzodiazepine receptor complex. Lormetazepam binds to the benzodiazepine receptor which in turn enhances the effect of the GABAa receptor producing its therapeutic effects as well as adverse effects. When lormetazepam binds to the benzodiazepine receptor sites in sufficient quantities it produces sedation which is used clinically as a therapeutic treatment for insomnia. Lormetazepam alters the brain electrical activity which has been studied via EEG readings. Changes in EEG can therefore be used to measure the sedative sleep promoting properties of lormetazepam.
# Indications
Insomnia. Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Lormetazepam is an intermediate acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or falling asleep. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.
# Side Effects
Side effects of lormetazepam are similar to other hypnotic benzodiazepines and can for the most part be regarded as a class effect. Some side effects can be enhanced when lormetazepam is combined with other drugs with similar effects eg alcohol and nonbenzodiazepine drugs, with subsequent increased drowsiness, amnesia or respiratory depression. Lormetazepam has been associated with adversely affecting immediate and delayed recall memory functions.
Side Effects List
- Somnolence
- paradoxical increase in aggression
- lightheadedness
- confusion
- muscle weakness
- ataxia (particularly in the elderly)
- anterograde amnesia
- headache
- vertigo
- hypotension
- salivation changes
- gastro-intestinal disturbances
- visual disturbances
- dysarthria
- tremor
- changes in libido
- incontinence
- urinary retention
- blood disorders and jaundice
- skin reactions
- dependence and withdrawal reactions
Residual 'hangover' effects after nighttime administration of lormetazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.
# Tolerance, Dependence and Withdrawal
It should be noted that the risks of tolerance, dependence and withdrawal are very low when the drug is used for 2 - 4 weeks only and that lormetazepam is generally a safe and effective drug when used for no longer than 2-4 weeks. Some sleep disturbance in the form of rebound insomnia can however occur even after short term usage of 7 days.Those with a history of addiction may be at increased risk of problems of tolerance and dependence especially those with a past history of dependency on sedative hypnotic drugs.
Tolerance
Lormetazepam as with other benzodiazepines is generally only recommended for short term use (2-4 weeks) due to tolerance and loss of efficacy. Tolerance to the and loss of the sedative effects of benzodiazepine hypnotics occurs within 14 days of regular use.
Dependence
Dependence is the medical term for addiction. Dependence can either be psychological or physical.
Psychological dependence can manifest itself as a reliance on a drug to cope with every day life or in the form of craving.
Physical dependence occurs due to physiological adaptions occurring as the body attempts to overcome the drugs effects which is known as tolerance and the continuing need to take the drug to avoid or suppress withdrawal symptoms which can sometimes resemble the original condition being treated. When the dose or the drug is discontinued withdrawal symptoms typically occur. Lormetazepam as with all other benzodiazepines produces both physical and psychological dependence but the main problem of concern is physical dependence which appears in the form of the benzodiazepine withdrawal syndrome after the dosage is reduced or the drug is stopped completely. The dependence induced by lormetazepam is related to changes in the sensitivity of the GABA-BZD receptor complex.
Withdrawal Symptoms
Withdrawal Symptoms which can occur from stopping benzodiazepines such as lormetazepam can include:
- rebound insomnia and nightmares
- anxiety, panic attacks and agorophobia
- clinical depression
- malaise
- lack of concentration
- abdominal discomfort
- depersonalisation and feelings of unreality
- emotional liability
- cognitive impairment
- tinnitus
- paraesthesiae, tingling, numbness and pain
- muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, blepharospasm
- excitability, jumpiness and restlessness
- stiffness
- sweats
Abrupt or over rapid withdrawal from high doses can provoke:
- epileptic seizures
- hallucinations (visual, auditory)
- misperceptions
Withdrawal symptoms typically subside after 4 - 8 weeks but in approximately 10 - 15% of individuals symptoms can perist for many months and in rare cases years.
Some "Withdrawal Symptoms" can emerge despite a constant dosage with the body needing extra dosage in order to feel normal. This is sometimes associated with dosage escalation.
Lormetazepam has a short to intermediate half life of approximately 10-12 hours. Shorter acting benzodiazepine compounds are generally associated with a more intense and immediate withdrawal reaction compared to longer acting benzodiazepines. For this reason it is generally recommended to cross from lormetazepam to an equivalent dose of diazepam to gradually taper the dosage. | Lormetazepam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lormetazepam is available as a generic or available under the following trade or brand names (Noctamid, Ergocalm, Loramet, Dilamet, Sedaben, Stilaze, Nocton, Pronoctan, Noctamide, Loretam, Minias, Aldosomnil) and is also sometimes known as methyllorazepam, is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.
Lormetazepam is not approved for sale in the United States or Canada, though it is licensed it the UK as 0.5 and 1 mg tablets for short term treatment (2-4 weeks) of severe or disabling insomnia. It is the most expensive hypnotic benzodiazepine on the UK market - costing upwards of £15 (trade price) for a 28 day supply of the 1mg variant. Recently however, prices have stabilised towards the £3 region. It's bioavailability was found to be 80%.[1]
# Mechanism of Action
Lormetazepam and other benzodiazepine drugs act as positive modulators at the GABAa-benzodiazepine receptor complex. Lormetazepam binds to the benzodiazepine receptor which in turn enhances the effect of the GABAa receptor producing its therapeutic effects as well as adverse effects. When lormetazepam binds to the benzodiazepine receptor sites in sufficient quantities it produces sedation which is used clinically as a therapeutic treatment for insomnia. Lormetazepam alters the brain electrical activity which has been studied via EEG readings.[2] Changes in EEG can therefore be used to measure the sedative sleep promoting properties of lormetazepam.
# Indications
Insomnia. Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Lormetazepam is an intermediate acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or falling asleep. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.[3]
# Side Effects
Side effects of lormetazepam are similar to other hypnotic benzodiazepines and can for the most part be regarded as a class effect.[4] Some side effects can be enhanced when lormetazepam is combined with other drugs with similar effects eg alcohol and nonbenzodiazepine drugs, with subsequent increased drowsiness, amnesia or respiratory depression. Lormetazepam has been associated with adversely affecting immediate and delayed recall memory functions.[5]
Side Effects List
- Somnolence
- paradoxical increase in aggression
- lightheadedness
- confusion
- muscle weakness
- ataxia (particularly in the elderly)
- anterograde amnesia
- headache
- vertigo
- hypotension
- salivation changes
- gastro-intestinal disturbances
- visual disturbances
- dysarthria
- tremor
- changes in libido
- incontinence
- urinary retention
- blood disorders and jaundice
- skin reactions
- dependence and withdrawal reactions
Residual 'hangover' effects after nighttime administration of lormetazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.[6]
# Tolerance, Dependence and Withdrawal
It should be noted that the risks of tolerance, dependence and withdrawal are very low when the drug is used for 2 - 4 weeks only and that lormetazepam is generally a safe and effective drug when used for no longer than 2-4 weeks. Some sleep disturbance in the form of rebound insomnia can however occur even after short term usage of 7 days.[7]Those with a history of addiction may be at increased risk of problems of tolerance and dependence especially those with a past history of dependency on sedative hypnotic drugs.
Tolerance
Lormetazepam as with other benzodiazepines is generally only recommended for short term use (2-4 weeks) due to tolerance and loss of efficacy. Tolerance to the and loss of the sedative effects of benzodiazepine hypnotics occurs within 14 days of regular use.[8]
Dependence
Dependence is the medical term for addiction. Dependence can either be psychological or physical.
Psychological dependence can manifest itself as a reliance on a drug to cope with every day life or in the form of craving.
Physical dependence occurs due to physiological adaptions occurring as the body attempts to overcome the drugs effects which is known as tolerance and the continuing need to take the drug to avoid or suppress withdrawal symptoms which can sometimes resemble the original condition being treated. When the dose or the drug is discontinued withdrawal symptoms typically occur. Lormetazepam as with all other benzodiazepines produces both physical and psychological dependence but the main problem of concern is physical dependence which appears in the form of the benzodiazepine withdrawal syndrome after the dosage is reduced or the drug is stopped completely. The dependence induced by lormetazepam is related to changes in the sensitivity of the GABA-BZD receptor complex.[9]
Withdrawal Symptoms
Withdrawal Symptoms which can occur from stopping benzodiazepines such as lormetazepam can include:[10]
- rebound insomnia and nightmares
- anxiety, panic attacks and agorophobia
- clinical depression
- malaise
- lack of concentration
- abdominal discomfort
- depersonalisation and feelings of unreality
- emotional liability
- cognitive impairment
- tinnitus
- paraesthesiae, tingling, numbness and pain
- muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, blepharospasm
- excitability, jumpiness and restlessness
- stiffness
- sweats
Abrupt or over rapid withdrawal from high doses can provoke:
- epileptic seizures
- hallucinations (visual, auditory)
- misperceptions
Withdrawal symptoms typically subside after 4 - 8 weeks but in approximately 10 - 15% of individuals symptoms can perist for many months[11] and in rare cases years.[12]
Some "Withdrawal Symptoms" can emerge despite a constant dosage with the body needing extra dosage in order to feel normal. This is sometimes associated with dosage escalation.
Lormetazepam has a short to intermediate half life of approximately 10-12 hours. Shorter acting benzodiazepine compounds are generally associated with a more intense and immediate withdrawal reaction compared to longer acting benzodiazepines. For this reason it is generally recommended to cross from lormetazepam to an equivalent dose of diazepam to gradually taper the dosage.[13] | https://www.wikidoc.org/index.php/Lormetazepam | |
c04bc8839faa629ff5f59ac404fcb4bfe1372732 | wikidoc | Lotus effect | Lotus effect
# Overview
The lotus effect in materials science is the observed superhydrophobic (also super hydrophobic or super-hydrophobic) and self-cleaning property found with lotus plants' leaves . In some Eastern cultures, the lotus plant is a symbol of purity. Although lotuses prefer to grow in muddy rivers and lakes, the leaves and flowers remain clean. Botanists who have studied lotus leaves have found that they have a natural cleaning mechanism. This cleaning mechanism was discovered by Wilhelm Barthlott in 1982. He also holds a patent .
The microscopic structure and surface chemistry of the leaves prevent them from being wetted by liquids having a contact angle of greater than 90° to an unstructured surface of the same material. With contact angles to water of up to 170°, droplets roll off a leaf's surface like mercury, taking mud, tiny insects, and contaminants with them. This is known as superhydrophobicity, or more commonly, the lotus effect. Water droplets on taro and nasturtium leaves exhibit similar behavior.
Some nanotechnologists have developed treatments, coatings, paints, roof tiles, fabrics and other surfaces that can stay dry and clean themselves in the same way as the lotus leaf. This can usually be achieved using special fluorochemical or silicone treatments on structured surfaces or with compositions containing micro-scale particulates. Super-hydrophobic coatings comprising Teflon™ microparticles have been used on medical diagnostic slides for over 30 years. It is possible to achieve such effects by using combinations of polyethylene glycol with glucose and sucrose (or any insoluble particulate) in conjunction with a hydrophobic substance.
In one method, an aluminium surface is made superhydrophobic by immersing it in sodium hydroxide for several hours (which roughens the surface) followed by spin coating a layer of perfluorononane to a thickness of 2 nanometers. This procedure increases the water contact angle from 67° to 168°, an effect that can be explained by Cassie's law. Electron microscopy shows that the aluminium surface resembles that of a lotus surface, with a porous microstructure containing trapped air. Any surface treatment that creates micro or nano scale roughness with features having a height to width ratio greater than one that is subsequently coated with a thin hydrohobic coating will exhibit the Lotus effect.
# Commercial uses
Clothing that repels water has already been developed and marketed by brands such as Gap and Dockers; it uses a fabric named Nano-Care. Water repelling glass panels have also been brought onto the market for use on the roofs of conservatories. StoCoat Lotusan is an exterior coating (paint) that mimics the microstructure of the lotus leaf surface, gaining similar water-repellent and self-cleaning properties, termed the Lotus-Effect. Water does not adhere to the surface, but rolls off the paint, picking up and washing away debris in the process. By remaining dry, the coating also resists mold, mildew, and algae. Though hydrophobic, the coating is highly permeable to water vapor. Lotus effect superhydrophobic coatings applied to microwave antennas can significantly reduce rain fade and the buildup of ice and snow. | Lotus effect
# Overview
The lotus effect in materials science is the observed superhydrophobic (also super hydrophobic or super-hydrophobic) and self-cleaning property found with lotus plants' leaves [1] [2] [3] [4] [5]. In some Eastern cultures, the lotus plant is a symbol of purity. Although lotuses prefer to grow in muddy rivers and lakes, the leaves and flowers remain clean. Botanists who have studied lotus leaves have found that they have a natural cleaning mechanism. This cleaning mechanism was discovered by Wilhelm Barthlott [6] in 1982. He also holds a patent [7].
The microscopic structure and surface chemistry of the leaves prevent them from being wetted by liquids having a contact angle of greater than 90° to an unstructured surface of the same material. With contact angles to water of up to 170°, droplets roll off a leaf's surface like mercury, taking mud, tiny insects, and contaminants with them. This is known as superhydrophobicity, or more commonly, the lotus effect. Water droplets on taro and nasturtium leaves exhibit similar behavior.
Some nanotechnologists have developed treatments, coatings, paints, roof tiles, fabrics and other surfaces that can stay dry and clean themselves in the same way as the lotus leaf. This can usually be achieved using special fluorochemical or silicone treatments on structured surfaces or with compositions containing micro-scale particulates. Super-hydrophobic coatings comprising Teflon™ microparticles have been used on medical diagnostic slides for over 30 years. It is possible to achieve such effects by using combinations of polyethylene glycol with glucose and sucrose (or any insoluble particulate) in conjunction with a hydrophobic substance.
In one method, an aluminium surface is made superhydrophobic by immersing it in sodium hydroxide for several hours (which roughens the surface) followed by spin coating a layer of perfluorononane to a thickness of 2 nanometers. [8] This procedure increases the water contact angle from 67° to 168°, an effect that can be explained by Cassie's law. Electron microscopy shows that the aluminium surface resembles that of a lotus surface, with a porous microstructure containing trapped air. Any surface treatment that creates micro or nano scale roughness with features having a height to width ratio greater than one that is subsequently coated with a thin hydrohobic coating will exhibit the Lotus effect.
# Commercial uses
Clothing that repels water has already been developed and marketed by brands such as Gap and Dockers; it uses a fabric named Nano-Care[9]. Water repelling glass panels have also been brought onto the market for use on the roofs of conservatories. StoCoat Lotusan is an exterior coating (paint) that mimics the microstructure of the lotus leaf surface, gaining similar water-repellent and self-cleaning properties, termed the Lotus-Effect. Water does not adhere to the surface, but rolls off the paint, picking up and washing away debris in the process. By remaining dry, the coating also resists mold, mildew, and algae. Though hydrophobic, the coating is highly permeable to water vapor.[10] Lotus effect superhydrophobic coatings applied to microwave antennas can significantly reduce rain fade and the buildup of ice and snow. | https://www.wikidoc.org/index.php/Lotus_effect | |
d180d8061da386f641cab7c9f8a713442cfa2c47 | wikidoc | Love-shyness | Love-shyness
# Overwiew
Love shyness is a phrase created by psychologist Brian G. Gilmartin to describe a specific type of severe chronic shyness. According to his definition, published in Shyness & Love: Causes, Consequences, and Treatments (1987), love-shy people find it difficult to be assertive in informal situations involving potential Romantic love|romantic or Sexuality|sexual partners. For example, a heterosexual love-shy male will have trouble initiating conversations with women because of strong feelings of anxiety.
Dr. Gilmartin Survey research|researched this phenomenon exclusively in heterosexual men, concluding that (1987, p.1) love-shyness "afflicts approximately 1.5 percent of all American males... will effectively prevent about 1.7 million males...from ever marrying and from ever experiencing any form of intimate sexual contact with women."
# Gilmartin's definition
Gilmartin had seven criteria for each "love-shy man" he included in his study:
- He is a virgin. He has not yet experienced sexual intercourse.
- He is a man who very rarely goes out socially with Woman|women.
- He is a person without a past history of any emotionally close, meaningful relationships of a Romantic love|romantic and/or Intimate relationship|sexual nature with any member of the opposite sex.
- He is a person who has Suffering|suffered and is continuing to suffer emotionally because of a lack of meaningful female companionship. In short, he is a male who desperately wishes to have a relationship with a woman, but does not have one because of his shyness. In other words, he is not a man who consciously chooses not to have romantic or intimate relationships; rather, he wants such relationships but cannot establish them.
- He is a man who becomes extremely anxiety-ridden over so much as the mere thought of assertiveness|asserting himself vis-à-vis a woman in a casual, friendly way. This is the essence of "love-shyness".
- He is a man who is strictly heterosexual in his romantic and erotic orientations. Again, he is a male who is in no way a homosexual.
- He is a male. There were no women interviewed in the study.
Gilmartin did not rule out the existence of female or homosexual love-shy people, but he doubted they would feel the same negative effects as heterosexual men, and suspected that the condition would manifest very differently in them, largely due to the societal roles that force heterosexual men into an "active" role in initiating relationships that do not subject women or homosexual men to the same pressures. Gilmartin explains, "he very shy young woman is no less likely to date and to marry than is the self-confident woman, non-shy woman . . . . In essence, even very shy women marry. Love-shy men cannot and do not marry irrespective of how strong their desires might be . . . . "
# Results of Gilmartin's research
According to Gilmartin, people of all ages, all sexual orientations, and all genders can be love-shy. However, in Gilmartin's opinion, the negative effects of love-shyness manifest themselves primarily in heterosexual men. Gilmartin's data collection included only heterosexual men. He studied 200 love-shy college students (aged 19-24), 100 older love-shy men (aged 35-50), and a comparison group of 200 "non-shy" college students. Gilmartin's non-shy men were not intended to represent the average male, and were recruited only if they were highly social.
## Temperament and personality
The love-shy men in Gilmartin's sample had significant differences in temperament from the non-shy men. They scored significantly lower on Extraversion, and higher on Neuroticism than the non-shy men on the Eysenck Personality Questionnaire. In Eysenck's terms, they had a "melancholic" temperament. Most of the love-shy men (and only few of the non-shy men) reported that their mothers had often said that they had been quiet babies, which Gilmartin suggests is evidence that love-shys are more likely to fit Jerome Kagan's description of behavioral inhibition.
A minority of the younger love-shys had some feelings of optimism in getting their problems fixed while all of the older love-shys felt very pessimistic about their problems and also felt cynical to the world and women in general. The older men expressed more anger in their interviews while the younger men were calmer.
## Interactions with peers and family life
Most of the love-shy men, but none of the non-shy men, reported never having any friends, not even aquaintances. The vast majority of love-shy men reported being Bullying|bullied by children their own age, while none of the non-shy men did, and love-shy men were less likely to fight back against bullies. Around half of the love-shy men reported being bullied or harassed as late as high school, while none of the non-shy men did. Even as adults, the love-shy men reported remaining Social isolation and abused by other people.
From the data Gilmartin uncovered about the love-shy's family life, they grew up in dysfunctional families. Most of the men reported that their parents and societal attitudes pressured them into being "real boys" because of the men's personalities as children. It is possible that their parents abuse and uncaring attitude to their son's emotions, desires, and interests were responsible for part of their social inhibitions. Even as grown men, the love-shy men's parents expressed that they were disappointed to have them as sons and still belittled them for their current situations. Most were upset that their sons never married and had no grandchildren to leave their heirlooms to. It was also stated that they seldom or even never visited their sons. Ironically, though most of the love-shy men disliked or even hated their parents, they visited them constantly, because they were the only people they could interact with and also to receive financial support despite also receiving heavy hazing. This is stated in the chapters of his book "Parents as a cause for love-shyness" and "The Family as a Hot Bed for rage and Belittlement".
In his recruited samples, Gilmartin had found only 14% of the self-confident university-age non-shy men had no sister around while growing up, as opposed to 59% of the university-aged love-shy men, with 71% of the 35-50 year-old love-shy men never having had a sister. In the same groups, over half of the self-confident non-love-shy young group had grown up with at least two sisters, compared to only 6% of the younger and 3% of the older love-shy men. Gilmartin also noted that none of the older love-shy men and very few of the younger love-shy men had any adults to rely on for emotional support growing up.
## Adjustment and anxiety disorders
Gilmartin's love-shy men were poorly-adjusted as they were unhappy with their lives and high in rates of anxiety disorders and possibly mental illnesses. He found that the love-shy men had considerably more violent fantasies, were very pessimistic and cynical about the world, were much more likely to believe that nobody cared about them, and were much more likely to have difficulties concentrating. He also found a tendency in some of the love-shy men to stare compulsively at women with whom they were infatuated or even stalking them, but without being able to talk to them, which sometimes got them in trouble with school authorities because of the perceived threat. Most of the love-shy men reported experiencing frequent feelings of depression. Gilmartin noted that about 40% of the older love-shy men had seriously considered committing suicide.
## Career, money, and education
Gilmartin noted that the 100 older love-shy men studied were experiencing well above average career instability. Even though almost all of these older love-shys had successfully completed higher education, their salaries were well below the US average. They were typically, if anything, underemployed and were working in low clerical jobs such as taxi driving, and door-to-door canvassers. At the time of Gilmartin's research (1979-1982), 3.6% of college graduates in the USA were unemployed. The unemployment rate for the older love-shy men was 16% because of their perceived bad past experiences with jobs. All of the love-shy men were in the lower middle class or lower.
Being single, the older love-shy men all lived in apartments. As a consequence of their social-sexual inhibitions, and subsequently limited social network, their financial situations were generally less fortunate, and many were forced to live in less attractive neighbourhoods. It is notable that none of the older love-shy men Gilmartin studied owned a home and their places of abode were rental apartments. While many of these men were excellent students, the effects of their shyness had a negative impact on their social lives and also their impression for employers. This diminished many opportunities in their careers in the same manner as it inhibited their love lives.
## Music
According to Gilmartin, the love-shy tended to prefer vocal love ballads such as Broadway theatre music, brassy jazz music, easy listening, film soundtracks, and light classical music but not traditional classical music. A few also mentioned having a strong liking for country and western. Rock n roll music of almost every kind was disliked by the love-shy but only on taste level, not on moral grounds. Gilmartin noted that surprisingly few of the love-shy men mentioned female singers.
Professor Gilmartin concludes that the majority of love-shy men prefer music with emotional/escapist themes and rich, beautiful melody. As a result, love-shy males dislike music that is noisy, loud, dissonant, or unmelodic in their point of view. The non-shy men Gilmartin interviewed typically enjoyed rock music and would only buy rock albums. The music love-shys enjoyed was considered boring by most of the non-shy men.
## Cinema
The movies (1945 to 1980) most often seen by the American love-shy in Gilmartin's study were:
- Jeremy (1973)
- David and Lisa (1962)
- Forbidden Games (1952)
- The Umbrellas of Cherbourg (1964)
- The Graduate (1967)
- Butterflies Are Free (1972)
- Marty (1955)
- Fiddler on the Roof (1971)
- Romeo and Juliet (1968 film)|Romeo and Juliet (1968)
- Nobody Waved Goodbye (1965)
According to Gilmartin, the full list of 63 repeatedly seen movies can be classified into two categories:
- "heavy", emotionally engrossing love stories, and
- escapist musicals with a strong romantic flavor.
## Other love-shy attributes
According to Gilmartin, many love-shy men show the following patterns:
- often feel women are more privileged (have it easier) than men and often envy this perception
- place great, often disproportionate importance on physical beauty (especially facial beauty) on both themselves and the women they are interested in
- had a physically difficult birth or needed a c-section to be born
- are not as likely to be interested in male friendships. Most of the love-shy men had feelings of misandry towards the same-sex.
- are under-developed in muscle tone
- were usually quiet as infants, while non-love-shy men are rarely so
- tend to be more interested in movies and music, and prefer watching different types of movies from non-love-shy men. Most of the love-shys interviewed hated sports that were of the "rough and tumble" nature, such as American football.
- are more interested in female oriented activities
- are less patriotic
- are more likely to be apolitical
- are less religion|religious but largely Spirituality|spiritual
- are very sensitive to petty stimuli, bright light, and syringe needles
- develop interest in females at an earlier age than usual, particularly in the third to fifth grade range
- often only want to have female children because of their strong positive opinion of the opposite sex and detest the idea of having male children due to bullying by male school bullies and lacking interest in male activities
- often have tense, nervous, angry, and/or two-faced mothers
- often was a victim of child abuse by the parents or a third party at a young age
- often were an only child
- often have no sisters, and rarely have more than one
- often had no adults to turn to for emotional support as children, and continue to be that way as adults
- often felt they had little influence on family decisions as children
- ones who had siblings achieved intimacy with relationships and were preferred by the parents
- suffer from depression because of the treatment from their parents and their lack of a social and sexual life
- often go through an excessive amount of psychological trauma, of which love-shyness can be the aftermath; many of the above items can be precursors of it
- hold their parents responsible because of some of the aforementioned limitations
However, these attributes are not limited to people who are love shy; these patterns have also been diagnosed in other sorts of medical conditions.
# Gilmartin's theory
## Causes of love-shyness
Gilmartin estimates that love-shyness afflicts approximately 1.5 percent of American males. According to Gilmartin, love-shyness is, like most human psychological characteristics, the result of some combination of biological (genetic/developmental) and environmental (culture|cultural, family|familial, religion|religious, etc.) factors (see also: nature versus nurture). Gilmartin believes that shyness is a condition which needs to be cured.
He mentions several possible biological causes of love-shyness, most notably low maternal testosterone during fetal development, nasal polyps, and hypoglycemia.
Crucial factors exacerbating negative development during the love-shy male's childhood are:
- School bullying. Love-shy boys are vulnerable to bullying from their peer group, due to their shyness and inhibition. Non-conformism to peer group norms also makes the boy a target through no fault of his own.
- Parental upbringing. Where a child receives primarily negative stimuli from his parents (e.g. corporal punishment, child abuse, verbal abuse, criticism, 'put-downs', negative comparisons, indifference) this will most likely cause the boy to retreat further and further into his 'shell'.
With so many negative stimuli from crucial relationships in one's childhood, the love-shy boy becomes a social isolation|social isolate. He learns to associate these crucial interactions (i.e. with parents, peer group) with hurt feelings and is likely to avoid social interaction. Social isolation becomes a 'vicious circle' for the love-shy individual as the years go by, and inhibits his chances in interaction with the opposite sex, as well as in other crucial areas of life such as his career.
## Love-shyness, sexual orientation, and gender
Gilmartin believes that love-shyness would have the most severe effect on heterosexual males, because of gender roles. He claims that it may be possible for both shy women and homosexual men to become involved in intimate relationships without needing to take any initiative, simply by waiting for a more assertive man to initiate the relationship or in the case of lesbians, a more assertive woman. According to Gilmartin, shy women are as likely or even more likely due to their love-shyness as non-shy women to date, to marry, and to have children, while this is not the case for heterosexual men. Love-shy heterosexual men normally have no informal social contact with women (virtually by definition). They cannot date, marriage|marry, or have children, and many of these men never experience any form of intimate sexual contact. Gilmartin found that third parties such as parents and friends are often inconsiderate of the difficulties of love-shy men, and are reluctant to aid them in finding girlfriends, because many view them as "unworthy" to obtain a girlfriend. He also noted that none of the love-shy men sought sex workers for moral reasons and fearing they would fall in love with them. And often love-shy men were often unable to obtain a mail order bride because the international marriage agency either viewed them as "mentally unstable" or were too impoverished to pay the mail order bride fees.
Gilmartin notes that love-shy men are frequently assumed to be homosexual, because of their perceived lack of interest in women and this would also cause homosexual men to make advances to them but the love-shy men would reject them. Interestingly, a small number of the non-shy men admitted to have experimenting with homosexual acts though none of the love-shy men had any sort of sexual activity in their life besides masturbation. One of the men mentioned having borderline bestiality leanings, another felt sexually stimulated by rubbing Barbie dolls against himself whilst naked, and another was a coprophiliac. Additionally, Gilmartin noted that many love-shy men are not interested in friendships with other men. This, combined with their lack of success in initiating contact with women, causes feelings of loneliness, alienation, and depression.
# Love-shyness and mainstream psychology
Love-shyness is not recognized as a mental disorder by the World Health Organization or American Psychiatric Association. It does share some characteristics with commonly recognized mental disorders, however.
Like people who have a specific social anxiety, love-shy people can be very anxious in informal social situations.
Like people who are afflicted with an avoidant personality disorder, love-shy people feel uncomfortable in many informal social situations, and typically avoid opportunities for social contact.
Some of the psychological and social problems of the love-shy men could be considered autistic because of the men's trouble in regards to peers, social interactions, and adjustment to change. Years later when asked in an email, Gilmartin felt that 40% of severely love-shy men would have Asperger Syndrome. But it will never be known if the men were autistic/aspergian or not because none were known to be diagnosed with either condition.
Love-shyness can also be interchangeable with involuntary celibacy.
# Treatment and hope for the love-shy and proposed societal changes
Gilmartin proposed that "practice dating" sessions would help the love-shy men overcome their problems with anxiety and eventually would help them find a partner. He also proposed that the medical community take a more serious view on shyness, for bullying in school to be outlawed, and for parents to stop conditioning their daughters into not taking initiative when it comes to courtship and dating.
He further recommended a new children's recreational organization, the "Coed Scouts", which would permit children to socialize with both genders.
Gilmartin also felt that the younger love shys would have a better chance at overcoming their shyness since they were treated less harshly by their peers than the older love-shy men were. However, his research has yet to be updated so it is unknown if any of the men were able to curtail their problems.
# Criticism of Gilmartin's writings
Gilmartin makes references to pseudoscience such as astrology, reincarnation, past life regression, and Kirlian aura (page 15) to support his conclusions which reviewer Elizabeth Rice Allgeier felt "waters down the potential impact of his writings" in her book review for the Journal of Sex Research. In a separate review of the book,
Jonathan M. Cheek suggested that comparable emphasis should
have been given to the study of love-shyness in women. | Love-shyness
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overwiew
Love shyness is a phrase created by psychologist Brian G. Gilmartin to describe a specific type of severe chronic shyness. According to his definition, published in Shyness & Love: Causes, Consequences, and Treatments (1987), love-shy people find it difficult to be assertive in informal situations involving potential Romantic love|romantic or Sexuality|sexual partners. For example, a heterosexual love-shy male will have trouble initiating conversations with women because of strong feelings of anxiety.
Dr. Gilmartin Survey research|researched this phenomenon exclusively in heterosexual men, concluding that (1987, p.1) love-shyness "afflicts approximately 1.5 percent of all American males...[and] will effectively prevent about 1.7 million [U.S.] males...from ever marrying and from ever experiencing any form of intimate sexual contact with women."
# Gilmartin's definition
Gilmartin had seven criteria for each "love-shy man" he included in his study:
- He is a virgin. He has not yet experienced sexual intercourse.
- He is a man who very rarely goes out socially with Woman|women.
- He is a person without a past history of any emotionally close, meaningful relationships of a Romantic love|romantic and/or Intimate relationship|sexual nature with any member of the opposite sex.
- He is a person who has Suffering|suffered and is continuing to suffer emotionally because of a lack of meaningful female companionship. In short, he is a male who desperately wishes to have a relationship with a woman, but does not have one because of his shyness. In other words, he is not a man who consciously chooses not to have romantic or intimate relationships; rather, he wants such relationships but cannot establish them.
- He is a man who becomes extremely anxiety-ridden over so much as the mere thought of assertiveness|asserting himself vis-à-vis a woman in a casual, friendly way. This is the essence of "love-shyness".
- He is a man who is strictly heterosexual in his romantic and erotic orientations. Again, he is a male who is in no way a homosexual.
- He is a male. There were no women interviewed in the study.
Gilmartin did not rule out the existence of female or homosexual love-shy people, but he doubted they would feel the same negative effects as heterosexual men, and suspected that the condition would manifest very differently in them, largely due to the societal roles that force heterosexual men into an "active" role in initiating relationships that do not subject women or homosexual men to the same pressures. Gilmartin explains, "[T]he very shy young woman is no less likely to date and to marry than is the self-confident woman, non-shy woman . . . . In essence, even very shy women marry. Love-shy men cannot and do not marry irrespective of how strong their desires might be . . . . "
# Results of Gilmartin's research
According to Gilmartin, people of all ages, all sexual orientations, and all genders can be love-shy. However, in Gilmartin's opinion, the negative effects of love-shyness manifest themselves primarily in heterosexual men. Gilmartin's data collection included only heterosexual men. He studied 200 love-shy college students (aged 19-24), 100 older love-shy men (aged 35-50), and a comparison group of 200 "non-shy" college students. Gilmartin's non-shy men were not intended to represent the average male, and were recruited only if they were highly social.
## Temperament and personality
The love-shy men in Gilmartin's sample had significant differences in temperament from the non-shy men. They scored significantly lower on Extraversion, and higher on Neuroticism than the non-shy men on the Eysenck Personality Questionnaire. In Eysenck's terms, they had a "melancholic" temperament. Most of the love-shy men (and only few of the non-shy men) reported that their mothers had often said that they had been quiet babies, which Gilmartin suggests is evidence that love-shys are more likely to fit Jerome Kagan's description of behavioral inhibition.
A minority of the younger love-shys had some feelings of optimism in getting their problems fixed while all of the older love-shys felt very pessimistic about their problems and also felt cynical to the world and women in general. The older men expressed more anger in their interviews while the younger men were calmer.
## Interactions with peers and family life
Most of the love-shy men, but none of the non-shy men, reported never having any friends, not even aquaintances. The vast majority of love-shy men reported being Bullying|bullied by children their own age, while none of the non-shy men did, and love-shy men were less likely to fight back against bullies. Around half of the love-shy men reported being bullied or harassed as late as high school, while none of the non-shy men did. Even as adults, the love-shy men reported remaining Social isolation and abused by other people.
From the data Gilmartin uncovered about the love-shy's family life, they grew up in dysfunctional families. Most of the men reported that their parents and societal attitudes pressured them into being "real boys" because of the men's personalities as children. It is possible that their parents abuse and uncaring attitude to their son's emotions, desires, and interests were responsible for part of their social inhibitions. Even as grown men, the love-shy men's parents expressed that they were disappointed to have them as sons and still belittled them for their current situations. Most were upset that their sons never married and had no grandchildren to leave their heirlooms to. It was also stated that they seldom or even never visited their sons. Ironically, though most of the love-shy men disliked or even hated their parents, they visited them constantly, because they were the only people they could interact with and also to receive financial support despite also receiving heavy hazing. This is stated in the chapters of his book "Parents as a cause for love-shyness" and "The Family as a Hot Bed for rage and Belittlement".
In his recruited samples, Gilmartin had found only 14% of the self-confident university-age non-shy men had no sister around while growing up, as opposed to 59% of the university-aged love-shy men, with 71% of the 35-50 year-old love-shy men never having had a sister. In the same groups, over half of the self-confident non-love-shy young group had grown up with at least two sisters, compared to only 6% of the younger and 3% of the older love-shy men. Gilmartin also noted that none of the older love-shy men and very few of the younger love-shy men had any adults to rely on for emotional support growing up.
## Adjustment and anxiety disorders
Gilmartin's love-shy men were poorly-adjusted as they were unhappy with their lives and high in rates of anxiety disorders and possibly mental illnesses. He found that the love-shy men had considerably more violent fantasies, were very pessimistic and cynical about the world, were much more likely to believe that nobody cared about them, and were much more likely to have difficulties concentrating. He also found a tendency in some of the love-shy men to stare compulsively at women with whom they were infatuated or even stalking them, but without being able to talk to them, which sometimes got them in trouble with school authorities because of the perceived threat. Most of the love-shy men reported experiencing frequent feelings of depression. Gilmartin noted that about 40% of the older love-shy men had seriously considered committing suicide.
## Career, money, and education
Gilmartin noted that the 100 older love-shy men studied were experiencing well above average career instability. Even though almost all of these older love-shys had successfully completed higher education, their salaries were well below the US average. They were typically, if anything, underemployed and were working in low clerical jobs such as taxi driving, and door-to-door canvassers. At the time of Gilmartin's research (1979-1982), 3.6% of college graduates in the USA were unemployed. The unemployment rate for the older love-shy men was 16% because of their perceived bad past experiences with jobs. All of the love-shy men were in the lower middle class or lower.
Being single, the older love-shy men all lived in apartments. As a consequence of their social-sexual inhibitions, and subsequently limited social network, their financial situations were generally less fortunate, and many were forced to live in less attractive neighbourhoods. It is notable that none of the older love-shy men Gilmartin studied owned a home and their places of abode were rental apartments. While many of these men were excellent students, the effects of their shyness had a negative impact on their social lives and also their impression for employers. This diminished many opportunities in their careers in the same manner as it inhibited their love lives.
## Music
According to Gilmartin, the love-shy tended to prefer vocal love ballads such as Broadway theatre music, brassy jazz music, easy listening, film soundtracks, and light classical music but not traditional classical music. A few also mentioned having a strong liking for country and western. Rock n roll music of almost every kind was disliked by the love-shy but only on taste level, not on moral grounds. Gilmartin noted that surprisingly few of the love-shy men mentioned female singers.
Professor Gilmartin concludes that the majority of love-shy men prefer music with emotional/escapist themes and rich, beautiful melody. As a result, love-shy males dislike music that is noisy, loud, dissonant, or unmelodic in their point of view. The non-shy men Gilmartin interviewed typically enjoyed rock music and would only buy rock albums. The music love-shys enjoyed was considered boring by most of the non-shy men.
## Cinema
The movies (1945 to 1980) most often seen by the American love-shy in Gilmartin's study were:
- Jeremy (1973)
- David and Lisa (1962)
- Forbidden Games (1952)
- The Umbrellas of Cherbourg (1964)
- The Graduate (1967)
- Butterflies Are Free (1972)
- Marty (1955)
- Fiddler on the Roof (1971)
- Romeo and Juliet (1968 film)|Romeo and Juliet (1968)
- Nobody Waved Goodbye (1965)
According to Gilmartin, the full list of 63 repeatedly seen movies can be classified into two categories:
- "heavy", emotionally engrossing love stories, and
- escapist musicals with a strong romantic flavor.
## Other love-shy attributes
According to Gilmartin, many love-shy men show the following patterns:
- often feel women are more privileged (have it easier) than men and often envy this perception
- place great, often disproportionate importance on physical beauty (especially facial beauty) on both themselves and the women they are interested in
- had a physically difficult birth or needed a c-section to be born
- are not as likely to be interested in male friendships. Most of the love-shy men had feelings of misandry towards the same-sex.
- are under-developed in muscle tone
- were usually quiet as infants, while non-love-shy men are rarely so
- tend to be more interested in movies and music, and prefer watching different types of movies from non-love-shy men. Most of the love-shys interviewed hated sports that were of the "rough and tumble" nature, such as American football.
- are more interested in female oriented activities
- are less patriotic
- are more likely to be apolitical
- are less religion|religious but largely Spirituality|spiritual
- are very sensitive to petty stimuli, bright light, and syringe needles
- develop interest in females at an earlier age than usual, particularly in the third to fifth grade range
- often only want to have female children because of their strong positive opinion of the opposite sex and detest the idea of having male children due to bullying by male school bullies and lacking interest in male activities
- often have tense, nervous, angry, and/or two-faced mothers
- often was a victim of child abuse by the parents or a third party at a young age
- often were an only child
- often have no sisters, and rarely have more than one
- often had no adults to turn to for emotional support as children, and continue to be that way as adults
- often felt they had little influence on family decisions as children
- ones who had siblings achieved intimacy with relationships and were preferred by the parents
- suffer from depression because of the treatment from their parents and their lack of a social and sexual life
- often go through an excessive amount of psychological trauma, of which love-shyness can be the aftermath; many of the above items can be precursors of it
- hold their parents responsible because of some of the aforementioned limitations
However, these attributes are not limited to people who are love shy; these patterns have also been diagnosed in other sorts of medical conditions.
# Gilmartin's theory
## Causes of love-shyness
Gilmartin estimates that love-shyness afflicts approximately 1.5 percent of American males. According to Gilmartin, love-shyness is, like most human psychological characteristics, the result of some combination of biological (genetic/developmental) and environmental (culture|cultural, family|familial, religion|religious, etc.) factors (see also: nature versus nurture). Gilmartin believes that shyness is a condition which needs to be cured.
He mentions several possible biological causes of love-shyness, most notably low maternal testosterone during fetal development, nasal polyps, and hypoglycemia.
Crucial factors exacerbating negative development during the love-shy male's childhood are:
- School bullying. Love-shy boys are vulnerable to bullying from their peer group, due to their shyness and inhibition. Non-conformism to peer group norms also makes the boy a target through no fault of his own.
- Parental upbringing. Where a child receives primarily negative stimuli from his parents (e.g. corporal punishment, child abuse, verbal abuse, criticism, 'put-downs', negative comparisons, indifference) this will most likely cause the boy to retreat further and further into his 'shell'.
With so many negative stimuli from crucial relationships in one's childhood, the love-shy boy becomes a social isolation|social isolate. He learns to associate these crucial interactions (i.e. with parents, peer group) with hurt feelings and is likely to avoid social interaction. Social isolation becomes a 'vicious circle' for the love-shy individual as the years go by, and inhibits his chances in interaction with the opposite sex, as well as in other crucial areas of life such as his career.
## Love-shyness, sexual orientation, and gender
Gilmartin believes that love-shyness would have the most severe effect on heterosexual males, because of gender roles. He claims that it may be possible for both shy women and homosexual men to become involved in intimate relationships without needing to take any initiative, simply by waiting for a more assertive man to initiate the relationship or in the case of lesbians, a more assertive woman. According to Gilmartin, shy women are as likely or even more likely due to their love-shyness as non-shy women to date, to marry, and to have children, while this is not the case for heterosexual men. Love-shy heterosexual men normally have no informal social contact with women (virtually by definition). They cannot date, marriage|marry, or have children, and many of these men never experience any form of intimate sexual contact. Gilmartin found that third parties such as parents and friends are often inconsiderate of the difficulties of love-shy men, and are reluctant to aid them in finding girlfriends, because many view them as "unworthy" to obtain a girlfriend. He also noted that none of the love-shy men sought sex workers for moral reasons and fearing they would fall in love with them. And often love-shy men were often unable to obtain a mail order bride because the international marriage agency either viewed them as "mentally unstable" or were too impoverished to pay the mail order bride fees.
Gilmartin notes that love-shy men are frequently assumed to be homosexual, because of their perceived lack of interest in women and this would also cause homosexual men to make advances to them but the love-shy men would reject them. Interestingly, a small number of the non-shy men admitted to have experimenting with homosexual acts though none of the love-shy men had any sort of sexual activity in their life besides masturbation. One of the men mentioned having borderline bestiality leanings, another felt sexually stimulated by rubbing Barbie dolls against himself whilst naked, and another was a coprophiliac. Additionally, Gilmartin noted that many love-shy men are not interested in friendships with other men. This, combined with their lack of success in initiating contact with women, causes feelings of loneliness, alienation, and depression.
# Love-shyness and mainstream psychology
Love-shyness is not recognized as a mental disorder by the World Health Organization or American Psychiatric Association. It does share some characteristics with commonly recognized mental disorders, however.
Like people who have a specific social anxiety, love-shy people can be very anxious in informal social situations.
Like people who are afflicted with an avoidant personality disorder, love-shy people feel uncomfortable in many informal social situations, and typically avoid opportunities for social contact.
Some of the psychological and social problems of the love-shy men could be considered autistic because of the men's trouble in regards to peers, social interactions, and adjustment to change. Years later when asked in an email, Gilmartin felt that 40% of severely love-shy men would have Asperger Syndrome. But it will never be known if the men were autistic/aspergian or not because none were known to be diagnosed with either condition.
Love-shyness can also be interchangeable with involuntary celibacy.
# Treatment and hope for the love-shy and proposed societal changes
Gilmartin proposed that "practice dating" sessions would help the love-shy men overcome their problems with anxiety and eventually would help them find a partner. He also proposed that the medical community take a more serious view on shyness, for bullying in school to be outlawed, and for parents to stop conditioning their daughters into not taking initiative when it comes to courtship and dating.
He further recommended a new children's recreational organization, the "Coed Scouts", which would permit children to socialize with both genders.
Gilmartin also felt that the younger love shys would have a better chance at overcoming their shyness since they were treated less harshly by their peers than the older love-shy men were. However, his research has yet to be updated so it is unknown if any of the men were able to curtail their problems.
# Criticism of Gilmartin's writings
Gilmartin makes references to pseudoscience such as astrology, reincarnation, past life regression, and Kirlian aura (page 15) to support his conclusions which reviewer Elizabeth Rice Allgeier felt "waters down the potential impact of his writings" in her book review for the Journal of Sex Research. In a separate review of the book,
Jonathan M. Cheek suggested that comparable emphasis should
have been given to the study of love-shyness in women. | https://www.wikidoc.org/index.php/Love-shyness | |
f5a5b73c5a5b74711b8c4ea0dd53b4e101deace6 | wikidoc | Loxommatidae | Loxommatidae
The Baphetids or Loxommatids were large tetrapod predators of the Late Carboniferous period (Namurian through Westphalian) of Europe. Fragmentary remains from the Early Carboniferous of Canada have been tentatively assigned to the group.
Not only are they included among the very early tetrapodomorphs, but they were also among the first of the Carboniferous fossil tetrapods to be found and were originally described in 1850 by William Dawson. They are known mainly from skulls; very little skeletal material has been found. But even from this quite a lot can be deduced. The presence of lateral lines and the long rows of needle-like teeth show that most were fish-eaters. Their best-known characteristic was a curious, keyhole-shaped orbit formed by excavation of the lacrimal and prefrontal bones in front of the eye. It has been suggested that this space accommodated a salt gland or some kind of electrosensory organ. Perhaps the better hypothesis is that the space allowed room for the contraction of an enlarged pterygoideus muscle. In that case, this skull modification would represent an early form of skull fenestration for jaw muscles.
The skull is shallow. Unlike the better-known embolomeres, the baphetid cheek and skull roof are sutured together. There is a strongly embayed spiracular ("otic") notch, but the stapes is distally broad, which seems to rule out a sensitive hearing apparatus. The palate is closed -- a primitive character, but very different from the temnospondyls. The coronoids bear no teeth or denticles, while the dentary has a double tooth row.
Since the taxon is based almost exclusively on skulls, the body is very poorly known. It is often said that the body was crocodile-like, but this appears to be largely supposition.
It is not clear whether all of the genera assigned to this group are really closely related. The traditional four genera of baphetids (Loxomma, Baphetes, Megalocephalus, and Spathicephalus) have recently been supplemented by Eucritta, a somewhat different form. It has also been suggested that Crassigyrinus may be closely related.
Baphetids have been previously considered primitive temnospondyls and more recently batrachosaurs (reptile-like amphibia). It is likely, however, that they represent one more of a number of early Carboniferous tetrapodomorph radiations. Computer-assisted phylogenetic analyses of a data matrix using characteristics of most of the major groups of terrestrial vertebrates place the Baphetids close to the ancestry of amniotes.
With the reinterpretation of Ichthyostega and its relatives as aquatic forms, baphetids are good candidates for the spot of first tetrapodomorph group to actually spend substantial time on land. If so, baphetids may be a rather important taxon. | Loxommatidae
The Baphetids or Loxommatids were large tetrapod predators of the Late Carboniferous period (Namurian through Westphalian) of Europe. Fragmentary remains from the Early Carboniferous of Canada have been tentatively assigned to the group.
Not only are they included among the very early tetrapodomorphs, but they were also among the first of the Carboniferous fossil tetrapods to be found and were originally described in 1850 by William Dawson. They are known mainly from skulls; very little skeletal material has been found. But even from this quite a lot can be deduced. The presence of lateral lines and the long rows of needle-like teeth show that most were fish-eaters. Their best-known characteristic was a curious, keyhole-shaped orbit formed by excavation of the lacrimal and prefrontal bones in front of the eye. It has been suggested that this space accommodated a salt gland or some kind of electrosensory organ.[1] Perhaps the better hypothesis is that the space allowed room for the contraction of an enlarged pterygoideus muscle. In that case, this skull modification would represent an early form of skull fenestration for jaw muscles.
The skull is shallow. Unlike the better-known embolomeres, the baphetid cheek and skull roof are sutured together. There is a strongly embayed spiracular ("otic") notch, but the stapes is distally broad, which seems to rule out a sensitive hearing apparatus. The palate is closed -- a primitive character, but very different from the temnospondyls. The coronoids bear no teeth or denticles, while the dentary has a double tooth row.
Since the taxon is based almost exclusively on skulls, the body is very poorly known. It is often said that the body was crocodile-like, but this appears to be largely supposition.
It is not clear whether all of the genera assigned to this group are really closely related. The traditional four genera of baphetids (Loxomma, Baphetes, Megalocephalus, and Spathicephalus) have recently been supplemented by Eucritta, a somewhat different form. It has also been suggested that Crassigyrinus may be closely related.
Baphetids have been previously considered primitive temnospondyls and more recently batrachosaurs (reptile-like amphibia). It is likely, however, that they represent one more of a number of early Carboniferous tetrapodomorph radiations. Computer-assisted phylogenetic analyses of a data matrix using characteristics of most of the major groups of terrestrial vertebrates place the Baphetids close to the ancestry of amniotes.
With the reinterpretation of Ichthyostega and its relatives as aquatic forms, baphetids are good candidates for the spot of first tetrapodomorph group to actually spend substantial time on land. If so, baphetids may be a rather important taxon. | https://www.wikidoc.org/index.php/Loxommatidae | |
6c07094ee8e426269c374cc9e95474ccf189d84e | wikidoc | Lubiprostone | Lubiprostone
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# Overview
Lubiprostone is a chloride channel activator that is FDA approved for the {{{indicationType}}} of chronic idiopathic constipation in adults, opioid-induced constipation in adults with chronic, non-cancer pain, irritable bowel syndrome with constipation in women ≥ 18 years old. Common adverse reactions include nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose is 24 mcg twice daily orally with food and water.
- Dosage in patients with hepatic impairment
- For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended starting dose is 16 mcg twice daily. For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg twice daily. If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response.
- Dosing Information
- The recommended dose is 8 mcg twice daily orally with food and water.
- Dosage in patients with hepatic impairment
- For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg once daily. If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response. Dosage adjustment is not required for patients with moderately impaired hepatic function (Child-Pugh Class B).
- Amitiza is indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain.
- Limitations of Use:
- Effectiveness of Amitiza in the treatment of opioid-induced constipation in patients taking diphenylheptaneopioids (e.g., methadone) has not been established.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lubiprostone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lubiprostone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lubiprostone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lubiprostone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lubiprostone in pediatric patients.
# Contraindications
- Amitiza is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
# Warnings
### Precautions
- Nausea
- Patients taking Amitiza may experience nausea. Concomitant administration of food with Amitiza may reduce symptoms of nausea.
- Diarrhea
- Amitiza should not be prescribed to patients that have severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Patients should be instructed to discontinue Amitiza and inform their physician if severe diarrhea occurs.
- Dyspnea
- In clinical trials, dyspnea was reported by 3%, 1%, and < 1% of the treated CIC, OIC, and IBS-C populations receiving Amitiza, respectively, compared to 0%, 1%, and < 1% of placebo-treated patients. There have been postmarketing reports of dyspnea when using Amitiza 24 mcg twice daily. Some patients have discontinued treatment because of dyspnea. These events have usually been described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within 30–60 minutes after taking the first dose. They generally resolve within a few hours after taking the dose, but recurrence has been frequently reported with subsequent doses.
- Bowel Obstruction
- In patients with symptoms suggestive of mechanical gastrointestinal obstruction, perform a thorough evaluation to confirm the absence of an obstruction prior to initiating therapy with Amitiza.
# 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 practice.
- During clinical development of Amitiza for CIC, OIC, and IBS-C, 1234 patients were treated with Amitiza for 6 months and 524 patients were treated for 1 year (not mutually exclusive).
- Chronic Idiopathic Constipation
- Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza 24 mcg twice daily in 1113 patients with chronic idiopathic constipation over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure (≤ 4 weeks). The placebo population (N = 316) had a mean age of 47.8 (range 21–81) years; was 87.3% female; 80.7% Caucasian, 10.1% African American, 7.3% Hispanic, 0.9% Asian; and 11.7% elderly (≥ 65 years of age). Of those patients treated with Amitiza 24 mcg twice daily (N=1113), the mean age was 50.3 (range 19-86) years; 86.9% were female; 86.1% Caucasian, 7.6% African American, 4.7% Hispanic, 1.0% Asian; and 16.7% elderly (≥ 65 years of age). Table 1 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 24 mcg twice daily and that occurred more frequently with study drug than placebo.
- The most common adverse reactions (incidence > 4%) in CIC were nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence.
- Nausea: Approximately 29% of patients who received Amitiza 24 mcg twice daily experienced nausea; 4% of patients had severe nausea and 9% of patients discontinued treatment due to nausea. The rate of nausea associated with Amitiza 24 mcg twice daily was lower among male (8%) and elderly (19%) patients. No patients in the clinical studies were hospitalized due to nausea.
- Diarrhea: Approximately 12% of patients who received Amitiza 24 mcg twice daily experienced diarrhea; 2% of patients had severe diarrhea and 2% of patients discontinued treatment due to diarrhea.
- Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving Amitiza.
- Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Amitiza 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite.
- Opioid-induced Constipation
- Adverse reactions in efficacy and long-term clinical studies: The data described below reflect exposure to Amitiza 24 mcg twice daily in 860 patients with OIC for up to 12 months and from 632 patients receiving placebo twice daily for up to 12 weeks. The total population (N = 1492) had a mean age of 50.4 (range 20–89) years; was 62.7% female; 82.7% Caucasian, 14.2% African American, 0.8% American Indian/Alaska Native, 0.8% Asian; 5.2% were of Hispanic ethnicity; and 8.8% were elderly (≥ 65 years of age). Table 2 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 24 mcg twice daily and that occurred more frequently with study drug than placebo.
- The most common adverse reactions (incidence > 4%) in OIC were nausea and diarrhea.
- Nausea: Approximately 11% of patients who received Amitiza 24 mcg twice daily experienced nausea; 1% of patients had severe nausea and 2% of patients discontinued treatment due to nausea.
- Diarrhea: Approximately 8% of patients who received Amitiza 24 mcg twice daily experienced diarrhea; 2% of patients had severe diarrhea and 1% of patients discontinued treatment due to diarrhea.
- Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Amitiza 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: fecal incontinence, blood potassium decreased.
- Irritable Bowel Syndrome with Constipation
- Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N = 1267) had a mean age of 46.5 (range 18–85) years; was 91.6% female; 77.5% Caucasian, 12.9% African American, 8.6% Hispanic, 0.4% Asian; and 8.0% elderly (≥ 65 years of age). Table 3 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 8 mcg twice daily and that occurred more frequently with study drug than placebo.
- The most common adverse reactions (incidence > 4%) in IBS-C were nausea, diarrhea, and abdominal pain.
- Nausea: Approximately 8% of patients who received Amitiza 8 mcg twice daily experienced nausea; 1% of patients had severe nausea and 1% of patients discontinued treatment due to nausea.
- Diarrhea: Approximately 7% of patients who received Amitiza 8 mcg twice daily experienced diarrhea; <1% of patients had severe diarrhea and <1% of patients discontinued treatment due to diarrhea.
- Less common adverse reactions: The following adverse reactions (assessed by investigator as probably related to treatment) occurred in less than 1% of patients receiving Amitiza 8 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria.
## Postmarketing Experience
- The following additional adverse reactions have been identified during post-approval use of Amitiza. 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.
- Voluntary reports of adverse reactions occurring with the use of Amitiza include the following: syncope, ischemic colitis, hypersensitivity/allergic-type reactions (including rash, swelling, and throat tightness), malaise, tachycardia, muscle cramps or muscle spasms, and asthenia.
# Drug Interactions
- No in vivo drug-drug interaction studies have been performed with Amitiza.
- Based upon the results of in vitro human microsome studies, there is low likelihood of pharmacokinetic drug-drug interactions. In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. Further in vitro studies indicate microsomal carbonyl reductase may be involved in the extensive biotransformation of lubiprostone to the metabolite M3. Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone. Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.
- Interaction potential with diphenylheptane opioids (e.g. methadone): Non-clinical studies have shown opioids of the diphenylheptane chemical class (e.g., methadone) to dose-dependently reduce the activation of ClC-2 by lubiprostone in the gastrointestinal tract. There is a possibility of a dose-dependent decrease in the efficacy of Amitiza in patients using diphenylheptane opioids.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Risk Summary
- There are no adequate and well-controlled studies with Amitiza in pregnant women. A dose dependent increase in fetal loss was observed in pregnant guinea pigs that received lubiprostone doses equivalent to 0.2 to 6 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2). Animal studies did not show an increase in structural malformations. Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Clinical Considerations
- Current available data suggest that miscarriage occurs in 15-18% of clinically recognized pregnancies, regardless of any drug exposure. Consider the risks and benefits of available therapies when treating a pregnant woman for chronic idiopathic constipation, opioid-induced constipation or irritable bowel syndrome with constipation.
- Animal Data
- In developmental toxicity studies, pregnant rats and rabbits received oral lubiprostone during organogenesis at doses up to approximately 338 times (rats) and approximately 34 times (rabbits) the maximum recommended human dose (MHRD) based on body surface area (mg/m2). Maximal animal doses were 2000 mcg/kg/day (rats) and 100 mcg/kg/day (rabbits). In rats, there were increased incidences of early resorptions and soft tissue malformations (situs inversus, cleft palate) at the 2000 mcg/kg/day dose; however, these effects were probably secondary to maternal toxicity. A dose-dependent increase in fetal loss occurred when guinea pigs received lubiprostone after the period of organogenesis, on days 40 to 53 of gestation, at daily oral doses of 1, 10, and 25 mcg/kg/day (approximately 0.2, 2 and 6 times the MRHD based on body surface area (mg/m2)). The potential of lubiprostone to cause fetal loss was also examined in pregnant Rhesus monkeys. Monkeys received lubiprostone post-organogenesis on gestation days 110 through 130 at daily oral doses of 10 and 30 mcg/kg/day (approximately 3 and 10 times the MHRD based on body surface area (mg/m2)). Fetal loss was noted in one monkey from the 10-mcg/kg dose group, which is within normal historical rates for this species. There was no drug-related adverse effect seen in monkeys.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lubiprostone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lubiprostone during labor and delivery.
### Nursing Mothers
- It is not known whether lubiprostone is excreted in human milk. In rats, neither lubiprostone nor its active metabolites were detectable in breast milk following oral administration of lubiprostone. Because lubiprostone increases fluid secretion in the intestine and intestinal motility, human milk-fed infants should be monitored for diarrhea. Caution should be exercised when Amitiza is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Lubiprostone with respect to pediatric patients.
### Geriatic Use
- Chronic Idiopathic Constipation
- The efficacy of Amitiza in the elderly (≥ 65 years of age) subpopulation was consistent with the efficacy in the overall study population. Of the total number of constipated patients treated in the dose-finding, efficacy, and long-term studies of Amitiza, 15.5% were ≥ 65 years of age, and 4.2% were ≥ 75 years of age. Elderly patients taking Amitiza 24 mcg twice daily experienced a lower rate of associated nausea compared to the overall study population taking Amitiza (19% vs. 29%, respectively).
- Opioid-induced Constipation
- The safety profile of Amitiza in the elderly (≥ 65 years of age) subpopulation (8.8% were ≥ 65 years of age and 1.6% were ≥ 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Amitiza did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
- Irritable Bowel Syndrome with Constipation
- The safety profile of Amitiza in the elderly (≥ 65 years of age) subpopulation (8.0% were ≥ 65 years of age and 1.8% were ≥ 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Amitiza did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Lubiprostone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lubiprostone with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is required in patients with renal impairment.
### Hepatic Impairment
- Patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C) experienced markedly higher systemic exposure of lubiprostone active metabolite M3, when compared to normal subjects. Clinical safety results demonstrated an increased incidence and severity of adverse events in subjects with greater severity of hepatic impairment.
- In case of chronic idiopathic constipation or opioid-induced constipation indications, the starting dosage of Amitiza should be reduced in patients with moderate hepatic impairment. The starting dose of Amitiza should be reduced in all patients with severe hepatic impairment, regardless of the indication. No dosing adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lubiprostone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lubiprostone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lubiprostone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lubiprostone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There have been two confirmed reports of overdosage with Amitiza. The first report involved a 3-year-old child who accidentally ingested 7 or 8 capsules of 24 mcg of Amitiza and fully recovered. The second report was a study patient who self-administered a total of 96 mcg of Amitiza per day for 8 days. The patient experienced no adverse reactions during this time. Additionally, in a Phase 1 cardiac repolarization study, 38 of 51 healthy volunteers given a single oral dose of 144 mcg of Amitiza (6 times the highest recommended dose) experienced an adverse event that was at least possibly related to the study drug. Adverse reactions that occurred in at least 1% of these volunteers included the following: nausea (45%), diarrhea (35%), vomiting (27%), dizziness (14%), headache (12%), abdominal pain (8%), flushing/hot flash (8%), retching (8%), dyspnea (4%), pallor (4%), stomach discomfort (4%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), and syncope (2%).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Lubiprostone in the drug label.
# Pharmacology
## Mechanism of Action
- Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion.
- By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium.
- Lubiprostone, via activation of apical ClC-2 channels in intestinal epithelial cells, bypasses the antisecretory action of opiates that results from suppression of secretomotor neuron excitability.
- Activation of ClC-2 by lubiprostone has also been shown to stimulate recovery of mucosal barrier function and reduce intestinal permeability via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.
## Structure
- Amitiza (lubiprostone) is a chloride channel activator for oral use.
- The chemical name for lubiprostone is (–)-7-pyran-5-yl]heptanoic acid. The molecular formula of lubiprostone is C20H32F2O5 with a molecular weight of 390.46 and a chemical structure as follows:
- Lubiprostone drug substance occurs as white, odorless crystals or crystalline powder, is very soluble in ether and ethanol, and is practically insoluble in hexane and water. Amitiza is available as an imprinted, oval, soft gelatin capsule in two strengths. Pink capsules contain 8 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, ferric oxide, titanium dioxide, and purified water. Orange capsules contain 24 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, FD&C Red #40, D&C Yellow #10, and purified water.
## Pharmacodynamics
- Although the pharmacologic effects of lubiprostone in humans have not been fully evaluated, animal studies have shown that oral administration of lubiprostone increases chloride ion transport into the intestinal lumen, enhances fluid secretion into the bowels, and improves fecal transit.
## Pharmacokinetics
- Lubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL). Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized. Gender has no effect on the pharmacokinetics of M3 following the oral administration of lubiprostone.
- Absorption
- Concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL) because lubiprostone has a low systemic availability following oral administration. Peak plasma levels of M3, after a single oral dose with 24 mcg of lubiprostone, occurred at approximately 1.10 hours. The Cmax was 41.5 pg/mL and the mean AUC0–t was 57.1 pg∙hr/mL. The AUC0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone.
- Distribution
- In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Studies in rats given radiolabeled lubiprostone indicate minimal distribution beyond the gastrointestinal tissues. Concentrations of radiolabeled lubiprostone at 48 hours post-administration were minimal in all tissues of the rats.
- Metabolism
- The results of both human and animal studies indicate that lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. These biotransformations are not mediated by the hepatic cytochrome P450 system but rather appear to be mediated by the ubiquitously expressed carbonyl reductase. M3, a metabolite of lubiprostone found in both humans and animals, is formed by the reduction of the carbonyl group at the 15-hydroxy moiety that consists of both α-hydroxy and β-hydroxy epimers. M3 makes up less than 10% of the dose of radiolabeled lubiprostone. Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption.
- Elimination
- Lubiprostone could not be detected in plasma; however, M3 has a t½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3H-labeled lubiprostone, 60% of total administered radioactivity was recovered in the urine within 24 hours and 30% of total administered radioactivity was recovered in the feces by 168 hours. Lubiprostone and M3 are only detected in trace amounts in human feces.
- Food Effect
- A study was conducted with a single 72-mcg dose of 3H-labeled lubiprostone to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that Cmax decreased by 55% while AUC0–∞ was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials.
- Special Populations
- Renal Impairment
- Sixteen subjects, 34–47 years old (8 severe renally impaired subjects ] (CrCl) 80 mL/min]), received a single oral 24-mcg dose of Amitiza. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL). Plasma concentrations of M3 were within the range of exposure from previous clinical experience with Amitiza.
- Hepatic Impairment
- Twenty-five subjects, 38–78 years old (9 with severe hepatic impairment , 8 with moderate impairment , and 8 with normal liver function), received either 12 mcg or 24 mcg of Amitiza under fasting conditions. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL) except for two subjects. In moderately and severely impaired subjects, the Cmax and AUC0–t of the active lubiprostone metabolite M3 were increased, as shown in Table 4.
- These results demonstrate that there is a correlation between increased exposure of M3 and severity of hepatic impairment.
## Nonclinical Toxicology
- Carcinogenesis
- Two 2-year oral (gavage) carcinogenicity studies (one in Crl:B6C3F1 mice and one in Sprague-Dawley rats) were conducted with lubiprostone. In the 2-year carcinogenicity study in mice, lubiprostone doses of 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the highest recommended human dose, respectively, based on body surface area) were used. In the 2-year rat carcinogenicity study, lubiprostone doses of 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the highest recommended human dose, respectively, based on body surface area) were used. In the mouse carcinogenicity study, there was no significant increase in any tumor incidences. There was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats at the 400 mcg/kg/day dose. In female rats, treatment with lubiprostone produced hepatocellular adenoma at the 400 mcg/kg/day dose.
- Mutagenesis
- Lubiprostone was not genotoxic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma (L5178Y TK +/–) forward mutation assay, the in vitro Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus assay.
- Impairment of Fertility
- Lubiprostone, at oral doses of up to 1000 mcg/kg/day, had no effect on the fertility and reproductive function of male and female rats. However, the number of implantation sites and live embryos were significantly reduced in rats at the 1000 mcg/kg/day dose as compared to control. The number of dead or resorbed embryos in the 1000 mcg/kg/day group was higher compared to the control group, but was not statistically significant. The 1000 mcg/kg/day dose in rats is approximately 169 times the highest recommended human dose of 48 mcg/day, based on body surface area.
# Clinical Studies
- Chronic Idiopathic Constipation
- Two double-blinded, placebo-controlled studies of identical design were conducted in patients with chronic idiopathic constipation. Chronic idiopathic constipation was defined as, on average, less than 3 spontaneous bowel movements (SBMs) per week (a SBM is a bowel movement occurring in the absence of laxative use) along with one or more of the following symptoms of constipation for at least 6 months prior to randomization: 1) very hard stools for at least a quarter of all bowel movements; 2) sensation of incomplete evacuation following at least a quarter of all bowel movements; and 3) straining with defecation at least a quarter of the time.
- Following a 2-week baseline/washout period, a total of 479 patients (mean age 47.2 years; 88.9% female; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% ≥ 65 years of age) were randomized and received Amitiza 24 mcg twice daily or placebo twice daily for 4 weeks. The primary endpoint of the studies was SBM frequency. The studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs during Week 1 than the placebo patients. In both studies, results similar to those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 5).
- In both studies, Amitiza demonstrated increases in the percentage of patients who experienced SBMs within the first 24 hours after administration when compared to placebo (56.7% vs. 36.9% in Study 1 and 62.9% vs. 31.9% in Study 2, respectively). Similarly, the time to first SBM was shorter for patients receiving Amitiza than for those receiving placebo.
- Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved with Amitiza versus placebo. The results were consistent in subpopulation analyses for gender, race, and elderly patients (≥ 65 years of age).
- During a 7-week randomized withdrawal study, patients who received Amitiza during a 4-week treatment period were then randomized to receive either placebo or to continue treatment with Amitiza. In Amitiza-treated patients randomized to placebo, SBM frequency rates returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on Amitiza maintained their response to therapy over the additional 3 weeks of treatment.
- Opioid-induced Constipation
- The efficacy of Amitiza in the treatment of opioid-induced constipation in patients receiving opioid therapy for chronic, non-cancer-related pain was assessed in three randomized, double-blinded, placebo-controlled studies. In Study 1, the median age was 52 years (range 20–82) and 63.1% were female. In Study 2, the median age was 50 years (range 21–77) and 64.4% were female. In Study 3, the median age was 50 years (range 21–89) and 60.1% were female. Patients had been receiving stable opioid therapy for at least 30 days prior to screening, which was to continue throughout the 12-week treatment period. At baseline, mean oral morphine equivalent daily doses (MEDDs) were 99 mg and 130 mg for placebo-treated and Amitiza-treated patients, respectively, in Study 1. Baseline mean MEDDs were 237 mg and 265 mg for placebo-treated and Amitiza-treated patients, respectively, in Study 2. In Study 3, baseline mean MEDDs were 330 mg and 373 mg for placebo-treated and Amitiza-treated patients, respectively. The Brief Pain Inventory-Short Form (BPI-SF) questionnaire was administered to patients at baseline and monthly during the treatment period to assess pain control. Patients had documented opioid-induced constipation at baseline, defined as having less than 3 spontaneous bowel movements (SBMs) per week, with at least 25% of SBMs associated with one or more of the following conditions: (1) hard to very hard stool consistency; (2) moderate to very severe straining; and/or (3) having a sensation of incomplete evacuation. Laxative use was discontinued at the beginning of the screening period and throughout the study. With the exception of the 48-hour period prior to first dose and for at least 72 hours (Study 1) or 1 week (Study 2 and Study 3) following first dose, use of rescue medication was allowed in cases where no bowel movement had occurred in a 3-day period. Median weekly SBM frequencies at baseline were 1.5 for placebo patients and 1.0 for Amitiza patients in Study 1 and, for both Study 2 and Study 3, median weekly SBM frequencies at baseline were 1.5 for both treatment groups.
- In Study 1, patients receiving non-diphenylheptane (e.g., non-methadone) opioids (n = 431) were randomized to receive placebo (n = 217) or Amitiza 24 mcg twice daily (n = 214) for 12 weeks. The primary efficacy analysis was a comparison of the proportion of “overall responders” in each treatment arm. A patient was considered an “overall responder” if ≥1 SBM improvement over baseline were reported for all treatment weeks for which data were available and ≥3 SBMs/week were reported for at least 9 of 12 treatment weeks. The proportion of patients in Study 1 qualifying as an “overall responder” was 27.1% in the group receiving Amitiza 24 mcg twice daily compared to 18.9% of patients receiving placebo twice daily (treatment difference = 8.2%; p-value = 0.03). Examination of gender and race subgroups did not identify differences in response to Amitiza among these subgroups. There were too few elderly patients (≥ 65 years of age) to adequately assess differences in effects in that population.
- In Study 2, patients receiving opioids (N = 418) were randomized to receive placebo (n = 208) or Amitiza 24 mcg twice daily (n = 210) for 12 weeks. Study 2 did not exclude patients receiving diphenylheptane opioids (e.g., methadone). The primary efficacy endpoint was the mean change from baseline in SBM frequency at Week 8; 3.3 vs. 2.4 for Amitiza and placebo-treated patients, respectively; treatment difference = 0.9; p-value = 0.004. The proportion of patients in Study 2 qualifying as an “overall responder,” as prespecified in Study 1, was 24.3% in the group receiving Amitiza compared to 15.4% of patients receiving placebo. In the subgroup of patients in Study 2 taking diphenylheptane opioids (baseline mean MEDDs of 691 mg and 672 mg for placebo and Amitiza patients, respectively), the proportion of patients qualifying as an “overall responder” was 20.5% (8/39) in the group receiving Amitiza compared to 6.3% (2/32) of patients receiving placebo. Examination of gender and race subgroups did not identify differences in response to Amitiza among these subgroups. There were too few elderly patients (≥ 65 years of age) to adequately assess differences in effects in that population.
- In Study 3, patients receiving opioids (N = 451) were randomized to placebo (n = 216) or Amitiza 24 mcg twice daily (n = 235) for 12 weeks. Study 3 did not exclude patients receiving diphenylheptane opioids (e.g., methadone). The primary efficacy endpoint was the change from baseline in SBM frequency at Week 8. The study did not demonstrate a statistically significant improvement in SBM frequency rates at Week 8 (mean change from baseline of 2.7 vs. 2.5 for Amitiza and placebo-treated patients, respectively; treatment difference = 0.2; p-value = 0.76). The proportion of patients in Study 3 qualifying as an “overall responder,” as prespecified in Study 1, was 15.3% in the patients receiving Amitiza compared to 13.0% of patients receiving placebo. In the subgroup of patients in Study 3 taking diphenylheptane opioids (baseline mean MEDDs of 730 mg and 992 mg for placebo and Amitiza patients, respectively), the proportion of patients qualifying as an “overall responder” was 2.1% (1/47) in the group receiving Amitiza compared to 12.2% (5/41) of patients receiving placebo.
- Irritable Bowel Syndrome with Constipation
- Two double-blinded, placebo-controlled studies of similar design were conducted in patients with IBS-C. IBS was defined as abdominal pain or discomfort occurring over at least 6 months with two or more of the following: 1) relieved with defecation; 2) onset associated with a change in stool frequency; and 3) onset associated with a change in stool form. Patients were sub-typed as having IBS-C if they also experienced two of three of the following: 1) 25% hard stools, and 3) > 25% SBMs associated with straining.
- Following a 4-week baseline/washout period, a total of 1154 patients (mean age 46.6 years; 91.6% female; 77.4% Caucasian, 13.2% African American, 8.5% Hispanic, 0.4% Asian; 8.3% ≥ 65 years of age) were randomized and received Amitiza 8 mcg twice daily (16 mcg/day) or placebo twice daily for 12 weeks. The primary efficacy endpoint was assessed weekly utilizing the patient's response to a global symptom relief question based on a 7-point, balanced scale ("significantly worse" to "significantly relieved"): "How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared to how you felt before you entered the study?"
- The primary efficacy analysis was a comparison of the proportion of "overall responders" in each arm. A patient was considered an "overall responder" if the criteria for being designated a "monthly responder" were met in at least 2 of the 3 months on study. A "monthly responder" was defined as a patient who had reported "significantly relieved" for at least 2 weeks of the month or at least "moderately relieved" in all 4 weeks of that month. During each monthly evaluation period, patients reporting "moderately worse" or "significantly worse" relief, an increase in rescue medication use, or those who discontinued due to lack of efficacy, were deemed non-responders.
- The percentage of patients in Study 1 qualifying as an "overall responder" was 13.8% in the group receiving Amitiza 8 mcg twice daily compared to 7.8% of patients receiving placebo twice daily. In Study 2, 12.1% of patients in the Amitiza 8 mcg group were "overall responders" versus 5.7% of patients in the placebo group. In both studies, the treatment differences between the placebo and Amitiza groups were statistically significant.
- Results in men: The two randomized, placebo-controlled, double-blinded studies comprised 97 (8.4%) male patients, which is insufficient to determine whether men with IBS-C respond differently to Amitiza from women.
- During a 4-week randomized withdrawal period following Study 1, patients who received Amitiza during the 12-week treatment period were re-randomized to receive either placebo or to continue treatment with Amitiza. In Amitiza-treated patients who were “overall responders” during Study 1 and who were re-randomized to placebo, SBM frequency rates did not result in worsening compared to baseline.
# How Supplied
- Amitiza is available as an oval, soft gelatin capsule containing 8 mcg or 24 mcg of lubiprostone with "SPI" printed on one side. Amitiza is available as follows:
- 8 mcg pink capsule
Bottles of 60 (NDC 64764-080-60)
- Bottles of 60 (NDC 64764-080-60)
- 24 mcg orange capsule
Bottles of 60 (NDC 64764-240-60)
Bottles of 100 (NDC 64764-240-10)
- Bottles of 60 (NDC 64764-240-60)
- Bottles of 100 (NDC 64764-240-10)
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Protect from light and extreme temperatures.
## Storage
There is limited information regarding Lubiprostone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Physicians and patients should periodically assess the need for continued therapy.
- Nausea, Dyspnea or Diarrhea
- Instruct patients to take Amitiza twice daily with food and water to reduce the occurrence of nausea. Patients taking Amitiza may experience dyspnea within an hour of the first dose. Dyspnea generally resolves within 3 hours, but may recur with repeat dosing. Patients on treatment who experience severe nausea, dyspnea, or diarrhea should notify their physician.
- Nursing Mothers
- Advise lactating women to monitor their human milk-fed infants for diarrhea while taking Amitiza.
# Precautions with Alcohol
- Alcohol-Lubiprostone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Amitiza®
# Look-Alike Drug Names
There is limited information regarding Lubiprostone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Lubiprostone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Lubiprostone is a chloride channel activator that is FDA approved for the {{{indicationType}}} of chronic idiopathic constipation in adults, opioid-induced constipation in adults with chronic, non-cancer pain, irritable bowel syndrome with constipation in women ≥ 18 years old. Common adverse reactions include nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose is 24 mcg twice daily orally with food and water.
- Dosage in patients with hepatic impairment
- For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended starting dose is 16 mcg twice daily. For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg twice daily. If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response.
- Dosing Information
- The recommended dose is 8 mcg twice daily orally with food and water.
- Dosage in patients with hepatic impairment
- For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg once daily. If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response. Dosage adjustment is not required for patients with moderately impaired hepatic function (Child-Pugh Class B).
- Amitiza is indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain.
- Limitations of Use:
- Effectiveness of Amitiza in the treatment of opioid-induced constipation in patients taking diphenylheptaneopioids (e.g., methadone) has not been established.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lubiprostone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lubiprostone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lubiprostone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lubiprostone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lubiprostone in pediatric patients.
# Contraindications
- Amitiza is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
# Warnings
### Precautions
- Nausea
- Patients taking Amitiza may experience nausea. Concomitant administration of food with Amitiza may reduce symptoms of nausea.
- Diarrhea
- Amitiza should not be prescribed to patients that have severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Patients should be instructed to discontinue Amitiza and inform their physician if severe diarrhea occurs.
- Dyspnea
- In clinical trials, dyspnea was reported by 3%, 1%, and < 1% of the treated CIC, OIC, and IBS-C populations receiving Amitiza, respectively, compared to 0%, 1%, and < 1% of placebo-treated patients. There have been postmarketing reports of dyspnea when using Amitiza 24 mcg twice daily. Some patients have discontinued treatment because of dyspnea. These events have usually been described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within 30–60 minutes after taking the first dose. They generally resolve within a few hours after taking the dose, but recurrence has been frequently reported with subsequent doses.
- Bowel Obstruction
- In patients with symptoms suggestive of mechanical gastrointestinal obstruction, perform a thorough evaluation to confirm the absence of an obstruction prior to initiating therapy with Amitiza.
# 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 practice.
- During clinical development of Amitiza for CIC, OIC, and IBS-C, 1234 patients were treated with Amitiza for 6 months and 524 patients were treated for 1 year (not mutually exclusive).
- Chronic Idiopathic Constipation
- Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza 24 mcg twice daily in 1113 patients with chronic idiopathic constipation over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure (≤ 4 weeks). The placebo population (N = 316) had a mean age of 47.8 (range 21–81) years; was 87.3% female; 80.7% Caucasian, 10.1% African American, 7.3% Hispanic, 0.9% Asian; and 11.7% elderly (≥ 65 years of age). Of those patients treated with Amitiza 24 mcg twice daily (N=1113), the mean age was 50.3 (range 19-86) years; 86.9% were female; 86.1% Caucasian, 7.6% African American, 4.7% Hispanic, 1.0% Asian; and 16.7% elderly (≥ 65 years of age). Table 1 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 24 mcg twice daily and that occurred more frequently with study drug than placebo.
- The most common adverse reactions (incidence > 4%) in CIC were nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence.
- Nausea: Approximately 29% of patients who received Amitiza 24 mcg twice daily experienced nausea; 4% of patients had severe nausea and 9% of patients discontinued treatment due to nausea. The rate of nausea associated with Amitiza 24 mcg twice daily was lower among male (8%) and elderly (19%) patients. No patients in the clinical studies were hospitalized due to nausea.
- Diarrhea: Approximately 12% of patients who received Amitiza 24 mcg twice daily experienced diarrhea; 2% of patients had severe diarrhea and 2% of patients discontinued treatment due to diarrhea.
- Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving Amitiza.
- Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Amitiza 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite.
- Opioid-induced Constipation
- Adverse reactions in efficacy and long-term clinical studies: The data described below reflect exposure to Amitiza 24 mcg twice daily in 860 patients with OIC for up to 12 months and from 632 patients receiving placebo twice daily for up to 12 weeks. The total population (N = 1492) had a mean age of 50.4 (range 20–89) years; was 62.7% female; 82.7% Caucasian, 14.2% African American, 0.8% American Indian/Alaska Native, 0.8% Asian; 5.2% were of Hispanic ethnicity; and 8.8% were elderly (≥ 65 years of age). Table 2 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 24 mcg twice daily and that occurred more frequently with study drug than placebo.
- The most common adverse reactions (incidence > 4%) in OIC were nausea and diarrhea.
- Nausea: Approximately 11% of patients who received Amitiza 24 mcg twice daily experienced nausea; 1% of patients had severe nausea and 2% of patients discontinued treatment due to nausea.
- Diarrhea: Approximately 8% of patients who received Amitiza 24 mcg twice daily experienced diarrhea; 2% of patients had severe diarrhea and 1% of patients discontinued treatment due to diarrhea.
- Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Amitiza 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: fecal incontinence, blood potassium decreased.
- Irritable Bowel Syndrome with Constipation
- Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N = 1267) had a mean age of 46.5 (range 18–85) years; was 91.6% female; 77.5% Caucasian, 12.9% African American, 8.6% Hispanic, 0.4% Asian; and 8.0% elderly (≥ 65 years of age). Table 3 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 8 mcg twice daily and that occurred more frequently with study drug than placebo.
- The most common adverse reactions (incidence > 4%) in IBS-C were nausea, diarrhea, and abdominal pain.
- Nausea: Approximately 8% of patients who received Amitiza 8 mcg twice daily experienced nausea; 1% of patients had severe nausea and 1% of patients discontinued treatment due to nausea.
- Diarrhea: Approximately 7% of patients who received Amitiza 8 mcg twice daily experienced diarrhea; <1% of patients had severe diarrhea and <1% of patients discontinued treatment due to diarrhea.
- Less common adverse reactions: The following adverse reactions (assessed by investigator as probably related to treatment) occurred in less than 1% of patients receiving Amitiza 8 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria.
## Postmarketing Experience
- The following additional adverse reactions have been identified during post-approval use of Amitiza. 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.
- Voluntary reports of adverse reactions occurring with the use of Amitiza include the following: syncope, ischemic colitis, hypersensitivity/allergic-type reactions (including rash, swelling, and throat tightness), malaise, tachycardia, muscle cramps or muscle spasms, and asthenia.
# Drug Interactions
- No in vivo drug-drug interaction studies have been performed with Amitiza.
- Based upon the results of in vitro human microsome studies, there is low likelihood of pharmacokinetic drug-drug interactions. In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. Further in vitro studies indicate microsomal carbonyl reductase may be involved in the extensive biotransformation of lubiprostone to the metabolite M3. Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone. Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.
- Interaction potential with diphenylheptane opioids (e.g. methadone): Non-clinical studies have shown opioids of the diphenylheptane chemical class (e.g., methadone) to dose-dependently reduce the activation of ClC-2 by lubiprostone in the gastrointestinal tract. There is a possibility of a dose-dependent decrease in the efficacy of Amitiza in patients using diphenylheptane opioids.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Risk Summary
- There are no adequate and well-controlled studies with Amitiza in pregnant women. A dose dependent increase in fetal loss was observed in pregnant guinea pigs that received lubiprostone doses equivalent to 0.2 to 6 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2). Animal studies did not show an increase in structural malformations. Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Clinical Considerations
- Current available data suggest that miscarriage occurs in 15-18% of clinically recognized pregnancies, regardless of any drug exposure. Consider the risks and benefits of available therapies when treating a pregnant woman for chronic idiopathic constipation, opioid-induced constipation or irritable bowel syndrome with constipation.
- Animal Data
- In developmental toxicity studies, pregnant rats and rabbits received oral lubiprostone during organogenesis at doses up to approximately 338 times (rats) and approximately 34 times (rabbits) the maximum recommended human dose (MHRD) based on body surface area (mg/m2). Maximal animal doses were 2000 mcg/kg/day (rats) and 100 mcg/kg/day (rabbits). In rats, there were increased incidences of early resorptions and soft tissue malformations (situs inversus, cleft palate) at the 2000 mcg/kg/day dose; however, these effects were probably secondary to maternal toxicity. A dose-dependent increase in fetal loss occurred when guinea pigs received lubiprostone after the period of organogenesis, on days 40 to 53 of gestation, at daily oral doses of 1, 10, and 25 mcg/kg/day (approximately 0.2, 2 and 6 times the MRHD based on body surface area (mg/m2)). The potential of lubiprostone to cause fetal loss was also examined in pregnant Rhesus monkeys. Monkeys received lubiprostone post-organogenesis on gestation days 110 through 130 at daily oral doses of 10 and 30 mcg/kg/day (approximately 3 and 10 times the MHRD based on body surface area (mg/m2)). Fetal loss was noted in one monkey from the 10-mcg/kg dose group, which is within normal historical rates for this species. There was no drug-related adverse effect seen in monkeys.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lubiprostone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lubiprostone during labor and delivery.
### Nursing Mothers
- It is not known whether lubiprostone is excreted in human milk. In rats, neither lubiprostone nor its active metabolites were detectable in breast milk following oral administration of lubiprostone. Because lubiprostone increases fluid secretion in the intestine and intestinal motility, human milk-fed infants should be monitored for diarrhea. Caution should be exercised when Amitiza is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Lubiprostone with respect to pediatric patients.
### Geriatic Use
- Chronic Idiopathic Constipation
- The efficacy of Amitiza in the elderly (≥ 65 years of age) subpopulation was consistent with the efficacy in the overall study population. Of the total number of constipated patients treated in the dose-finding, efficacy, and long-term studies of Amitiza, 15.5% were ≥ 65 years of age, and 4.2% were ≥ 75 years of age. Elderly patients taking Amitiza 24 mcg twice daily experienced a lower rate of associated nausea compared to the overall study population taking Amitiza (19% vs. 29%, respectively).
- Opioid-induced Constipation
- The safety profile of Amitiza in the elderly (≥ 65 years of age) subpopulation (8.8% were ≥ 65 years of age and 1.6% were ≥ 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Amitiza did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
- Irritable Bowel Syndrome with Constipation
- The safety profile of Amitiza in the elderly (≥ 65 years of age) subpopulation (8.0% were ≥ 65 years of age and 1.8% were ≥ 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Amitiza did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Lubiprostone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lubiprostone with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is required in patients with renal impairment.
### Hepatic Impairment
- Patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C) experienced markedly higher systemic exposure of lubiprostone active metabolite M3, when compared to normal subjects. Clinical safety results demonstrated an increased incidence and severity of adverse events in subjects with greater severity of hepatic impairment.
- In case of chronic idiopathic constipation or opioid-induced constipation indications, the starting dosage of Amitiza should be reduced in patients with moderate hepatic impairment. The starting dose of Amitiza should be reduced in all patients with severe hepatic impairment, regardless of the indication. No dosing adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lubiprostone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lubiprostone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lubiprostone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lubiprostone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There have been two confirmed reports of overdosage with Amitiza. The first report involved a 3-year-old child who accidentally ingested 7 or 8 capsules of 24 mcg of Amitiza and fully recovered. The second report was a study patient who self-administered a total of 96 mcg of Amitiza per day for 8 days. The patient experienced no adverse reactions during this time. Additionally, in a Phase 1 cardiac repolarization study, 38 of 51 healthy volunteers given a single oral dose of 144 mcg of Amitiza (6 times the highest recommended dose) experienced an adverse event that was at least possibly related to the study drug. Adverse reactions that occurred in at least 1% of these volunteers included the following: nausea (45%), diarrhea (35%), vomiting (27%), dizziness (14%), headache (12%), abdominal pain (8%), flushing/hot flash (8%), retching (8%), dyspnea (4%), pallor (4%), stomach discomfort (4%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), and syncope (2%).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Lubiprostone in the drug label.
# Pharmacology
## Mechanism of Action
- Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion.
- By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium.
- Lubiprostone, via activation of apical ClC-2 channels in intestinal epithelial cells, bypasses the antisecretory action of opiates that results from suppression of secretomotor neuron excitability.
- Activation of ClC-2 by lubiprostone has also been shown to stimulate recovery of mucosal barrier function and reduce intestinal permeability via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.
## Structure
- Amitiza (lubiprostone) is a chloride channel activator for oral use.
- The chemical name for lubiprostone is (–)-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid. The molecular formula of lubiprostone is C20H32F2O5 with a molecular weight of 390.46 and a chemical structure as follows:
- Lubiprostone drug substance occurs as white, odorless crystals or crystalline powder, is very soluble in ether and ethanol, and is practically insoluble in hexane and water. Amitiza is available as an imprinted, oval, soft gelatin capsule in two strengths. Pink capsules contain 8 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, ferric oxide, titanium dioxide, and purified water. Orange capsules contain 24 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, FD&C Red #40, D&C Yellow #10, and purified water.
## Pharmacodynamics
- Although the pharmacologic effects of lubiprostone in humans have not been fully evaluated, animal studies have shown that oral administration of lubiprostone increases chloride ion transport into the intestinal lumen, enhances fluid secretion into the bowels, and improves fecal transit.
## Pharmacokinetics
- Lubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL). Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized. Gender has no effect on the pharmacokinetics of M3 following the oral administration of lubiprostone.
- Absorption
- Concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL) because lubiprostone has a low systemic availability following oral administration. Peak plasma levels of M3, after a single oral dose with 24 mcg of lubiprostone, occurred at approximately 1.10 hours. The Cmax was 41.5 pg/mL and the mean AUC0–t was 57.1 pg∙hr/mL. The AUC0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone.
- Distribution
- In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Studies in rats given radiolabeled lubiprostone indicate minimal distribution beyond the gastrointestinal tissues. Concentrations of radiolabeled lubiprostone at 48 hours post-administration were minimal in all tissues of the rats.
- Metabolism
- The results of both human and animal studies indicate that lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. These biotransformations are not mediated by the hepatic cytochrome P450 system but rather appear to be mediated by the ubiquitously expressed carbonyl reductase. M3, a metabolite of lubiprostone found in both humans and animals, is formed by the reduction of the carbonyl group at the 15-hydroxy moiety that consists of both α-hydroxy and β-hydroxy epimers. M3 makes up less than 10% of the dose of radiolabeled lubiprostone. Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption.
- Elimination
- Lubiprostone could not be detected in plasma; however, M3 has a t½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3H-labeled lubiprostone, 60% of total administered radioactivity was recovered in the urine within 24 hours and 30% of total administered radioactivity was recovered in the feces by 168 hours. Lubiprostone and M3 are only detected in trace amounts in human feces.
- Food Effect
- A study was conducted with a single 72-mcg dose of 3H-labeled lubiprostone to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that Cmax decreased by 55% while AUC0–∞ was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials.
- Special Populations
- Renal Impairment
- Sixteen subjects, 34–47 years old (8 severe renally impaired subjects [[[creatinine clearance]] (CrCl) < 20 mL/min] who required hemodialysis and 8 control subjects with normal renal function [CrCl > 80 mL/min]), received a single oral 24-mcg dose of Amitiza. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL). Plasma concentrations of M3 were within the range of exposure from previous clinical experience with Amitiza.
- Hepatic Impairment
- Twenty-five subjects, 38–78 years old (9 with severe hepatic impairment [Child-Pugh Class C], 8 with moderate impairment [Child-Pugh Class B], and 8 with normal liver function), received either 12 mcg or 24 mcg of Amitiza under fasting conditions. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL) except for two subjects. In moderately and severely impaired subjects, the Cmax and AUC0–t of the active lubiprostone metabolite M3 were increased, as shown in Table 4.
- These results demonstrate that there is a correlation between increased exposure of M3 and severity of hepatic impairment.
## Nonclinical Toxicology
- Carcinogenesis
- Two 2-year oral (gavage) carcinogenicity studies (one in Crl:B6C3F1 mice and one in Sprague-Dawley rats) were conducted with lubiprostone. In the 2-year carcinogenicity study in mice, lubiprostone doses of 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the highest recommended human dose, respectively, based on body surface area) were used. In the 2-year rat carcinogenicity study, lubiprostone doses of 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the highest recommended human dose, respectively, based on body surface area) were used. In the mouse carcinogenicity study, there was no significant increase in any tumor incidences. There was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats at the 400 mcg/kg/day dose. In female rats, treatment with lubiprostone produced hepatocellular adenoma at the 400 mcg/kg/day dose.
- Mutagenesis
- Lubiprostone was not genotoxic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma (L5178Y TK +/–) forward mutation assay, the in vitro Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus assay.
- Impairment of Fertility
- Lubiprostone, at oral doses of up to 1000 mcg/kg/day, had no effect on the fertility and reproductive function of male and female rats. However, the number of implantation sites and live embryos were significantly reduced in rats at the 1000 mcg/kg/day dose as compared to control. The number of dead or resorbed embryos in the 1000 mcg/kg/day group was higher compared to the control group, but was not statistically significant. The 1000 mcg/kg/day dose in rats is approximately 169 times the highest recommended human dose of 48 mcg/day, based on body surface area.
# Clinical Studies
- Chronic Idiopathic Constipation
- Two double-blinded, placebo-controlled studies of identical design were conducted in patients with chronic idiopathic constipation. Chronic idiopathic constipation was defined as, on average, less than 3 spontaneous bowel movements (SBMs) per week (a SBM is a bowel movement occurring in the absence of laxative use) along with one or more of the following symptoms of constipation for at least 6 months prior to randomization: 1) very hard stools for at least a quarter of all bowel movements; 2) sensation of incomplete evacuation following at least a quarter of all bowel movements; and 3) straining with defecation at least a quarter of the time.
- Following a 2-week baseline/washout period, a total of 479 patients (mean age 47.2 [range 20–81] years; 88.9% female; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% ≥ 65 years of age) were randomized and received Amitiza 24 mcg twice daily or placebo twice daily for 4 weeks. The primary endpoint of the studies was SBM frequency. The studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs during Week 1 than the placebo patients. In both studies, results similar to those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 5).
- In both studies, Amitiza demonstrated increases in the percentage of patients who experienced SBMs within the first 24 hours after administration when compared to placebo (56.7% vs. 36.9% in Study 1 and 62.9% vs. 31.9% in Study 2, respectively). Similarly, the time to first SBM was shorter for patients receiving Amitiza than for those receiving placebo.
- Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved with Amitiza versus placebo. The results were consistent in subpopulation analyses for gender, race, and elderly patients (≥ 65 years of age).
- During a 7-week randomized withdrawal study, patients who received Amitiza during a 4-week treatment period were then randomized to receive either placebo or to continue treatment with Amitiza. In Amitiza-treated patients randomized to placebo, SBM frequency rates returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on Amitiza maintained their response to therapy over the additional 3 weeks of treatment.
- Opioid-induced Constipation
- The efficacy of Amitiza in the treatment of opioid-induced constipation in patients receiving opioid therapy for chronic, non-cancer-related pain was assessed in three randomized, double-blinded, placebo-controlled studies. In Study 1, the median age was 52 years (range 20–82) and 63.1% were female. In Study 2, the median age was 50 years (range 21–77) and 64.4% were female. In Study 3, the median age was 50 years (range 21–89) and 60.1% were female. Patients had been receiving stable opioid therapy for at least 30 days prior to screening, which was to continue throughout the 12-week treatment period. At baseline, mean oral morphine equivalent daily doses (MEDDs) were 99 mg and 130 mg for placebo-treated and Amitiza-treated patients, respectively, in Study 1. Baseline mean MEDDs were 237 mg and 265 mg for placebo-treated and Amitiza-treated patients, respectively, in Study 2. In Study 3, baseline mean MEDDs were 330 mg and 373 mg for placebo-treated and Amitiza-treated patients, respectively. The Brief Pain Inventory-Short Form (BPI-SF) questionnaire was administered to patients at baseline and monthly during the treatment period to assess pain control. Patients had documented opioid-induced constipation at baseline, defined as having less than 3 spontaneous bowel movements (SBMs) per week, with at least 25% of SBMs associated with one or more of the following conditions: (1) hard to very hard stool consistency; (2) moderate to very severe straining; and/or (3) having a sensation of incomplete evacuation. Laxative use was discontinued at the beginning of the screening period and throughout the study. With the exception of the 48-hour period prior to first dose and for at least 72 hours (Study 1) or 1 week (Study 2 and Study 3) following first dose, use of rescue medication was allowed in cases where no bowel movement had occurred in a 3-day period. Median weekly SBM frequencies at baseline were 1.5 for placebo patients and 1.0 for Amitiza patients in Study 1 and, for both Study 2 and Study 3, median weekly SBM frequencies at baseline were 1.5 for both treatment groups.
- In Study 1, patients receiving non-diphenylheptane (e.g., non-methadone) opioids (n = 431) were randomized to receive placebo (n = 217) or Amitiza 24 mcg twice daily (n = 214) for 12 weeks. The primary efficacy analysis was a comparison of the proportion of “overall responders” in each treatment arm. A patient was considered an “overall responder” if ≥1 SBM improvement over baseline were reported for all treatment weeks for which data were available and ≥3 SBMs/week were reported for at least 9 of 12 treatment weeks. The proportion of patients in Study 1 qualifying as an “overall responder” was 27.1% in the group receiving Amitiza 24 mcg twice daily compared to 18.9% of patients receiving placebo twice daily (treatment difference = 8.2%; p-value = 0.03). Examination of gender and race subgroups did not identify differences in response to Amitiza among these subgroups. There were too few elderly patients (≥ 65 years of age) to adequately assess differences in effects in that population.
- In Study 2, patients receiving opioids (N = 418) were randomized to receive placebo (n = 208) or Amitiza 24 mcg twice daily (n = 210) for 12 weeks. Study 2 did not exclude patients receiving diphenylheptane opioids (e.g., methadone). The primary efficacy endpoint was the mean change from baseline in SBM frequency at Week 8; 3.3 vs. 2.4 for Amitiza and placebo-treated patients, respectively; treatment difference = 0.9; p-value = 0.004. The proportion of patients in Study 2 qualifying as an “overall responder,” as prespecified in Study 1, was 24.3% in the group receiving Amitiza compared to 15.4% of patients receiving placebo. In the subgroup of patients in Study 2 taking diphenylheptane opioids (baseline mean [median] MEDDs of 691 [403] mg and 672 [450] mg for placebo and Amitiza patients, respectively), the proportion of patients qualifying as an “overall responder” was 20.5% (8/39) in the group receiving Amitiza compared to 6.3% (2/32) of patients receiving placebo. Examination of gender and race subgroups did not identify differences in response to Amitiza among these subgroups. There were too few elderly patients (≥ 65 years of age) to adequately assess differences in effects in that population.
- In Study 3, patients receiving opioids (N = 451) were randomized to placebo (n = 216) or Amitiza 24 mcg twice daily (n = 235) for 12 weeks. Study 3 did not exclude patients receiving diphenylheptane opioids (e.g., methadone). The primary efficacy endpoint was the change from baseline in SBM frequency at Week 8. The study did not demonstrate a statistically significant improvement in SBM frequency rates at Week 8 (mean change from baseline of 2.7 vs. 2.5 for Amitiza and placebo-treated patients, respectively; treatment difference = 0.2; p-value = 0.76). The proportion of patients in Study 3 qualifying as an “overall responder,” as prespecified in Study 1, was 15.3% in the patients receiving Amitiza compared to 13.0% of patients receiving placebo. In the subgroup of patients in Study 3 taking diphenylheptane opioids (baseline mean [median] MEDDs of 730 [518] mg and 992 [480] mg for placebo and Amitiza patients, respectively), the proportion of patients qualifying as an “overall responder” was 2.1% (1/47) in the group receiving Amitiza compared to 12.2% (5/41) of patients receiving placebo.
- Irritable Bowel Syndrome with Constipation
- Two double-blinded, placebo-controlled studies of similar design were conducted in patients with IBS-C. IBS was defined as abdominal pain or discomfort occurring over at least 6 months with two or more of the following: 1) relieved with defecation; 2) onset associated with a change in stool frequency; and 3) onset associated with a change in stool form. Patients were sub-typed as having IBS-C if they also experienced two of three of the following: 1) < 3 spontaneous bowel movements (SBMs) per week, 2) > 25% hard stools, and 3) > 25% SBMs associated with straining.
- Following a 4-week baseline/washout period, a total of 1154 patients (mean age 46.6 [range 18–85] years; 91.6% female; 77.4% Caucasian, 13.2% African American, 8.5% Hispanic, 0.4% Asian; 8.3% ≥ 65 years of age) were randomized and received Amitiza 8 mcg twice daily (16 mcg/day) or placebo twice daily for 12 weeks. The primary efficacy endpoint was assessed weekly utilizing the patient's response to a global symptom relief question based on a 7-point, balanced scale ("significantly worse" to "significantly relieved"): "How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared to how you felt before you entered the study?"
- The primary efficacy analysis was a comparison of the proportion of "overall responders" in each arm. A patient was considered an "overall responder" if the criteria for being designated a "monthly responder" were met in at least 2 of the 3 months on study. A "monthly responder" was defined as a patient who had reported "significantly relieved" for at least 2 weeks of the month or at least "moderately relieved" in all 4 weeks of that month. During each monthly evaluation period, patients reporting "moderately worse" or "significantly worse" relief, an increase in rescue medication use, or those who discontinued due to lack of efficacy, were deemed non-responders.
- The percentage of patients in Study 1 qualifying as an "overall responder" was 13.8% in the group receiving Amitiza 8 mcg twice daily compared to 7.8% of patients receiving placebo twice daily. In Study 2, 12.1% of patients in the Amitiza 8 mcg group were "overall responders" versus 5.7% of patients in the placebo group. In both studies, the treatment differences between the placebo and Amitiza groups were statistically significant.
- Results in men: The two randomized, placebo-controlled, double-blinded studies comprised 97 (8.4%) male patients, which is insufficient to determine whether men with IBS-C respond differently to Amitiza from women.
- During a 4-week randomized withdrawal period following Study 1, patients who received Amitiza during the 12-week treatment period were re-randomized to receive either placebo or to continue treatment with Amitiza. In Amitiza-treated patients who were “overall responders” during Study 1 and who were re-randomized to placebo, SBM frequency rates did not result in worsening compared to baseline.
# How Supplied
- Amitiza is available as an oval, soft gelatin capsule containing 8 mcg or 24 mcg of lubiprostone with "SPI" printed on one side. Amitiza is available as follows:
- 8 mcg pink capsule
Bottles of 60 (NDC 64764-080-60)
- Bottles of 60 (NDC 64764-080-60)
- 24 mcg orange capsule
Bottles of 60 (NDC 64764-240-60)
Bottles of 100 (NDC 64764-240-10)
- Bottles of 60 (NDC 64764-240-60)
- Bottles of 100 (NDC 64764-240-10)
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Protect from light and extreme temperatures.
## Storage
There is limited information regarding Lubiprostone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Physicians and patients should periodically assess the need for continued therapy.
- Nausea, Dyspnea or Diarrhea
- Instruct patients to take Amitiza twice daily with food and water to reduce the occurrence of nausea. Patients taking Amitiza may experience dyspnea within an hour of the first dose. Dyspnea generally resolves within 3 hours, but may recur with repeat dosing. Patients on treatment who experience severe nausea, dyspnea, or diarrhea should notify their physician.
- Nursing Mothers
- Advise lactating women to monitor their human milk-fed infants for diarrhea while taking Amitiza.
# Precautions with Alcohol
- Alcohol-Lubiprostone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Amitiza®[1]
# Look-Alike Drug Names
There is limited information regarding Lubiprostone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lubiprostone | |
7a6621ed4333c044acbf0bff328927f2954da3ec | wikidoc | Luliconazole | Luliconazole
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# Overview
Luliconazole is a azole antifungal that is FDA approved for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis. Common adverse reactions include application site reactions.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- LUZU (luliconazole) Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older.
### Dosage
- For topical use only. LUZU Cream, 1% is not for ophthalmic, oral, or intravaginal use.
- When treating interdigital tinea pedis, a thin layer of LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for two (2) weeks.
- When treating tinea cruris or tinea corporis, LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for one (1) week.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Luliconazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Luliconazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Luliconazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Luliconazole in pediatric patients.
# Contraindications
- None
# Warnings
There is limited information regarding Luliconazole Warnings' in the drug label.
# 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.
- In three Phase 3 clinical trials, 616 subjects were exposed to LUZU Cream, 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied LUZU Cream, 1% or vehicle cream once daily for 14 days or 7 days, respectively, to affected and adjacent areas. During clinical trials with LUZU Cream, 1%, the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the LUZU and vehicle arms. Most adverse reactions were mild in severity.
## Postmarketing Experience
- The following adverse reactions have been identified during postmarketing use of luliconazole cream, 1%: contact dermatitis and cellulitis. 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.
# Drug Interactions
- The potential of luliconazole to inhibit cytochrome P-450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated in vitro. Based on in vitro assessment, luliconazole at therapeutic doses, particularly when applied to patients with moderate to severe tinea cruris, may inhibit the activity of CYP2C19 and CYP3A4. However, no in vivo drug interaction trials have been conducted to evaluate the effect of luliconazole on other drugs that are substrates of CYP2C19 and CYP3A4.
- Luliconazole is not expected to inhibit CYPs 1A2, 2C9 and 2D6 based on in vitro assessment. The induction potential of luliconazole on CYP enzymes has not been evaluated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of LUZU Cream, 1% in pregnant women. LUZU Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- The animal multiples of human exposure calculations were based on daily dose body surface area (BSA) comparisons (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 1% cream per day (1.33 mg/kg/day for a 60 kg individual which is equivalent to 49.2 mg/m2/day).
- Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 7-17) to pregnant female rats. No treatment related effects on maternal toxicity or malformations were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Increased incidences of skeletal variation (14th rib) were noted at 25 mg/kg/day. No treatment related effects on skeletal variation were noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons).
- Subcutaneous doses of 4, 20 and 100 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 6-18) to pregnant female rabbits. No treatment related effects on maternal toxicity, embryofetal toxicity or malformations were noted at 100 mg/kg/day (24 times the MRHD based on BSA comparisons).
- In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered from the beginning of organogenesis (gestation day 7) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). No treatment effects on postnatal development were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Luliconazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Luliconazole during labor and delivery.
### Nursing Mothers
- It is not known whether luliconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LUZU Cream, 1% is administered to women who are breastfeeding.
### Pediatric Use
- The safety and effectiveness of LUZU Cream, 1% in pediatric patients have not been established. The number of pediatric subjects ≥12 years of age were too small to adequately assess safety and efficacy.
### Geriatic Use
- Of the total number of subjects in clinical studies of LUZU Cream, 1%, 8 percent were 65 and over, while 1.4 percent were 75 and over. 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.
### Gender
There is no FDA guidance on the use of Luliconazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Luliconazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Luliconazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Luliconazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Luliconazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Luliconazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- topical
### Monitoring
There is limited information regarding Monitoring of Luliconazole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Luliconazole in the drug label.
# Overdosage
There is limited information regarding Overdose of Luliconazole in the drug label.
# Pharmacology
## Mechanism of Action
- Luliconazole is an antifungal that belongs to the azole class. Although the exact mechanism of action against dermatophytes is unknown, luliconazole appears to inhibit ergosterol synthesis by inhibiting the enzyme lanosterol demethylase. Inhibition of this enzyme’s activity by azoles results in decreased amounts of ergosterol, a constituent of fungal cell membranes, and a corresponding accumulation of lanosterol.
## Structure
- LUZU (luliconazole) Cream, 1% contains 1% luliconazole, an azole antifungal agent, in a white cream for topical application.
- Luliconazole is (2E)-2--2-imidazol-1-ylacetonitrile. Its structural formula is:
- The molecular formula is C14H9Cl2N3S2 with a molecular weight of 354.28. Luliconazole is the R-enantiomer and contains one chiral center. The double bond adjacent to the dithiolane group is in the E configuration.
- LUZU Cream, 1% contains 10 mg of luliconazole per gram of cream in a vehicle consisting of benzyl alcohol, butylated hydroxytoluene, cetostearyl alcohol, isopropyl myristate, medium-chain triglycerides, methylparaben, polysorbate 60, propylene glycol, purified water, and sorbitan monostearate.
## Pharmacodynamics
At therapeutic doses, LUZU Cream, 1% is not expected to prolong QTc to any clinically relevant extent.
## Pharmacokinetics
- Luliconazole is the R enantiomer of a chiral molecule. The potential for inter-conversion between R and S enantiomers in humans has not been assessed. Information on the pharmacokinetics of luliconazole presented below refers to both R enantiomer and S enantiomer, if any, combined.
- Luliconazole is >99% protein bound in plasma.
- In a pharmacokinetic trial, 12 subjects with moderate to severe tinea pedis and 8 subjects with moderate to severe tinea cruris applied a mean daily amount of approximately 3.5 grams of LUZU Cream, 1% to the affected and surrounding areas once daily for 15 days. Plasma concentrations of luliconazole on Day 15 were measurable in all subjects and fluctuated little during the 24 hour interval. In subjects with tinea pedis, the mean ± SD of the maximum concentration (Cmax) was 0.40 ± 0.76 ng/mL after the first dose and 0.93 ± 1.23 ng/mL after the final dose. The mean time to reach Cmax (Tmax) was 16.9 ± 9.39 hours after the first dose and 5.8 ± 7.61 hours after the final dose. Exposure to luliconazole, as expressed by area under the concentration time curve (AUC0–24 was 6.88 ± 14.50 ng*hr/mL after the first dose and 18.74 ± 27.05 ng*hr/mL after the final dose. In subjects with tinea cruris, the mean ± SD Cmax was 4.91 ± 2.51 ng/mL after the first dose and 7.36 ± 2.66 ng/mL after the final dose. The mean Tmax was 21.0 ± 5.55 hours after the first dose and 6.5 ± 8.25 hours after the final dose. Exposure to luliconazole, as expressed by AUC0–24 was 85.1 ± 43.69 ng*hr/mL after the first dose and 121.74 ± 53.36 ng*hr/mL after the final dose.
### Microbiology
- To date, a mechanism of resistance to luliconazole has not been described.
- LUZU Cream, 1% has been shown to be active against most isolates of the following fungi, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:
## Nonclinical Toxicology
- Long-term studies to evaluate the carcinogenic potential of LUZU Cream, 1% have not been conducted.
- Luliconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosomal aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus test).
- In a fertility study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered prior to and during mating and through early pregnancy. Treatment related effects on reproductive function were noted in females (decreased live embryos and decreased corpus luteum) at 5 and 25 mg/kg/day and males (decreased sperm counts) at 25 mg/kg/day. No treatment related effects on fertility or reproductive function were noted at 1 mg/kg/day (0.1× MRHD based on BSA comparisons).
# Clinical Studies
- The safety and efficacy of LUZU (luliconazole) Cream, 1% was evaluated in two randomized, double-blind, vehicle-controlled, multi-center clinical trials in 423 subjects with a clinical and culture-confirmed diagnosis of interdigital tinea pedis. Subjects were randomized to receive LUZU Cream, 1% or vehicle. Subjects applied either LUZU Cream, 1% or vehicle cream to the entire area of the forefeet including all interdigital web spaces and approximately 2.5 cm (1 in) of the surrounding area of the foot once daily for 14 days.
- The mean age of the study population was 41 years; 82% were male; 53% were White and 40% were Black or African American. Signs and symptoms of tinea pedis (erythema, scaling, and pruritus), KOH exam and dermatophyte culture were assessed at baseline, end-of-treatment (Day 14), 2 and 4 weeks post-treatment.
- Overall treatment success was defined as complete clearance (clinical cure and mycological cure) at 4 weeks post-treatment. LUZU Cream, 1% demonstrated completed clearance in subjects with interdigital tinea pedis. Treatment outcomes at 4 weeks post-treatment are summarized in Table 1.
- The safety and efficacy of LUZU (luliconazole) Cream, 1% was evaluated in a randomized, double-blind, vehicle-controlled, multi-center clinical trial in 256 subjects with a clinical and culture confirmed diagnosis of tinea cruris. Subjects were randomized to receive LUZU Cream, 1% or vehicle. Subjects applied either LUZU Cream, 1% or vehicle cream to the affected area and approximately 2.5 cm (1 in) of the surrounding area once daily for 7 days.
- The mean age of the study population was 40 years; 83% were male; 58% were White and 34% were Black or African American. Signs and symptoms of tinea cruris (erythema, scaling, and pruritus), positive KOH exam and dermatophyte culture were assessed at baseline, end-of-treatment (Day 7), 2 and 3 weeks post-treatment.
- Overall treatment success was defined as complete clearance (clinical cure and mycological cure) at 3 weeks post-treatment. LUZU Cream, 1% demonstrated completed clearance in subjects with tinea cruris. Treatment outcomes at 3 weeks post treatment are summarized in Table 2.
# How Supplied
- LUZU (luliconazole) Cream, 1% is a white cream supplied in tubes as follows:
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Inform patients that LUZU Cream, 1% is for topical use only. LUZU Cream, 1% is not intended for intravaginal or ophthalmic use.
### PATIENT INFORMATION
# Precautions with Alcohol
- Alcohol-Luliconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LUZU®
# Look-Alike Drug Names
There is limited information regarding look alike drug names.
# Drug Shortage Status
# Price | Luliconazole
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
Luliconazole is a azole antifungal that is FDA approved for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis. Common adverse reactions include application site reactions.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- LUZU (luliconazole) Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older.
### Dosage
- For topical use only. LUZU Cream, 1% is not for ophthalmic, oral, or intravaginal use.
- When treating interdigital tinea pedis, a thin layer of LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for two (2) weeks.
- When treating tinea cruris or tinea corporis, LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for one (1) week.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Luliconazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Luliconazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Luliconazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Luliconazole in pediatric patients.
# Contraindications
- None
# Warnings
There is limited information regarding Luliconazole Warnings' in the drug label.
# 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.
- In three Phase 3 clinical trials, 616 subjects were exposed to LUZU Cream, 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied LUZU Cream, 1% or vehicle cream once daily for 14 days or 7 days, respectively, to affected and adjacent areas. During clinical trials with LUZU Cream, 1%, the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the LUZU and vehicle arms. Most adverse reactions were mild in severity.
## Postmarketing Experience
- The following adverse reactions have been identified during postmarketing use of luliconazole cream, 1%: contact dermatitis and cellulitis. 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.
# Drug Interactions
- The potential of luliconazole to inhibit cytochrome P-450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated in vitro. Based on in vitro assessment, luliconazole at therapeutic doses, particularly when applied to patients with moderate to severe tinea cruris, may inhibit the activity of CYP2C19 and CYP3A4. However, no in vivo drug interaction trials have been conducted to evaluate the effect of luliconazole on other drugs that are substrates of CYP2C19 and CYP3A4.
- Luliconazole is not expected to inhibit CYPs 1A2, 2C9 and 2D6 based on in vitro assessment. The induction potential of luliconazole on CYP enzymes has not been evaluated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of LUZU Cream, 1% in pregnant women. LUZU Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- The animal multiples of human exposure calculations were based on daily dose body surface area (BSA) comparisons (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 1% cream per day (1.33 mg/kg/day for a 60 kg individual which is equivalent to 49.2 mg/m2/day).
- Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 7-17) to pregnant female rats. No treatment related effects on maternal toxicity or malformations were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Increased incidences of skeletal variation (14th rib) were noted at 25 mg/kg/day. No treatment related effects on skeletal variation were noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons).
- Subcutaneous doses of 4, 20 and 100 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 6-18) to pregnant female rabbits. No treatment related effects on maternal toxicity, embryofetal toxicity or malformations were noted at 100 mg/kg/day (24 times the MRHD based on BSA comparisons).
- In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered from the beginning of organogenesis (gestation day 7) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). No treatment effects on postnatal development were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Luliconazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Luliconazole during labor and delivery.
### Nursing Mothers
- It is not known whether luliconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LUZU Cream, 1% is administered to women who are breastfeeding.
### Pediatric Use
- The safety and effectiveness of LUZU Cream, 1% in pediatric patients have not been established. The number of pediatric subjects ≥12 years of age were too small to adequately assess safety and efficacy.
### Geriatic Use
- Of the total number of subjects in clinical studies of LUZU Cream, 1%, 8 percent were 65 and over, while 1.4 percent were 75 and over. 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.
### Gender
There is no FDA guidance on the use of Luliconazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Luliconazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Luliconazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Luliconazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Luliconazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Luliconazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- topical
### Monitoring
There is limited information regarding Monitoring of Luliconazole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Luliconazole in the drug label.
# Overdosage
There is limited information regarding Overdose of Luliconazole in the drug label.
# Pharmacology
## Mechanism of Action
- Luliconazole is an antifungal that belongs to the azole class. Although the exact mechanism of action against dermatophytes is unknown, luliconazole appears to inhibit ergosterol synthesis by inhibiting the enzyme lanosterol demethylase. Inhibition of this enzyme’s activity by azoles results in decreased amounts of ergosterol, a constituent of fungal cell membranes, and a corresponding accumulation of lanosterol.
## Structure
- LUZU (luliconazole) Cream, 1% contains 1% luliconazole, an azole antifungal agent, in a white cream for topical application.
- Luliconazole is (2E)-2-[(4R)-4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-2-imidazol-1-ylacetonitrile. Its structural formula is:
- The molecular formula is C14H9Cl2N3S2 with a molecular weight of 354.28. Luliconazole is the R-enantiomer and contains one chiral center. The double bond adjacent to the dithiolane group is in the E configuration.
- LUZU Cream, 1% contains 10 mg of luliconazole per gram of cream in a vehicle consisting of benzyl alcohol, butylated hydroxytoluene, cetostearyl alcohol, isopropyl myristate, medium-chain triglycerides, methylparaben, polysorbate 60, propylene glycol, purified water, and sorbitan monostearate.
## Pharmacodynamics
At therapeutic doses, LUZU Cream, 1% is not expected to prolong QTc to any clinically relevant extent.
## Pharmacokinetics
- Luliconazole is the R enantiomer of a chiral molecule. The potential for inter-conversion between R and S enantiomers in humans has not been assessed. Information on the pharmacokinetics of luliconazole presented below refers to both R enantiomer and S enantiomer, if any, combined.
- Luliconazole is >99% protein bound in plasma.
- In a pharmacokinetic trial, 12 subjects with moderate to severe tinea pedis and 8 subjects with moderate to severe tinea cruris applied a mean daily amount of approximately 3.5 grams of LUZU Cream, 1% to the affected and surrounding areas once daily for 15 days. Plasma concentrations of luliconazole on Day 15 were measurable in all subjects and fluctuated little during the 24 hour interval. In subjects with tinea pedis, the mean ± SD of the maximum concentration (Cmax) was 0.40 ± 0.76 ng/mL after the first dose and 0.93 ± 1.23 ng/mL after the final dose. The mean time to reach Cmax (Tmax) was 16.9 ± 9.39 hours after the first dose and 5.8 ± 7.61 hours after the final dose. Exposure to luliconazole, as expressed by area under the concentration time curve (AUC0–24 was 6.88 ± 14.50 ng*hr/mL after the first dose and 18.74 ± 27.05 ng*hr/mL after the final dose. In subjects with tinea cruris, the mean ± SD Cmax was 4.91 ± 2.51 ng/mL after the first dose and 7.36 ± 2.66 ng/mL after the final dose. The mean Tmax was 21.0 ± 5.55 hours after the first dose and 6.5 ± 8.25 hours after the final dose. Exposure to luliconazole, as expressed by AUC0–24 was 85.1 ± 43.69 ng*hr/mL after the first dose and 121.74 ± 53.36 ng*hr/mL after the final dose.
### Microbiology
- To date, a mechanism of resistance to luliconazole has not been described.
- LUZU Cream, 1% has been shown to be active against most isolates of the following fungi, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:
## Nonclinical Toxicology
- Long-term studies to evaluate the carcinogenic potential of LUZU Cream, 1% have not been conducted.
- Luliconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosomal aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus test).
- In a fertility study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered prior to and during mating and through early pregnancy. Treatment related effects on reproductive function were noted in females (decreased live embryos and decreased corpus luteum) at 5 and 25 mg/kg/day and males (decreased sperm counts) at 25 mg/kg/day. No treatment related effects on fertility or reproductive function were noted at 1 mg/kg/day (0.1× MRHD based on BSA comparisons).
# Clinical Studies
- The safety and efficacy of LUZU (luliconazole) Cream, 1% was evaluated in two randomized, double-blind, vehicle-controlled, multi-center clinical trials in 423 subjects with a clinical and culture-confirmed diagnosis of interdigital tinea pedis. Subjects were randomized to receive LUZU Cream, 1% or vehicle. Subjects applied either LUZU Cream, 1% or vehicle cream to the entire area of the forefeet including all interdigital web spaces and approximately 2.5 cm (1 in) of the surrounding area of the foot once daily for 14 days.
- The mean age of the study population was 41 years; 82% were male; 53% were White and 40% were Black or African American. Signs and symptoms of tinea pedis (erythema, scaling, and pruritus), KOH exam and dermatophyte culture were assessed at baseline, end-of-treatment (Day 14), 2 and 4 weeks post-treatment.
- Overall treatment success was defined as complete clearance (clinical cure and mycological cure) at 4 weeks post-treatment. LUZU Cream, 1% demonstrated completed clearance in subjects with interdigital tinea pedis. Treatment outcomes at 4 weeks post-treatment are summarized in Table 1.
- The safety and efficacy of LUZU (luliconazole) Cream, 1% was evaluated in a randomized, double-blind, vehicle-controlled, multi-center clinical trial in 256 subjects with a clinical and culture confirmed diagnosis of tinea cruris. Subjects were randomized to receive LUZU Cream, 1% or vehicle. Subjects applied either LUZU Cream, 1% or vehicle cream to the affected area and approximately 2.5 cm (1 in) of the surrounding area once daily for 7 days.
- The mean age of the study population was 40 years; 83% were male; 58% were White and 34% were Black or African American. Signs and symptoms of tinea cruris (erythema, scaling, and pruritus), positive KOH exam and dermatophyte culture were assessed at baseline, end-of-treatment (Day 7), 2 and 3 weeks post-treatment.
- Overall treatment success was defined as complete clearance (clinical cure and mycological cure) at 3 weeks post-treatment. LUZU Cream, 1% demonstrated completed clearance in subjects with tinea cruris. Treatment outcomes at 3 weeks post treatment are summarized in Table 2.
# How Supplied
- LUZU (luliconazole) Cream, 1% is a white cream supplied in tubes as follows:
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Inform patients that LUZU Cream, 1% is for topical use only. LUZU Cream, 1% is not intended for intravaginal or ophthalmic use.
### PATIENT INFORMATION
# Precautions with Alcohol
- Alcohol-Luliconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LUZU®[1]
# Look-Alike Drug Names
There is limited information regarding look alike drug names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Luliconazole | |
012607e148c7551c2170590e43831732a267fa70 | wikidoc | Luteal phase | Luteal phase
The luteal phase (or secretory phase) is the latter phase of the estrous cycle in animals, and the menstrual cycle in humans and great apes. It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis. The main hormone controlling this stage is progesterone, which is significantly higher during the luteal phase than other phases of the cycle.
Some sources define the end of the luteal phase to be a distinct "ischemic phase".
# Luteal phase defect
Luteal phase defect (LPD) is believed to interfere with the implantation of embryos The lactational amenorrhea method of birth control works primarily by preventing ovulation, but is also known to cause LPD. | Luteal phase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
The luteal phase (or secretory phase) is the latter phase of the estrous cycle in animals, and the menstrual cycle in humans and great apes. It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis. The main hormone controlling this stage is progesterone, which is significantly higher during the luteal phase than other phases of the cycle.[1]
Some sources define the end of the luteal phase to be a distinct "ischemic phase".[2]
# Luteal phase defect
Luteal phase defect (LPD) is believed to interfere with the implantation of embryos[3] The lactational amenorrhea method of birth control works primarily by preventing ovulation, but is also known to cause LPD. | https://www.wikidoc.org/index.php/Luteal_phase | |
87ba87425b3a318fe7dd59720b72f45dcc1440e9 | wikidoc | Lymph vessel | Lymph vessel
# Overview
In anatomy, lymph vessels are thin walled, valved structures that carry lymph. As part of the lymphatic system, lymph vessels are complimentary with the vascular system. In contrast to the vascular system, which carries blood under pressure to the entire body, lymph is not under pressure and is propelled in a passive fashion, assisted by the aforementioned valves. Fluid that leaks from the vascular system is returned to general circulation via lymphatic vessels.
Generally, lymph flows away from the tissues to lymph nodes and eventually to either the right lymphatic duct or the largest lymph vessel in the body, the thoracic duct. These vessels drain into the right and left subclavian veins respectively.
# Function
Lymph vessels act as a reservoir from plasma and other substances including cells that leaked from the vascular system and transport lymph fluid back from the tissues to the circulatory system. Without functioning lymph vessels, lymph cannot be effectively drained and edema typically results.
# Additional images
- Lymphatic system
- Section across portal canal of pig. X 250. | Lymph vessel
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In anatomy, lymph vessels are thin walled, valved structures that carry lymph. As part of the lymphatic system, lymph vessels are complimentary with the vascular system. In contrast to the vascular system, which carries blood under pressure to the entire body, lymph is not under pressure and is propelled in a passive fashion, assisted by the aforementioned valves. Fluid that leaks from the vascular system is returned to general circulation via lymphatic vessels.
Generally, lymph flows away from the tissues to lymph nodes and eventually to either the right lymphatic duct or the largest lymph vessel in the body, the thoracic duct. These vessels drain into the right and left subclavian veins respectively.
# Function
Lymph vessels act as a reservoir from plasma and other substances including cells that leaked from the vascular system and transport lymph fluid back from the tissues to the circulatory system. Without functioning lymph vessels, lymph cannot be effectively drained and edema typically results.
# Additional images
- Lymphatic system
- Section across portal canal of pig. X 250.
# External links
- Lymphatic+Vessels at the US National Library of Medicine Medical Subject Headings (MeSH)
- Template:BiowebUW
- Essentials of Human Physiology by Thomas M. Nosek. Section 3/3ch9/s3ch9_5.
Template:Lymphatic system
ca:Vas limfàtic
da:Lymfekar
de:Lymphozyten
eo:Limfocito
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Lymph_vessel | |
4fe72a4a73ff02d5907c63f9d4f9024b0cd4e049 | wikidoc | Lábrea fever | Lábrea fever
# Overview
Lábrea fever, also known as Lábrea's black fever and Lábrea hepatitis, is a lethal tropical viral infection discovered in the 1950s in the city of Lábrea, in the Brazilian Amazon basi], where it occurs mostly in the area south of the Amazon River, in the states of Acre, Amazonas and Rondônia. The disease has also been diagnosed in Colombia and Peru. The similar form in Colombia has been named Santa Marta fever.
Its main manifestation is a fulminant hepatitis which may kill in less than a week, and which characteristically affects children and young adults, and more males than females. It is accompanied also by an encephalitis in many cases. The disease is highly lethal: in a study carried out in 1986 at Boca do Acre, also in the Amazon, 39 patients out of 44 died in the acute phase of the disease. Survivors may develop chronic disease.
# Symptoms and signs
Lábrea fever has a sudden onset, with jaundice (bilious color of the skin), anorexia (lack of appetite), hematemesis (blood vomit), headache, fever and severe prostration. Death occurs by acute liver failure (ALF). In the last phase, neurological symptoms such as agitation, delirium, convulsions and hemorrhagic coma commonly appear.
# Etiology
Lábrea fever is a coinfection or superinfection of hepatitis D or delta virus and hepatitis B (HBV). The infection by delta virus may occur in a patient who already has the HBV, or both viruses may infect at the same time a previously uninfected patient. Delta virus can only multiply in the presence of HBV, therefore vaccination against HBV prevents infection. Thus, American and Brazilian scientists have determined that the delta virusa, virus, which is a small circular RNA virus, is normally unable to cause illness by itself, due to a defect. When it is combined with HBV, Lábrea hepatitis may ensue. The main discovery of delta virus and HBV association was done by Dr. Gilberta Bensabath, a leading tropical virologist of the Instituto Evandro Chagas, of Belém, state of Pará, and her collaborators.
Infected patients show extensive destruction of liver tissue, with steatosis of a particular type (microsteatosis, characterized by small fat droplets inside the cells), and infiltration of large numbers of inflammatory cells called morula cells, comprised mainly by macrophages containing delta virus antigens.
In the 1987 Boca do Acre study, scientists did an epidemiological survey and reported delta virus infection in 24% of asymptomatic HBV carriers, 29% of acute nonfulminant hepatitis B cases, 74% of fulminant hepatitis B cases, and 100% of chronic hepatitis B cases. The delta virus seems to be endemic in the Amazon region.
# Treatment and prevention
Treatment is similar to hepatitis B, but due to its high lethality, more aggressive therapeutic approaches are recommended in the acute phase. In absence of a specific vaccine against delta virus, the vaccine against HBV must be given soon after birth in risk groups. | Lábrea fever
# Overview
Lábrea fever, also known as Lábrea's black fever and Lábrea hepatitis, is a lethal tropical viral infection discovered in the 1950s in the city of Lábrea, in the Brazilian Amazon basi], where it occurs mostly in the area south of the Amazon River, in the states of Acre, Amazonas and Rondônia. The disease has also been diagnosed in Colombia and Peru. The similar form in Colombia has been named Santa Marta fever.
Its main manifestation is a fulminant hepatitis which may kill in less than a week, and which characteristically affects children and young adults, and more males than females. It is accompanied also by an encephalitis in many cases. The disease is highly lethal: in a study carried out in 1986 at Boca do Acre, also in the Amazon, 39 patients out of 44 died in the acute phase of the disease.[1] Survivors may develop chronic disease.
# Symptoms and signs
Lábrea fever has a sudden onset, with jaundice (bilious color of the skin), anorexia (lack of appetite), hematemesis (blood vomit), headache, fever and severe prostration. Death occurs by acute liver failure (ALF). In the last phase, neurological symptoms such as agitation, delirium, convulsions and hemorrhagic coma commonly appear.
# Etiology
Lábrea fever is a coinfection or superinfection of hepatitis D or delta virus and hepatitis B (HBV).[1] The infection by delta virus may occur in a patient who already has the HBV, or both viruses may infect at the same time a previously uninfected patient. Delta virus can only multiply in the presence of HBV, therefore vaccination against HBV prevents infection. Thus, American and Brazilian scientists have determined that the delta virusa, virus, which is a small circular RNA virus, is normally unable to cause illness by itself, due to a defect. When it is combined with HBV, Lábrea hepatitis may ensue. The main discovery of delta virus and HBV association was done by Dr. Gilberta Bensabath, a leading tropical virologist of the Instituto Evandro Chagas, of Belém, state of Pará, and her collaborators.
Infected patients show extensive destruction of liver tissue, with steatosis of a particular type (microsteatosis, characterized by small fat droplets inside the cells), and infiltration of large numbers of inflammatory cells called morula cells, comprised mainly by macrophages containing delta virus antigens.
In the 1987 Boca do Acre study, scientists did an epidemiological survey and reported delta virus infection in 24% of asymptomatic HBV carriers, 29% of acute nonfulminant hepatitis B cases, 74% of fulminant hepatitis B cases, and 100% of chronic hepatitis B cases. The delta virus seems to be endemic in the Amazon region.
# Treatment and prevention
Treatment is similar to hepatitis B, but due to its high lethality, more aggressive therapeutic approaches are recommended in the acute phase. In absence of a specific vaccine against delta virus, the vaccine against HBV must be given soon after birth in risk groups. | https://www.wikidoc.org/index.php/L%C3%83%C2%A1brea_fever | |
cca21f9e18260cb9465157c13b8e5dc7056dbb4b | wikidoc | Lévy process | Lévy process
In probability theory, a Lévy process, named after the French mathematician Paul Lévy, is any continuous-time stochastic process that starts at 0, admits càdlàg modification and has "stationary independent increments" — this phrase will be explained below. The most well-known examples are the Wiener process and the Poisson process.
# Properties
## Independent increments
A continuous-time stochastic process assigns a random variable Xt to each point t ≥ 0 in time. In effect it is a random function of t. The increments of such a process are the differences Xs − Xt between its values at different times t < s. To call the increments of a process independent means that increments Xs − Xt and Xu − Xv are independent random variables whenever the two time intervals do not overlap and, more generally, any finite number of increments assigned to pairwise non-overlapping time intervals are mutually (not just pairwise) independent.
## Stationary increments
To call the increments stationary means that the probability distribution of any increment Xs − Xt depends only on the length s − t of the time interval; increments with equally long time intervals are identically distributed.
In the Wiener process, the probability distribution of Xs − Xt is normal with expected value 0 and variance s − t.
In the Poisson process, the probability distribution of Xs − Xt is a Poisson distribution with expected value λ(s − t), where λ > 0 is the "intensity" or "rate" of the process.
## Divisibility
The probability distributions of the increments of any Lévy process are infinitely divisible. There is a Lévy process for each infinitely divisible probability distribution.
## Moments
In any Lévy process with finite moments, the nth moment \mu_n(t) = E(X_t^n) is a polynomial function of t; these functions satisfy a binomial identity:
# Lévy-Khinchin representation
It is possible to characterise all Lévy processes by looking at their characteristic function. This leads to the Lévy-Khinchin representation. If X_t is a Lévy process, then its characteristic function satisfies the following relation:
\int_{\mathbb{R}\backslash\{0\}} \big( e^{i\theta x}-1 -i\theta x \mathbf{I}_{|x|<1}\big)\,W(dx) \Bigg)
where a \in \mathbb{R}, \sigma\ge 0 and \mathbf{I} is the indicator function. The Lévy measure W must be such that
A Lévy process can be seen as comprising of three components: a drift, a diffusion component and a jump component. These three components, and thus the Lévy-Khinchin representation of the process, are fully determined by the Lévy-Khinchin triplet (a,\sigma^2, W). So one can see that a purely continuous Lévy process is a Brownian motion with drift. | Lévy process
In probability theory, a Lévy process, named after the French mathematician Paul Lévy, is any continuous-time stochastic process that starts at 0, admits càdlàg modification and has "stationary independent increments" — this phrase will be explained below. The most well-known examples are the Wiener process and the Poisson process.
# Properties
## Independent increments
A continuous-time stochastic process assigns a random variable Xt to each point t ≥ 0 in time. In effect it is a random function of t. The increments of such a process are the differences Xs − Xt between its values at different times t < s. To call the increments of a process independent means that increments Xs − Xt and Xu − Xv are independent random variables whenever the two time intervals do not overlap and, more generally, any finite number of increments assigned to pairwise non-overlapping time intervals are mutually (not just pairwise) independent.
## Stationary increments
To call the increments stationary means that the probability distribution of any increment Xs − Xt depends only on the length s − t of the time interval; increments with equally long time intervals are identically distributed.
In the Wiener process, the probability distribution of Xs − Xt is normal with expected value 0 and variance s − t.
In the Poisson process, the probability distribution of Xs − Xt is a Poisson distribution with expected value λ(s − t), where λ > 0 is the "intensity" or "rate" of the process.
## Divisibility
The probability distributions of the increments of any Lévy process are infinitely divisible. There is a Lévy process for each infinitely divisible probability distribution.
## Moments
In any Lévy process with finite moments, the nth moment <math>\mu_n(t) = E(X_t^n)</math> is a polynomial function of t; these functions satisfy a binomial identity:
# Lévy-Khinchin representation
It is possible to characterise all Lévy processes by looking at their characteristic function. This leads to the Lévy-Khinchin representation. If <math> X_t </math> is a Lévy process, then its characteristic function satisfies the following relation:
\int_{\mathbb{R}\backslash\{0\}} \big( e^{i\theta x}-1 -i\theta x \mathbf{I}_{|x|<1}\big)\,W(dx) \Bigg)
</math>
where <math>a \in \mathbb{R}</math>, <math>\sigma\ge 0</math> and <math>\mathbf{I}</math> is the indicator function. The Lévy measure <math>W</math> must be such that
A Lévy process can be seen as comprising of three components: a drift, a diffusion component and a jump component. These three components, and thus the Lévy-Khinchin representation of the process, are fully determined by the Lévy-Khinchin triplet <math>(a,\sigma^2, W)</math>. So one can see that a purely continuous Lévy process is a Brownian motion with drift.
# External links
- Applebaum, David (December 2004), "Lévy Processes—From Probability to Finance and Quantum Groups" (PDF), Notices of the American Mathematical Society, Providence, RI: American Mathematical Society, 51 (11): 1336–1347, ISSN 1088-9477CS1 maint: Date and year (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}
de:Lévy-Prozess
fa:نمو مانا
nl:Lévyproces
uk:Процес з незалежними приростами
Template:WS | https://www.wikidoc.org/index.php/L%C3%A9vy_process | |
6dcad8b050fa8d3ac53e62b1c838c494d017aa4c | wikidoc | MIRACL Study | MIRACL Study
# Objective
To assess whether early initiation of treatment with a statin can reduce the occurrence of these early events.
# Methods
The Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) trial was a randomized, double-blinded trial wherein 3086 adults (18 years and above) with unstable angina or non-Q-wave MI were randomly assigned to receive treatment with atorvastatin (80 mg/day) or placebo between 24 and 96 hours after hospital admission and followed-up through 16 weeks. Primary predefined end point event was defined as time to death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency re-hospitalization.
# Results
- Primary end point occurred in 14.8% in patients treated with atorvastatin compared with 17.4% in the placebo group.
- No significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the two groups.
- Atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency re-hospitalization.
# Conclusion
After an acute coronary event early treatment with 80 mg/day atorvastatin reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring re-hospitalization. | MIRACL Study
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To assess whether early initiation of treatment with a statin can reduce the occurrence of these early events.
# Methods
The Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) trial was a randomized, double-blinded trial wherein 3086 adults (18 years and above) with unstable angina or non-Q-wave MI were randomly assigned to receive treatment with atorvastatin (80 mg/day) or placebo between 24 and 96 hours after hospital admission and followed-up through 16 weeks. Primary predefined end point event was defined as time to death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency re-hospitalization.
# Results
- Primary end point occurred in 14.8% in patients treated with atorvastatin compared with 17.4% in the placebo group.
- No significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the two groups.
- Atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency re-hospitalization.
# Conclusion
After an acute coronary event early treatment with 80 mg/day atorvastatin reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring re-hospitalization.[1][2] | https://www.wikidoc.org/index.php/MIRACL_Study | |
74a7851575beb3d8b5e26a99194feec4e5e728f7 | wikidoc | MMRV vaccine | MMRV vaccine
The MMRV vaccine combines the attenuated virus MMR (measles, mumps, rubella) vaccine with the addition of chickenpox vaccine.
One MMRV vaccine, approved in 2005 for use in the United States by the Food and Drug Administration for children ages twelve months through twelve years, is called ProQuad. The vaccine is administered via injection for protection against four viral infectious diseases, and contains about ten times more chickenpox vaccine than the Varivax brand varicella vaccine. The quadruple vaccine, marketed by pharmaceutical giant Merck, is generally administered to children around the age of one year.
A MMRV vaccine called Priorix Tetra by GlaxoSmithKline, targeted at children 1-2 years of age, has been approved in Germany and Australia.
# Motivation
The World Health Organization recommends vaccinating against measles, mumps, rubella (German measles), and varicella (chickenpox) because the risks of these diseases far outweigh the risks of vaccinating against them. In particular, the World Health Organization recommends varicella vaccination in countries where the vaccine is affordable, the disease is a relatively important problem, and high and sustained coverage can be achieved. The U.S. and a few other countries have widely implemented this. MMR and varicella vaccine are given at roughly the same time and a booster injection is recommended for both. The MMRV vaccine, a combined MMR and varicella vaccine, simplifies administration of the vaccines.
# Availability
In May, 2007, the manufacturer Merck announced that, due to manufacturing problems in the chickenpox component, the Merck vaccine ProQuad is not available. In August 2007, Merck announced that they did not know whether ProQuad would be made available in 2008 due to an issue with its bulk manufacturing process, but their goal was to restore its availability as soon as possible.
# Contraindications
- For individuals who are moderately or severely ill, it is generally recommended that they wait until after recovery before getting ProQuad. No such precautions are recommended for minor illnesses, such as a cold.
- It is recommended that aspirin or aspirin containing products should be avoided for at least six weeks after receiving ProQuad vaccine. A serious condition called Reye's Syndrome has been reported in patients with chicken pox.
- Individuals should not receive ProQuad without first consulting their doctor if there is a history of a life-threatening allergic reaction to gelatin, eggs, the antibiotic neomycin, or a previous MMR or chicken pox vaccine
Doctors are advised to be aware of whether or not a patient has HIV, AIDS or another disease that affects the immune system, is taking a medication that affects the immune system, has cancer, a fever or active untreated tuberculosis, is receiving cancer treatment, or has ever had a low platelet count (a blood disorder). ·
# Adverse events
Rare but serious adverse events reported following ProQuad vaccination include allergic reactions, including swelling of the lips, tongue, or face; difficulty breathing or closing of the throat; hives; paleness; weakness; dizziness; a fast heart beat; deafness; long-term seizures, coma, or lowered consciousness; permanent brain damage; seizures (jerking or staring) caused by fever; or temporary low platelet count. According to information from CDC, MMRV vaccine has been associated with higher rates of fever (up to about 1 person in 5) and measles-like rash (about 1 person in 20) compared with MMR and varicella vaccines given separately. | MMRV vaccine
The MMRV vaccine combines the attenuated virus MMR (measles, mumps, rubella) vaccine with the addition of chickenpox vaccine.
One MMRV vaccine, approved in 2005 for use in the United States by the Food and Drug Administration for children ages twelve months through twelve years, is called ProQuad. The vaccine is administered via injection for protection against four viral infectious diseases, and contains about ten times more chickenpox vaccine than the Varivax brand varicella vaccine. The quadruple vaccine, marketed by pharmaceutical giant Merck, is generally administered to children around the age of one year.
A MMRV vaccine called Priorix Tetra [1] by GlaxoSmithKline, targeted at children 1-2 years of age, has been approved in Germany and Australia. [2]
# Motivation
The World Health Organization recommends vaccinating against measles, mumps, rubella (German measles), and varicella (chickenpox) because the risks of these diseases far outweigh the risks of vaccinating against them. In particular, the World Health Organization recommends varicella vaccination in countries where the vaccine is affordable, the disease is a relatively important problem, and high and sustained coverage can be achieved. The U.S. and a few other countries have widely implemented this. MMR and varicella vaccine are given at roughly the same time and a booster injection is recommended for both. The MMRV vaccine, a combined MMR and varicella vaccine, simplifies administration of the vaccines.[3]
# Availability
In May, 2007, the manufacturer Merck announced that, due to manufacturing problems in the chickenpox component, the Merck vaccine ProQuad is not available. In August 2007, Merck announced that they did not know whether ProQuad would be made available in 2008 due to an issue with its bulk manufacturing process, but their goal was to restore its availability as soon as possible.[4]
# Contraindications
- For individuals who are moderately or severely ill, it is generally recommended that they wait until after recovery before getting ProQuad. No such precautions are recommended for minor illnesses, such as a cold.
- It is recommended that aspirin or aspirin containing products should be avoided for at least six weeks after receiving ProQuad vaccine. A serious condition called Reye's Syndrome has been reported in patients with chicken pox.
- Individuals should not receive ProQuad without first consulting their doctor if there is a history of a life-threatening allergic reaction to gelatin, eggs, the antibiotic neomycin, or a previous MMR or chicken pox vaccine
Doctors are advised to be aware of whether or not a patient has HIV, AIDS or another disease that affects the immune system, is taking a medication that affects the immune system, has cancer, a fever or active untreated tuberculosis, is receiving cancer treatment, or has ever had a low platelet count (a blood disorder). ·
# Adverse events
Rare but serious adverse events reported following ProQuad vaccination include allergic reactions, including swelling of the lips, tongue, or face; difficulty breathing or closing of the throat; hives; paleness; weakness; dizziness; a fast heart beat; deafness; long-term seizures, coma, or lowered consciousness; permanent brain damage; seizures (jerking or staring) caused by fever; or temporary low platelet count. According to information from CDC, MMRV vaccine has been associated with higher rates of fever (up to about 1 person in 5) and measles-like rash (about 1 person in 20) compared with MMR and varicella vaccines given separately.[5] | https://www.wikidoc.org/index.php/MMRV_vaccine | |
852c86ec7c5ebf6d6a168bb7311a2810e130964e | wikidoc | MS Bike Tour | MS Bike Tour
MS Bike Tour or MS 150 refers to any of a series of charity bicycle rides organized by the National Multiple Sclerosis Society in various locations around the United States, Canada and Australia.
The purpose of the rides is to raise money for the multiple sclerosis research done by the National MS Society. In the United States the rides are badged 'MS 150' and typically take place over the course of two days and, as the name implies, are generally around 150 miles long. There are also other shorter, 1-day rides. The rides generally leave from and arrive at large cities in order to be accessible to the most people. The rides vary greatly in the number of participants. One ride, from Houston to Austin, has been capped at 13,000 riders in 2006 to prevent overcrowding. In Australia, the ride is called 'Sydney to the Gong', referring to the city Wollongong, 90km south of Sydney.
# About MS
Multiple Sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS). The myelin, whose function is to surround and protect the nerve fibers of the CNS, deteriorates leaving lesions called sclerosis. It has a wide range of symptoms that can come and go “including vision lost, paralysis, numbness, and walking difficulties’” (National Multiple Society, 2006). These unpredictable symptoms make it hard for doctors to diagnose the disease. The National Multiple Sclerosis Society began in 1946 to help fight against MS. The foundation “supports more MS research, offers more services for people with MS, provides more professional education programs, and furthers more MS advocacy efforts than any other MS organization in the world”. In its effort to accomplish its goals each year the foundation holds multiple events for the general public to participate in and support the fight against MS.
The MS Bike Tours are one of the more recent events that the organization has supported. The tour began about 22 years ago in certain select cities. The tour has been one of the largest funding raising events for the MS Society. Today these tours occur in 48 states and there are several held in Canada.
The length of the tour varies depending on the individual event. They can be as short as 30 miles, or as long as 180 miles. People can participate by riding, volunteering their time, or pledging money. The event aims to pull the whole community together by gathering support from local businesses, elected officials, residents, and local MS sufferers. Each event is usually a very successful fund-raiser, with 75 percent of the money raised going towards research.
# Tours
## North American
Around 48 state chapters support this event yearly. Last year over 100,000 participants raised $67 million dollars for the organization. Canada had over 10,000 participants who raised $7.1 million dollars. Each year the tour grows in number, as it becomes more and more well known. Currently there are over a 100 tours that run from April to November. Each tour is unique and different with many advantages for participating in the event.
The society gives the event a lot of free rein in what each individual chapter chooses to support. This creates a huge appeal to organizers all over. Each chapter focuses on what the community can support and participate in. This allows for the most efficient fund rising. Chapters decide the length, the date, and the location.
The largest bike tour is the Lone Star Chapter of Texas. “To date, the Lone Star Chapter's MS 150 Bike Tours have raised over $47 million,” for the National Multiple Society (InsideMS, 2005). The chapter hosts three two-day events starting with the BP MS 150 riding in April. The ride is a two-day event starting in Houston and finishing in Austin. It is the largest North American tour of it kind today, as well as the “largest non-profit sporting event in Texas” (Lone Star Chapter, 2006). The next event is the Sam’s Club MS 150 tour riding in May. It runs from Frisco to Fort Worth. Then in October is the Valero MS 150, which riders from San Antonio to Corpus Christi. The chapter hits the major cities to draw in more support from the media and public.
## Australian
A yearly event, with 2 distance options available. One options is St Peters in Sydney Park to Stuart Park, Wollongong, a 90km ride. The other option is a shorter 56km ride from Heathcote High School, Heathcote to Stuart Park, Wollongong. In 2007, the event was held on the 4th November.
# Riders
100,000 riders participated in 2006, raising $67 million in the fight against MS.
The rider undertakes the biggest challenge of all, enduring the pain and pleasure of benefiting the fight against MS. Riders range from as young as “6 years old to 82 years old”. Most riders choose the traditional street-racing bikes that are sold at local bike shops. Others prefer tandem or recumbent bicycles, while others use hand operated cycles, and even unicycles. Any bike can be used as long as it does not cause any immediate danger to the rider or the other participants. Depending on the terrain, certain bicycle types can perform better than others.
Rider safety is the top priority in these rides. Each tour has to comply with all of the National MS Society safety guidelines. The chapters also must obey all state and local laws. Every tour secures all roads and trails for the bikers before the event. Some rules, if broken, can be cause for immediate removal from the event. Helmets are a requirement for riders, as they can prevent head injuries in the case of an accident.
During the event, police and volunteers set up along the route with HAM Radios and safety kits to help riders that are in need of assistance. At regularly spaced rest stops, there are minor medical services, refreshments, technical support personnel and bathrooms for riders in need.
A rider pledges to raise a certain minimum amount of money by the tour date to participate. For each chapter the pledges are different, the lowest coming in at $125 (Tappan Zee Bike Tour) and the highest being $350 (BP MS 150). To encourage riders to reach high amounts of fund raising, some chapters have 300 or 150 clubs for the riders who raise the most money.
To help promote awareness and understanding of the disease the National Multiple Sclerosis Society recently started a new program for riders. The program called Champions Against MS teams up riders and locals with Multiple Sclerosis. The riders receive bandanas signed by their "buddy", to display their support for them. “This connection fosters education, awareness, gratitude, and most importantly, hope, through the symbol of the bright red bandana.”
# Volunteers
Most events require as many riders as volunteers. Volunteers help promote and excite the public about finding the cure. Volunteers help setup the whole event. They get there before everyone else and leave after everyone else. Volunteers complete a wide range of jobs throughout the events. There are the typical odd jobs including setup, trash, take down, clean up, and check in, but any service are welcomed and needed for the events to run smoothly. Some unusual positions are team cook, masseuse, and bike rack attendant.
Most tours also use volunteer services to provide for the safety and comfort of the riders while on the course. This includes SAG (support and gear) for riders who are weary or are having technical difficulties with equipment, off-duty medical personnel who volunteer to provide minor medical attention and/or evaluation of major medical issues, off-duty law enforcement officials in local municipalities to provide traffic control, and motorcycle riders who patrol the route - offering encouragement, minor technical assistance, "first responder" duties in accidents.
Some tours also solicit HAM radio operators to provide a communications network between rest stops, and on the route as a whole. HAM radios operate at a greater distance than CB radio, and provides a "party line" so general announcements can be made over the air, instead of having to call each and every volunteer on a cellular telephone.
The most important job for the volunteer is not only completing there tasks but to motivate and support all the riders. Volunteers are known for being loud energetic people. Some dress up for the event with unusual clothing, wigs and things, and others wear loud noisemakers, bells and whistles. Even some riders wear the unthinkable. These normally obnoxious items provide support for the rider and encouragement to complete the race. At every stop and on some stretches of road volunteers lend a helping hand to the riders and give them a boost in energy.
# Celebrity Support
Over the years, many influential people have worked at the MS Bike tours.
Country singer Clay Walker was diagnosed with MS in 1996. His disease has progressed slowly allowing him to continue to enjoy a normal life. Since his diagnosis, he has chosen “to focus on getting the most out of everything he still has.” A Houston native, he attends the annual BP MS 150 and encourages other suffers that even with MS anything can be accomplished.
Texas Governor Richard Perry and Houston Mayor Bill White both rode in the Texas BP MS 150 in 2004. White rode from the beginning at Tully Stadium to the end in Austin, while Perry rode the last 10 miles of the ride into Austin.
National talk show host Montel Williams supports the tour as well. Montel also suffers from the disease and in 1999 he revealed his battle with the disease to the public. Since then, he has founded his own MS bike tour in New York. The tour is a 20-mile ride open to all people in Sag Harbor, NY.
Other affected celebrities and passionate supporters are singer Alan Osmond from The Osmonds, comedian Jonathan Katz, movie producer Carl Laemmle Jr., singer and actress Lena Horne.
Most tours also offer a mixture of local celebrity figures, such as governmental figures, radio and television station personalities and prominent businesses and their owners.
# Sponsors
Corporate sponsors provide a large amount of support to the foundation. Their support is responsible for a large amount of the funds that are raised. Sponsors range from large corporations with ties to the local communities, but also include local business support as well. They help unity the community in the goal of finding a cure for MS.
There are five levels for sponsors. First is the title sponsor, which provides the biggest pledge. Then there are the platinum, gold, silver, and bronze sponsors. The other sponsors are radio stations, transportation companies, and hotels. These sponsors generally offer their services in lieu of or in addition to a financial contribution.
Local radio and television stations send personalities to play music, provide commentary and announce each of the riders coming into the finish lines. Transportation companies provide buses and cars to shuttle riders home. Hotels provide discounted accommodations for the riders as well. Riders who ride for sponsor companies usually receive a jersey with that sponsors corporate name on it.
Most sponsors also set up tents for its riders at the finish lines on both days. Typically, the tents provide food and beverages, as well as some luxuries like massages for the riders. | MS Bike Tour
MS Bike Tour or MS 150 refers to any of a series of charity bicycle rides organized by the National Multiple Sclerosis Society in various locations around the United States, Canada and Australia.
The purpose of the rides is to raise money for the multiple sclerosis research done by the National MS Society. In the United States the rides are badged 'MS 150' and typically take place over the course of two days and, as the name implies, are generally around 150 miles long. There are also other shorter, 1-day rides. The rides generally leave from and arrive at large cities in order to be accessible to the most people. The rides vary greatly in the number of participants. One ride, from Houston to Austin, has been capped at 13,000 riders in 2006 to prevent overcrowding.[1] In Australia, the ride is called 'Sydney to the Gong', referring to the city Wollongong, 90km south of Sydney.[2]
# About MS
Multiple Sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS). The myelin, whose function is to surround and protect the nerve fibers of the CNS, deteriorates leaving lesions called sclerosis. It has a wide range of symptoms that can come and go “including vision lost, paralysis, numbness, and walking difficulties’” (National Multiple Society, 2006). These unpredictable symptoms make it hard for doctors to diagnose the disease. The National Multiple Sclerosis Society began in 1946 to help fight against MS. The foundation “supports more MS research, offers more services for people with MS, provides more professional education programs, and furthers more MS advocacy efforts than any other MS organization in the world”.[3] In its effort to accomplish its goals each year the foundation holds multiple events for the general public to participate in and support the fight against MS.
The MS Bike Tours are one of the more recent events that the organization has supported. The tour began about 22 years ago in certain select cities. The tour has been one of the largest funding raising events for the MS Society. Today these tours occur in 48 states and there are several held in Canada.
The length of the tour varies depending on the individual event. They can be as short as 30 miles, or as long as 180 miles. People can participate by riding, volunteering their time, or pledging money. The event aims to pull the whole community together by gathering support from local businesses, elected officials, residents, and local MS sufferers. Each event is usually a very successful fund-raiser, with 75 percent of the money raised going towards research.[citation needed]
# Tours
## North American
Around 48 state chapters support this event yearly. Last year over 100,000 participants raised $67 million dollars for the organization. Canada had over 10,000 participants who raised $7.1 million dollars. Each year the tour grows in number, as it becomes more and more well known. Currently there are over a 100 tours that run from April to November. Each tour is unique and different with many advantages for participating in the event.[3]
The society gives the event a lot of free rein in what each individual chapter chooses to support. This creates a huge appeal to organizers all over. Each chapter focuses on what the community can support and participate in. This allows for the most efficient fund rising. Chapters decide the length, the date, and the location.
The largest bike tour is the Lone Star Chapter of Texas. “To date, the Lone Star Chapter's MS 150 Bike Tours have raised over $47 million,” for the National Multiple Society (InsideMS, 2005). The chapter hosts three two-day events starting with the BP MS 150 riding in April. The ride is a two-day event starting in Houston and finishing in Austin. It is the largest North American tour of it kind today, as well as the “largest non-profit sporting event in Texas” (Lone Star Chapter, 2006). The next event is the Sam’s Club MS 150 tour riding in May. It runs from Frisco to Fort Worth. Then in October is the Valero MS 150, which riders from San Antonio to Corpus Christi. The chapter hits the major cities to draw in more support from the media and public.
## Australian
A yearly event, with 2 distance options available. One options is St Peters in Sydney Park to Stuart Park, Wollongong, a 90km ride. The other option is a shorter 56km ride from Heathcote High School, Heathcote to Stuart Park, Wollongong. In 2007, the event was held on the 4th November. [4]
# Riders
100,000 riders participated in 2006, raising $67 million in the fight against MS. [1]
The rider undertakes the biggest challenge of all, enduring the pain and pleasure of benefiting the fight against MS. Riders range from as young as “6 years old to 82 years old”.[5] Most riders choose the traditional street-racing bikes that are sold at local bike shops. Others prefer tandem or recumbent bicycles, while others use hand operated cycles, and even unicycles.[6] Any bike can be used as long as it does not cause any immediate danger to the rider or the other participants. Depending on the terrain, certain bicycle types can perform better than others.
Rider safety is the top priority in these rides. Each tour has to comply with all of the National MS Society safety guidelines. The chapters also must obey all state and local laws. Every tour secures all roads and trails for the bikers before the event. Some rules, if broken, can be cause for immediate removal from the event. Helmets are a requirement for riders, as they can prevent head injuries in the case of an accident.
During the event, police and volunteers set up along the route with HAM Radios and safety kits to help riders that are in need of assistance. At regularly spaced rest stops, there are minor medical services, refreshments, technical support personnel and bathrooms for riders in need.
A rider pledges to raise a certain minimum amount of money by the tour date to participate. For each chapter the pledges are different, the lowest coming in at $125 (Tappan Zee Bike Tour) and the highest being $350 (BP MS 150).[3] To encourage riders to reach high amounts of fund raising, some chapters have 300 or 150 clubs for the riders who raise the most money.
To help promote awareness and understanding of the disease the National Multiple Sclerosis Society recently started a new program for riders. The program called Champions Against MS teams up riders and locals with Multiple Sclerosis. The riders receive bandanas signed by their "buddy", to display their support for them. “This connection fosters education, awareness, gratitude, and most importantly, hope, through the symbol of the bright red bandana.”[3]
# Volunteers
Most events require as many riders as volunteers. Volunteers help promote and excite the public about finding the cure. Volunteers help setup the whole event. They get there before everyone else and leave after everyone else. Volunteers complete a wide range of jobs throughout the events. There are the typical odd jobs including setup, trash, take down, clean up, and check in, but any service are welcomed and needed for the events to run smoothly. Some unusual positions are team cook, masseuse, and bike rack attendant.
Most tours also use volunteer services to provide for the safety and comfort of the riders while on the course. This includes SAG (support and gear) for riders who are weary or are having technical difficulties with equipment, off-duty medical personnel who volunteer to provide minor medical attention and/or evaluation of major medical issues, off-duty law enforcement officials in local municipalities to provide traffic control, and motorcycle riders who patrol the route - offering encouragement, minor technical assistance, "first responder" duties in accidents.
Some tours also solicit HAM radio operators to provide a communications network between rest stops, and on the route as a whole. HAM radios operate at a greater distance than CB radio, and provides a "party line" so general announcements can be made over the air, instead of having to call each and every volunteer on a cellular telephone.
The most important job for the volunteer is not only completing there tasks but to motivate and support all the riders. Volunteers are known for being loud energetic people. Some dress up for the event with unusual clothing, wigs and things, and others wear loud noisemakers, bells and whistles. Even some riders wear the unthinkable. These normally obnoxious items provide support for the rider and encouragement to complete the race. At every stop and on some stretches of road volunteers lend a helping hand to the riders and give them a boost in energy.
# Celebrity Support
Over the years, many influential people have worked at the MS Bike tours.
Country singer Clay Walker was diagnosed with MS in 1996. His disease has progressed slowly allowing him to continue to enjoy a normal life. Since his diagnosis, he has chosen “to focus on getting the most out of everything he still has.”[7] A Houston native, he attends the annual BP MS 150 and encourages other suffers that even with MS anything can be accomplished. [8]
Texas Governor Richard Perry and Houston Mayor Bill White both rode in the Texas BP MS 150 in 2004. White rode from the beginning at Tully Stadium to the end in Austin, while Perry rode the last 10 miles of the ride into Austin.[9]
National talk show host Montel Williams supports the tour as well. Montel also suffers from the disease and in 1999 he revealed his battle with the disease to the public. Since then, he has founded his own MS bike tour in New York. The tour is a 20-mile ride open to all people in Sag Harbor, NY.[10]
Other affected celebrities and passionate supporters are singer Alan Osmond from The Osmonds, comedian Jonathan Katz, movie producer Carl Laemmle Jr., singer and actress Lena Horne.[11]
Most tours also offer a mixture of local celebrity figures, such as governmental figures, radio and television station personalities and prominent businesses and their owners.
# Sponsors
Corporate sponsors provide a large amount of support to the foundation. Their support is responsible for a large amount of the funds that are raised. Sponsors range from large corporations with ties to the local communities, but also include local business support as well. They help unity the community in the goal of finding a cure for MS.
There are five levels for sponsors. First is the title sponsor, which provides the biggest pledge. Then there are the platinum, gold, silver, and bronze sponsors. The other sponsors are radio stations, transportation companies, and hotels. These sponsors generally offer their services in lieu of or in addition to a financial contribution.
Local radio and television stations send personalities to play music, provide commentary and announce each of the riders coming into the finish lines. Transportation companies provide buses and cars to shuttle riders home. Hotels provide discounted accommodations for the riders as well. Riders who ride for sponsor companies usually receive a jersey with that sponsors corporate name on it.[12]
Most sponsors also set up tents for its riders at the finish lines on both days. Typically, the tents provide food and beverages, as well as some luxuries like massages for the riders. | https://www.wikidoc.org/index.php/MS_Bike_Tour | |
bb19b48f62872cedfffba155311619eb2af4344a | wikidoc | Mace (spray) | Mace (spray)
Mace is a tear gas in the form of an aerosol spray which propels the lachrymator mixed with a volatile solvent. It is sometimes used as a self-defense device. This form of mace is legal in very few countries, thus its use is becoming uncommon.
The original formulation consisted of 1% CN gas in a solvent of 2-butanol, propylene glycol, cyclohexene, and dipropylene glycol methyl ether. Some formulations now also include Oleoresin Capsicum (active ingredient in pepper spray).
Mace was originally manufactured under the name "Chemical Mace" by Lake Erie Chemical (a former division of Smith & Wesson) in 1962, but is now a registered trademark of Mace Security International. The Mace sold today by Mace Security International is pepper spray rather than tear gas. Many other companies now manufacture similar products.
# Mace vs. pepper spray
Due to the current brand-name use of the term "Mace" to refer to pepper sprays and the fact that mace is illegal in most Western countries, it is very difficult to find information on traditional mace. "Mace" and "Pepper Spray" are frequently used interchangeably.
# Training
Most law enforcement agencies require that their personnel become certified on similar aerosol spray devices such as pepper spray before using them in the field. Inert units which use the same mechanism but spray an inactive saccharine solution are also used for training purposes.
# Effect
The effect of Mace varies on humans. Most common is a burning sensation on the area affected with the spray. If in contact with eyes it causes automatic closing of the eyes due to intense pain if open. This along with a feeling of suffocating if inhaled it causes the person to be very vulnerable and dependent, resulting in easy overpowering (for example, law enforcement officials over a suspect). Effects can be minimal on those under the influence of alcohol or drugs. The duration of the effects vary from 30 minutes up to 2 hours, depending on the person and treatment.
# Mace in History
During the September 11, 2001 terrorist attacks Mace was supposedly used by the hijackers of American Airlines Flight 11 to prevent entry to the first-class area and keep passengers at the rear of the plane. The official 9/11 Commission Report states that "The hijackers quickly gained control and sprayed Mace, pepper spray, or some other irritant in the first-class cabin, in order to force the passengers and flight attendants toward the rear of the plane." | Mace (spray)
Mace is a tear gas in the form of an aerosol spray which propels the lachrymator mixed with a volatile solvent. It is sometimes used as a self-defense device. This form of mace is legal in very few countries, thus its use is becoming uncommon.
The original formulation consisted of 1% CN gas in a solvent of 2-butanol, propylene glycol, cyclohexene, and dipropylene glycol methyl ether. Some formulations now also include Oleoresin Capsicum (active ingredient in pepper spray).
Mace was originally manufactured under the name "Chemical Mace" by Lake Erie Chemical (a former division of Smith & Wesson) in 1962, but is now a registered trademark of Mace Security International. The Mace sold today by Mace Security International is pepper spray rather than tear gas. Many other companies now manufacture similar products.
# Mace vs. pepper spray
Due to the current brand-name use of the term "Mace" to refer to pepper sprays and the fact that mace is illegal in most Western countries, it is very difficult to find information on traditional mace. "Mace" and "Pepper Spray" are frequently used interchangeably.
# Training
Most law enforcement agencies require that their personnel become certified on similar aerosol spray devices such as pepper spray before using them in the field. Inert units which use the same mechanism but spray an inactive saccharine solution are also used for training purposes. [1]
# Effect
The effect of Mace varies on humans. Most common is a burning sensation on the area affected with the spray. If in contact with eyes it causes automatic closing of the eyes due to intense pain if open. This along with a feeling of suffocating if inhaled it causes the person to be very vulnerable and dependent, resulting in easy overpowering (for example, law enforcement officials over a suspect). Effects can be minimal on those under the influence of alcohol or drugs. The duration of the effects vary from 30 minutes up to 2 hours, depending on the person and treatment.
# Mace in History
During the September 11, 2001 terrorist attacks Mace was supposedly used by the hijackers of American Airlines Flight 11 to prevent entry to the first-class area and keep passengers at the rear of the plane. The official 9/11 Commission Report states that "The hijackers quickly gained control and sprayed Mace, pepper spray, or some other irritant in the first-class cabin, in order to force the passengers and flight attendants toward the rear of the plane."[1] | https://www.wikidoc.org/index.php/Mace_(spray) | |
e5deb16bcbf9b95b1291158a972355f001b4db8a | wikidoc | Macrocytosis | Macrocytosis
Macrocytosis is the enlargement of red blood cells with near-constant haemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories).
# Causes
Most commonly this etiology is bone marrow dysplasia primary to alcohol abuse. Other causes may include:
- Vitamin B12 or folate deficiency
- hypothyroidism
- Hydroxyurea (patient information)
- reticulocytosis
- liver disease
- myeloproliferative disease
# Complications
No complications arise from macrocytosis itself and a prognosis will be determined from its aetiology. | Macrocytosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Macrocytosis is the enlargement of red blood cells with near-constant haemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories).
# Causes
Most commonly this etiology is bone marrow dysplasia primary to alcohol abuse. Other causes may include:
- Vitamin B12 or folate deficiency
- hypothyroidism
- Hydroxyurea (patient information)
- reticulocytosis
- liver disease
- myeloproliferative disease
# Complications
No complications arise from macrocytosis itself and a prognosis will be determined from its aetiology.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Macrocytosis | |
bbc0a54d936a13b45da1b8246fc01d04ebf5b979 | wikidoc | Macula densa | Macula densa
In the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the thick ascending limb of Henle (TALH) at the point of return of the nephron to the vascular pole of its parent glomerulus glomerular vascular pole.
The cells of the macula densa are sensitive to the ionic content and water volume of the fluid in the TALH, producing molecular signals that promote renin secretion by other cells of the juxtaglomerular apparatus. The release of renin is an essential component of the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure and volume.
# Histology
The cells of the macula densa cells are taller and have more prominent nuclei than surrounding cells of the thick ascending limb of Henle.
The close proximity and prominence of the nuclei cause this segment of the TALH wall to appear darker in microscopic preparations, hence the name macula densa.
# Function
A decrease in blood pressure results in a decreased concentration of sodium and chloride ions at the macula densa. (This is due to reduced filtration by the glomerulus: less filtrate is expelled into Bowman's space and the proximal convoluted tubule; the resulting fluid reaching the macula will have a lower sodium chloride concentration after the sodium chloride is removed along the thick ascending limb of Henle.)
In response, the macula densa cells release prostaglandins, which triggers granular juxtaglomerular cells lining the afferent arterioles to release renin into the bloodstream. (The juxtoglomerular cells can also release renin independently of the macula densa, as they are also triggered by baroreceptors lining the arterioles, and release renin if a fall in blood pressure in the arterioles is detected.) Furthermore, activation of the sympathetic nervous system stimulates renin release through activation of beta-1 receptors. | Macula densa
In the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the thick ascending limb of Henle (TALH) at the point of return of the nephron to the vascular pole of its parent glomerulus glomerular vascular pole.
The cells of the macula densa are sensitive to the ionic content and water volume of the fluid in the TALH, producing molecular signals that promote renin secretion by other cells of the juxtaglomerular apparatus.[1] The release of renin is an essential component of the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure and volume.
# Histology
The cells of the macula densa cells are taller and have more prominent nuclei than surrounding cells of the thick ascending limb of Henle.
The close proximity and prominence of the nuclei cause this segment of the TALH wall to appear darker in microscopic preparations[2], hence the name macula densa.
# Function
A decrease in blood pressure results in a decreased concentration of sodium and chloride ions at the macula densa. (This is due to reduced filtration by the glomerulus: less filtrate is expelled into Bowman's space and the proximal convoluted tubule; the resulting fluid reaching the macula will have a lower sodium chloride concentration after the sodium chloride is removed along the thick ascending limb of Henle.)
In response, the macula densa cells release prostaglandins, which triggers granular juxtaglomerular cells lining the afferent arterioles to release renin into the bloodstream. (The juxtoglomerular cells can also release renin independently of the macula densa, as they are also triggered by baroreceptors lining the arterioles, and release renin if a fall in blood pressure in the arterioles is detected.) Furthermore, activation of the sympathetic nervous system stimulates renin release through activation of beta-1 receptors. | https://www.wikidoc.org/index.php/Macula_densa | |
66c74339a32f044ac12437dfed7ff45385771b9f | wikidoc | Malacoplakia | Malacoplakia
Malakoplakia or Malacoplakia is a rare inflammatory condition which makes its presence known as a papule, plaque or ulceration that usually affects the genitourinary tract.:274 However, it may also be associated with other bodily organs. It was initially described in the early 1900s as soft yellowish plaques found on the mucosa of the urinary bladder. Microscopically it is characterized by the presence of foamy histiocytes with basophilic inclusions called Michaelis-Gutmann bodies.
It usually involves gram negative bacteria.
# Causes
Malakoplakia is thought to result from the insufficient killing of bacteria by macrophages. Therefore, the partially digested bacteria accumulate in macrophages and leads to a deposition of iron and calcium. The impairment of bactericidal activity manifests itself as the formation of an ulcer, plaque or papule.
Malakoplakia is associated with patients with a history of immunosuppression due to lymphoma, diabetes mellitus, renal transplantation, or because of long-term therapy with systemic corticosteroids.
# Treatment
Today, antibiotics are used for treatment of malakoplakia.
# Antimicrobial therapy
- Malacoplakia
- Preferred regimen (1): Bethanechol chloride AND Ciprofloxacin 400 mg IV q12h
- Preferred regimen (2): Bethanechol chloride AND TMP-SMX 2 mg/kg (TMP component IV q6h) | Malacoplakia
Malakoplakia or Malacoplakia is a rare inflammatory condition which makes its presence known as a papule, plaque or ulceration that usually affects the genitourinary tract.[1]:274 However, it may also be associated with other bodily organs. It was initially described in the early 1900s as soft yellowish plaques found on the mucosa of the urinary bladder. Microscopically it is characterized by the presence of foamy histiocytes with basophilic inclusions called Michaelis-Gutmann bodies.
It usually involves gram negative bacteria.[2]
# Causes
Malakoplakia is thought to result from the insufficient killing of bacteria by macrophages. Therefore, the partially digested bacteria accumulate in macrophages and leads to a deposition of iron and calcium. The impairment of bactericidal activity manifests itself as the formation of an ulcer, plaque or papule.
Malakoplakia is associated with patients with a history of immunosuppression due to lymphoma, diabetes mellitus, renal transplantation, or because of long-term therapy with systemic corticosteroids.
# Treatment
Today, antibiotics are used for treatment of malakoplakia.
# Antimicrobial therapy
- Malacoplakia[3]
- Preferred regimen (1): Bethanechol chloride AND Ciprofloxacin 400 mg IV q12h
- Preferred regimen (2): Bethanechol chloride AND TMP-SMX 2 mg/kg (TMP component IV q6h) | https://www.wikidoc.org/index.php/Malacoplakia | |
9aaa15496fe9020e58cb15266dddf59df0d03caa | wikidoc | Malleability | Malleability
Malleability is a mechanical property of matter, but is most commonly used in reference to metals and metalloids. A malleable metal is capable of being flattened into thin sheets without cracking by the processes of hammering or rolling. This property is important in metalworking, as materials that crack or break under pressure cannot be hammered or rolled. Malleable materials can be formed using stamping or pressing, whereas brittle metals and plastics must be molded.
Malleability occurs as a result of the specific type of bond found in metals (Main article: metallic bond). In metallic bonds, valence shell electrons are delocalized and shared between many atoms. This is often referred to as the "sea of electrons" and is responsible for many properties of metal. The delocalized electrons allow metal atoms to slide past one another without being subjected to strong repulsive forces that would cause other materials to shatter.
Gold is the most malleable metal, followed by aluminium. Many plastics, and amorphous solids such as Play-Doh are also malleable.
It also means changeable, as in "we are all malleable".
See also ductility and deformation.
ar:قابلة للطرق
ca:Mal·leabilitat
de:Verformbarkeit
fa:چکشخواری
is:Mótanleiki
it:Malleabilità
ms:Kebolehtempaan
simple:Malleability
ur:طروقیہ | Malleability
Malleability is a mechanical property of matter, but is most commonly used in reference to metals and metalloids. A malleable metal is capable of being flattened into thin sheets without cracking by the processes of hammering or rolling. This property is important in metalworking, as materials that crack or break under pressure cannot be hammered or rolled. Malleable materials can be formed using stamping or pressing, whereas brittle metals and plastics must be molded.
Malleability occurs as a result of the specific type of bond found in metals (Main article: metallic bond). In metallic bonds, valence shell electrons are delocalized and shared between many atoms. This is often referred to as the "sea of electrons" and is responsible for many properties of metal. The delocalized electrons allow metal atoms to slide past one another without being subjected to strong repulsive forces that would cause other materials to shatter.
Gold is the most malleable metal, followed by aluminium. Many plastics, and amorphous solids such as Play-Doh are also malleable.
It also means changeable, as in "we are all malleable".
See also ductility and deformation.
Template:WikiDoc Sources
Template:Jb1
ar:قابلة للطرق
ca:Mal·leabilitat
de:Verformbarkeit
fa:چکشخواری
is:Mótanleiki
it:Malleabilità
ms:Kebolehtempaan
simple:Malleability
ur:طروقیہ | https://www.wikidoc.org/index.php/Malleability | |
a12dd8a98777c51759121ec6ebb61cdec9782bf2 | wikidoc | Mallinckrodt | Mallinckrodt
Mallinckrodt Incorporated is a set of pharmaceutical, chemical, imaging, and respiratory equipment suppliers based in the St. Louis, Missouri area, which were recently purchased by Tyco Healthcare (Tyco International) and which have been proposed for further reorganization. One division, Mallinckrodt Baker, was produced by merger with the chemical supplier founded by John Townshend Baker.
Mallinckrodt is the sole legal source for cocaine in the United States, which it receives from a Stepan Company plant in Maywood, New Jersey, which is the only firm in the U.S. licensed to import coca leaves. Federal restrictions also bar the importation of drugs such as Esterom manufactured from cocaine, which therefore requires that they use this supplier. Mallinckrodt is also one of the U.S. importers of opium from India.
The Mallinckrodt General Clinical Research Center received contributions from Edward Mallinckrodt, Jr., who headed the firm in the 1940s.
The legal decision Mallinckrodt, Inc. v. Medipart, Inc., 976 F.2d 700, 708 (Fed. Cir. 1992)) established a right of patent holders to limit the use of their products post-sale, and was cited in Arizona Cartridge Remanufacturers Association Inc. v. Lexmark International Inc., the decision that end-user licensing agreements on software boxes can be enforced against customers. | Mallinckrodt
Mallinckrodt Incorporated is a set of pharmaceutical, chemical, imaging, and respiratory equipment suppliers based in the St. Louis, Missouri area, which were recently purchased by Tyco Healthcare (Tyco International) and which have been proposed for further reorganization.[1] One division, Mallinckrodt Baker, was produced by merger with the chemical supplier founded by John Townshend Baker.
Mallinckrodt is the sole legal source for cocaine in the United States, which it receives from a Stepan Company plant in Maywood, New Jersey, which is the only firm in the U.S. licensed to import coca leaves. Federal restrictions also bar the importation of drugs such as Esterom manufactured from cocaine, which therefore requires that they use this supplier.[2] Mallinckrodt is also one of the U.S. importers of opium from India.[3]
The Mallinckrodt General Clinical Research Center received contributions from Edward Mallinckrodt, Jr., who headed the firm in the 1940s.
The legal decision Mallinckrodt, Inc. v. Medipart, Inc., 976 F.2d 700, 708 (Fed. Cir. 1992)) established a right of patent holders to limit the use of their products post-sale, and was cited in Arizona Cartridge Remanufacturers Association Inc. v. Lexmark International Inc., the decision that end-user licensing agreements on software boxes can be enforced against customers. | https://www.wikidoc.org/index.php/Mallinckrodt | |
9b1ecd1efd7c36aead1341a77ab9cf3dd826235c | wikidoc | Malnutrition | Malnutrition
# Overview
Malnutrition is a general term for a medical condition caused by an improper or insufficient diet. It most often refers to undernutrition resulting from inadequate consumption, poor absorption, or excessive loss of nutrients, but the term can also encompass overnutrition, resulting from overeating or excessive intake of specific nutrients. An individual will experience malnutrition if the appropriate amount of, or quality of nutrients comprising a healthy diet are not consumed for an extended period of time. An extended period of malnutrition can result in starvation, disease, and infection.
Malnutrition is the lack of sufficient nutrients to maintain healthy bodily functions and is typically associated with extreme poverty in economically developing countries. It is a common cause of reduced intelligence in parts of the world affected by famine. Malnutrition as the result of inappropriate dieting, overeating or the absence of a "balanced diet" is often observed in economically developed countries (eg. as indicated by increasing levels of obesity).
Most commonly, malnourished people either do not have enough calories in their diet, or are eating a diet that lacks protein, vitamins, or trace minerals. Medical problems arising from malnutrition are commonly referred to as deficiency diseases. Scurvy is a well-known and now rare form of malnutrition, in which the victim is deficient in vitamin C.
Common forms of malnutrition include protein-energy malnutrition (PEM) and micronutrient malnutrition. PEM refers to inadequate availability or absorption of energy and proteins in the body. Micronutrient malnutrition refers to inadequate availability of some essential nutrients such as vitamins and trace elements that are required by the body in small quantities. Micronutrient deficiencies lead to a variety of diseases and impair normal functioning of the body. Deficiency in micronutrients such as Vitamin A reduces the capacity of the body to resist diseases. Deficiency in iron, iodine and vitamin A is widely prevalent and represent a major public health challenge. An array of afflictions ranging from stunted growth, reduced intelligence and various cognitive abilities, reduced sociability, reduced leadership and assertiveness, reduced activity and energy, reduced muscle growth and strength, and poorer health overall are directly implicated to nutrient deficiencies. Also, another, although rare, effect of malnutrition is black spots appearing on the skin.
Hunger is the normal psychological response brought on by the physiological condition of needing food. Hunger can also affect the mental state of a person, and is often used as a metonym for general undernourishment.
# Causes of Malnutrition
- Famine
- Poverty
- Digestive disease
- Malabsorption
- Depression
- Anorexia nervosa
- Bulimia nervosa
- Untreated diabetes mellitus
- Fasting
- Coma
- Alcoholism and other certain drug addictions
- Over-consumption of fat and sugar
- Overpopulation
- Industrial food processing
# Statistics
Number of undernourished people (million) in 2001-2003, according to the FAO, the following countries had 5 million or more undernourished people :
Note: This table measures "undernourishment", as defined by FAO, and represents the number of people consuming (on average for years 2001 to 2003) less than the minimum amount of food energy (measured in kilocalories per capita per day) necessary for the average person to stay in good health while performing light physical activity. It is a conservative indicator that does not takes into account the extra needs of people performing extrenous physical activity, nor seasonal variations in food consumption or other sources of variability such as inter-individual differences in energy requirements.
Malnutrition and undernourishment are cumulative or average situations, and not the work of a single day's food intake (or lack thereof). This table does not represent the number of people who "went to bed hungry today."
The U.S. Department of Agriculture reported that in 2003, only 1 out of 200 U.S. households with children became so severely food insecure that any of the children went hungry even once during the year. A substantially larger proportion of these same households (3.8 percent) had adult members who were hungry at least one day during the year because of their households' inability to afford enough food.
# Effects
An extended period of malnutrition can result in starvation or deficiency diseases such as scurvy. There may also be a grey discoloration of the nail beds. Malnutrition increases the risk of infection and infectious disease; for example, it is a major risk factor in the onset of active tuberculosis.
Malnutrition appears to increase activity and movement in many animals - for example an experiment on spiders showed increased activity and predation in starved spiders, resulting in larger weight gain. This pattern is seen in many animals, including humans while sleeping. It even occurs in rats with their cerebral cortex or stomachs completely removed. Increased activity on hamster wheels occurred when rats were deprived not only of food, but also water or B vitamins such as thiamine This response may increase the animal's chance of finding food, though it has also been speculated the emigration response relieves pressure on the home population. | Malnutrition
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Malnutrition is a general term for a medical condition caused by an improper or insufficient diet. It most often refers to undernutrition resulting from inadequate consumption, poor absorption, or excessive loss of nutrients, but the term can also encompass overnutrition, resulting from overeating or excessive intake of specific nutrients. An individual will experience malnutrition if the appropriate amount of, or quality of nutrients comprising a healthy diet are not consumed for an extended period of time. An extended period of malnutrition can result in starvation, disease, and infection.
Malnutrition is the lack of sufficient nutrients to maintain healthy bodily functions and is typically associated with extreme poverty in economically developing countries. It is a common cause of reduced intelligence in parts of the world affected by famine. [1] Malnutrition as the result of inappropriate dieting, overeating or the absence of a "balanced diet" is often observed in economically developed countries (eg. as indicated by increasing levels of obesity).
Most commonly, malnourished people either do not have enough calories in their diet, or are eating a diet that lacks protein, vitamins, or trace minerals. Medical problems arising from malnutrition are commonly referred to as deficiency diseases. Scurvy is a well-known and now rare form of malnutrition, in which the victim is deficient in vitamin C.
Common forms of malnutrition include protein-energy malnutrition (PEM) and micronutrient malnutrition. PEM refers to inadequate availability or absorption of energy and proteins in the body. Micronutrient malnutrition refers to inadequate availability of some essential nutrients such as vitamins and trace elements that are required by the body in small quantities. Micronutrient deficiencies lead to a variety of diseases and impair normal functioning of the body. Deficiency in micronutrients such as Vitamin A reduces the capacity of the body to resist diseases. Deficiency in iron, iodine and vitamin A is widely prevalent and represent a major public health challenge. An array of afflictions ranging from stunted growth, reduced intelligence and various cognitive abilities, reduced sociability, reduced leadership and assertiveness, reduced activity and energy, reduced muscle growth and strength, and poorer health overall are directly implicated to nutrient deficiencies. Also, another, although rare, effect of malnutrition is black spots appearing on the skin.
Hunger is the normal psychological response brought on by the physiological condition of needing food. Hunger can also affect the mental state of a person, and is often used as a metonym for general undernourishment.
# Causes of Malnutrition
- Famine
- Poverty
- Digestive disease
- Malabsorption
- Depression
- Anorexia nervosa
- Bulimia nervosa
- Untreated diabetes mellitus
- Fasting
- Coma
- Alcoholism and other certain drug addictions
- Over-consumption of fat and sugar
- Overpopulation[2]
- Industrial food processing
# Statistics
Number of undernourished people (million) in 2001-2003, according to the FAO, the following countries had 5 million or more undernourished people [2]:
Note: This table measures "undernourishment", as defined by FAO, and represents the number of people consuming (on average for years 2001 to 2003) less than the minimum amount of food energy (measured in kilocalories per capita per day) necessary for the average person to stay in good health while performing light physical activity. It is a conservative indicator that does not takes into account the extra needs of people performing extrenous physical activity, nor seasonal variations in food consumption or other sources of variability such as inter-individual differences in energy requirements.
Malnutrition and undernourishment are cumulative or average situations, and not the work of a single day's food intake (or lack thereof). This table does not represent the number of people who "went to bed hungry today."
The U.S. Department of Agriculture reported that in 2003, only 1 out of 200 U.S. households with children became so severely food insecure that any of the children went hungry even once during the year. A substantially larger proportion of these same households (3.8 percent) had adult members who were hungry at least one day during the year because of their households' inability to afford enough food.[3]
# Effects
An extended period of malnutrition can result in starvation or deficiency diseases such as scurvy. There may also be a grey discoloration of the nail beds. Malnutrition increases the risk of infection and infectious disease; for example, it is a major risk factor in the onset of active tuberculosis.[3]
Malnutrition appears to increase activity and movement in many animals - for example an experiment on spiders showed increased activity and predation in starved spiders, resulting in larger weight gain.[4] This pattern is seen in many animals, including humans while sleeping.[5] It even occurs in rats with their cerebral cortex or stomachs completely removed.[6] Increased activity on hamster wheels occurred when rats were deprived not only of food, but also water or B vitamins such as thiamine[7] This response may increase the animal's chance of finding food, though it has also been speculated the emigration response relieves pressure on the home population.[5] | https://www.wikidoc.org/index.php/Malnourished | |
d8b4f6e35ef8ca95570471e711976881be0bcba0 | wikidoc | Malocclusion | Malocclusion
# Overview
A malocclusion refers to the misalignment of teeth and/or incorrect relation between the teeth of the two dental arches. The upper arch is called the maxilla and the lower is called the mandible.
# Presentation
Most people have some degree of malocclusion, although it isn't usually serious enough to require treatment. Those who have more severe malocclusions may require orthodontic and sometimes surgical treatment (orthognatic surgery) to correct the problem. Correction of malocclusion may reduce risk of tooth decay and help relieve excessive pressure on the temporomandibular joint. Orthodontic treatment is also used to align for aesthetic reasons.
Malocclusions may be coupled with skeletal disharmony of the face, where the relations between the upper and lower jaws are not appropriate. In these cases, the dental problem is typically derived from the skeletal disharmony.
# Classification
Malocclusions can be divided mainly into three types, depending on the sagittal relations of teeth and jaws, by Angle's classification method. However, there are also e.g. crowding of teeth and other conditions, not directly fitting into this classification.
Many authors have tried to classify or modify Angle's classification. This has resulted in many subtypes.
## Angle's classification method
Edward Angle, who is considered the father of modern orthodontics, was the first to classify malocclusion. He based his classifications on the relative position of the maxillary first molar. According to Angle, the mesiobuccal cusp of the upper first molar should rest on the mesiobuccal groove of the mandibular first molar. Any variations from this resulted in malocclusion types. It is also possible to have different classes of maloclusion on left and right sides.
It is estimated that approximately 18% of the United States population suffers from an over sided malocclusion, while only 11% suffer from an under malocclusion.
- Class I: Here the molar relationship of the occlusion is normal or as described for the maxillary first molar, but the other teeth have problems like spacing, crowding, over or under eruption, etc.
- Class II: ("overbite") In this situation, the upper molars are placed not in the mesiobuccal groove but anteriorly to it. Usually the mesiobuccal cusp rests in between the first mandibular molars and second premolars. There are two subtypes:
Class II Division 1: The molar relationships are like that of Class II and the anterior teeth are protruded.
Class II Division 2: The molar relationships are class II but the central are retroclined and the lateral teeth are seen overlapping the centrals.
- Class II Division 1: The molar relationships are like that of Class II and the anterior teeth are protruded.
- Class II Division 2: The molar relationships are class II but the central are retroclined and the lateral teeth are seen overlapping the centrals.
- Class III: (prognathism, "underbite" or "negative overjet") is when the lower front teeth are more prominent than the upper front teeth. In this case the patient has very often a large mandible or a short maxillary bone.
# Crowding of teeth
Crowding of teeth is where there is insufficient room for the normal complement of adult teeth.
## Cause
Crowding of teeth is recognized as an affliction that stems in part from a modern western lifestyle. We do not know for sure whether it is due to the consistency of western diets; a result of mouthbreathing; or the result of an early loss of deciduous (milk, baby) teeth due to decay. It is also possible that Homo sapiens have evolved smaller jaws without a reduction in the number of teeth they will house happening at the same time.
## Treatment
Crowding of the teeth is treated with orthodontics, often with, tooth extraction, dental braces, followed by growth modification in children or jaw surgery (orthognathic surgery) in adults.
# Other conditions
Other kind of malocclusions are due to vertical discrepancies. Long faces may lead to open bite, while short faces can be coupled to a deep bite. However, there are many other more common causes for open bites such as tongue thrusting, thumb sucking, etc, and likewise for deep bites.
Malocclusions can also be secondary to transversal skeletal discrepancy or to a skeletal asymmetry.
# Image Gallery
- Class I with severe crowding and labially erupted canines
- Class II molar relationship | Malocclusion
Editor in Chief: Berna Zorkun DMD [1]
# Overview
A malocclusion refers to the misalignment of teeth and/or incorrect relation between the teeth of the two dental arches. The upper arch is called the maxilla and the lower is called the mandible.
# Presentation
Most people have some degree of malocclusion, although it isn't usually serious enough to require treatment. Those who have more severe malocclusions may require orthodontic and sometimes surgical treatment (orthognatic surgery) to correct the problem. Correction of malocclusion may reduce risk of tooth decay and help relieve excessive pressure on the temporomandibular joint. Orthodontic treatment is also used to align for aesthetic reasons.
Malocclusions may be coupled with skeletal disharmony of the face, where the relations between the upper and lower jaws are not appropriate. In these cases, the dental problem is typically derived from the skeletal disharmony.
# Classification
Malocclusions can be divided mainly into three types, depending on the sagittal relations of teeth and jaws, by Angle's classification method. However, there are also e.g. crowding of teeth and other conditions, not directly fitting into this classification.
Many authors have tried to classify or modify Angle's classification. This has resulted in many subtypes.
## Angle's classification method
Edward Angle, who is considered the father of modern orthodontics, was the first to classify malocclusion. He based his classifications on the relative position of the maxillary first molar.[1] According to Angle, the mesiobuccal cusp of the upper first molar should rest on the mesiobuccal groove of the mandibular first molar. Any variations from this resulted in malocclusion types. It is also possible to have different classes of maloclusion on left and right sides.
It is estimated that approximately 18% of the United States population suffers from an over sided malocclusion, while only 11% suffer from an under malocclusion.
- Class I: Here the molar relationship of the occlusion is normal or as described for the maxillary first molar, but the other teeth have problems like spacing, crowding, over or under eruption, etc.
- Class II: ("overbite") In this situation, the upper molars are placed not in the mesiobuccal groove but anteriorly to it. Usually the mesiobuccal cusp rests in between the first mandibular molars and second premolars. There are two subtypes:
Class II Division 1: The molar relationships are like that of Class II and the anterior teeth are protruded.
Class II Division 2: The molar relationships are class II but the central are retroclined and the lateral teeth are seen overlapping the centrals.
- Class II Division 1: The molar relationships are like that of Class II and the anterior teeth are protruded.
- Class II Division 2: The molar relationships are class II but the central are retroclined and the lateral teeth are seen overlapping the centrals.
- Class III: (prognathism, "underbite" or "negative overjet") is when the lower front teeth are more prominent than the upper front teeth. In this case the patient has very often a large mandible or a short maxillary bone.
# Crowding of teeth
Crowding of teeth is where there is insufficient room for the normal complement of adult teeth.
## Cause
Crowding of teeth is recognized as an affliction that stems in part from a modern western lifestyle. We do not know for sure whether it is due to the consistency of western diets; a result of mouthbreathing; or the result of an early loss of deciduous (milk, baby) teeth due to decay. It is also possible that Homo sapiens have evolved smaller jaws without a reduction in the number of teeth they will house happening at the same time.
## Treatment
Crowding of the teeth is treated with orthodontics, often with, tooth extraction, dental braces, followed by growth modification in children or jaw surgery (orthognathic surgery) in adults.
# Other conditions
Other kind of malocclusions are due to vertical discrepancies. Long faces may lead to open bite, while short faces can be coupled to a deep bite. However, there are many other more common causes for open bites such as tongue thrusting, thumb sucking, etc, and likewise for deep bites.
Malocclusions can also be secondary to transversal skeletal discrepancy or to a skeletal asymmetry.
# Image Gallery
- Class I with severe crowding and labially erupted canines
- Class II molar relationship | https://www.wikidoc.org/index.php/Malocclusion | |
d6b90bdb89d2f57f0314977e3f27f392855ec4c0 | wikidoc | Malonic acid | Malonic acid
Malonic acid (IUPAC systematic name: propanedioic acid) is a dicarboxylic acid with structure CH2(COOH)2. The ionised form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's ethyl ester. The name originates from Latin malum, meaning apple.
# Biochemistry
The calcium salt of malonic acid occurs in high concentrations in beetroot.
# Organic synthesis
A classical preparation of malonic acid starts from acetic acid. This acid is chlorinated to chloroacetic acid. Sodium carbonate generates the sodium salt which is then reacted with sodium cyanide to the cyano acetic acid salt in a nucleophilic substitution. The nitrile group can be hydrolysed with sodium hydroxide to sodium malonate and acidification affords malonic acid.
# Organic reactions
In a well known reaction malonic acid condenses with urea to barbituric acid. Malonic acid is frequently used as an enolate in Knoevenagel condensations or condensed with acetone to form Meldrum's acid. | Malonic acid
Template:Chembox new
Malonic acid (IUPAC systematic name: propanedioic acid) is a dicarboxylic acid with structure CH2(COOH)2. The ionised form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's ethyl ester. The name originates from Latin malum, meaning apple.
# Biochemistry
The calcium salt of malonic acid occurs in high concentrations in beetroot.
# Organic synthesis
A classical preparation of malonic acid starts from acetic acid[1]. This acid is chlorinated to chloroacetic acid. Sodium carbonate generates the sodium salt which is then reacted with sodium cyanide to the cyano acetic acid salt in a nucleophilic substitution. The nitrile group can be hydrolysed with sodium hydroxide to sodium malonate and acidification affords malonic acid.
# Organic reactions
In a well known reaction malonic acid condenses with urea to barbituric acid. Malonic acid is frequently used as an enolate in Knoevenagel condensations or condensed with acetone to form Meldrum's acid.
# External links
- MSDS http://physchem.ox.ac.uk [1]
- MSDS http://avogadro.chem.iastate.edu [2]
- pH spectrum http://www.Theoprax-Research.com Disodium Malonate
- pH spectrum http://www.Theoprax-Research.com Malonic acid copper complex | https://www.wikidoc.org/index.php/Malonic_acid | |
5a0caa4bd68c4afd77b09afab123a0ebf39deed8 | wikidoc | Methaqualone | Methaqualone
# Overview
Methaqualone, brand name Quaalude (sometimes stylized Quāālude) /ˈkweɪluːd/ in the US and Mandrax in the UK, is a central nervous system (CNS) depressant of the quinazolinone class that acts as a sedative and hypnotic.
The sedative–hypnotic activity of methaqualone was first noted by Indian researchers in the 1950s and in 1962 methaqualone itself was patented in the US by Wallace and Tiernan. Its use peaked in the early 1970s as a hypnotic, for the treatment of insomnia, and as a sedative and muscle relaxant. It is still produced and used clandestinely as a recreational drug throughout the world. The drug was popular in the 1970s disco club scene.
# History
Methaqualone was first synthesized in India in 1951 by Indra Kishore Kacker and Syed Hussain Zaheer, for use as an antimalarial drug. By 1965 it was the most commonly prescribed sedative in Britain, where it has been sold legally under the names Malsed, Malsedin, and Renoval. In 1965 a methaqualone/antihistamine combination was sold as the sedative drug Mandrax, by Roussel Laboratories (now part of Sanofi-Aventis). In 1972 it was the sixth-bestselling sedative in the US, where it was legal under the brand name Quaalude.
Quaalude in the United States was originally manufactured in 1965 by the Fort Washington, Pennsylvania, based pharmaceutical firm William H. Rorer Inc. The drug name "Quaalude" shared a stylistic reference to another drug marketed by the firm, Maalox, and was a portmanteau of the phrase "quiet interlude".
In 1978, Rorer sold the rights to manufacture Quaalude to the Lemmon Company of Sellersville, Pennsylvania. At that time, Rorer chairman John Eckman commented on Quaalude's bad reputation stemming from illegal manufacture and use of methaqualone, and illegal sale and use of legally prescribed Quaalude:
Both companies still regarded Quaalude as an excellent sleeping drug. Lemmon, well aware of Quaalude's public image problems, used advertisements in medical journals to urge physicians "not to permit the abuses of illegal users to deprive a legitimate patient of the drug". Lemmon also marketed a small quantity under another name, Mequin, so doctors could prescribe the drug without the negative connotations.
The rights to Quaalude were held by the JB Roerig & Company division of Pfizer, before the drug was discontinued in the United States in 1985, mainly due to its psychological addictiveness and recreational use.
# Uses
## Medical
Methaqualone is a depressant that increases the activity of the GABA receptors in the brain and nervous system. When GABA activity is increased, blood pressure drops and the breathing and pulse rates slow, leading to a state of deep relaxation. These properties explain why methaqualone was originally mainly prescribed for insomnia.
Methaqualone peaks in the bloodstream within several hours, with a half-life of 20–60 hours. Regular users build up a physical tolerance, requiring larger doses for the same effect. Overdose can lead to nervous system shutdown, coma and death.
Methaqualone is not recommended for use while pregnant and is in pregnancy category D. In Canada, methaqualone is listed in Schedule III of the Controlled Drugs and Substances Act and requires a prescription. It is banned in India.
## Recreational
Methaqualone became increasingly popular as a recreational drug in the late 1960s and early 1970s, known variously as 'ludes or sopers (also soapers) in the U.S. and mandrakes and mandies in the UK and Australia.
The drug was often used by people who went dancing at glam rock clubs in the early 1970s and at discos in the late 1970s. (One slang term for Quaalude was disco biscuits.) In the mid-1970s there were bars in Manhattan called juice bars that only served non-alcoholic drinks that catered to people who liked to dance on methaqualone.
Smoking methaqualone, either by itself or as an adulterant added to various legal and illegal smoking mixtures, gained popularity in the US for a few years during the mid-1970s. Because the various binders and inert ingredients that were contained in the pill form were toxic when smoked, this practice was roundly decried by the medical community as a serious health risk. Smoking methaqualone pills can lead to emphysema and other chronic lung disorders, most notably talcosis.
The drug was more tightly regulated in Britain under the Misuse of Drugs Act 1971 and in the U.S. from 1973. It was withdrawn from many developed markets in the early 1980s. In the United States it was withdrawn in 1982 and made a Schedule I drug in 1984. It has a DEA ACSCN of 2565 and in 2013 the aggregate annual manufacturing quota for the US was 10 grams. Mention of its possible use in some types of cancer and AIDS has periodically appeared in the literature since the late 1980s; research does not appear to have reached an advanced stage. The DEA has also added the methaqualone analogue mecloqualone (also a result of some incomplete clandestine syntheses) to Schedule I
as ACSCN 2572, and zero manufacturing quota.
Gene Haislip, the former head of the Chemical Control Division of the Drug Enforcement Administration (DEA), told the PBS documentary program Frontline: "We beat 'em." By working with governments and manufacturers around the world, the DEA was able to halt production and, Haislip says, "eliminated the problem".
Methaqualone was manufactured in the United States under the name Quaalude by the pharmaceutical firms Rorer and Lemmon with the numbers 714 stamped on the tablet, so people often referred to Quaalude as 714s, "Lemmons", or "Lemmon 7s". Methaqualone was also manufactured in the US under the trade names Sopor and Parest. After the legal manufacture of the drug ended in the United States in 1982, underground laboratories in Mexico continued illegal manufacture of methaqualone all through the 1980s, continuing the use of the "714" stamp, until their popularity waned in the early 1990s.
Methaqualone is one of the most commonly used recreational drugs in South Africa. It is also popular elsewhere in Africa and in India. Commonly known as Mandrax, M-pills, buttons, or smarties, a mixture of crushed mandrax and cannabis is smoked, usually through a smoking pipe made from the neck of a broken bottle. Wouter Basson (q.v.) produced 200 kilos of powder methaqualone and 100 000 Mandrax tablets as part of the massive drug cache that disappeared into the underground after the end of Apartheid and replacement of the National Party by the ANC in office, along with the famous "Basson Brownies", capsules of pure MDMA. The drugs were manufactured under the aegis of Project Coast, which included research into the use of anticholinergics, cocaine, empathogens, and depressants as riot-control agents.
# Effects
Effects can include drowsiness, reduced heart rate, reduced respiration, increased sexual arousal (aphrodisia), and paresthesias (numbness of the fingers and toes). Larger doses can bring about respiratory depression, slurred speech, headache, and photophobia (a symptom of excessive sensitivity to light).
## Overdose
An overdose can cause delirium, convulsions, hypertonia, hyperreflexia, vomiting, kidney failure, coma, and death through cardiac or respiratory arrest. It resembles barbiturate poisoning, but with increased motor difficulties and a lower incidence of cardiac or respiratory depression. The standard one tablet adult dosage of Quaalude was 75 mg; a dose of 8000 mg is lethal. However, a dose as little as 2000 mg could also be lethal, especially if taken with an alcoholic beverage.
# Drug testing
Urine drug test of gas-liquid chromatography (GLC) confirmation up to 72 hours after the last intake is a practical way of detecting methaqualone use.
To avoid a false positive Substance Abuse and Mental Health Services Administration (SAMHSA) determined the initial cut off level of 300 ng/ml for forensic and workplace drug testing of methaqualone. Only after testing at over 200 ng/ml is a person be considered positive, and possibly subject to penalties or workplace disciplinary action. As reported by Quest Diagnostics in 2011, methaqualone had a 0% positive drug testing rate in the US, making it one of the least used recreational drugs in that year. | Methaqualone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Methaqualone, brand name Quaalude (sometimes stylized Quāālude[1]) /ˈkweɪluːd/ in the US and Mandrax in the UK, is a central nervous system (CNS) depressant of the quinazolinone class that acts as a sedative and hypnotic.
The sedative–hypnotic activity of methaqualone was first noted by Indian researchers in the 1950s and in 1962 methaqualone itself was patented in the US by Wallace and Tiernan.[2] Its use peaked in the early 1970s as a hypnotic, for the treatment of insomnia, and as a sedative and muscle relaxant. It is still produced and used clandestinely as a recreational drug throughout the world. The drug was popular in the 1970s disco club scene.
# History
Methaqualone was first synthesized in India in 1951 by Indra Kishore Kacker and Syed Hussain Zaheer, for use as an antimalarial drug.[3][4] By 1965 it was the most commonly prescribed sedative in Britain, where it has been sold legally under the names Malsed, Malsedin, and Renoval. In 1965 a methaqualone/antihistamine combination was sold as the sedative drug Mandrax, by Roussel Laboratories (now part of Sanofi-Aventis). In 1972 it was the sixth-bestselling sedative in the US,[5] where it was legal under the brand name Quaalude.
Quaalude in the United States was originally manufactured in 1965 by the Fort Washington, Pennsylvania, based pharmaceutical firm William H. Rorer Inc. The drug name "Quaalude" shared a stylistic reference to another drug marketed by the firm, Maalox, and was a portmanteau of the phrase "quiet interlude".[6]
In 1978, Rorer sold the rights to manufacture Quaalude to the Lemmon Company of Sellersville, Pennsylvania. At that time, Rorer chairman John Eckman commented on Quaalude's bad reputation stemming from illegal manufacture and use of methaqualone, and illegal sale and use of legally prescribed Quaalude:
Both companies still regarded Quaalude as an excellent sleeping drug. Lemmon, well aware of Quaalude's public image problems, used advertisements in medical journals to urge physicians "not to permit the abuses of illegal users to deprive a legitimate patient of the drug". Lemmon also marketed a small quantity under another name, Mequin, so doctors could prescribe the drug without the negative connotations.
The rights to Quaalude were held by the JB Roerig & Company division of Pfizer, before the drug was discontinued in the United States in 1985, mainly due to its psychological addictiveness and recreational use.[7]
# Uses
## Medical
Methaqualone is a depressant that increases the activity of the GABA receptors in the brain and nervous system. When GABA activity is increased, blood pressure drops and the breathing and pulse rates slow, leading to a state of deep relaxation. These properties explain why methaqualone was originally mainly prescribed for insomnia.[8]
Methaqualone peaks in the bloodstream within several hours, with a half-life of 20–60 hours. Regular users build up a physical tolerance, requiring larger doses for the same effect. Overdose can lead to nervous system shutdown, coma and death.[9]
Methaqualone is not recommended for use while pregnant and is in pregnancy category D.[10] In Canada, methaqualone is listed in Schedule III of the Controlled Drugs and Substances Act and requires a prescription.[11][12] It is banned in India.[13]
## Recreational
Methaqualone became increasingly popular as a recreational drug in the late 1960s and early 1970s, known variously as 'ludes or sopers (also soapers) in the U.S. and mandrakes and mandies in the UK and Australia.
The drug was often used by people who went dancing at glam rock clubs in the early 1970s and at discos in the late 1970s. (One slang term for Quaalude was disco biscuits.) In the mid-1970s there were bars in Manhattan called juice bars that only served non-alcoholic drinks that catered to people who liked to dance on methaqualone.[14]
Smoking methaqualone, either by itself or as an adulterant added to various legal and illegal smoking mixtures, gained popularity in the US for a few years during the mid-1970s. Because the various binders and inert ingredients that were contained in the pill form were toxic when smoked, this practice was roundly decried by the medical community as a serious health risk. Smoking methaqualone pills can lead to emphysema and other chronic lung disorders, most notably talcosis.
The drug was more tightly regulated in Britain under the Misuse of Drugs Act 1971 and in the U.S. from 1973. It was withdrawn from many developed markets in the early 1980s. In the United States it was withdrawn in 1982 and made a Schedule I drug in 1984. It has a DEA ACSCN of 2565 and in 2013 the aggregate annual manufacturing quota for the US was 10 grams. Mention of its possible use in some types of cancer and AIDS has periodically appeared in the literature since the late 1980s; research does not appear to have reached an advanced stage. The DEA has also added the methaqualone analogue mecloqualone (also a result of some incomplete clandestine syntheses) to Schedule I
as ACSCN 2572, and zero manufacturing quota.
Gene Haislip, the former head of the Chemical Control Division of the Drug Enforcement Administration (DEA), told the PBS documentary program Frontline: "We beat 'em." By working with governments and manufacturers around the world, the DEA was able to halt production and, Haislip says, "eliminated the problem".[15][16][17]
Methaqualone was manufactured in the United States under the name Quaalude by the pharmaceutical firms Rorer and Lemmon with the numbers 714 stamped on the tablet, so people often referred to Quaalude as 714s, "Lemmons", or "Lemmon 7s". Methaqualone was also manufactured in the US under the trade names Sopor and Parest. After the legal manufacture of the drug ended in the United States in 1982, underground laboratories in Mexico continued illegal manufacture of methaqualone all through the 1980s, continuing the use of the "714" stamp, until their popularity waned in the early 1990s.
Methaqualone is one of the most commonly used recreational drugs in South Africa.[18][19] It is also popular elsewhere in Africa and in India.[19] Commonly known as Mandrax, M-pills, buttons, or smarties, a mixture of crushed mandrax and cannabis is smoked, usually through a smoking pipe made from the neck of a broken bottle. Wouter Basson (q.v.) produced 200 kilos of powder methaqualone and 100 000 Mandrax tablets as part of the massive drug cache that disappeared into the underground after the end of Apartheid and replacement of the National Party by the ANC in office, along with the famous "Basson Brownies", capsules of pure MDMA. The drugs were manufactured under the aegis of Project Coast, which included research into the use of anticholinergics, cocaine, empathogens, and depressants as riot-control agents.
# Effects
Effects can include drowsiness, reduced heart rate, reduced respiration, increased sexual arousal (aphrodisia), and paresthesias (numbness of the fingers and toes). Larger doses can bring about respiratory depression, slurred speech, headache, and photophobia (a symptom of excessive sensitivity to light).
## Overdose
An overdose can cause delirium, convulsions, hypertonia, hyperreflexia, vomiting, kidney failure, coma, and death through cardiac or respiratory arrest. It resembles barbiturate poisoning, but with increased motor difficulties and a lower incidence of cardiac or respiratory depression. The standard one tablet adult dosage of Quaalude was 75 mg; a dose of 8000 mg is lethal. However, a dose as little as 2000 mg could also be lethal, especially if taken with an alcoholic beverage.
# Drug testing
Urine drug test of gas-liquid chromatography (GLC) confirmation up to 72 hours after the last intake is a practical way of detecting methaqualone use.[20]
To avoid a false positive Substance Abuse and Mental Health Services Administration (SAMHSA) determined the initial cut off level of 300 ng/ml for forensic and workplace drug testing of methaqualone. Only after testing at over 200 ng/ml is a person be considered positive, and possibly subject to penalties or workplace disciplinary action.[21] As reported by Quest Diagnostics in 2011, methaqualone had a 0% positive drug testing rate in the US, making it one of the least used recreational drugs in that year.[22] | https://www.wikidoc.org/index.php/Mandrax | |
23d5256a22b9700cca2812b8f6e827a95081fb3e | wikidoc | Mantoux test | Mantoux test
Synonyms and keywords: PPD, TB skin test, TST, tst
# Overview
The Mantoux tuberculin skin test (TST) is the standard method of determining whether a person is infected with Mycobacterium tuberculosis. Reliable administration and reading of the TST requires standardization of procedures, training, supervision, and practice.
# Procedure
The TST is performed by injecting 0.1 ml of tuberculin purified protein derivative (PPD) into the inner surface of the forearm. The injection should be made with a tuberculin syringe, with the needle bevel facing upward. The TST is an intradermal injection. When placed correctly, the injection should produce a pale elevation of the skin (a wheal) 6 to 10 mm in diameter.
The skin test reaction should be read between 48 and 72 hours after administration. A patient who does not return within 72 hours will need to be rescheduled for another skin test.
The reaction should be measured in millimeters of the induration (palpable, raised, hardened area or swelling). The reader should not measure erythema (redness). The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis).
# Classification of Tuberculin Reaction
Skin test interpretation depends on two factors:
- Measurement in millimeters of the induration.
- Person’s risk of being infected with TB and of progression to disease if infected.
# Contraindications
TST is contraindicated only for persons who have had a severe reaction (e.g., necrosis, blistering, anaphylactic shock, or ulcerations) to a previous TST. It is not contraindicated for any other persons, including infants, children, pregnant women, persons who are HIV-infected, or persons who have been vaccinated with BCG.
# False-Poisitve and False-Negative Reactions
In some persons who are infected with M. tuberculosis, the ability to react to tuberculin may wane over time. When given a TST years after infection, these persons may have a false-negative reaction. However, the TST may stimulate the immune system, causing a positive, or boosted reaction to subsequent tests. Giving a second TST after an initial negative TST reaction is called two-step testing.
# Two-step Testing
Two-step testing is useful for the initial skin testing of adults who are going to be retested periodically, such as health care workers or nursing home residents. This two-step approach can reduce the likelihood that a boosted reaction to a subsequent TST will be misinterpreted as a recent infection. | Mantoux test
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
Synonyms and keywords: PPD, TB skin test, TST, tst
# Overview
The Mantoux tuberculin skin test (TST) is the standard method of determining whether a person is infected with Mycobacterium tuberculosis. Reliable administration and reading of the TST requires standardization of procedures, training, supervision, and practice.
# Procedure
The TST is performed by injecting 0.1 ml of tuberculin purified protein derivative (PPD) into the inner surface of the forearm. The injection should be made with a tuberculin syringe, with the needle bevel facing upward. The TST is an intradermal injection. When placed correctly, the injection should produce a pale elevation of the skin (a wheal) 6 to 10 mm in diameter.
The skin test reaction should be read between 48 and 72 hours after administration. A patient who does not return within 72 hours will need to be rescheduled for another skin test.
The reaction should be measured in millimeters of the induration (palpable, raised, hardened area or swelling). The reader should not measure erythema (redness). The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis).
# Classification of Tuberculin Reaction
Skin test interpretation depends on two factors:
- Measurement in millimeters of the induration.
- Person’s risk of being infected with TB and of progression to disease if infected.
# Contraindications
TST is contraindicated only for persons who have had a severe reaction (e.g., necrosis, blistering, anaphylactic shock, or ulcerations) to a previous TST. It is not contraindicated for any other persons, including infants, children, pregnant women, persons who are HIV-infected, or persons who have been vaccinated with BCG.
# False-Poisitve and False-Negative Reactions
In some persons who are infected with M. tuberculosis, the ability to react to tuberculin may wane over time. When given a TST years after infection, these persons may have a false-negative reaction. However, the TST may stimulate the immune system, causing a positive, or boosted reaction to subsequent tests. Giving a second TST after an initial negative TST reaction is called two-step testing.
# Two-step Testing
Two-step testing is useful for the initial skin testing of adults who are going to be retested periodically, such as health care workers or nursing home residents. This two-step approach can reduce the likelihood that a boosted reaction to a subsequent TST will be misinterpreted as a recent infection. | https://www.wikidoc.org/index.php/Mantoux_Tuberculin_Skin_Test | |
671c713b714c76f2cb1055fa7ee30cd5922107d1 | wikidoc | Marc Lacroix | Marc Lacroix
# Overview
Marc Lacroix is a biochemist (educated at University of Liège) and a researcher (born 1963 in Verviers, Wallonia, Belgium) who specializes in breast cancer biology, metastasis and therapy .
He works at Institut Jules Bordet (Brussels, Belgium).
# Earlier work
# Recent work
The amount of data on breast cancer available for the scientific and medical community is growing rapidly. According to PubMed, a search engine offering access to the MEDLINE database of citations and abstracts of biomedical research articles, 7918 papers containing the expression «breast cancer» were published in 2006. Their number was 3592 in 1996, 1455 in 1986 and only 626 in 1976. In general, the older information is overlayed by more recent data and forgotten to some extent. In 2004, Lacroix and colleagues collected and assembled data from hundreds of articles related to the biology, pathology and genetics of in situ, invasive and metastatic breast cancers. These papers were covering a time period of about 25 years. Lacroix et al. concluded that despite undergoing increasing genetic alteration, most individual breast cancers rather surprisingly maintain their phenotype when they evolve from in situ to the metastatic state . This conclusion was in opposition to a progression model widely accepted at that time, which was suggesting that carcinoma in situ could evolve into invasive carcinoma and subsequently produce metastases through an accumulation of molecular abnormalities possibly allowing extensive phenotype changes and subsequent gain of aggressiveness.
# Bibliography: articles in scientific and medical journals
- ↑ Body, JJ (1994). "lymphocyte calcitonin receptors". Calcified Tissue International. 55: 109–113. PMID 7953975. 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}
- ↑ Jin, L (1995). "Antiestrogenic activity of 2 11-beta-estradiol derivatives on MCF-7 breast cancer cells". Steroids. 60: 512–518. PMID 8539793. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1995). "Keratinocytes modulate the biosynthetic phenotype of dermal fibroblasts at a pretranslational level in human skin equivalent". Archives of Dermatological Research. 287: 659–664. PMID 8534130. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1996). "Effects of secretory products of breast cancer cells on osteoblast-like cells". Breast Cancer Research and Treatment. 38: 209–216. PMID 8861839. Unknown parameter |coauthors= ignored (help)
- ↑ Siwek, B (1997). "Secretory products of breast cancer cells specifically affect human osteoblastic cells: Partial characterization of active factors". Journal of Bone and Mineral Research. 12: 552–560. PMID 9101366. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1997). "c-fos". Calcified Tissue International. 60: 513–519. PMID 9164825. Unknown parameter |coauthors= ignored (help)
- ↑ Borras, M (1997). "Estrogen receptor-negative/progesterone receptor-positive Evsa-T mammary tumor cells: a model for assessing the biological property of this peculiar phenotype of breast cancers". Cancer Letters. 120: 23–30. PMID 9570382. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1998). "Breast cancer cell response to calcitonin: Modulation by growth-regulating agents". European Journal of Pharmacology. 344: 279–286. PMID 9600664. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1998). "interleukin-11". Cancer Letters. 127: 29–35. PMID 9619855. Unknown parameter |coauthors= ignored (help)
- ↑ Siwek, B (1998). "Establishment and characterization of three new breast-cancer cell lines". International Journal of Cancer. 76: 677–683. PMID 9610725. Unknown parameter |coauthors= ignored (help)
- ↑ Sotiriou, C (1999). "The aspirin metabolite salicylate inhibits breast cancer cells growth and their synthesis of the osteolytic cytokines interleukins-6 and-11". Anticancer Research. 19: 2997–3006. PMID 10652584. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2000). "Protein production by osteoblasts: modulation by breast cancer cell-derived factors". Breast Cancer Research and Treatment. 61: 59–67. PMID 10930090. Unknown parameter |coauthors= ignored (help)
- ↑ Maaroufi, Y (2000). "Estrogen receptor of primary breast cancers: evidence for intracellular proteolysis". Breast Cancer Research. 2: 444–454. PMID 11056692. Unknown parameter |coauthors= ignored (help)
- ↑ Sotiriou, C (2001). "Interleukins-6 and-11 expression in primary breast cancer and subsequent development of bone metastases". Cancer Letters. 169: 87–95. PMID 11410329. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2001). "Estrogen receptor analysis in primary breast tumors by ligand-binding assay, immmocytochemical assay, and northern blot: a comparison". Breast Cancer Research and Treatment. 67: 263–271. PMID 11561772. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2002). "A low-density DNA microarray for analysis of markers in breast cancer". International Journal of Biological Markers. 17: 5–23. PMID 11936587. Unknown parameter |coauthors= ignored (help)
- ↑ Rivas, A (2002). "Estrogenic effect of a series of bisphenol analogues on gene and protein expression in MCF-7 breast cancer cells". Journal of Steroid Biochemistry and Molecular Biology. 82: 45–53. PMID 12429138. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2004). "Relevance of breast cancer cell lines as models for breast tumours: an update". Breast Cancer Research and Treatment. 83: 249–289. PMID 14758095. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2004). "About GATA3, HNF3A, and XBP1, three genes co-expressed with the oestrogen receptor-alpha gene (ESR1) in breast cancer". Molecular and Cellular Endocrinology. 219: 1–7. PMID 15149721. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2004). "Gene regulation by phorbol 12-myristate 13-acetate in MCF-7 and MDA-MB-231, two breast cancer cell lines exhibiting highly different phenotypes". Oncology Reports. 12: 701–707. PMID 15375488. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2005). "The "portait" of hereditary breast cancer". Breast Cancer Research and Treatment. 89: 297–304. PMID 15754129. Unknown parameter |coauthors= ignored (help)
- ↑ De Longueville, F (2005). "Molecular characterization of breast cancer cell lines by a low-density microarray". International Journal of Oncology. 27: 881–892. PMID 16142302. Unknown parameter |coauthors= ignored (help)
- ↑ Toillon, RA (2005). "Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells". Breast Cancer Research and Treatment. 93: 207–215. PMID 16136271. Unknown parameter |coauthors= ignored (help)
- ↑ Leclercq, G (2006). "Estrogen receptor alpha: impact of ligands on intracellular shuttling and turnover rate in breast cancer cells". Current Cancer Drug Targets. 6: 39–64. PMID 16475975. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2006). "P53 and breast cancer, an update". Endocrine-Related Cancer. 13: 293–325. PMID 16728565. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix., M (2006). "Significance, detection and markers of disseminated breast cancer cells". Endocrine-Related Cancer. 13: 1033–1067. PMID 17158753.
- ↑ Toillon, RA (2007). "Estrogens decrease gamma-rays induced senescence and maintain cell cycle progression in breast cancer cells independently of p53". International Journal of Radiation Oncology, Biology, Physics. 67: 1187–1200. PMID 17336220. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2004). "Stable 'portrait' of breast tumors during progression: data from biology, pathology and genetics". Endocrine-Related Cancer. 11: 497–522. PMID 15369451. Unknown parameter |coauthors= ignored (help)
# Bibliography: invited chapters in thematic books
- Leclercq G, Lacroix M, Seo HS, Larsimont D. "Mechanisms regulating oestrogen receptor alpha expression in breast cancer.", in "Molecular Mechanisms of Action of Steroid Hormone Receptors" 65-75 (2002). Editors: Marija Krstic-Demonacos & Constantinos Demonacos, Research Signpost Publishers, Trivandrum, India, ISBN 81-7736-129-5, /
- Lacroix M, Leclercq G. "An updated view on cell lines as in vitro models for breast tumors.", in "Focus on Breast Cancer Research" 131-182 (2004). Editor: Andrew P. Yao, Nova Science Publishers, Inc, 400 Oser Ave, Ste 1600, Hauppauge, NY 11788-3635 USA, ISBN 1-59033-961-4,
- Sotiriou C, Desmedt C, Durbecq V, Dal Lago L, Lacroix M, Cardoso F, Piccart M. "Genomic and molecular classification of breast cancer.", in "Molecular Oncology of Breast Cancer" 81-95 (2004). Editors: Jeffrey S. Ross and Gabriel N. Hortobagy, Jones and Bartlett Publishers, 40 Tall Pine Drive, Sudbury, MA 01776 USA, ISBN 0-76374-810-2,
- Lacroix M, Leclercq G. "Hereditary breast cancer: an update on genotype and phenotype.",in "New Breast Cancer Research" 27-51 (2006). Editor: Andrew P. Yao, Nova Science Publishers, Inc, 400 Oser Ave, Ste 1600, Hauppauge, NY 11788-3635 USA, ISBN 1-59454-932-X,
- (in press) Lacroix M. "An update on tumor suppressor genes in breast cancer.", in "Tumor Suppressor Genes" (2007). Editor: Katherine R. Polinsky, Nova Science Publishers, Inc, 400 Oser Ave, Ste 1600, Hauppauge, NY 11788-3635 USA, ISBN 1-60021-693-5, | Marc Lacroix
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Marc Lacroix is a biochemist (educated at University of Liège) and a researcher (born 1963 in Verviers, Wallonia, Belgium) who specializes in breast cancer biology, metastasis and therapy [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] .
He works at Institut Jules Bordet (Brussels, Belgium).
# Earlier work
# Recent work
The amount of data on breast cancer available for the scientific and medical community is growing rapidly. According to PubMed, a search engine offering access to the MEDLINE database of citations and abstracts of biomedical research articles, 7918 papers containing the expression «breast cancer» were published in 2006. Their number was 3592 in 1996, 1455 in 1986 and only 626 in 1976. In general, the older information is overlayed by more recent data and forgotten to some extent. In 2004, Lacroix and colleagues collected and assembled data from hundreds of articles related to the biology, pathology and genetics of in situ, invasive and metastatic breast cancers. These papers were covering a time period of about 25 years. Lacroix et al. concluded that despite undergoing increasing genetic alteration, most individual breast cancers rather surprisingly maintain their phenotype when they evolve from in situ to the metastatic state [28]. This conclusion was in opposition to a progression model widely accepted at that time, which was suggesting that carcinoma in situ could evolve into invasive carcinoma and subsequently produce metastases through an accumulation of molecular abnormalities possibly allowing extensive phenotype changes and subsequent gain of aggressiveness.
# Bibliography: articles in scientific and medical journals
- ↑ Body, JJ (1994). "lymphocyte calcitonin receptors". Calcified Tissue International. 55: 109–113. PMID 7953975. 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}
- ↑ Jin, L (1995). "Antiestrogenic activity of 2 11-beta-estradiol derivatives on MCF-7 breast cancer cells". Steroids. 60: 512–518. PMID 8539793. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1995). "Keratinocytes modulate the biosynthetic phenotype of dermal fibroblasts at a pretranslational level in human skin equivalent". Archives of Dermatological Research. 287: 659–664. PMID 8534130. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1996). "Effects of secretory products of breast cancer cells on osteoblast-like cells". Breast Cancer Research and Treatment. 38: 209–216. PMID 8861839. Unknown parameter |coauthors= ignored (help)
- ↑ Siwek, B (1997). "Secretory products of breast cancer cells specifically affect human osteoblastic cells: Partial characterization of active factors". Journal of Bone and Mineral Research. 12: 552–560. PMID 9101366. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1997). "c-fos". Calcified Tissue International. 60: 513–519. PMID 9164825. Unknown parameter |coauthors= ignored (help)
- ↑ Borras, M (1997). "Estrogen receptor-negative/progesterone receptor-positive Evsa-T mammary tumor cells: a model for assessing the biological property of this peculiar phenotype of breast cancers". Cancer Letters. 120: 23–30. PMID 9570382. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1998). "Breast cancer cell response to calcitonin: Modulation by growth-regulating agents". European Journal of Pharmacology. 344: 279–286. PMID 9600664. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (1998). "interleukin-11". Cancer Letters. 127: 29–35. PMID 9619855. Unknown parameter |coauthors= ignored (help)
- ↑ Siwek, B (1998). "Establishment and characterization of three new breast-cancer cell lines". International Journal of Cancer. 76: 677–683. PMID 9610725. Unknown parameter |coauthors= ignored (help)
- ↑ Sotiriou, C (1999). "The aspirin metabolite salicylate inhibits breast cancer cells growth and their synthesis of the osteolytic cytokines interleukins-6 and-11". Anticancer Research. 19: 2997–3006. PMID 10652584. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2000). "Protein production by osteoblasts: modulation by breast cancer cell-derived factors". Breast Cancer Research and Treatment. 61: 59–67. PMID 10930090. Unknown parameter |coauthors= ignored (help)
- ↑ Maaroufi, Y (2000). "Estrogen receptor of primary breast cancers: evidence for intracellular proteolysis". Breast Cancer Research. 2: 444–454. PMID 11056692. Unknown parameter |coauthors= ignored (help)
- ↑ Sotiriou, C (2001). "Interleukins-6 and-11 expression in primary breast cancer and subsequent development of bone metastases". Cancer Letters. 169: 87–95. PMID 11410329. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2001). "Estrogen receptor analysis in primary breast tumors by ligand-binding assay, immmocytochemical assay, and northern blot: a comparison". Breast Cancer Research and Treatment. 67: 263–271. PMID 11561772. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2002). "A low-density DNA microarray for analysis of markers in breast cancer". International Journal of Biological Markers. 17: 5–23. PMID 11936587. Unknown parameter |coauthors= ignored (help)
- ↑ Rivas, A (2002). "Estrogenic effect of a series of bisphenol analogues on gene and protein expression in MCF-7 breast cancer cells". Journal of Steroid Biochemistry and Molecular Biology. 82: 45–53. PMID 12429138. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2004). "Relevance of breast cancer cell lines as models for breast tumours: an update". Breast Cancer Research and Treatment. 83: 249–289. PMID 14758095. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2004). "About GATA3, HNF3A, and XBP1, three genes co-expressed with the oestrogen receptor-alpha gene (ESR1) in breast cancer". Molecular and Cellular Endocrinology. 219: 1–7. PMID 15149721. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2004). "Gene regulation by phorbol 12-myristate 13-acetate in MCF-7 and MDA-MB-231, two breast cancer cell lines exhibiting highly different phenotypes". Oncology Reports. 12: 701–707. PMID 15375488. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2005). "The "portait" of hereditary breast cancer". Breast Cancer Research and Treatment. 89: 297–304. PMID 15754129. Unknown parameter |coauthors= ignored (help)
- ↑ De Longueville, F (2005). "Molecular characterization of breast cancer cell lines by a low-density microarray". International Journal of Oncology. 27: 881–892. PMID 16142302. Unknown parameter |coauthors= ignored (help)
- ↑ Toillon, RA (2005). "Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells". Breast Cancer Research and Treatment. 93: 207–215. PMID 16136271. Unknown parameter |coauthors= ignored (help)
- ↑ Leclercq, G (2006). "Estrogen receptor alpha: impact of ligands on intracellular shuttling and turnover rate in breast cancer cells". Current Cancer Drug Targets. 6: 39–64. PMID 16475975. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2006). "P53 and breast cancer, an update". Endocrine-Related Cancer. 13: 293–325. PMID 16728565. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix., M (2006). "Significance, detection and markers of disseminated breast cancer cells". Endocrine-Related Cancer. 13: 1033–1067. PMID 17158753.
- ↑ Toillon, RA (2007). "Estrogens decrease gamma-rays induced senescence and maintain cell cycle progression in breast cancer cells independently of p53". International Journal of Radiation Oncology, Biology, Physics. 67: 1187–1200. PMID 17336220. Unknown parameter |coauthors= ignored (help)
- ↑ Lacroix, M (2004). "Stable 'portrait' of breast tumors during progression: data from biology, pathology and genetics". Endocrine-Related Cancer. 11: 497–522. PMID 15369451. Unknown parameter |coauthors= ignored (help)
# Bibliography: invited chapters in thematic books
- Leclercq G, Lacroix M, Seo HS, Larsimont D. "Mechanisms regulating oestrogen receptor alpha expression in breast cancer.", in "Molecular Mechanisms of Action of Steroid Hormone Receptors" 65-75 (2002). Editors: Marija Krstic-Demonacos & Constantinos Demonacos, Research Signpost Publishers, Trivandrum, India, ISBN 81-7736-129-5, http://www.ressign.com/
- Lacroix M, Leclercq G. "An updated view on cell lines as in vitro models for breast tumors.", in "Focus on Breast Cancer Research" 131-182 (2004). Editor: Andrew P. Yao, Nova Science Publishers, Inc, 400 Oser Ave, Ste 1600, Hauppauge, NY 11788-3635 USA, ISBN 1-59033-961-4, https://www.novapublishers.com/catalog/product_info.php?products_id=593
- Sotiriou C, Desmedt C, Durbecq V, Dal Lago L, Lacroix M, Cardoso F, Piccart M. "Genomic and molecular classification of breast cancer.", in "Molecular Oncology of Breast Cancer" 81-95 (2004). Editors: Jeffrey S. Ross and Gabriel N. Hortobagy, Jones and Bartlett Publishers, 40 Tall Pine Drive, Sudbury, MA 01776 USA, ISBN 0-76374-810-2, http://www.jbpub.com/catalog/0763748102/table_of_contents.htm
- Lacroix M, Leclercq G. "Hereditary breast cancer: an update on genotype and phenotype.",in "New Breast Cancer Research" 27-51 (2006). Editor: Andrew P. Yao, Nova Science Publishers, Inc, 400 Oser Ave, Ste 1600, Hauppauge, NY 11788-3635 USA, ISBN 1-59454-932-X, https://www.novapublishers.com/catalog/product_info.php?products_id=4134
- (in press) Lacroix M. "An update on tumor suppressor genes in breast cancer.", in "Tumor Suppressor Genes" (2007). Editor: Katherine R. Polinsky, Nova Science Publishers, Inc, 400 Oser Ave, Ste 1600, Hauppauge, NY 11788-3635 USA, ISBN 1-60021-693-5, http://www.novapublishers.com/catalog/product_info.php?products_id=5679 | https://www.wikidoc.org/index.php/Marc_Lacroix | |
a65dd1e3ac5208deaba088612fd2673e363dafee | wikidoc | Marius Romme | Marius Romme
# Overview
Professor Marius Romme MD PhD was a professor for social psychiatry at the Medical Faculty of the University of Maastricht (Netherlands) from 1974 to 1999, as well as consultant psychiatrist at the Community Mental Health Centre in Maastricht. He is now visiting professor at the Mental Health Policy Centre, University of Central England in Birmingham.
He is best known for his work on hearing voices (auditory hallucinations) and regarded as the founder and principle theorist for the Hearing Voices Movement.
Romme has stated that schizophrenia "is a harmful concept" and that delusions, hearing voices and hallucinations, so-called "symptoms" of schizophrenia are not related to an illness but may be reactions to traumatic and troubling events in life.
# Publications
Publications/articles by Professor Marius Romme et al:
Escher, A.D.M.A.C., Romme, M.A.J., Breuls,M., Driessen,G., (1987). Maatschappelijk kwetsbaar en langdurig psychiatrisch ziek zijn. Tijdschrift voor Psychiatrie, 29:5,266-281.
Escher, A.D.M.A.C.,Romme, M.A.J.(1989).Stemmen horen. Positieve effecten van leren omgaan met stemmen. Tijdschrift voor Ziekenverpleging 24, p. 784-788
Escher, A.D.M.A.C.,Romme, M.A.J.(1991).Het dagboek als communicatiemiddel bij auditieve hallucinaties. Tijdschrift voor Ziekenverpleging (TVZ) 15 augustus 1991 543-547 Escher., A.D.M.A.C. (1993)Stemmen horen: ziekte, gave, topervaring of fase in een groeiproces? Klankspiegel, maart 1993
Escher, A., Romme, M. (1998) Small talk: voice-hearing in Children. Open Mind July/August.
Escher, A., Romme, M., Buiks, A., Delespaul, Ph., Van Os, J., (2002a) Independent course of childhood auditory hallucinations: a sequential 3-year follow-up study. British Journal of Psychiatry . 181 (suppl. 43), s10-s18
Escher, A., Romme, M., Buiks, A., Delespaul, Ph., Van Os, J., (2002b) Formation of delusional ideation in adolescents hearing voices: a prospective study. American Journal of Medical Genetics. 114: 913-920
Escher, A.D.M., Romme,M.A.J., Buiks, A., Delespaul, Ph., Van Os, J., (2002) Kinderen en jeugdigen die stemmen horen: een prospectief driejarig onderzoek. Tijdschrift van de Vereniging voor kinder en jeugdpsychotherapie. Jaargang 29, nr. 4. blz. 4-21.
Escher, A., Romme, M., (2002). Het Maastrichts Interview voor kinderen en Jeugdigen (MIK). Tijdschrift van de Vereniging voor kinder en jeugdpsychotherapie. Jaargang 29, nr. 4. blz. 22-45.
Escher, A., Delespaul, P., Romme, M., Buiks, A., Van Os. J. (2003) Coping defence and depression in adolescents hearing voices. Journal of Mental Health. 12,1,91-99
Escher, A. D., Romme, M. A., et al. (2003). Formación de la ideación delirante en adolescentes con alucinaciones auditivas: un estudio prospectivo. Intervención en crisis y tratamiento agudo de los trastornos psiquiátricos graves. P. Pichot, J. Ezcurra, A. González-Pinto and M. Gutiérrz Fraile. Madrid, Aula Médica Ediciones: 185-208.
Escher, A., Morris, M., Buiks, A., Delespaul, Ph., Van Os, J., Romme, M. (2004) Determinants of outcome in the pathways through care for children hearing voices. International Journal of social Welfare. 13, 208-222
Pennings, M.H.A., Romme, M.A.J. ,. Buiks, A.A.J.G.M. (1996) Auditieve hallucinaties bij patiënten en niet-patiënten. Tijdschrift voor Psychiatrie.
Noorthoorn, E.,Dijkman,C., Escher,A., Romme,M. (1988) Resultaten van de enquête, in Omgaan met stemmen horen. Blz. 199-214. Uitgever; Vakgroep Sociale psychiatrie, Rijksuniversiteit Limburg. Noorthoorn,O., Romme, M.A.J.,Escher A.D.M.A.C. (1990). Wat kunnen mensen die stemmen horen de psychiatrie leren?. Sociale Dienstverlening in Nederland. Analyse en evaluatie (Red. E.K. Hicks) p. 60-70
Romme, M.A.J.,Escher,A.,Radstake,D.,Breuls,M(1987). Een indeling in groepen van patiënten met een langdurige psychiatrische patiëntencarrière. Tijdschrift voor Psychiatrie, 29,4,197-211.
Romme, M.A.J. & Escher, A.D.M.A.C. (1987) Leren omgaan met het horen van stemmen. Maandblad Geestelijk Volksgezondheid 718, p 825-831.
Romme,M.A.J., Escher,A.D.M.A.C. (1988).eds. Research to practice in Community Psychiatry. van Gorkum, Maastricht/Assen.
Romme, M.A.J., Escher,A.D.M.A.C., Habets, V.P.M.J.H.(1988). Omgaan met stemmen horen. (red). Universiteit Maastricht, vakgroep sociale Psychiatrie.
Romme, M.A.J. & Escher, A.D.M.A.C.: Hearing Voices (1989) Schizophrenia Bulletin 15 (2): 209 - 216
Romme, M.A.J. & Escher, A.D.M.A.C. (1989). Effects of mutual contacts from people with auditory hallucinations. Perspectief no 3, 37-43, July 1989
Romme, M.A.J. & Escher, A.D.M.A.C. (1989). Stimmen hőren inKontakt, Zeitschrift der HPE Österreich nr 116, Oktober 1989
Romme, M.A.J., Escher,A.D.M.A.C. (1990) Effecten van het onderlinge contact tussen mensen die stemmen horen. Oostland no 2, 8-14,
Romme, M.A.J. & Escher, A.D.M.A.C. (1990). Heard but not seen. Open Mind No 49, 16-18,
Romme, M.A.J. & Escher, A.D.M.A.C. (1991). Sense in voices. Open Mind 53, The mental health magazine, 9 November
Romme, M.A.J. & Escher, A.D.M.A.C. (1991).Undire le Voci. Spazi della Menten nr. 8, December 1991 p 3-9
Romme, M.A.J., Honig, A., Noorthoorn, O., Escher, A.D.M.A.C. (1991) Coping with voices: an emancipatory approach. British Journal of psychiatry 161, 99-103
M. Romme, A. Honig, E. O. Noorthorn & S. Escher: Coping with hearing voices: an emanciapatory approach (1992) British Journal of Psychiatry
Marius Romme and Sandra Escher: (Eds.), Accepting Voices (1993, second edition 1998), 258 pages, MIND Publications, London.
Marius Romme and Sandra Escher: (Eds) Understanding voices: coping with auditory hallucinations and confusing realities (1996) First published by Rijksuniversitiet Maastricht, Limburg, Holland and also English edition, Handsell Publications
Romme, M.A.J., Escher, A.D.M.A.C (1997) Stimmen hőren akzeptieren. Psychiatrie-Verlag. Bonn.
Romme, M.A.J., Escher, A.D.M.A.C (1997) Acceptare le voice. Giuffrè editore. Milano
Romme, M.A.J., Escher, A.D.M.A.C (1997) Na compananhia das voces. Editorial Estampa, Lda., Lisboa Portugal
Romme, M.A.J., Escher, A.D.M.A.C (1997) Moniääniset. Printway Oy, Vantaa.Finland.
Romme, M.A.J., Escher, A.D.M.A.C. (1998) Πризиание Ґоλосов. Geneva Initiative on Psychiatrie, Zwitserland.
Romme, M.A.J., Escher, A.D.M.A.C. (1999). Omgaan met stemmen horen. Stichting Positieve Gezondheidszorg. Bemelen.
Romme, M.A.J., Escher, A.D.M.A.C. (1999) Stemmen horen accepteren. Tirion, Baarn.
Romme, M.A.J., Escher, A.D.M.A.C. (1999) Stimmenhören Akzeptieren, Neunplus 1 Berlin. Duitsland.
Marius Romme and Sandra Escher: Making Sense of Voices - A guide for professionals who work with voice hearers: (2000) MIND Publications
Romme, M.A.J., Escher, A.D.M.A.C (2003) Förstå och hantera roster. RSNH. Riksförbundet för Social och Mental Hälsa.Stockholm. Sweden
Romme, M.A.J., Escher, A.D.M.A.C (2003) Giv stemmerne mening. Systime Academic. Århus, Denmark.
Romme & Escher (2005). Managing Distressing Voice Hearing Experiences In Wellness Recovery Action Plan. Mary Ellen Copeland edited by Piers Allott. P.Sefton Recovery Group, Liverpool, UK. P. 114-118.
Romme, Marius, Morris, Mervyn. The harmful concept of Schizophrenia, Mental Health Nursing, 7 - 11 March 2007 | Marius Romme
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Professor Marius Romme MD PhD was a professor for social psychiatry at the Medical Faculty of the University of Maastricht (Netherlands) from 1974 to 1999, as well as consultant psychiatrist at the Community Mental Health Centre in Maastricht. He is now visiting professor at the Mental Health Policy Centre, University of Central England in Birmingham.
He is best known for his work on hearing voices (auditory hallucinations) and regarded as the founder and principle theorist for the Hearing Voices Movement.
Romme has stated that schizophrenia "is a harmful concept" and that delusions, hearing voices and hallucinations, so-called "symptoms" of schizophrenia are not related to an illness but may be reactions to traumatic and troubling events in life. [2]
# Publications
Publications/articles by Professor Marius Romme et al:
Escher, A.D.M.A.C., Romme, M.A.J., Breuls,M., Driessen,G., (1987). Maatschappelijk kwetsbaar en langdurig psychiatrisch ziek zijn. Tijdschrift voor Psychiatrie, 29:5,266-281.
Escher, A.D.M.A.C.,Romme, M.A.J.(1989).Stemmen horen. Positieve effecten van leren omgaan met stemmen. Tijdschrift voor Ziekenverpleging 24, p. 784-788
Escher, A.D.M.A.C.,Romme, M.A.J.(1991).Het dagboek als communicatiemiddel bij auditieve hallucinaties. Tijdschrift voor Ziekenverpleging (TVZ) 15 augustus 1991 543-547 Escher., A.D.M.A.C. (1993)Stemmen horen: ziekte, gave, topervaring of fase in een groeiproces? Klankspiegel, maart 1993
Escher, A., Romme, M. (1998) Small talk: voice-hearing in Children. Open Mind July/August.
Escher, A., Romme, M., Buiks, A., Delespaul, Ph., Van Os, J., (2002a) Independent course of childhood auditory hallucinations: a sequential 3-year follow-up study. British Journal of Psychiatry . 181 (suppl. 43), s10-s18
Escher, A., Romme, M., Buiks, A., Delespaul, Ph., Van Os, J., (2002b) Formation of delusional ideation in adolescents hearing voices: a prospective study. American Journal of Medical Genetics. 114: 913-920
Escher, A.D.M., Romme,M.A.J., Buiks, A., Delespaul, Ph., Van Os, J., (2002) Kinderen en jeugdigen die stemmen horen: een prospectief driejarig onderzoek. Tijdschrift van de Vereniging voor kinder en jeugdpsychotherapie. Jaargang 29, nr. 4. blz. 4-21.
Escher, A., Romme, M., (2002). Het Maastrichts Interview voor kinderen en Jeugdigen (MIK). Tijdschrift van de Vereniging voor kinder en jeugdpsychotherapie. Jaargang 29, nr. 4. blz. 22-45.
Escher, A., Delespaul, P., Romme, M., Buiks, A., Van Os. J. (2003) Coping defence and depression in adolescents hearing voices. Journal of Mental Health. 12,1,91-99
Escher, A. D., Romme, M. A., et al. (2003). Formación de la ideación delirante en adolescentes con alucinaciones auditivas: un estudio prospectivo. Intervención en crisis y tratamiento agudo de los trastornos psiquiátricos graves. P. Pichot, J. Ezcurra, A. González-Pinto and M. Gutiérrz Fraile. Madrid, Aula Médica Ediciones: 185-208.
Escher, A., Morris, M., Buiks, A., Delespaul, Ph., Van Os, J., Romme, M. (2004) Determinants of outcome in the pathways through care for children hearing voices. International Journal of social Welfare. 13, 208-222
Pennings, M.H.A., Romme, M.A.J. ,. Buiks, A.A.J.G.M. (1996) Auditieve hallucinaties bij patiënten en niet-patiënten. Tijdschrift voor Psychiatrie.
Noorthoorn, E.,Dijkman,C., Escher,A., Romme,M. (1988) Resultaten van de enquête, in Omgaan met stemmen horen. Blz. 199-214. Uitgever; Vakgroep Sociale psychiatrie, Rijksuniversiteit Limburg. Noorthoorn,O., Romme, M.A.J.,Escher A.D.M.A.C. (1990). Wat kunnen mensen die stemmen horen de psychiatrie leren?. Sociale Dienstverlening in Nederland. Analyse en evaluatie (Red. E.K. Hicks) p. 60-70
Romme, M.A.J.,Escher,A.,Radstake,D.,Breuls,M(1987). Een indeling in groepen van patiënten met een langdurige psychiatrische patiëntencarrière. Tijdschrift voor Psychiatrie, 29,4,197-211.
Romme, M.A.J. & Escher, A.D.M.A.C. (1987) Leren omgaan met het horen van stemmen. Maandblad Geestelijk Volksgezondheid 718, p 825-831.
Romme,M.A.J., Escher,A.D.M.A.C. (1988).eds. Research to practice in Community Psychiatry. van Gorkum, Maastricht/Assen.
Romme, M.A.J., Escher,A.D.M.A.C., Habets, V.P.M.J.H.(1988). Omgaan met stemmen horen. (red). Universiteit Maastricht, vakgroep sociale Psychiatrie.
Romme, M.A.J. & Escher, A.D.M.A.C.: Hearing Voices (1989) Schizophrenia Bulletin 15 (2): 209 - 216
Romme, M.A.J. & Escher, A.D.M.A.C. (1989). Effects of mutual contacts from people with auditory hallucinations. Perspectief no 3, 37-43, July 1989
Romme, M.A.J. & Escher, A.D.M.A.C. (1989). Stimmen hőren inKontakt, Zeitschrift der HPE Österreich nr 116, Oktober 1989
Romme, M.A.J., Escher,A.D.M.A.C. (1990) Effecten van het onderlinge contact tussen mensen die stemmen horen. Oostland no 2, 8-14,
Romme, M.A.J. & Escher, A.D.M.A.C. (1990). Heard but not seen. Open Mind No 49, 16-18,
Romme, M.A.J. & Escher, A.D.M.A.C. (1991). Sense in voices. Open Mind 53, The mental health magazine, 9 November
Romme, M.A.J. & Escher, A.D.M.A.C. (1991).Undire le Voci. Spazi della Menten nr. 8, December 1991 p 3-9
Romme, M.A.J., Honig, A., Noorthoorn, O., Escher, A.D.M.A.C. (1991) Coping with voices: an emancipatory approach. British Journal of psychiatry 161, 99-103
M. Romme, A. Honig, E. O. Noorthorn & S. Escher: Coping with hearing voices: an emanciapatory approach (1992) British Journal of Psychiatry
Marius Romme and Sandra Escher: (Eds.), Accepting Voices (1993, second edition 1998), 258 pages, MIND Publications, London.
Marius Romme and Sandra Escher: (Eds) Understanding voices: coping with auditory hallucinations and confusing realities (1996) First published by Rijksuniversitiet Maastricht, Limburg, Holland and also English edition, Handsell Publications
Romme, M.A.J., Escher, A.D.M.A.C (1997) Stimmen hőren akzeptieren. Psychiatrie-Verlag. Bonn.
Romme, M.A.J., Escher, A.D.M.A.C (1997) Acceptare le voice. Giuffrè editore. Milano
Romme, M.A.J., Escher, A.D.M.A.C (1997) Na compananhia das voces. Editorial Estampa, Lda., Lisboa Portugal
Romme, M.A.J., Escher, A.D.M.A.C (1997) Moniääniset. Printway Oy, Vantaa.Finland.
Romme, M.A.J., Escher, A.D.M.A.C. (1998) Πризиание Ґоλосов. Geneva Initiative on Psychiatrie, Zwitserland.
Romme, M.A.J., Escher, A.D.M.A.C. (1999). Omgaan met stemmen horen. Stichting Positieve Gezondheidszorg. Bemelen.
Romme, M.A.J., Escher, A.D.M.A.C. (1999) Stemmen horen accepteren. Tirion, Baarn.
Romme, M.A.J., Escher, A.D.M.A.C. (1999) Stimmenhören Akzeptieren, Neunplus 1 Berlin. Duitsland.
Marius Romme and Sandra Escher: Making Sense of Voices - A guide for professionals who work with voice hearers: (2000) MIND Publications
Romme, M.A.J., Escher, A.D.M.A.C (2003) Förstå och hantera roster. RSNH. Riksförbundet för Social och Mental Hälsa.Stockholm. Sweden
Romme, M.A.J., Escher, A.D.M.A.C (2003) Giv stemmerne mening. Systime Academic. Århus, Denmark.
Romme & Escher (2005). Managing Distressing Voice Hearing Experiences In Wellness Recovery Action Plan. Mary Ellen Copeland edited by Piers Allott. P.Sefton Recovery Group, Liverpool, UK. P. 114-118.
Romme, Marius, Morris, Mervyn. The harmful concept of Schizophrenia, Mental Health Nursing, 7 - 11 March 2007 | https://www.wikidoc.org/index.php/Marius_Romme | |
d9b4bfe8d96a0a954eb3c7d097297893952b4ed5 | wikidoc | Martial arts | Martial arts
Martial arts are systems of codified practices and traditions of training for combat. They may be studied for various reasons including combat skills, fitness, self-defense, sport, self-cultivation/meditation, mental discipline, character development and building self-confidence, or any combination of the above.
There is a great diversity and abundance of martial arts but, broadly speaking, martial arts share a common goal: to defeat a person physically or to defend oneself from physical threat. Some martial arts are linked to spiritual or religious beliefs/philosophies such as Buddhism or Shinto while others have their own spiritual/non-spiritual code of honor.
While each style has unique facets that makes it different from other martial arts, a common characteristic is the systemization of fighting techniques. One common method of training, particularly in the Asian martial arts, is the form or kata; these are sets or routines of techniques that are performed alone, or sometimes with a partner.
The word 'martial' derives from the name of Mars, the Roman god of war. The term 'Martial Arts' literally means arts of Mars. This term comes from 15th century Europeans who were referring to their own fighting arts that are today known as Historical Fencing. A practitioner of martial arts is referred to as a martial artist.
# Scope
Martial arts vary widely, and may focus on a specific area or combination of areas, but they can be broadly grouped into focusing on strikes, grappling, or weapons training. Below is a list of examples that make extensive use of one these areas; it is not an exhaustive list of all arts covering the area, nor are these necessarily the only areas covered by the art but are the focus or best known part as examples of the area:
Striking
- Punching - Boxing (Western), Wing Chun
- Kicking - Capoeira, Savate, Taekwondo
- Other strikes (e.g. Elbows, knees, open-hand) - Muay Thai, Karate, Shaolin Kung Fu
Grappling
- Throwing - Glima, Judo, Jujutsu, Sambo, Shuai jiao
- Joint lock - Aikido, Brazilian Jiu-Jitsu, Hapkido
- Pinning Techniques - Judo, Wrestling
Weaponry
- Traditional Weaponry - Fencing, Gatka, Kendo, Silambam, Kali
- Modern Weaponry - Eskrima, Jogo do Pau, Jukendo
Many martial arts, especially those from Asia, also teach side disciplines which pertain to medicinal practices. This is particularly prevalent in traditional Chinese martial arts which may teach bone-setting, qigong, acupuncture, acupressure (tui na), and other aspects of traditional Chinese medicine.
Martial arts are commonly associated with East Asian cultures, but are by no means unique to Asia. Throughout Europe there was an extensive system of combat martial arts, collectively referred to as Historical European martial arts, that existed until modern times and is now being reconstructed by several organizations while Savate is a French kicking style developed by sailors and street fighters. In the Americas Native Americans have a tradition of open-handed martial arts, that includes wrestling and Hawaiians have historically practiced arts featuring small and large joint manipulation, a mix of origins occur in the athletic movements of Capoeira that was created in Brazil by slaves, based on skills brought with them from Africa.
# History
The history of martial arts around the world is complex. Most groups of people have had to physically defend themselves at some time and have developed fighting techniques for that purpose. Development of many martial arts was related to military development, but many of those techniques have been rendered technologically obsolete over the centuries. In the modern day, most populations would be more likely to face adversaries wielding firearms than melee weapons during battle. Furthermore, the preservation of a martial art requires many years of teaching at the hands of a skilled instructor to pass on the art for a single generation. Given these circumstances, many martial arts from previous eras have not been passed down to following generations.
## In Asia
### Early history
The foundation of the Asian martial arts is likely a blend of early Chinese and Indian arts. Extensive trade occurred between these nations beginning around 600 B.C., with diplomats, merchants, and monks traveling the Silk Roads. During the Warring States period of Chinese history (480-221 B.C.) extensive development in martial philosophy and strategy emerged, as described by Sun Tzu in The Art of War (c. 350 B.C.)
An early legend in martial arts tells the tale of the Indian monk Bodhidharma (also called Daruma), believed to have lived around 550 A.D. He is credited with founding the meditative philosophy of Zen Buddhism and influencing the unarmed combat arts of the Shaolin temple in China. The martial virtues of discipline, humility, restraint and respect are attributed to this philosophy.
The teaching of martial arts in Asia has historically followed the cultural traditions of teacher-disciple apprenticeship. Students are trained in a strictly hierarchical system by a master instructor: Sifu in Cantonese or Shifu in Mandarin; Guru in Sanskrit, Hindi, Telugu and Malay; Sensei in Japanese; Sa Bum Nim in Korean; Kalari Gurukkal or kalari asaan in Malayalam; Asaan in Tamil; Achan in Thai; Guro in Tagalog and Saya in Myanmar, . The instructor is expected to directly supervise their students' training, and the students are expected to memorize and recite as closely as possible the rules and basic training routines of the school.
In the warrior Kshatriya caste of South Asia, organised martial traditions were studied as a part of the Dharma (duty) of the caste. The senior teachers were called Gurus and taught martial arts at gurukuls to the shishyas (students).
Some method of certification can be involved, where one's skills would be tested for mastery before being allowed to study further; in some systems, there may not be any such certifications, only years of close personal practice and evaluation under a master, much like an apprenticeship, until the master deems one's skills satisfactory. This pedagogy, while still preserved and respected in many traditional styles, has weakened to varying degrees in others and is even actively rejected by some schools, especially in the West.
Throughout Asia martial arts were practiced as can be seen in the art, history and current traditions in Vietnam, Cambodia, Thailand, Myanmar (Burma), and the Philippines. In many countries local arts like Te in Okinawa, Kenjutsu and Ju-Jutsu in Japan, and Taekyon and Soobak in Korea mixed with other martial arts and evolved to produce some of the more well-known martial arts in the late nineteenth and twentieth centuries like Karate, Aikido, and Taekwondo.
### Modern history
The Western interest in East Asian Martial arts dates back to the late 19th Century AD, due to the increase in trade between America with China and Japan. Relatively few Westerners actually practiced the arts, considering it to be mere performance.
Edward William Barton-Wright, a railway engineer who had studied Jujutsu while working in Japan between 1894–97, was the first man known to have taught Asian martial arts in Europe. He also founded an eclectic martial arts style named Bartitsu which combined jujutsu, judo, boxing, savate and stick fighting.
During the late 19th century and early 20th century, catch wrestling contests became immensely popular in Europe.
During pre-war and World War Two shows the practicality of martial arts in the modern world and were used by Japanese, US, Nepalese (Gurkha) commandos as well as Resistance groups, such as in the Philippines, (see Raid at Los Baños) but not so excessively or at all for common soldiers.
However Asian martial arts remained largely unknown in the West even as late as the 1950s; for example, in the 1959 popular fiction Goldfinger, Karate was described to readers in near-mythical terms and it was credible for British unarmed combat experts to be represented as completely unaware of martial arts of this kind. The novel describes the protagonist James Bond, an expert in unarmed combat, as utterly ignorant of Karate and its demonstrations, and describes the Korean 'Oddjob' in these terms:
Goldfinger said, "Have you ever heard of Karate? No? Well that man is one of the three in the world who have achieved the Black Belt in Karate. Karate is a branch of judo, but it is to judo what a Spandau is to a catapult...".
Such a description in a popular novel assumed and relied upon karate being almost unknown in the West; and it linked karate with judo, whereas in reality karate is a distinct art almost unrelated to judo.
As Western influence grew in East Asia a greater number of military personnel spent time in China, Japan, and Korea. Exposure to martial arts during the Korean war was also significant. Gradually some soldiers saw the value of Eastern martial arts and began training in them.
With large numbers of American servicemen stationed in Japan after World War II, the adoption of techniques and the gradual transmission of entire systems of martial arts to the West started. It was in the 1950s, however, when this exportation of systems really began to gain momentum. Large groups of U.S. military personnel were taught Korean arts (Taekwondo) during the Korean conflict. In the early 1970s, martial arts movies, in particular those of martial artist and actor Bruce Lee, furthered the popularity of martial arts.
This exportation of the martial arts led to such styles as sport karate, which became a major international sport, with professional fighters, big prizes, television coverage, and sponsorship deals. This also lead to the creation of modern martial arts such as Brazilian Jiu-jitsu. Brazilian Jiu-jitsu is a derivative of Kodokan Judo, extended and influenced by the no holds barred combat traditions of Brazil; it has been highly effective in mixed martial arts competitions around the world.
The later 1970s and 1980s witnessed an increased media interest in the martial arts, thanks in part to Asian and Hollywood martial arts movies and very popular television shows like "Kung Fu", "Martial Law" and "The Green Hornet" that incorporated martial arts moments or themes. Jackie Chan and Jet Li are prominent movie figures who have been responsible for promoting Chinese martial arts in recent years.
## In Europe
Main article: Historical European martial arts
In Europe, the martial arts declined with the rise of the firearms. As a consequence, martial arts with historical roots in Europe do not exist today to the same extent as in Asia, since the traditional martial arts either died out or developed into sports. Swordplay developed into fencing. Boxing as well as forms of wrestling have endured. European martial arts have mostly adapted to changing technology so that while some traditional arts still exist, military personnel are trained in skills like bayonet combat and marksmanship. These skills do not fall under the common use of the term, but may still be considered "martial arts".
This is not to say Europe was not rich in historical martial arts traditions. Martial arts existed in classical European civilization, most notably in Greece where sports were integral to the way of life. Boxing (pygme, pyx), Wrestling (pale) and Pankration (from pan, meaning "all", and kratos, meaning "power" or "strength") were represented in the Ancient Olympic Games. The Romans produced Gladiatorial combat as a public spectacle.
Khridoli (Georgian: ხრიდოლი) is an ancient Georgian martial art, which includes fighting with bare hands and different types of weapons.
Glima is an unarmed Scandinavian martial art with, as some sources indicate, roots in the Viking age. The tradition of glima has been kept alive as Iceland's national sport.
Some traditional martial arts have been preserved in one form or another. For example, boxing, wrestling, archery, and fencing were preserved by being made into sports; of course this has changed the emphases of these arts significantly. Notably, savate still has a very strong following in modern-day France. Other martial arts, such as sabre duelling as mensur have been outlawed but practised secretly.
A number of historical fencing forms and manuals have survived, and many groups are working to reconstruct older European martial arts. The process of reconstruction combines intensive study of detailed combat treatises produced from 1400–1900 A.D. and practical training or "pressure testing" of various techniques and tactics. This includes such styles as sword and shield, two-handed swordfighting, halberd fighting, jousting and other types of melee weapons combat. This reconstruction effort and modern outgrowth of the historical methods is generally referred to as Western martial arts. Many Medieval martial arts manuals have survived, the most famous being Johannes Lichtenauer's Fechtbuch (Sword Tome) of the 14th century. Today the Lichtenauer's tome forms the basis of German school of swordsmanship.
Another aspect of the reconstruction effort involves more historically recent martial arts and combat sports, such as those practiced during the 1800s and 1900s. A partial list would include bare-knuckle boxing, Bartitsu, quarterstaff fencing according to late 1800 s rules, etc.
Some European weapon systems have also survived as folk sports and as self-defense methods. These include stick-fighting systems such as Jogo do Pau of Portugal and the Juego del Palo style(s) of the Canary Islands.
Other martial arts evolved into sports that no longer recognized as combative. One example is the pommel horse event in men's gymnastics, an exercise which itself is derived from the sport of Equestrian vaulting. Cavalryriders needed to be able to change positions on their horses quickly, rescue fallen allies, fight effectively on horseback and dismount at a gallop. Training these skills on a stationery barrel evolved into sport of gymnastics' pommel horse exercise. More ancient origins exist for the shot put and the javelin throw, both weapons utilized extensively by the Romans.
## In the Americas
The native peoples of North America and South America had their own martial training which began in childhood. Many Native American men considered themselves warriors and trained to use the bows, knives, blowguns, spears, and war clubs. War-clubs were the preferred martial weapon because Native American warriors could raise their social status by killing enemies in single combat face to face. Warriors honed their archery and war club skills through lifelong training. The European colonists (and later, Asian immigrants) brought over their own martial arts such as boxing, fencing and wrestling.
Capoeira, with roots in Africa, is a martial art originating in Brazil that involves a high degree of flexibility and endurance. It consists of kicks, elbow strikes, head butts, and sweeps. Brazilian Jiu Jitsu is an adaptation of pre-World War II Judo and jujutsu. Created by Carlos Gracie and his brother Hélio, it was restructured into a sport with a large focus on groundwork. This system has become a popular martial art and proved to be effective in mixed martial arts competitions such as the UFC and PRIDE.
As of 2003, over 1.5 million US citizens practice martial arts.
## In Africa
African knives may be classified by shape—typically into the 'f' group and the 'circular' group—and have often been incorrectly described as throwing knives.There are also wrestling and grappling techniques found in West Africa. "Stick fighting" formed an important part of Zulu culture in South Africa.
## Internationally
Every village and tribe around the world had a few experienced fighters who passed on their knowledge; however, it is difficult to pass on a fighting system, so almost all of these have been lost as their practical relevance has declined. A few have nonetheless survived for one reason or another, examples of this are Capoeira and some related arts in Cuba, Haiti and Trinidad and Tobago, which were preserved partly through their relationship with Candomblé, Santería, Vodou, and other syncretic religions. Of these, only Capoeira has risen to worldwide prominence.
Archery, Boxing, Fencing, Javelin, Judo, Wrestling and Tae Kwon Do are the martial arts that are featured as events in the modern Summer Olympic Games.
Martial arts also developed among military and police forces to be used as:
- arrest and self-defense methods. Examples include; Krav Maga: a self-defense system developed by the Special armed forces of Israel, San Shou: developed for Chinese armed forces, Kombato: developed for the Brazilian armed forces, Rough and Tumble (RAT): originally developed for the South African special forces (Reconnaissance Commandos) (now taught in a civilian capacity).
- tactical arts for use in close quarter combat warfare, i.e. Military Martial arts e.g. UAC (British), LINE (USA)
Other combative systems having their origins in the modern military include Soviet Bojewoje (Combat) Sambo.
# On the modern battlefield
Some traditional martial concepts have seen new use within modern military training. Perhaps the most recent example of this is point shooting which relies on muscle memory to more effectively utilize a firearm in a variety of awkward situations, much the way an iaidoka would master movements with their sword.
During the World War II era William E. Fairbairn, a Shanghai policeman and a leading Western expert on Asian fighting techniques, was recruited during World War II by the Special Operations Executive (SOE) to teach Jujutsu to UK, U.S. and Canadian Special Forces. The book Kill or Get Killed, written by Colonel Rex Applegate, became a classic military treatise on hand-to-hand combat. This fighting method was called Defendu.
Traditional hand-to-hand, knife, and spear techniques continue to see use in the composite systems developed for today's wars. Examples of this include the US Army's Combatives system developed by Matt Larsen, the Israeli army trains its soldiers in Krav Maga, the US Marine Corps's Marine Corps Martial Arts Program (MCMAP), and Chinese San Shou.
Unarmed dagger defenses identical to that found in the fechtbuch of Fiore dei Liberi and the Codex Wallerstein were integrated into the U.S. Army's training manuals in 1942 and continue to influence today's systems along with other traditional systems such as Kali and Escrima.
The bayonet, which has its origin in the spear, has seen use by the British Army as recently as the Iraq War.
# Testing and competition
Testing or evaluation is important to martial art practitioners of many disciplines who wish to determine their progression or own level of skill in specific contexts. Students within individual martial art systems often undergo periodic testing and grading by their own teacher in order to advance to a higher level of recognized achievement, such as a different belt color or title. The type of testing used varies from system to system but may include forms or sparring.
Various forms and sparring are commonly used in martial art exhibitions and tournaments. Some competitions pit practitioners of different disciplines against each other using a common set of rules, these are referred to as mixed martial arts competitions. Rules for sparring vary between art and organization but can generally be divided into light-contact, medium-contact, and full-contact variants, reflecting the amount of force that should be used on an opponent.
## Light and medium-contact
These types of sparring restrict the amount of force that may be used to hit an opponent, in the case of light sparring this is usual to 'touch' contact, e.g. a punch should be 'pulled' as soon as or before contact is made. In medium-contact the punch would not be 'pulled' but not hit with full force. As the amount of force used is restricted, the aim of these types of sparing is not to knock out an opponent; a point system is used in competitions.
A referee acts to monitor for fouls and to control the match, while judges mark down scores, as in boxing. Particular targets may be prohibited (such as the face or groin), certain techniques may be forbidden, and fighters may be required to wear protective equipment on their head, hands, chest, groin, shins or feet. In some styles, competitors score points based on the landing of a single technique as judged by the referee, whereupon they will briefly stop the match, award a point, then restart it. Alternatively, sparring may continue with the point noted by the judges.
Some critics of point-sparring feel that this method of training teaches habits that result in lower combat effectiveness. Lighter-contact sparring may be used exclusively, as training for full contact, for children, or when heavy contact would be inappropriate.
## Full-contact
"Full-contact" sparring or fighting is considered by many to be requisite in learning realistic unarmed combat. Full-contact sparring is different from light and medium-contact sparring in several ways, e.g. reduced or eliminated use of protective gear. Kyokushin karate requires advanced practitioners to engage in bare-knuckled, full-contact sparring while wearing only a karate gi and groin protector. Full contact sparring may include a wider variety of permitted attacks and contact zones on the body, excluding a limited number of forbidden techniques such as biting, breaking fingers, striking the groin, and attacking the eyes. Full-contact sparring may involve full-force attacks intended to disable the opponent, either by knockout or direct submission. If a point system is used, (in some competitions, such as the UFC 1, there is none) there is often a lower emphasis on scoring points to win by judges' decision.
Due to these factors, full-contact matches tend to be more aggressive in character. Nearly all MMA leagues such as UFC, PRIDE, Pancrase, Shooto use full-contact rules, as do professional boxing organizations. Rulesets mandate the use of protective gloves and forbid certain techniques or actions during a match, such as punching the back of the head. Brazilian Jiu-Jitsu and Judo matches do not allow striking, but are full-contact in the sense that full force is applied during grappling and submissions.
Some practitioners believe that winning a sport match by rules is not an important matter in hand-to-hand combat. Many of these practitioners may prefer not to participate in most types of rule-based martial art competition (even one such as modern vale tudo), electing instead to study fighting techniques with little or no regard to competitive rules or, perhaps, ethical concerns and the law (the techniques practiced may include attacking vulnerable spots such as the groin or the eyes). Nonetheless, others maintain that, given proper precautions such as a referee and a ring doctor, full-contact matches with basic rules serves as a useful gauge of one's overall fighting ability, including striking, grappling and finishing hold.
# Martial sport
Judo and Tae Kwon Do as well as western archery, boxing, javelin, wrestling and fencing are currently events in the Summer Olympic Games. Chinese wushu recently failed in its bid to be included, but is still actively performed in tournaments across the world. Practitioners in some arts such as kickboxing and Brazilian Jiu-Jitsu often train for sport matches, whereas those in other arts such as Aikido and Wing Chun generally spurn such competitions. Some schools believe that competition breeds better and more efficient practitioners, and gives a sense of good sportsmanship. Others believe that the rules under which competition takes place have diminished the combat effectiveness of martial arts or encourage a kind of practice which focuses on winning trophies rather than the more traditional focus such as cultivating a particular moral character.
As part of the response to sport martial arts, new forms of competition are being held such as the Ultimate Fighting Championship in the U.S. or Pancrase, and the PRIDE in Japan which are also known as mixed martial arts (or MMA) events. The original UFC was fought under very few rules allowing all martial arts styles to enter and not be limited by the rule set.
Some martial artists also compete in non-sparring competitions such as breaking or choreographed techniques poomse, kata or aka. Modern variations of the martial arts include dance-influenced competitions such as tricking.
Some martial traditions have been influenced by governments to become more sport-like for political purposes. The central impetus for the attempt by the People's Republic of China in transforming Chinese martial arts into the committee-regulated sport of Wushu was suppressing what they saw as the potentially subversive aspects of martial training, especially under the traditional system of family lineages.
# Dance
As mentioned above, some martial arts in various cultures can be performed in dance-like settings for various reasons, such as for evoking ferocity in preparation for battle or showing off skill in a more stylized manner. Many such martial arts incorporate music, especially strong percussive rhythms.
Examples of such war dances include:
- Buza - From Russia.
- Panther Dance - Burmese Bando with swords (dha)
- Gymnopaidiai - ancient Sparta
- European Sword dance or Weapon dance of various kinds
- Haka - New Zealand
- Sabre Dance - depicted in Khachaturian's ballet Gayane
- Maasai moran (warrior age-set) dances
- Aduk-Aduk - Brunei
- Ayyalah - Qatar
- Khattak Dance - Afghanistan
- Brazil's Capoeira, as well as some similar Afro-Caribbean arts
- Dannsa Biodag - Scotland and Scottish sword dances
- Hula & Lua - from the traditions of indigenous Hawaiian | Martial arts
Martial arts are systems of codified practices and traditions of training for combat. They may be studied for various reasons including combat skills, fitness, self-defense, sport, self-cultivation/meditation, mental discipline, character development and building self-confidence, or any combination of the above.
There is a great diversity and abundance of martial arts but, broadly speaking, martial arts share a common goal: to defeat a person physically or to defend oneself from physical threat. Some martial arts are linked to spiritual or religious beliefs/philosophies such as Buddhism or Shinto while others have their own spiritual/non-spiritual code of honor.
While each style has unique facets that makes it different from other martial arts, a common characteristic is the systemization of fighting techniques. One common method of training, particularly in the Asian martial arts, is the form or kata; these are sets or routines of techniques that are performed alone, or sometimes with a partner.[1]
The word 'martial' derives from the name of Mars, the Roman god of war. The term 'Martial Arts' literally means arts of Mars. This term comes from 15th century Europeans who were referring to their own fighting arts that are today known as Historical Fencing. A practitioner of martial arts is referred to as a martial artist.
# Scope
Martial arts vary widely, and may focus on a specific area or combination of areas, but they can be broadly grouped into focusing on strikes, grappling, or weapons training. Below is a list of examples that make extensive use of one these areas; it is not an exhaustive list of all arts covering the area, nor are these necessarily the only areas covered by the art but are the focus or best known part as examples of the area:
Striking
- Punching - Boxing (Western), Wing Chun
- Kicking - Capoeira, Savate, Taekwondo
- Other strikes (e.g. Elbows, knees, open-hand) - Muay Thai, Karate, Shaolin Kung Fu
Grappling
- Throwing - Glima, Judo, Jujutsu, Sambo, Shuai jiao
- Joint lock - Aikido, Brazilian Jiu-Jitsu, Hapkido
- Pinning Techniques - Judo, Wrestling
Weaponry
- Traditional Weaponry - Fencing, Gatka, Kendo, Silambam, Kali
- Modern Weaponry - Eskrima, Jogo do Pau, Jukendo
Many martial arts, especially those from Asia, also teach side disciplines which pertain to medicinal practices. This is particularly prevalent in traditional Chinese martial arts which may teach bone-setting, qigong, acupuncture, acupressure (tui na), and other aspects of traditional Chinese medicine.[2]
Martial arts are commonly associated with East Asian cultures, but are by no means unique to Asia. Throughout Europe there was an extensive system of combat martial arts, collectively referred to as Historical European martial arts, that existed until modern times and is now being reconstructed by several organizations while Savate is a French kicking style developed by sailors and street fighters. In the Americas Native Americans have a tradition of open-handed martial arts, that includes wrestling and Hawaiians have historically practiced arts featuring small and large joint manipulation, a mix of origins occur in the athletic movements of Capoeira that was created in Brazil by slaves, based on skills brought with them from Africa.
# History
Template:Refimprovesect
The history of martial arts around the world is complex. Most groups of people have had to physically defend themselves at some time and have developed fighting techniques for that purpose. Development of many martial arts was related to military development, but many of those techniques have been rendered technologically obsolete over the centuries. In the modern day, most populations would be more likely to face adversaries wielding firearms than melee weapons during battle. Furthermore, the preservation of a martial art requires many years of teaching at the hands of a skilled instructor to pass on the art for a single generation. Given these circumstances, many martial arts from previous eras have not been passed down to following generations.[3]
## In Asia
### Early history
The foundation of the Asian martial arts is likely a blend of early Chinese and Indian arts. Extensive trade occurred between these nations beginning around 600 B.C., with diplomats, merchants, and monks traveling the Silk Roads. During the Warring States period of Chinese history (480-221 B.C.) extensive development in martial philosophy and strategy emerged, as described by Sun Tzu in The Art of War (c. 350 B.C.)
An early legend in martial arts tells the tale of the Indian monk Bodhidharma (also called Daruma), believed to have lived around 550 A.D. He is credited with founding the meditative philosophy of Zen Buddhism and influencing the unarmed combat arts of the Shaolin temple in China. The martial virtues of discipline, humility, restraint and respect are attributed to this philosophy.[4]
The teaching of martial arts in Asia has historically followed the cultural traditions of teacher-disciple apprenticeship. Students are trained in a strictly hierarchical system by a master instructor: Sifu in Cantonese or Shifu in Mandarin; Guru in Sanskrit, Hindi, Telugu and Malay; Sensei in Japanese; Sa Bum Nim in Korean; Kalari Gurukkal or kalari asaan in Malayalam; Asaan in Tamil; Achan in Thai; Guro in Tagalog and Saya in Myanmar, . The instructor is expected to directly supervise their students' training, and the students are expected to memorize and recite as closely as possible the rules and basic training routines of the school.
In the warrior Kshatriya caste of South Asia, organised martial traditions were studied as a part of the Dharma (duty) of the caste. The senior teachers were called Gurus and taught martial arts at gurukuls to the shishyas (students).
Some method of certification can be involved, where one's skills would be tested for mastery before being allowed to study further; in some systems, there may not be any such certifications, only years of close personal practice and evaluation under a master, much like an apprenticeship, until the master deems one's skills satisfactory.[citation needed] This pedagogy, while still preserved and respected in many traditional styles, has weakened to varying degrees in others and is even actively rejected by some schools, especially in the West.
Throughout Asia martial arts were practiced as can be seen in the art, history and current traditions in Vietnam, Cambodia, Thailand, Myanmar (Burma), and the Philippines. In many countries local arts like Te in Okinawa,[5] Kenjutsu and Ju-Jutsu in Japan,[6] and Taekyon and Soobak in Korea[7] mixed with other martial arts and evolved to produce some of the more well-known martial arts in the late nineteenth and twentieth centuries like Karate, Aikido, and Taekwondo.
### Modern history
The Western interest in East Asian Martial arts dates back to the late 19th Century AD, due to the increase in trade between America with China and Japan. Relatively few Westerners actually practiced the arts, considering it to be mere performance.
Edward William Barton-Wright, a railway engineer who had studied Jujutsu while working in Japan between 1894–97, was the first man known to have taught Asian martial arts in Europe. He also founded an eclectic martial arts style named Bartitsu which combined jujutsu, judo, boxing, savate and stick fighting.
During the late 19th century and early 20th century, catch wrestling contests became immensely popular in Europe.
During pre-war and World War Two shows the practicality of martial arts in the modern world and were used by Japanese, US, Nepalese (Gurkha) commandos as well as Resistance groups, such as in the Philippines, (see Raid at Los Baños) but not so excessively or at all for common soldiers.
However Asian martial arts remained largely unknown in the West even as late as the 1950s; for example, in the 1959 popular fiction Goldfinger, Karate was described to readers in near-mythical terms and it was credible for British unarmed combat experts to be represented as completely unaware of martial arts of this kind. The novel describes the protagonist James Bond, an expert in unarmed combat, as utterly ignorant of Karate and its demonstrations, and describes the Korean 'Oddjob' in these terms:
Goldfinger said, "Have you ever heard of Karate? No? Well that man is one of the three in the world who have achieved the Black Belt in Karate. Karate is a branch of judo, but it is to judo what a Spandau is to a catapult...".[9]
Such a description in a popular novel assumed and relied upon karate being almost unknown in the West; and it linked karate with judo, whereas in reality karate is a distinct art almost unrelated to judo.
As Western influence grew in East Asia a greater number of military personnel spent time in China, Japan, and Korea. Exposure to martial arts during the Korean war was also significant. Gradually some soldiers saw the value of Eastern martial arts and began training in them.
With large numbers of American servicemen stationed in Japan after World War II, the adoption of techniques and the gradual transmission of entire systems of martial arts to the West started. It was in the 1950s, however, when this exportation of systems really began to gain momentum. Large groups of U.S. military personnel were taught Korean arts (Taekwondo) during the Korean conflict. In the early 1970s, martial arts movies, in particular those of martial artist and actor Bruce Lee, furthered the popularity of martial arts.
This exportation of the martial arts led to such styles as sport karate, which became a major international sport, with professional fighters, big prizes, television coverage, and sponsorship deals. This also lead to the creation of modern martial arts such as Brazilian Jiu-jitsu. Brazilian Jiu-jitsu is a derivative of Kodokan Judo, extended and influenced by the no holds barred combat traditions of Brazil; it has been highly effective in mixed martial arts competitions around the world.
The later 1970s and 1980s witnessed an increased media interest in the martial arts, thanks in part to Asian and Hollywood martial arts movies and very popular television shows like "Kung Fu", "Martial Law" and "The Green Hornet" that incorporated martial arts moments or themes. Jackie Chan and Jet Li are prominent movie figures who have been responsible for promoting Chinese martial arts in recent years.
## In Europe
Main article: Historical European martial arts
In Europe, the martial arts declined with the rise of the firearms. As a consequence, martial arts with historical roots in Europe do not exist today to the same extent as in Asia, since the traditional martial arts either died out or developed into sports. Swordplay developed into fencing. Boxing as well as forms of wrestling have endured. European martial arts have mostly adapted to changing technology so that while some traditional arts still exist, military personnel are trained in skills like bayonet combat and marksmanship. These skills do not fall under the common use of the term, but may still be considered "martial arts".
This is not to say Europe was not rich in historical martial arts traditions. Martial arts existed in classical European civilization, most notably in Greece where sports were integral to the way of life. Boxing (pygme, pyx), Wrestling (pale) and Pankration (from pan, meaning "all", and kratos, meaning "power" or "strength") were represented in the Ancient Olympic Games. The Romans produced Gladiatorial combat as a public spectacle.
Khridoli (Georgian: ხრიდოლი) is an ancient Georgian martial art, which includes fighting with bare hands and different types of weapons.
Glima is an unarmed Scandinavian martial art with, as some sources indicate, roots in the Viking age.[10] The tradition of glima has been kept alive as Iceland's national sport.
Some traditional martial arts have been preserved in one form or another. For example, boxing, wrestling, archery, and fencing were preserved by being made into sports; of course this has changed the emphases of these arts significantly. Notably, savate still has a very strong following in modern-day France. Other martial arts, such as sabre duelling as mensur have been outlawed but practised secretly.
A number of historical fencing forms and manuals have survived, and many groups are working to reconstruct older European martial arts. The process of reconstruction combines intensive study of detailed combat treatises produced from 1400–1900 A.D. and practical training or "pressure testing" of various techniques and tactics. This includes such styles as sword and shield, two-handed swordfighting, halberd fighting, jousting and other types of melee weapons combat. This reconstruction effort and modern outgrowth of the historical methods is generally referred to as Western martial arts. Many Medieval martial arts manuals have survived, the most famous being Johannes Lichtenauer's Fechtbuch (Sword Tome) of the 14th century. Today the Lichtenauer's tome forms the basis of German school of swordsmanship.
Another aspect of the reconstruction effort involves more historically recent martial arts and combat sports, such as those practiced during the 1800s and 1900s. A partial list would include bare-knuckle boxing, Bartitsu, quarterstaff fencing according to late 1800 s rules, etc.
Some European weapon systems have also survived as folk sports and as self-defense methods. These include stick-fighting systems such as Jogo do Pau of Portugal and the Juego del Palo style(s) of the Canary Islands.
Other martial arts evolved into sports that no longer recognized as combative. One example is the pommel horse event in men's gymnastics, an exercise which itself is derived from the sport of Equestrian vaulting. Cavalryriders needed to be able to change positions on their horses quickly, rescue fallen allies, fight effectively on horseback and dismount at a gallop. Training these skills on a stationery barrel evolved into sport of gymnastics' pommel horse exercise. More ancient origins exist for the shot put and the javelin throw, both weapons utilized extensively by the Romans.
## In the Americas
The native peoples of North America and South America had their own martial training which began in childhood. Many Native American men considered themselves warriors and trained to use the bows, knives, blowguns, spears, and war clubs. War-clubs were the preferred martial weapon because Native American warriors could raise their social status by killing enemies in single combat face to face.[citation needed] Warriors honed their archery and war club skills through lifelong training. The European colonists (and later, Asian immigrants) brought over their own martial arts such as boxing, fencing and wrestling.
Capoeira, with roots in Africa, is a martial art originating in Brazil that involves a high degree of flexibility and endurance. It consists of kicks, elbow strikes, head butts, and sweeps. Brazilian Jiu Jitsu is an adaptation of pre-World War II Judo and jujutsu. Created by Carlos Gracie and his brother Hélio, it was restructured into a sport with a large focus on groundwork. This system has become a popular martial art and proved to be effective in mixed martial arts competitions such as the UFC and PRIDE.[11]
As of 2003, over 1.5 million US citizens practice martial arts.[12]
## In Africa
African knives may be classified by shape—typically into the 'f' group and the 'circular' group—and have often been incorrectly described as throwing knives.[13]There are also wrestling and grappling techniques found in West Africa. "Stick fighting" formed an important part of Zulu culture in South Africa.
## Internationally
Every village and tribe around the world had a few experienced fighters who passed on their knowledge[citation needed]; however, it is difficult to pass on a fighting system, so almost all of these have been lost as their practical relevance has declined. A few have nonetheless survived for one reason or another, examples of this are Capoeira and some related arts in Cuba, Haiti and Trinidad and Tobago, which were preserved partly through their relationship with Candomblé, Santería, Vodou, and other syncretic religions.[citation needed] Of these, only Capoeira has risen to worldwide prominence.
Archery, Boxing, Fencing, Javelin, Judo, Wrestling and Tae Kwon Do are the martial arts that are featured as events in the modern Summer Olympic Games.
Martial arts also developed among military and police forces to be used as:
- arrest and self-defense methods. Examples include; Krav Maga: a self-defense system developed by the Special armed forces of Israel, San Shou: developed for Chinese armed forces, Kombato: developed for the Brazilian armed forces, Rough and Tumble (RAT): originally developed for the South African special forces (Reconnaissance Commandos) (now taught in a civilian capacity).
- tactical arts for use in close quarter combat warfare, i.e. Military Martial arts e.g. UAC (British), LINE (USA)
Other combative systems having their origins in the modern military include Soviet Bojewoje (Combat) Sambo.
# On the modern battlefield
Some traditional martial concepts have seen new use within modern military training. Perhaps the most recent example of this is point shooting which relies on muscle memory to more effectively utilize a firearm in a variety of awkward situations, much the way an iaidoka would master movements with their sword.
During the World War II era William E. Fairbairn, a Shanghai policeman and a leading Western expert on Asian fighting techniques, was recruited during World War II by the Special Operations Executive (SOE) to teach Jujutsu to UK, U.S. and Canadian Special Forces. The book Kill or Get Killed, written by Colonel Rex Applegate, became a classic military treatise on hand-to-hand combat. This fighting method was called Defendu.
Traditional hand-to-hand, knife, and spear techniques continue to see use in the composite systems developed for today's wars. Examples of this include the US Army's Combatives system developed by Matt Larsen, the Israeli army trains its soldiers in Krav Maga, the US Marine Corps's Marine Corps Martial Arts Program (MCMAP), and Chinese San Shou.
Unarmed dagger defenses identical to that found in the fechtbuch of Fiore dei Liberi and the Codex Wallerstein were integrated into the U.S. Army's training manuals in 1942[14] and continue to influence today's systems along with other traditional systems such as Kali and Escrima.
The bayonet, which has its origin in the spear, has seen use by the British Army as recently as the Iraq War.[15]
# Testing and competition
Testing or evaluation is important to martial art practitioners of many disciplines who wish to determine their progression or own level of skill in specific contexts. Students within individual martial art systems often undergo periodic testing and grading by their own teacher in order to advance to a higher level of recognized achievement, such as a different belt color or title. The type of testing used varies from system to system but may include forms or sparring.
Various forms and sparring are commonly used in martial art exhibitions and tournaments. Some competitions pit practitioners of different disciplines against each other using a common set of rules, these are referred to as mixed martial arts competitions. Rules for sparring vary between art and organization but can generally be divided into light-contact, medium-contact, and full-contact variants, reflecting the amount of force that should be used on an opponent.
## Light and medium-contact
These types of sparring restrict the amount of force that may be used to hit an opponent, in the case of light sparring this is usual to 'touch' contact, e.g. a punch should be 'pulled' as soon as or before contact is made. In medium-contact the punch would not be 'pulled' but not hit with full force. As the amount of force used is restricted, the aim of these types of sparing is not to knock out an opponent; a point system is used in competitions.
A referee acts to monitor for fouls and to control the match, while judges mark down scores, as in boxing. Particular targets may be prohibited (such as the face or groin), certain techniques may be forbidden, and fighters may be required to wear protective equipment on their head, hands, chest, groin, shins or feet. In some styles, competitors score points based on the landing of a single technique as judged by the referee, whereupon they will briefly stop the match, award a point, then restart it. Alternatively, sparring may continue with the point noted by the judges.
Some critics of point-sparring feel that this method of training teaches habits that result in lower combat effectiveness. Lighter-contact sparring may be used exclusively, as training for full contact, for children, or when heavy contact would be inappropriate.
## Full-contact
"Full-contact" sparring or fighting is considered by many to be requisite in learning realistic unarmed combat. Full-contact sparring is different from light and medium-contact sparring in several ways, e.g. reduced or eliminated use of protective gear. Kyokushin karate requires advanced practitioners to engage in bare-knuckled, full-contact sparring while wearing only a karate gi and groin protector. Full contact sparring may include a wider variety of permitted attacks and contact zones on the body, excluding a limited number of forbidden techniques such as biting, breaking fingers, striking the groin, and attacking the eyes. Full-contact sparring may involve full-force attacks intended to disable the opponent, either by knockout or direct submission. If a point system is used, (in some competitions, such as the UFC 1, there is none) there is often a lower emphasis on scoring points to win by judges' decision.
Due to these factors, full-contact matches tend to be more aggressive in character. Nearly all MMA leagues such as UFC, PRIDE, Pancrase, Shooto use full-contact rules, as do professional boxing organizations. Rulesets mandate the use of protective gloves and forbid certain techniques or actions during a match, such as punching the back of the head. Brazilian Jiu-Jitsu and Judo matches do not allow striking, but are full-contact in the sense that full force is applied during grappling and submissions.
Some practitioners believe that winning a sport match by rules is not an important matter in hand-to-hand combat. Many of these practitioners may prefer not to participate in most types of rule-based martial art competition (even one such as modern vale tudo), electing instead to study fighting techniques with little or no regard to competitive rules or, perhaps, ethical concerns and the law (the techniques practiced may include attacking vulnerable spots such as the groin or the eyes). Nonetheless, others maintain that, given proper precautions such as a referee and a ring doctor, full-contact matches with basic rules serves as a useful gauge of one's overall fighting ability, including striking, grappling and finishing hold.
# Martial sport
Judo and Tae Kwon Do as well as western archery, boxing, javelin, wrestling and fencing are currently events in the Summer Olympic Games. Chinese wushu recently failed in its bid to be included, but is still actively performed in tournaments across the world. Practitioners in some arts such as kickboxing and Brazilian Jiu-Jitsu often train for sport matches, whereas those in other arts such as Aikido and Wing Chun generally spurn such competitions. Some schools believe that competition breeds better and more efficient practitioners, and gives a sense of good sportsmanship. Others believe that the rules under which competition takes place have diminished the combat effectiveness of martial arts or encourage a kind of practice which focuses on winning trophies rather than the more traditional focus such as cultivating a particular moral character.
As part of the response to sport martial arts, new forms of competition are being held such as the Ultimate Fighting Championship in the U.S. or Pancrase, and the PRIDE in Japan which are also known as mixed martial arts (or MMA) events. The original UFC was fought under very few rules allowing all martial arts styles to enter and not be limited by the rule set.
Some martial artists also compete in non-sparring competitions such as breaking or choreographed techniques poomse, kata or aka. Modern variations of the martial arts include dance-influenced competitions such as tricking.
Some martial traditions have been influenced by governments to become more sport-like for political purposes. The central impetus for the attempt by the People's Republic of China in transforming Chinese martial arts into the committee-regulated sport of Wushu was suppressing what they saw as the potentially subversive aspects of martial training, especially under the traditional system of family lineages.[16]
# Dance
As mentioned above, some martial arts in various cultures can be performed in dance-like settings for various reasons, such as for evoking ferocity in preparation for battle or showing off skill in a more stylized manner. Many such martial arts incorporate music, especially strong percussive rhythms.
Examples of such war dances include:
- Buza - From Russia.
- Panther Dance - Burmese Bando with swords (dha)
- Gymnopaidiai - ancient Sparta
- European Sword dance or Weapon dance of various kinds
- Haka - New Zealand
- Sabre Dance - depicted in Khachaturian's ballet Gayane
- Maasai moran (warrior age-set) dances
- Aduk-Aduk - Brunei
- Ayyalah - Qatar
- Khattak Dance - Afghanistan
- Brazil's Capoeira, as well as some similar Afro-Caribbean arts
- Dannsa Biodag - Scotland and Scottish sword dances
- Hula & Lua - from the traditions of indigenous Hawaiian | https://www.wikidoc.org/index.php/Martial_arts | |
99333e14f75bedf8b1c80eff626401384aab1c4e | wikidoc | Virilization | Virilization
# Overview
In biology and medicine, virilization refers to the biological development of sex differences, changes which make a male body different from a female body. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology of gender contexts: prenatal sexual differentiation, the postnatal changes of normal male puberty, and excessive androgen effects in girls or women.
# Prenatal virilization
In the prenatal period, virilization refers to closure of the perineum, thinning and rugation of the scrotum, growth of the phallus, and closure of the urethral groove to the tip of the penis. In this context masculinization is synonymous with virilization. Prenatal virilization of genetic females and undervirilization of genetic males are common causes of ambiguous genitalia and intersex conditions.
Undervirilization can occur if a genetic male cannot produce enough androgen or the body tissues cannot respond to it. Extreme undervirilization occurs when no significant androgen can be produced or the body is completely insensitive to it, and results in a female body. Partial undervirilization produces ambiguous genitalia part way between male and female. The mildest degree of undervirilization may be a slightly small penis with hypospadias. Examples of undervirilization are androgen insensitivity syndrome, 5 alpha reductase deficiency, and some forms of congenital adrenal hyperplasia.
Prenatal virilization (or masculinization) of a genetically female fetus can occur when an excessive amount of androgen is produced by the fetal adrenal glands or is present in maternal blood. In the severest form of congenital adrenal hyperplasia complete masculinization of a genetically female fetus results in an apparently normal baby boy with no palpable testes. More often, the virilization is partial and the genitalia are ambiguous.
# Normal virilization
In common as well as medical usage, virilization often refers to the process of normal male puberty, in which testosterone changes a boy's body into a man's. These effects include growth of the penis and testes, accelerated growth, development of pubic hair and other androgenic hair of face, torso, and limbs, deepening of the voice, increased musculature, thickening of the jaw, prominence of the neck cartilage, and broadening of the shoulders.
# Abnormal childhood virilization
Virilization can occur in childhood in either boys or girls due to excessive amounts of androgens. Typical effects of virilization in children are pubic hair, accelerated growth and bone maturation, increased muscle strength, acne, adult body odor, and sometimes growth of the penis. In a boy, virilization may signal precocious puberty, while congenital adrenal hyperplasia and androgen producing tumors (usually) of the gonads or adrenals are occasional causes in both sexes.
# virilization in adolescent or adult women
Virilization in a woman can manifest as clitoral enlargement, increased muscle strength, acne, hirsutism, frontal hair thinning, deepening of the voice, and menstrual disruption due to anovulation.
Some of the possible causes of virilization in women are:
- Polycystic ovary syndrome
- Androgen-producing tumors of the
-varies
adrenal glands
pituitary gland
- ovaries
- adrenal glands
- pituitary gland
- Hypothyroidism
- Anabolic steroid exposure
- Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (late-onset)
## Causes
## Drug Causes
- Fluoxymesterone,
- Nandrolone | Virilization
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In biology and medicine, virilization refers to the biological development of sex differences, changes which make a male body different from a female body. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology of gender contexts: prenatal sexual differentiation, the postnatal changes of normal male puberty, and excessive androgen effects in girls or women.
# Prenatal virilization
In the prenatal period, virilization refers to closure of the perineum, thinning and rugation of the scrotum, growth of the phallus, and closure of the urethral groove to the tip of the penis. In this context masculinization is synonymous with virilization. Prenatal virilization of genetic females and undervirilization of genetic males are common causes of ambiguous genitalia and intersex conditions.
Undervirilization can occur if a genetic male cannot produce enough androgen or the body tissues cannot respond to it. Extreme undervirilization occurs when no significant androgen can be produced or the body is completely insensitive to it, and results in a female body. Partial undervirilization produces ambiguous genitalia part way between male and female. The mildest degree of undervirilization may be a slightly small penis with hypospadias. Examples of undervirilization are androgen insensitivity syndrome, 5 alpha reductase deficiency, and some forms of congenital adrenal hyperplasia.
Prenatal virilization (or masculinization) of a genetically female fetus can occur when an excessive amount of androgen is produced by the fetal adrenal glands or is present in maternal blood. In the severest form of congenital adrenal hyperplasia complete masculinization of a genetically female fetus results in an apparently normal baby boy with no palpable testes. More often, the virilization is partial and the genitalia are ambiguous.
# Normal virilization
In common as well as medical usage, virilization often refers to the process of normal male puberty, in which testosterone changes a boy's body into a man's. These effects include growth of the penis and testes, accelerated growth, development of pubic hair and other androgenic hair of face, torso, and limbs, deepening of the voice, increased musculature, thickening of the jaw, prominence of the neck cartilage, and broadening of the shoulders.
# Abnormal childhood virilization
Virilization can occur in childhood in either boys or girls due to excessive amounts of androgens. Typical effects of virilization in children are pubic hair, accelerated growth and bone maturation, increased muscle strength, acne, adult body odor, and sometimes growth of the penis. In a boy, virilization may signal precocious puberty, while congenital adrenal hyperplasia and androgen producing tumors (usually) of the gonads or adrenals are occasional causes in both sexes.
# virilization in adolescent or adult women
Virilization in a woman can manifest as clitoral enlargement, increased muscle strength, acne, hirsutism, frontal hair thinning, deepening of the voice, and menstrual disruption due to anovulation.
Some of the possible causes of virilization in women are:
- Polycystic ovary syndrome
- Androgen-producing tumors of the
ovaries
adrenal glands
pituitary gland
- ovaries
- adrenal glands
- pituitary gland
- Hypothyroidism
- Anabolic steroid exposure
- Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (late-onset)
## Causes
## Drug Causes
- Fluoxymesterone,
- Nandrolone | https://www.wikidoc.org/index.php/Masculinization | |
dc49acc7225953c43b658fa457652fe80550cfb7 | wikidoc | Masturbation | Masturbation
Masturbation refers to sexual stimulation, especially of one's own genitals and often to the point of orgasm, which is performed manually, by other types of bodily contact (except for sexual intercourse), by use of objects or tools, or by some combination of these methods. Masturbation is the most common form of autoeroticism, and the two words are often used as synonyms, although masturbation with a partner (mutual masturbation) is also common. Animal masturbation has been observed in many species, both in the wild and in captivity.
# Etymology
The word masturbation is believed to derive from either the Greek word mezea (μεζεα, "penes") or the Latin manus ("hand") and the Latin turbare ("to disturb"). A competing etymology based on the Latin manu stuprare ("to defile with the hand") is said by the Oxford English Dictionary to be an "old conjecture". The esoteric and little-used synonym manustupration is similarly derived from manus stuprare.
While "masturbation" is the medical term for this practice, many other terms and expressions are in common use. "Onanism" is a term with religious roots. In the vernacular, terms such as "pleasuring oneself", "wanking", and "jerking off" are common. See masturbate in Wikisaurus for many others.
# Masturbation techniques
Ways of masturbating common to members of both sexes include pressing or rubbing the genital area, either with the fingers or against an object such as a pillow; inserting fingers or an object into the anus (see anal masturbation); and stimulating the penis or vulva with electric vibrators, which may also be inserted into the vagina or anus. Members of both sexes may also enjoy touching, rubbing, or pinching the nipples or other erogenous zones while masturbating. Both sexes sometimes apply lubricating substances to intensify sensation.
Reading or viewing pornography, or sexual fantasy, are often common adjuncts to masturbation. Often people will call upon memories during masturbation. Masturbation activities are often ritualised. Various fetishes and paraphilias can also play a part in the masturbation ritual. Some potentially harmful or fatal activities include autoerotic asphyxiation and self-bondage.
Some people get sexual pleasure by inserting objects into the urethra (the tube through which urine and, in men, semen, flows). If these objects are urethral sounds, the practice is known as "sounding". Other objects such as ball point pens and thermometers are sometimes used, although this practice can lead to injury and/or infection. Some people masturbate by using machines that simulate intercourse.
Men and women may masturbate until they are close to orgasm, stop for a while to reduce excitement, and then resume masturbating. They may repeat this cycle multiple times. This "stop and go" build up can achieve even stronger orgasms. Rarely, people quit stimulation just before orgasm to retain the heightened energy that normally comes down after orgasm due to the release of prolactin hormone. Doing this could lead to temporary discomfort due to pelvic congestion.
Austrian psychoanalyst Wilhelm Reich in his 1922 essay Concerning Specific Forms of Masturbation tried to identify healthy and unhealthy forms of masturbation. He tried to relate the way people masturbated to their degree of inclination towards the opposite sex and to their psycho-sexual pathologies.
## Female
Female masturbation techniques include a woman stroking or rubbing her vulva, especially her clitoris, with her index and/or middle fingers. Sometimes one or more fingers may be inserted into her vagina to repeatedly stroke the frontal wall of her vagina where her g-spot is located.
Masturbation aids such as a vibrator, dildo or Ben Wa balls can also be used to stimulate the vagina and clitoris. Many women caress their breasts or stimulate a nipple with the free hand, if these are receptive areas for sexual stimulation. Anal stimulation is also enjoyed by some. Lubrication is sometimes used during masturbation, especially when penetration is involved, but this is not universal and many women find their natural lubrication sufficient.
Common positions include lying on back or face down, sitting, squatting, kneeling or standing. In a bath or shower a female may direct tap water at her clitoris and vulva. Lying face down one may use the hands, one may straddle a pillow, the corner or edge of the bed, a partner's leg or some scrunched-up clothing and "hump" her vulva and clitoris against it. Standing up, a chair, the corner of an item of furniture or even a washing machine can be used to stimulate her clitoris through her labia and clothing.
In the 1920s, Havelock Ellis reported that turn-of-the-century seamstresses using treadle-operated sewing machines could achieve orgasm by sitting near the edge of their chairs.
Women can sexually stimulate themselves by crossing their legs tightly and clenching the muscles in their legs, creating pressure on the genitals. This can potentially be done in public without observers noticing. Some masturbate using only pressure applied to the clitoris without direct contact, for example by pressing the palm or ball of the hand against underwear or other clothing.
Thoughts, fantasies and memories of previous instances of arousal and orgasm can produce sexual arousal. Some women even claim to be able to orgasm spontaneously by force of will alone, but that ability, if it exists at all, may not strictly qualify as masturbation as no physical stimulus is involved.
Sex therapists will sometimes recommend that female patients take time to masturbate to orgasm, especially if they have not done so before.
## Male
Male masturbation techniques are also influenced by a number of factors and personal preferences. Techniques may also differ between circumcised and uncircumcised males, as some techniques which may work for one can often be quite painful for the other.
The most common male masturbation technique is simply to hold the penis with a loose fist and then to move the hand up and down the shaft until orgasm and ejaculation take place. The speed of the hand motion will vary from male to male, although it is not uncommon for the speed to increase as ejaculation nears and for it to decrease during the ejaculation itself. When uncircumcised, stimulation of the penis in this way comes from the "pumping" of the foreskin. This gliding motion of the foreskin reduces friction. When circumcised, there is more direct contact between the hand and the glans, thus a personal lubricant is sometimes used to reduce friction. Sometimes, if too much pressure is applied, it may be rubbed sore for a time.
Circumcised or not, men may rub or massage the glans, the rim of the glans, and the frenular delta.
Another technique is to place just the index finger and thumb around the penis about halfway along the penis and move the skin up and down. A variation on this is to place the fingers and thumb on the penis as if playing a flute, and then shuttle them back and forth. Another common technique is to lie face down on a comfortable surface such as a mattress or pillow and rub the penis against it until orgasm is achieved. This technique may include the use of a simulacrum, or artificial vagina.
There are many other variations on male masturbation techniques. Some men place both hands directly on their penis during masturbation, while others use their free hand to fondle their testicles, nipples, or other parts of their body. Some may keep their hand stationary while pumping into it with pelvic thrusts in order to simulate the motions of sexual intercourse. Others may also use vibrators and other sexual devices more commonly associated with female masturbation. A few extremely flexible males can reach and stimulate their penis with their tongue or lips, and so perform autofellatio.
The prostate gland is one of the organs that contributes fluid to semen. As the prostate is touch-sensitive, some directly stimulate it using a well-lubricated finger or dildo inserted through the anus into the rectum. Stimulating the prostate from outside, via pressure on the perineum, can be pleasurable as well. Semen is sometimes ejaculated onto a tissue or some other item.
A somewhat controversial ejaculation control technique is to put pressure on the perineum, about halfway between the scrotum and the anus, just before ejaculating. This can, however, redirect semen into the bladder (referred to as retrograde ejaculation). If repeated on a regular basis, this technique could cause long term damage due to the pressure put on the nerves and blood vessels in the perineum. A dry orgasm is one that is reached while withholding ejaculation (or where retrograde ejaculation has taken place). Proponents of dry orgasm say that this is a learnable skill that can shorten the refractory period.
# Mutual masturbation
Mutual masturbation is a sexual act where two or more people stimulate themselves or one another sexually, usually with the hands.
This may be done in situations where the participants do not feel physically able, that it is socially inappropriate or they do not want full sexual intercourse, but still wish to enjoy a mutual sexual act. It is also part of a full repertoire of sexual intercourse, where it may be used as an interlude, foreplay or simply as an alternative to penetration. For some people, it is the primary sexual activity of choice above all others, perhaps because it enables the individuals to see each other face to face and leaves the hands free to caress, as in frottage.
Mutual masturbation is practiced by people of all sexual orientations. If used as an alternative to penile-vaginal penetration, the aim may be to preserve virginity or to prevent pregnancy. Some people choose it as it achieves sexual satisfaction without actual sex, possibly seeing it as an alternative to casual sex.
# Masturbation frequency, age and sex
Frequency of masturbation is determined by many factors, e.g., one's resistance to sexual tension, hormone levels influencing sexual arousal, sexual habits, peer influences, health and one's attitude to masturbation formed by culture. Medical causes have also been associated with masturbation.
Different studies have found that masturbation is frequent in humans. Alfred Kinsey's studies have shown that 92% of men and 62% of women have masturbated during lifespan. Similar results have been found in British national probability survey. It was found that 95% of men and 71% of woman masturbated at some point in their lives. 73% of men and 37% of woman reported masturbating in the four weeks before their interview, while 53% of men and 18% of woman reported masturbating in previous seven days.
"Forty-eight female college students were asked to complete a sexual attitudes questionnaire in which a frequency of masturbation scale was embedded. Twenty-four of the women (the experimental group) then individually viewed an explicit modeling film involving female masturbation. One month later, all subjects again completed the same questionnaire. Subjects in the experimental group also completed a questionnaire evaluating aspects of the film. Results indicated that the experimental group reported a significant increase in the average monthly frequency of masturbation, as compared to the control group. This same group, however, reported that the film had no effect on sexual attitudes or behavior."
A 2004 survey by Toronto magazine NOW was answered by an unspecified number of thousands. The results show that an overwhelming majority of the males – 81% – began masturbating between the ages of 10 and 15. Among females, the same figure was a more modest majority of 55%. (Note that surveys on sexual practices are prone to self-selection bias.) It is not uncommon however to begin much earlier, and this is more frequent among females: 18% had begun by the time they turned 10, and 6% already by the time they turned 6. Being the main outlet of child sexuality, masturbation has been observed in very young children. In the book Human Sexuality: Diversity in Contemporary America, by Strong, Devault and Sayad, the authors point out, "A baby boy may laugh in his crib while playing with his erect penis (although he does not ejaculate). Baby girls sometimes move their bodies rhythmically, almost violently, appearing to experience orgasm."
A Canadian survey of Now magazine readers (cited above), has it that the frequency of masturbation declines after the age of 17. Many males masturbate daily, or even more frequently, well into their 20s and sometimes far beyond. This decline is more drastic among females, and more gradual among males. While females aged 13–17 masturbated almost once a day on average (and almost as often as their male peers), adult women only masturbated 8–9 times a month, compared to the 18–22 among men. Adolescent youths report being able to masturbate to ejaculation around six times per day, though some men in older middle age report being hard pressed to ejaculate even once per day. On the other hand healthy 21-28 year old males are able to masturbate at least 8-10 times per day if they are not stressed. The survey does not give a full demographic breakdown of respondents, however, and the sexual history of respondents to this poll, who are readers of an urban Toronto lifestyle magazine, may not extend to the general population.
It appears that females are less likely to masturbate while in a heterosexual relationship than men. Popular belief asserts that individuals of either sex who are not in sexually active relationships tend to masturbate more frequently than those who are; however, much of the time this is not true as masturbation alone or with a partner is often a feature of a relationship. Contrary to conventional wisdom, several studies actually reveal a positive correlation between the frequency of masturbation and the frequency of intercourse. One study reported a significantly higher rate of masturbation in gay men and women who were in a relationship.
Among some cultures, such as the Hopi in Arizona, the Wogeno in Oceania, and the Dahomeans and Namu of Africa, masturbation is encouraged, including regular masturbation between males. In certain Melanesian communities this is expected between older and younger boys. One interesting twist is the Sambia tribe of New Guinea. This tribe has rituals and rites of passage surrounding manhood which involve frequent ejaculation through fellatio. Semen is valued and masturbation is seen as a waste of semen and is therefore frowned upon even though frequent ejaculation is encouraged. The capacity and need to ejaculate is nurtured for years from an early age through fellatio so that it can be consumed rather than wasted. Semen is ingested for strength and is considered in the same line as mothers' milk.
Other cultures have rites of passage into manhood that culminate in the first ejaculation of a male, usually by the hands of a tribal elder. In some tribes such as the Agta, Philippines, stimulation of the genitals is encouraged from an early age. Upon puberty, the young male is then paired off with a "wise elder" or "witch doctor" who uses masturbation to build his ability to ejaculate in preparation for a ceremony. The ceremony culminates in a public ejaculation before a celebration. The ejaculate is saved in a wad of animal skin and worn later to help conceive children. In this and other tribes, the measure of manhood is actually associated more with the amount of ejaculate and his need than penis size. Frequent ejaculation through masturbation from an early age fosters frequent ejaculation well into adulthood.
Masturbation is becoming accepted as a healthy practice and safe method for sharing pleasure without some of the dangers that can accompany intercourse. It is socially accepted and even celebrated in certain circles. Group masturbation events can be easily found online. Masturbation marathons are yearly events and are occurring across the globe. These events provide a supportive environment where masturbation can be performed openly among young and old without embarrassment. Participants talk openly with onlookers while masturbating to share techniques and describe their pleasure.
# Evolutionary purpose
Masturbation may increase fertility during intercourse.
Female masturbation alters conditions in the vagina, cervix and uterus, in ways that can alter the chances of conception from intercourse, depending on the timing of the masturbation. A woman's orgasm between one minute before and up to 45 minutes after insemination favors the chances of that sperm reaching her egg. If, for example, she has had intercourse with more than one male, such an orgasm can increase the likelihood of a pregnancy by one of them. Female masturbation can also provide protection against cervical infections by increasing the acidity of the cervical mucus and by moving debris out of the cervix.
In males, masturbation flushes out old sperm with low motility from the male's genital tract. The next ejaculate then contains more fresh sperm, which have higher chances of achieving conception during intercourse. If more than one male has intercourse with a female, the sperm with the highest motility will compete more effectively.
# Health and psychological effects
## Benefits
The physical benefits of masturbation and having an orgasm or ejaculating creates heightened arousal while epinephrine courses through the body, producing the flushed face, shallow breath and post-climactic euphoria. It is held in many mental health circles that masturbation can relieve depression, stress and lead to a higher sense of self-worth (Hurlbert & Whittaker, 1991). Masturbation can also be particularly useful in relationships where one partner wants more sex than the other – in which case masturbation provides a balancing effect and thus a more harmonious relationship.
Mutual masturbation, the act by which two or more partners stimulate themselves in the presence of each other, allows a couple to reveal the "map to pleasure centers". Witnessing a partner masturbate is an educational activity to find out the method a partner pleases him- or herself, allowing each partner to learn exactly how the other enjoys being touched.
In 2003, an Australian research team led by Graham Giles of The Cancer Council Australia concluded that frequent masturbation by males appears to help prevent the development of prostate cancer. The study also indicated that this would be more helpful than ejaculation through sexual intercourse because intercourse can transmit diseases that may increase the risk of cancer instead. Also, frequent ejaculation is more easily obtained and sustained over time with the aid of masturbation.
A study published in 1997 found an inverse association between death from coronary heart disease and frequency of orgasm even given the risk that myocardial ischaemia and myocardial infarction can be triggered by sexual activity. Excerpt, "The association between frequency or orgasm and all cause mortality was also examined using the midpoint of each response category recoded as number of orgasms per year. The age adjusted odds ratio for an increase of 100 orgasms per year was 0.64 (0.44 to 0.95)." That is, a difference between any two subjects appeared when one subject ejaculated at around two or more more times per week than the other. Assuming a broad range average of between 3 to 5 ejaculations per week for healthy males, this would mean 5 to 7 ejaculations per week. This is consistent with a 2003 Australia article on the benefits against prostate cancer.
Masturbation is also seen as a sexual technique that protects individuals from the risk of contracting sexually transmitted diseases. Support for such a view, and for making it part of the American sex education curriculum, led to the dismissal of US Surgeon General Joycelyn Elders during the Clinton administration.
Sexual climax, from masturbation or otherwise, leaves one in a relaxed and contented state. This is frequently followed closely by drowsiness and sleep – particularly when one masturbates in bed.
Some people actually consider masturbation as a cardiovascular workout. And while doctors have no proof of this actually being true, those suffering from cardiovascular disorders (particularly those recovering from myocardial infarction, or heart attacks) should resume physical activity (including sexual intercourse and masturbation) gradually and with the frequency and rigor which their physical status will allow. This limitation can serve as encouragement to follow through with physical therapy sessions to help improve endurance.
## Blood pressure
Both sex and masturbation lower blood pressure. A small study has shown that in one test group, recent full intercourse resulted in the lowest average blood pressure in stressful situations. Masturbation then led to lower blood pressure than did no recent sexual activity.
## Insertion
Objects inserted into the vagina or anus should be clean and of a kind that will not scratch or break. Care should be taken not to fully insert anything into the anus – any object used should have a flared or flanged base; otherwise retrieval can require medical intervention. Modern dildos and anal plugs are designed with this feature.
## Pregnancy
Masturbation involving both a man and a woman (see mutual masturbation) can result in pregnancy only if semen contacts the vulva. Masturbation with a partner can also theoretically result in transmission of sexually transmitted diseases by contact with bodily fluids.
## Problems for males
A man whose penis has suffered a blunt trauma or injury during intercourse may rarely sustain a penile fracture or suffer from Peyronie's disease. Phimosis is "a contracted foreskin (that) may cause trouble by hurting when an attempt is made to pull the foreskin back". In these cases, any energetic manipulation of the penis can be problematic.
Lawrence I. Sank thought that masturbating prone (lying face downward) could be responsible for sexual problems in some men including anorgasmia and erectile dysfunction. He based this theory on four men he examined and coined the term traumatic masturbatory syndrome to describe it. As of 2007, no follow-up research has been conducted and the idea is not familiar or widely-held within the medical community. Some authors, however, continue to give it credence.
## Compulsive masturbation
Sigmond Freud pointed out that every normal child usually experiments with many types of autoerotic sexual stimulation. Social repressions of sexuality reached their peak in the victorian era when popular authors wrote books threatening young children with mental deficiency or insanity if they indulged in any form of masturbation. Actually there is no scientific evidence of any causative relationship between autoeroticism and any form of mental disorder. Though mentally disturbed persons characteristically show poor judgment in expressing sexuality, this may be understood as a symptom rather than a cause.
Each child however, must learn the apropriate social and legal limitations relating to expressing sexuality.
Masturbating frequently presents no physical, mental or emotional risk in itself, but masturbation can be used to relieve boredom or stress. In either case, as with any "nervous habit", it is more helpful to consider the causes of the boredom or of the stress, rather than try to repress the masturbation.
There is some discussion between professionals and other interested parties as to the existence or validity of sexual addictions. Nevertheless, there are lists of warning signs such as when sexual activity affects a person's ability to function in everyday life, or is placing them at risk, for example, of pursuing illegal or destructive activities. Very frequent and compulsive masturbation may be seen as a sign of sexual addiction.
# Masturbation in history and society
## Antiquity
There are depictions of male masturbation in prehistoric rock paintings around the world. Most early people seem to have connected human sexuality with abundance in nature. A clay figurine of the 4th millennium BC from a temple site on the island of Malta, depicts a woman masturbating. However, in the ancient world depictions of male masturbation are far more common.
From the earliest records, ancient Sumer had a relaxed attitude toward sex, and masturbation was a popular technique for enhancing potency, either alone or with a partner.
Male masturbation became an even more important image in ancient Egypt: when performed by a god it could be considered a creative or magical act: the god Atum was believed to have created the universe by masturbating to ejaculation, and the ebb and flow of the Nile was attributed to the frequency of his ejaculations. Egyptian pharoahs, in response to this, were at one time required to masturbate ceremonially into the Nile.
The ancient Greeks had a more relaxed attitude toward masturbation than the Egyptians did, regarding the act as a normal and healthy substitute for other forms of sexual pleasure. They considered it a safety valve against destructive sexual frustration. The Greeks also dealt with female masturbation in both their art and writings. One common term used for it was anaphlan, which roughly translates as "up-fire."
Diogenes, speaking in jest, credited the god Hermes with its invention: he allegedly took pity on his son Pan, who was pining for Echo but unable to seduce her, and taught him the trick of masturbation in order to relieve his suffering. Pan in his turn taught the habit to young shepherds.
## Religious views
Religions vary broadly in their views of masturbation, from completely impermissible to encouraged as a way to achieve greater spirituality (see, for example Tantric sexuality and Taoist sexual practices).
## Philosophical arguments
Immanuel Kant regarded masturbation as a violation of the moral law. In the Metaphysics of Morals (1797) he made the a posteriori argument that 'such an unnatural use of one's sexual attributes' strikes 'everyone upon his thinking of it' as 'a violation of one's duty to himself', and suggested that it was regarded as immoral even to give it its proper name (unlike the case of the similarly undutiful act of suicide). He went on, however, to acknowledge that 'it is not so easy to produce a rational demonstration of the inadmissibility of that unnatural use', but ultimately concluded that its immorality lay in the fact that 'a man gives up his personality … when he uses himself merely as a means for the gratification of an animal drive'.
Subsequent critics of masturbation tended to argue against it on more physiological grounds, however (see medical attitudes).
## Medical attitudes
The first use of the word "onanism" to consistently and specifically refer to masturbation appears to be Onania, an anonymous pamphlet first distributed in London in 1716. In it was a bombastic tirade, drawing on familiar themes of sin and vice, this time in particular against the "heinous sin" of "self-pollution". After dire warnings that those who so indulged would suffer impotence, gonorrhea, epilepsy and a wasting of the faculties (included were letters and testimonials supposedly from young men ill and dying from the effects of compulsive masturbation) the pamphlet then goes on to recommend as an effective remedy a "Strengthening Tincture" at 10 shillings a bottle and a "Prolific Powder" at 12 shillings a bag, available from a local shop.
One of the many horrified by the descriptions of malady in Onania was the notable Swiss physician Samuel-Auguste Tissot. In 1760, he published L'Onanisme, his own comprehensive medical treatise on the purported ill-effects of masturbation. Citing case studies of young male masturbators amongst his patients in Lausanne, Switzerland as basis for his reasoning, Tissot argued that semen was an "essential oil" and "stimulus" that, when lost from the body in great amounts, would cause "a perceptible reduction of strength, of memory and even of reason; blurred vision, all the nervous disorders, all types of gout and rheumatism, weakening of the organs of generation, blood in the urine, disturbance of the appetite, headaches and a great number of other disorders."
Though Tissot's ideas are now considered conjectural at best, his treatise was presented as a scholarly, scientific work in a time when experimental physiology was practically nonexistent. The authority with which the work was subsequently treated – Tissot's arguments were even acknowledged and echoed by luminaries such as Kant and Voltaire – arguably turned the perception of masturbation in Western medicine over the next two centuries into that of a debilitating illness.
This continued well into the Victorian Era, where such medical censure of masturbation was in line with the widespread social conservatism and opposition to open sexual behavior common at the time. There were recommendations to have boys' pants constructed so that the genitals could not be touched through the pockets, for schoolchildren to be seated at special desks to prevent their crossing their legs in class and for girls to be forbidden from riding horses and bicycles because the sensations these activities produce were considered too similar to masturbation. Boys and young men who nevertheless continued to indulge in the practice were branded as "weak-minded." Many "remedies" were devised, including eating a bland, meatless diet. This approach was promoted by Dr. John Harvey Kellogg (inventor of corn flakes) and Rev. Sylvester Graham (inventor of Graham crackers). The medical literature of the times describes procedures for electric shock treatment, infibulation, restraining devices like chastity belts and straitjackets, cauterization or – as a last resort – wholesale surgical excision of the genitals. Routine neonatal circumcision was widely adopted in the United States and the UK at least partly because of its believed preventive effect against masturbation (see also History of male circumcision). In later decades, the more drastic of these measures were increasingly replaced with psychological techniques, such as warnings that masturbation led to blindness, hairy hands or stunted growth. Some of these persist as myths even today.
At the same time, the supposed medical condition of hysteria—from the Greek hystera or uterus—was being treated by what would now be described as medically administered or medically prescribed masturbation for women. Techniques included use of the earliest vibrators and rubbing the genitals with placebo creams.
Medical attitudes toward masturbation began to change at the beginning of the 20th century when H. Havelock Ellis, in his seminal 1897 work Studies in the Psychology of Sex, questioned Tissot's premises, cheerfully named famous men of the era who masturbated and then set out to disprove (with the work of more recent physicians) each of the claimed diseases of which masturbation was purportedly the cause. "We reach the conclusion," he wrote, "that in the case of moderate masturbation in healthy, well-born individuals, no seriously pernicious results necessarily follow."
Robert Baden-Powell, the founder of The Scout Association, incorporated a passage in the 1914 edition of Scouting for Boys warning against the dangers of masturbation. This passage stated that the individual should run away from the temptation by performing physical activity which was supposed to tire the individual so that masturbation could not be performed. By 1930, however, Dr. F. W. W. Griffin, editor of The Scouter, had written in a book for Rover Scouts that the temptation to masturbate was "a quite natural stage of development" and, citing Ellis' work, held that "the effort to achieve complete abstinence was a very serious error."
The works of Sexologist Alfred Kinsey during the 1940s and 1950s insisted that masturbation was an instinctive behavior for both males and females, citing the results of Gallup Poll surveys indicating how common it was in the United States. Some critics of this theory held that his research was biased and that the Gallup Poll method was redundant for defining "natural behavior".
In 1994, when the Surgeon General of the United States, Dr. Joycelyn Elders, mentioned as an aside that it should be mentioned in school curricula that masturbation was safe and healthy, she was forced to resign, with opponents asserting that she was promoting the teaching of how to masturbate. Many believe this was the result of her long history of promoting controversial viewpoints and not due solely to her public mention of masturbation. Her case led to the coining of a new and humorous slang term for masturbation: "firing the surgeon general."
## Law
The legal status of masturbation throughout history has varied from virtually unlimited acceptance to complete illegality. In a 1640s law code for the Puritan colony of New Haven, Connecticut in the 17th century "blasphemers, homosexuals and masturbators" were eligible for the death penalty.
## Masturbate-a-thon
Masturbate-a-thons are public, charity events that are "intended to encourage people to explore safer sex, talk about masturbation and lift the taboos that still surround the subject."
May is considered "Masturbation Month" by an evolving, loosely connected group of masturbation activists, including Betty Dodson, Joani Blank, Susan Block, Kyla Zellers, Carol Queen, and Dr. Gary Francis Fanning Jr.
# Euphemisms
Because masturbation is often an uncomfortable topic among peers, a huge variety of euphemisms and dysphemisms have been invented to describe it. For a complete list of terms, see the entry for masturbate in Wikisaurus.
# Masturbation in other animal species
Masturbatory behavior has been documented in a very wide range of species. Individuals of some species have been known to create tools for masturbation purposes. | Masturbation
Masturbation refers to sexual stimulation, especially of one's own genitals and often to the point of orgasm, which is performed manually, by other types of bodily contact (except for sexual intercourse), by use of objects or tools, or by some combination of these methods.[1] Masturbation is the most common form of autoeroticism, and the two words are often used as synonyms, although masturbation with a partner (mutual masturbation) is also common. Animal masturbation has been observed in many species, both in the wild and in captivity.[2][3][4]
# Etymology
The word masturbation is believed to derive from either the Greek word mezea (μεζεα, "penes") or the Latin manus ("hand") and the Latin turbare ("to disturb").[5] A competing etymology based on the Latin manu stuprare ("to defile with the hand") is said by the Oxford English Dictionary to be an "old conjecture". The esoteric and little-used synonym manustupration is similarly derived from manus stuprare.
While "masturbation" is the medical term for this practice, many other terms and expressions are in common use. "Onanism" is a term with religious roots. In the vernacular, terms such as "pleasuring oneself", "wanking", and "jerking off" are common. See masturbate in Wikisaurus for many others.
# Masturbation techniques
Ways of masturbating common to members of both sexes include pressing or rubbing the genital area, either with the fingers or against an object such as a pillow; inserting fingers or an object into the anus (see anal masturbation); and stimulating the penis or vulva with electric vibrators, which may also be inserted into the vagina or anus. Members of both sexes may also enjoy touching, rubbing, or pinching the nipples or other erogenous zones while masturbating. Both sexes sometimes apply lubricating substances to intensify sensation.
Reading or viewing pornography, or sexual fantasy, are often common adjuncts to masturbation. Often people will call upon memories during masturbation. Masturbation activities are often ritualised. Various fetishes and paraphilias can also play a part in the masturbation ritual. Some potentially harmful or fatal activities include autoerotic asphyxiation and self-bondage.
Some people get sexual pleasure by inserting objects into the urethra (the tube through which urine and, in men, semen, flows).[6] If these objects are urethral sounds, the practice is known as "sounding".[7] Other objects such as ball point pens and thermometers are sometimes used, although this practice can lead to injury and/or infection.[8] Some people masturbate by using machines that simulate intercourse.
Men and women may masturbate until they are close to orgasm, stop for a while to reduce excitement, and then resume masturbating. They may repeat this cycle multiple times. This "stop and go" build up can achieve even stronger orgasms. Rarely, people quit stimulation just before orgasm to retain the heightened energy that normally comes down after orgasm[9] due to the release of prolactin hormone. Doing this could lead to temporary discomfort due to pelvic congestion.
Austrian psychoanalyst Wilhelm Reich in his 1922 essay Concerning Specific Forms of Masturbation tried to identify healthy and unhealthy forms of masturbation. He tried to relate the way people masturbated to their degree of inclination towards the opposite sex and to their psycho-sexual pathologies.
## Female
Female masturbation techniques include a woman stroking or rubbing her vulva, especially her clitoris, with her index and/or middle fingers. Sometimes one or more fingers may be inserted into her vagina to repeatedly stroke the frontal wall of her vagina where her g-spot is located.[10]
Masturbation aids such as a vibrator, dildo or Ben Wa balls can also be used to stimulate the vagina and clitoris. Many women caress their breasts or stimulate a nipple with the free hand, if these are receptive areas for sexual stimulation. Anal stimulation is also enjoyed by some. Lubrication is sometimes used during masturbation, especially when penetration is involved, but this is not universal and many women find their natural lubrication sufficient.
Common positions include lying on back or face down, sitting, squatting, kneeling or standing. In a bath or shower a female may direct tap water at her clitoris and vulva. Lying face down one may use the hands, one may straddle a pillow, the corner or edge of the bed, a partner's leg or some scrunched-up clothing and "hump" her vulva and clitoris against it. Standing up, a chair, the corner of an item of furniture or even a washing machine can be used to stimulate her clitoris through her labia and clothing.
In the 1920s, Havelock Ellis reported that turn-of-the-century seamstresses using treadle-operated sewing machines could achieve orgasm by sitting near the edge of their chairs.[11]
Women can sexually stimulate themselves by crossing their legs tightly and clenching the muscles in their legs, creating pressure on the genitals. This can potentially be done in public without observers noticing. Some masturbate using only pressure applied to the clitoris without direct contact, for example by pressing the palm or ball of the hand against underwear or other clothing.
Thoughts, fantasies and memories of previous instances of arousal and orgasm can produce sexual arousal. Some women even claim to be able to orgasm spontaneously by force of will alone, but that ability, if it exists at all, may not strictly qualify as masturbation as no physical stimulus is involved.[12][13]
Sex therapists will sometimes recommend that female patients take time to masturbate to orgasm, especially if they have not done so before.[14][15]
## Male
Male masturbation techniques are also influenced by a number of factors and personal preferences. Techniques may also differ between circumcised and uncircumcised males, as some techniques which may work for one can often be quite painful for the other.
The most common male masturbation technique is simply to hold the penis with a loose fist and then to move the hand up and down the shaft until orgasm and ejaculation take place. The speed of the hand motion will vary from male to male, although it is not uncommon for the speed to increase as ejaculation nears and for it to decrease during the ejaculation itself. When uncircumcised, stimulation of the penis in this way comes from the "pumping" of the foreskin. This gliding motion of the foreskin reduces friction. When circumcised, there is more direct contact between the hand and the glans, thus a personal lubricant is sometimes used to reduce friction. Sometimes, if too much pressure is applied, it may be rubbed sore for a time.
Circumcised or not, men may rub or massage the glans, the rim of the glans, and the frenular delta.
Another technique is to place just the index finger and thumb around the penis about halfway along the penis and move the skin up and down. A variation on this is to place the fingers and thumb on the penis as if playing a flute, and then shuttle them back and forth. Another common technique is to lie face down on a comfortable surface such as a mattress or pillow and rub the penis against it until orgasm is achieved. This technique may include the use of a simulacrum, or artificial vagina.
There are many other variations on male masturbation techniques. Some men place both hands directly on their penis during masturbation, while others use their free hand to fondle their testicles, nipples, or other parts of their body. Some may keep their hand stationary while pumping into it with pelvic thrusts in order to simulate the motions of sexual intercourse. Others may also use vibrators and other sexual devices more commonly associated with female masturbation. A few extremely flexible males can reach and stimulate their penis with their tongue or lips, and so perform autofellatio.
The prostate gland is one of the organs that contributes fluid to semen. As the prostate is touch-sensitive, some directly stimulate it using a well-lubricated finger or dildo inserted through the anus into the rectum. Stimulating the prostate from outside, via pressure on the perineum, can be pleasurable as well. Semen is sometimes ejaculated onto a tissue or some other item.
A somewhat controversial ejaculation control technique is to put pressure on the perineum, about halfway between the scrotum and the anus, just before ejaculating. This can, however, redirect semen into the bladder (referred to as retrograde ejaculation). If repeated on a regular basis, this technique could cause long term damage due to the pressure put on the nerves and blood vessels in the perineum. A dry orgasm is one that is reached while withholding ejaculation (or where retrograde ejaculation has taken place). Proponents of dry orgasm say that this is a learnable skill that can shorten the refractory period.
# Mutual masturbation
Mutual masturbation is a sexual act where two or more people stimulate themselves or one another sexually, usually with the hands.
This may be done in situations where the participants do not feel physically able, that it is socially inappropriate or they do not want full sexual intercourse, but still wish to enjoy a mutual sexual act. It is also part of a full repertoire of sexual intercourse, where it may be used as an interlude, foreplay or simply as an alternative to penetration. For some people, it is the primary sexual activity of choice above all others, perhaps because it enables the individuals to see each other face to face and leaves the hands free to caress, as in frottage.
Mutual masturbation is practiced by people of all sexual orientations. If used as an alternative to penile-vaginal penetration, the aim may be to preserve virginity or to prevent pregnancy. Some people choose it as it achieves sexual satisfaction without actual sex, possibly seeing it as an alternative to casual sex.
# Masturbation frequency, age and sex
Frequency of masturbation is determined by many factors, e.g., one's resistance to sexual tension, hormone levels influencing sexual arousal, sexual habits, peer influences, health and one's attitude to masturbation formed by culture.[16] Medical causes have also been associated with masturbation.[17][18][19]
Different studies have found that masturbation is frequent in humans. Alfred Kinsey's studies have shown that 92% of men and 62% of women have masturbated during lifespan.[13] Similar results have been found in British national probability survey. It was found that 95% of men and 71% of woman masturbated at some point in their lives. 73% of men and 37% of woman reported masturbating in the four weeks before their interview, while 53% of men and 18% of woman reported masturbating in previous seven days.[20]
"Forty-eight female college students were asked to complete a sexual attitudes questionnaire in which a frequency of masturbation scale was embedded. Twenty-four of the women (the experimental group) then individually viewed an explicit modeling film involving female masturbation. One month later, all subjects again completed the same questionnaire. Subjects in the experimental group also completed a questionnaire evaluating aspects of the film. Results indicated that the experimental group reported a significant increase in the average monthly frequency of masturbation, as compared to the control group. This same group, however, reported that the film had no effect on sexual attitudes or behavior."
A 2004 survey by Toronto magazine NOW was answered by an unspecified number of thousands.[21] The results show that an overwhelming majority of the males – 81% – began masturbating between the ages of 10 and 15. Among females, the same figure was a more modest majority of 55%. (Note that surveys on sexual practices are prone to self-selection bias.) It is not uncommon however to begin much earlier, and this is more frequent among females: 18% had begun by the time they turned 10, and 6% already by the time they turned 6. Being the main outlet of child sexuality, masturbation has been observed in very young children. In the book Human Sexuality: Diversity in Contemporary America, by Strong, Devault and Sayad, the authors point out, "A baby boy may laugh in his crib while playing with his erect penis (although he does not ejaculate). Baby girls sometimes move their bodies rhythmically, almost violently, appearing to experience orgasm."
A Canadian survey of Now magazine readers (cited above), has it that the frequency of masturbation declines after the age of 17. Many males masturbate daily, or even more frequently, well into their 20s and sometimes far beyond. This decline is more drastic among females, and more gradual among males. While females aged 13–17 masturbated almost once a day on average (and almost as often as their male peers), adult women only masturbated 8–9 times a month, compared to the 18–22 among men. Adolescent youths report being able to masturbate to ejaculation around six times per day, though some men in older middle age report being hard pressed to ejaculate even once per day. On the other hand healthy 21-28 year old males are able to masturbate at least 8-10 times per day if they are not stressed. The survey does not give a full demographic breakdown of respondents, however, and the sexual history of respondents to this poll, who are readers of an urban Toronto lifestyle magazine, may not extend to the general population.
It appears that females are less likely to masturbate while in a heterosexual relationship than men. Popular belief asserts that individuals of either sex who are not in sexually active relationships tend to masturbate more frequently than those who are; however, much of the time this is not true as masturbation alone or with a partner is often a feature of a relationship. Contrary to conventional wisdom, several studies actually reveal a positive correlation between the frequency of masturbation and the frequency of intercourse. One study reported a significantly higher rate of masturbation in gay men and women who were in a relationship.[22][20][23][24]
Among some cultures, such as the Hopi in Arizona, the Wogeno in Oceania, and the Dahomeans and Namu of Africa, masturbation is encouraged, including regular masturbation between males. In certain Melanesian communities this is expected between older and younger boys. One interesting twist is the Sambia tribe of New Guinea. This tribe has rituals and rites of passage surrounding manhood which involve frequent ejaculation through fellatio. Semen is valued and masturbation is seen as a waste of semen and is therefore frowned upon even though frequent ejaculation is encouraged. The capacity and need to ejaculate is nurtured for years from an early age through fellatio so that it can be consumed rather than wasted. Semen is ingested for strength and is considered in the same line as mothers' milk.[25]
Other cultures have rites of passage into manhood that culminate in the first ejaculation of a male, usually by the hands of a tribal elder. In some tribes such as the Agta, Philippines, stimulation of the genitals is encouraged from an early age.[26] Upon puberty, the young male is then paired off with a "wise elder" or "witch doctor" who uses masturbation to build his ability to ejaculate in preparation for a ceremony. The ceremony culminates in a public ejaculation before a celebration. The ejaculate is saved in a wad of animal skin and worn later to help conceive children. In this and other tribes, the measure of manhood is actually associated more with the amount of ejaculate and his need than penis size. Frequent ejaculation through masturbation from an early age fosters frequent ejaculation well into adulthood.[27]
Masturbation is becoming accepted as a healthy practice and safe method for sharing pleasure without some of the dangers that can accompany intercourse. It is socially accepted and even celebrated in certain circles. Group masturbation events can be easily found online. Masturbation marathons are yearly events and are occurring across the globe. These events provide a supportive environment where masturbation can be performed openly among young and old without embarrassment. Participants talk openly with onlookers while masturbating to share techniques and describe their pleasure.[28][29]
# Evolutionary purpose
Masturbation may increase fertility during intercourse.
Female masturbation alters conditions in the vagina, cervix and uterus, in ways that can alter the chances of conception from intercourse, depending on the timing of the masturbation. A woman's orgasm between one minute before and up to 45 minutes after insemination favors the chances of that sperm reaching her egg. If, for example, she has had intercourse with more than one male, such an orgasm can increase the likelihood of a pregnancy by one of them.[30][31] Female masturbation can also provide protection against cervical infections by increasing the acidity of the cervical mucus and by moving debris out of the cervix.[31]
In males, masturbation flushes out old sperm with low motility from the male's genital tract. The next ejaculate then contains more fresh sperm, which have higher chances of achieving conception during intercourse. If more than one male has intercourse with a female, the sperm with the highest motility will compete more effectively.[32][33][34]
# Health and psychological effects
## Benefits
The physical benefits of masturbation and having an orgasm or ejaculating creates heightened arousal while epinephrine courses through the body, producing the flushed face, shallow breath and post-climactic euphoria.[35] It is held in many mental health circles that masturbation can relieve depression, stress and lead to a higher sense of self-worth (Hurlbert & Whittaker, 1991). Masturbation can also be particularly useful in relationships where one partner wants more sex than the other – in which case masturbation provides a balancing effect and thus a more harmonious relationship.[36]
Mutual masturbation, the act by which two or more partners stimulate themselves in the presence of each other, allows a couple to reveal the "map to [their] pleasure centers". Witnessing a partner masturbate is an educational activity to find out the method a partner pleases him- or herself, allowing each partner to learn exactly how the other enjoys being touched.[37]
In 2003, an Australian research team led by Graham Giles of The Cancer Council Australia[38] concluded that frequent masturbation by males appears to help prevent the development of prostate cancer. The study also indicated that this would be more helpful than ejaculation through sexual intercourse because intercourse can transmit diseases that may increase the risk of cancer instead. Also, frequent ejaculation is more easily obtained and sustained over time with the aid of masturbation.
A study published in 1997 found an inverse association between death from coronary heart disease and frequency of orgasm even given the risk that myocardial ischaemia and myocardial infarction can be triggered by sexual activity. Excerpt, "The association between frequency or orgasm and all cause mortality was also examined using the midpoint of each response category recoded as number of orgasms per year. The age adjusted odds ratio for an increase of 100 orgasms per year was 0.64 (0.44 to 0.95)." That is, a difference between any two subjects appeared when one subject ejaculated at around two or more more times per week than the other. Assuming a broad range average of between 3 to 5 ejaculations per week for healthy males, this would mean 5 to 7 ejaculations per week. This is consistent with a 2003 Australia article on the benefits against prostate cancer.[39]
Masturbation is also seen as a sexual technique that protects individuals from the risk of contracting sexually transmitted diseases. Support for such a view, and for making it part of the American sex education curriculum, led to the dismissal of US Surgeon General Joycelyn Elders during the Clinton administration.
Sexual climax, from masturbation or otherwise, leaves one in a relaxed and contented state. This is frequently followed closely by drowsiness and sleep – particularly when one masturbates in bed.
Some people actually consider masturbation as a cardiovascular workout.[40] And while doctors have no proof of this actually being true, those suffering from cardiovascular disorders (particularly those recovering from myocardial infarction, or heart attacks) should resume physical activity (including sexual intercourse and masturbation) gradually and with the frequency and rigor which their physical status will allow. This limitation can serve as encouragement to follow through with physical therapy sessions to help improve endurance.
## Blood pressure
Both sex and masturbation lower blood pressure. A small study has shown that in one test group, recent full intercourse resulted in the lowest average blood pressure in stressful situations. Masturbation then led to lower blood pressure than did no recent sexual activity.[41]
## Insertion
Objects inserted into the vagina or anus should be clean and of a kind that will not scratch or break. Care should be taken not to fully insert anything into the anus – any object used should have a flared or flanged base; otherwise retrieval can require medical intervention. Modern dildos and anal plugs are designed with this feature.
## Pregnancy
Masturbation involving both a man and a woman (see mutual masturbation) can result in pregnancy only if semen contacts the vulva. Masturbation with a partner can also theoretically result in transmission of sexually transmitted diseases by contact with bodily fluids.
## Problems for males
A man whose penis has suffered a blunt trauma or injury during intercourse may rarely sustain a penile fracture[42] or suffer from Peyronie's disease.[43] Phimosis is "a contracted foreskin (that) may cause trouble by hurting when an attempt is made to pull the foreskin back".[44] In these cases, any energetic manipulation of the penis can be problematic.
Lawrence I. Sank[45] thought that masturbating prone (lying face downward) could be responsible for sexual problems in some men including anorgasmia and erectile dysfunction. He based this theory on four men he examined and coined the term traumatic masturbatory syndrome to describe it. As of 2007, no follow-up research has been conducted and the idea is not familiar or widely-held within the medical community. Some authors, however, continue to give it credence.[46][47]
## Compulsive masturbation
Sigmond Freud pointed out that every normal child usually experiments with many types of autoerotic sexual stimulation. Social repressions of sexuality reached their peak in the victorian era when popular authors wrote books threatening young children with mental deficiency or insanity if they indulged in any form of masturbation. Actually there is no scientific evidence of any causative relationship between autoeroticism and any form of mental disorder. Though mentally disturbed persons characteristically show poor judgment in expressing sexuality, this may be understood as a symptom rather than a cause.
Each child however, must learn the apropriate social and legal limitations relating to expressing sexuality.
Masturbating frequently presents no physical, mental or emotional risk in itself,[48] but masturbation can be used to relieve boredom or stress. In either case, as with any "nervous habit", it is more helpful to consider the causes of the boredom or of the stress, rather than try to repress the masturbation.[49]
There is some discussion between professionals and other interested parties as to the existence or validity of sexual addictions. Nevertheless, there are lists of warning signs such as when sexual activity affects a person's ability to function in everyday life, or is placing them at risk, for example, of pursuing illegal or destructive activities. Very frequent and compulsive masturbation may be seen as a sign of sexual addiction.[50]
# Masturbation in history and society
## Antiquity
There are depictions of male masturbation in prehistoric rock paintings around the world. Most early people seem to have connected human sexuality with abundance in nature. A clay figurine of the 4th millennium BC from a temple site on the island of Malta, depicts a woman masturbating. However, in the ancient world depictions of male masturbation are far more common.
From the earliest records, ancient Sumer had a relaxed attitude toward sex, and masturbation was a popular technique for enhancing potency, either alone or with a partner.[51][52]
Male masturbation became an even more important image in ancient Egypt: when performed by a god it could be considered a creative or magical act: the god Atum was believed to have created the universe by masturbating to ejaculation, and the ebb and flow of the Nile was attributed to the frequency of his ejaculations. Egyptian pharoahs, in response to this, were at one time required to masturbate ceremonially into the Nile.[53]
The ancient Greeks had a more relaxed attitude toward masturbation than the Egyptians did, regarding the act as a normal and healthy substitute for other forms of sexual pleasure. They considered it a safety valve against destructive sexual frustration. The Greeks also dealt with female masturbation in both their art and writings. One common term used for it was anaphlan, which roughly translates as "up-fire."
Diogenes, speaking in jest, credited the god Hermes with its invention: he allegedly took pity on his son Pan, who was pining for Echo but unable to seduce her, and taught him the trick of masturbation in order to relieve his suffering. Pan in his turn taught the habit to young shepherds.[54]
## Religious views
Religions vary broadly in their views of masturbation, from completely impermissible[55] to encouraged as a way to achieve greater spirituality (see, for example Tantric sexuality and Taoist sexual practices).
## Philosophical arguments
Immanuel Kant regarded masturbation as a violation of the moral law. In the Metaphysics of Morals (1797) he made the a posteriori argument that 'such an unnatural use of one's sexual attributes' strikes 'everyone upon his thinking of it' as 'a violation of one's duty to himself', and suggested that it was regarded as immoral even to give it its proper name (unlike the case of the similarly undutiful act of suicide). He went on, however, to acknowledge that 'it is not so easy to produce a rational demonstration of the inadmissibility of that unnatural use', but ultimately concluded that its immorality lay in the fact that 'a man gives up his personality … when he uses himself merely as a means for the gratification of an animal drive'.
Subsequent critics of masturbation tended to argue against it on more physiological grounds, however (see medical attitudes).
## Medical attitudes
The first use of the word "onanism" to consistently and specifically refer to masturbation appears to be Onania, an anonymous pamphlet first distributed in London in 1716. In it was a bombastic tirade, drawing on familiar themes of sin and vice, this time in particular against the "heinous sin" of "self-pollution". After dire warnings that those who so indulged would suffer impotence, gonorrhea, epilepsy and a wasting of the faculties (included were letters and testimonials supposedly from young men ill and dying from the effects of compulsive masturbation) the pamphlet then goes on to recommend as an effective remedy a "Strengthening Tincture" at 10 shillings a bottle and a "Prolific Powder" at 12 shillings a bag, available from a local shop.
One of the many horrified by the descriptions of malady in Onania was the notable Swiss physician Samuel-Auguste Tissot. In 1760, he published L'Onanisme, his own comprehensive medical treatise on the purported ill-effects of masturbation. Citing case studies of young male masturbators amongst his patients in Lausanne, Switzerland as basis for his reasoning, Tissot argued that semen was an "essential oil" and "stimulus" that, when lost from the body in great amounts, would cause "a perceptible reduction of strength, of memory and even of reason; blurred vision, all the nervous disorders, all types of gout and rheumatism, weakening of the organs of generation, blood in the urine, disturbance of the appetite, headaches and a great number of other disorders."
Though Tissot's ideas are now considered conjectural at best, his treatise was presented as a scholarly, scientific work in a time when experimental physiology was practically nonexistent. The authority with which the work was subsequently treated – Tissot's arguments were even acknowledged and echoed by luminaries such as Kant and Voltaire – arguably turned the perception of masturbation in Western medicine over the next two centuries into that of a debilitating illness.
This continued well into the Victorian Era, where such medical censure of masturbation was in line with the widespread social conservatism and opposition to open sexual behavior common at the time.[56][57] There were recommendations to have boys' pants constructed so that the genitals could not be touched through the pockets, for schoolchildren to be seated at special desks to prevent their crossing their legs in class and for girls to be forbidden from riding horses and bicycles because the sensations these activities produce were considered too similar to masturbation. Boys and young men who nevertheless continued to indulge in the practice were branded as "weak-minded."[58] Many "remedies" were devised, including eating a bland, meatless diet. This approach was promoted by Dr. John Harvey Kellogg (inventor of corn flakes) and Rev. Sylvester Graham (inventor of Graham crackers). The medical literature of the times describes procedures for electric shock treatment, infibulation, restraining devices like chastity belts and straitjackets, cauterization or – as a last resort – wholesale surgical excision of the genitals. Routine neonatal circumcision was widely adopted in the United States and the UK at least partly because of its believed preventive effect against masturbation (see also History of male circumcision). In later decades, the more drastic of these measures were increasingly replaced with psychological techniques, such as warnings that masturbation led to blindness, hairy hands or stunted growth. Some of these persist as myths even today.
At the same time, the supposed medical condition of hysteria—from the Greek hystera or uterus—was being treated by what would now be described as medically administered or medically prescribed masturbation for women. Techniques included use of the earliest vibrators and rubbing the genitals with placebo creams.[59]
Medical attitudes toward masturbation began to change at the beginning of the 20th century when H. Havelock Ellis, in his seminal 1897 work Studies in the Psychology of Sex, questioned Tissot's premises, cheerfully named famous men of the era who masturbated and then set out to disprove (with the work of more recent physicians) each of the claimed diseases of which masturbation was purportedly the cause. "We reach the conclusion," he wrote, "that in the case of moderate masturbation in healthy, well-born individuals, no seriously pernicious results necessarily follow."
Robert Baden-Powell, the founder of The Scout Association, incorporated a passage in the 1914 edition of Scouting for Boys warning against the dangers of masturbation. This passage stated that the individual should run away from the temptation by performing physical activity which was supposed to tire the individual so that masturbation could not be performed. By 1930, however, Dr. F. W. W. Griffin, editor of The Scouter, had written in a book for Rover Scouts that the temptation to masturbate was "a quite natural stage of development" and, citing Ellis' work, held that "the effort to achieve complete abstinence was a very serious error."
The works of Sexologist Alfred Kinsey during the 1940s and 1950s insisted that masturbation was an instinctive behavior for both males and females, citing the results of Gallup Poll surveys indicating how common it was in the United States. Some critics of this theory held that his research was biased and that the Gallup Poll method was redundant for defining "natural behavior".
In 1994, when the Surgeon General of the United States, Dr. Joycelyn Elders, mentioned as an aside that it should be mentioned in school curricula that masturbation was safe and healthy, she was forced to resign,[60] with opponents asserting that she was promoting the teaching of how to masturbate. Many believe this was the result of her long history of promoting controversial viewpoints and not due solely to her public mention of masturbation. Her case led to the coining of a new and humorous slang term for masturbation: "firing the surgeon general."[61]
## Law
The legal status of masturbation throughout history has varied from virtually unlimited acceptance to complete illegality. In a 1640s law code for the Puritan colony of New Haven, Connecticut in the 17th century "blasphemers, homosexuals and masturbators" were eligible for the death penalty.[62]
## Masturbate-a-thon
Masturbate-a-thons are public, charity events that are "intended to encourage people to explore safer sex, talk about masturbation and lift the taboos that still surround the subject."[63]
May is considered "Masturbation Month" by an evolving, loosely connected group of masturbation activists, including Betty Dodson, Joani Blank, Susan Block, Kyla Zellers, Carol Queen, and Dr. Gary Francis Fanning Jr.
# Euphemisms
Because masturbation is often an uncomfortable topic among peers, a huge variety of euphemisms and dysphemisms have been invented to describe it. For a complete list of terms, see the entry for masturbate in Wikisaurus.
# Masturbation in other animal species
Masturbatory behavior has been documented in a very wide range of species. Individuals of some species have been known to create tools for masturbation purposes.[3] | https://www.wikidoc.org/index.php/Masturbate | |
201ded199e8ee6171f964064f44311f3313fa387 | wikidoc | Matching law | Matching law
In operant conditioning, the matching law is a quantitative relationship that holds between the relative rates of response and the relative rates of reinforcement in concurrent schedules of reinforcement. It applies reliably when non-human subjects are exposed to concurrent variable interval schedules; its applicability in other situations is less clear, depending on the assumptions made and the details of the experimental situation.
Stated simply, the matching law suggests that an animal's response rate to a scenario will be proportionate to the amount/duration of positive reinforcement delivered.
The matching law was first formulated by R. J. Herrnstein (1961) following an experiment with pigeons on concurrent variable interval schedules. Pigeons were presented with two buttons in a Skinner box, each which led to varying rates of food reward. The pigeons tended to peck the button that yielded the greater food reward more often than the other button; however, they did so at a rate that was similar to the rate of reward.
If R1 and R2 are the rate of responses on two schedules that yield obtained (as distinct from programmed) rates of reinforcement Rf1 and Rf2, the strict matching law holds that the relative response rate R1/(R1+R2) matches, that is, equals, the relative reinforcement rate Rf1/(Rf1+Rf2). That is,
\frac{R_1}{R_1+R_2}=\frac{Rf_1}{Rf_1+Rf_2}
This relationship can also be stated in terms of response and reinforcement ratios:
\frac{R_1}{R_2}=\frac{Rf_1}{Rf_2}
Subsequent research has shown that data normally depart from strict matching, but are fitted to a very good approximation by a power function generalization of the strict matching (Baum, 1974),
\frac{R_1}{R_2}=b \left(\frac{Rf_1}{Rf_2}\right)^s
This is more conveniently expressed in logarithmic form
log\left(\frac{R_1}{R_2}\right)=b+s \cdot log\left(\frac{Rf_1}{Rf_2}\right)
The constants b and s are referred to as bias and sensitivity respectively. This generalized matching law accounts for high proportions of the variance in most experiments on concurrent variable interval schedules in non-humans. Values of b depend on details of the experiment set up, but values of s are consistently found to be around 0.8, whereas the value required for strict matching would be 1.0 (Baum, 1974; Davison & McCarthy, 1988).
The matching law is theoretically important for two reasons. First, it offers a simple quantification of behaviour which is capable of extension to a number of other situations. Secondly, it appears to offer a lawful, predictive account of choice; as Herrnstein (1970) expressed it, under an operant analysis, choice is nothing but behavior set into the context of other behavior. It thus challenges any idea of free will, in exactly the way B. F. Skinner had argued that the experimental analysis of behavior should, in his book Beyond freedom and dignity. However this challenge is only serious if the scope of the matching law can be extended from pigeons to humans. When human participants perform under concurrent schedules of reinforcement, matching has been observed in some experiment (e.g. Bradshaw et al, 1976), but wide deviations from matching have been found in others (e.g. Horne & Lowe, 1993). The matching law has generated a great deal of research, much of it presented to the Society for Quantitative Analysis of Behavior. | Matching law
In operant conditioning, the matching law is a quantitative relationship that holds between the relative rates of response and the relative rates of reinforcement in concurrent schedules of reinforcement. It applies reliably when non-human subjects are exposed to concurrent variable interval schedules; its applicability in other situations is less clear, depending on the assumptions made and the details of the experimental situation.
Stated simply, the matching law suggests that an animal's response rate to a scenario will be proportionate to the amount/duration of positive reinforcement delivered.
The matching law was first formulated by R. J. Herrnstein (1961) following an experiment with pigeons on concurrent variable interval schedules. Pigeons were presented with two buttons in a Skinner box, each which led to varying rates of food reward. The pigeons tended to peck the button that yielded the greater food reward more often than the other button; however, they did so at a rate that was similar to the rate of reward.
If R1 and R2 are the rate of responses on two schedules that yield obtained (as distinct from programmed) rates of reinforcement Rf1 and Rf2, the strict matching law holds that the relative response rate R1/(R1+R2) matches, that is, equals, the relative reinforcement rate Rf1/(Rf1+Rf2). That is,
<math>\frac{R_1}{R_1+R_2}=\frac{Rf_1}{Rf_1+Rf_2}</math>
This relationship can also be stated in terms of response and reinforcement ratios:
<math>\frac{R_1}{R_2}=\frac{Rf_1}{Rf_2}</math>
Subsequent research has shown that data normally depart from strict matching, but are fitted to a very good approximation by a power function generalization of the strict matching (Baum, 1974),
<math>\frac{R_1}{R_2}=b \left(\frac{Rf_1}{Rf_2}\right)^s</math>
This is more conveniently expressed in logarithmic form
<math>log\left(\frac{R_1}{R_2}\right)=b+s \cdot log\left(\frac{Rf_1}{Rf_2}\right)</math>
The constants b and s are referred to as bias and sensitivity respectively. This generalized matching law accounts for high proportions of the variance in most experiments on concurrent variable interval schedules in non-humans. Values of b depend on details of the experiment set up, but values of s are consistently found to be around 0.8, whereas the value required for strict matching would be 1.0 (Baum, 1974; Davison & McCarthy, 1988).
The matching law is theoretically important for two reasons. First, it offers a simple quantification of behaviour which is capable of extension to a number of other situations. Secondly, it appears to offer a lawful, predictive account of choice; as Herrnstein (1970) expressed it, under an operant analysis, choice is nothing but behavior set into the context of other behavior. It thus challenges any idea of free will, in exactly the way B. F. Skinner had argued that the experimental analysis of behavior should, in his book Beyond freedom and dignity. However this challenge is only serious if the scope of the matching law can be extended from pigeons to humans. When human participants perform under concurrent schedules of reinforcement, matching has been observed in some experiment (e.g. Bradshaw et al, 1976), but wide deviations from matching have been found in others (e.g. Horne & Lowe, 1993). The matching law has generated a great deal of research, much of it presented to the Society for Quantitative Analysis of Behavior. | https://www.wikidoc.org/index.php/Matching_law | |
73df2464870ac4e947cd7c2996793ba6babed0be | wikidoc | Trandolapril | Trandolapril
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
## Hypertension
- Dosing Information（without diuretics)
- Recommended initial dosage(for non-black patients): 1 mg PO qd
- Recommended initial dosage(for black patients): 2 mg PO qd
- Generally, dosage adjustments should be made at intervals of at least 1 week
- Required dosage for most patients: 4-8 mg PO qd (4 mg PO bid if the inadequately treated)
- Dosing information (with diuretics)
- The diuretic should, if possible, be discontinued two to three days prior to beginning therapy with Mavik in case the occurrence of hypotension.
- If the blood pressure is not controlled with Mavik alone, diuretic therapy should be resumed.
- If the diuretic cannot be discontinued, an initial dose of 0.5 mg Mavik should be used with careful medical supervision for several hours until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response.
- Special notice: Concomitant administration of Mavik with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium.
## Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction
- Dosing information
- Recommended starting dosage: 1 mg PO qd
- Followed-by: 4 mg PO qd (If a 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.)
## Dosage Adjustment in Renal Impairment or Hepatic Cirrhosis
- Dosing information
- Initial dosage: 0.5 mg/day and have their dosage titrated to the optimal response.
## Acute ST segment elevation myocardial infarction
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA)
- Class of Recommendation: Class IIa
- Strength of Evidence: Level A
- Dosing Information/Recommendation
- Test dosageL: 0.5 mg/kg ; titrate up to 4 mg/day as tolerated.
## Prophylaxis treatment of Cardiovascular event risk
- Dosing information
- 4 mg/day
- Dosing information
- 2-4 mg/day
- 1 mg/day
- 2 mg/day
- Dosing information
- 1 mg PO qd-3 mg PO bid
- Do not co-administer aliskiren with Mavik in patients with diabetes
- Presumably because angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including Mavik, may be subject to a variety of adverse reactions, some of them serious.
## Anaphylactoid Reactions During Desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.
## Anaphylactoid Reactions During Membrane Exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
## Head and Neck Angioedema
- In controlled trials ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients.
- Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including Mavik. Symptoms suggestive of angioedema or facial edema occurred in 0.13% of Mavik-treated patients. Two of the four cases were life-threatening and resolved without treatment or with medication (corticosteroids). Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with Mavik should be discontinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, emergency therapy, including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3 to 0.5 mL) should be promptly administered.
## Intestinal Angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
## Hypotension
- Mavik can cause symptomatic hypotension. Like other ACE inhibitors, Mavik has only rarely been associated with symptomatic hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been salt- or volume-depleted as a result of prolonged treatment with diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating treatment with Mavik. In controlled and uncontrolled studies, hypotension was reported as an adverse event in 0.6% of patients and led to discontinuations in 0.1% of patients.
- In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and rarely, with acute renal failure and death. In such patients, Mavik therapy should be started at the recommended dose under close medical supervision. These patients should be followed closely during the first 2 weeks of treatment and, thereafter, whenever the dosage of Mavik or diuretic is increased. Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease.
- If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal saline may be administered intravenously. A transient hypotensive response is not a contraindication to further doses; however, lower doses of Mavik or reduced concomitant diuretic therapy should be considered.
## Neutropenia/Agranulocytosis
- Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of trandolapril are insufficient to show that trandolapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.
## Hepatic Failure
- ACE inhibitors rarely have been associated with a syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice should discontinue the ACE inhibitor and receive appropriate medical follow-up.
## Fetal Toxicity
## Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Mavik as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Mavik, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Mavik for hypotension, oliguria, and hyperkalemia.
- Doses of 0.8 mg/kg/day (9.4 mg/m2/day) in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg woman.
## Precautions
## General
## Impaired Renal Function
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Mavik (trandolapril), may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
- Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when ACE inhibitors have been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or the ACE inhibitor may be required. Evaluation of hypertensive patients should always include assessment of renal function.
## Hyperkalemia and Potassium-sparing Diuretics
- In clinical trials, hyperkalemia (serum potassium > 6.00 mEq/L) occurred in approximately 0.4% of hypertensive patients receiving Mavik. In most cases, elevated serum potassium levels were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Mavik.
## Cough
- Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of a relationship to dose.
## Surgery/Anesthesia
- In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Mavik will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
- Headache and fatigue were all seen in more than 1% of Mavik-treated patients but were more frequently seen on placebo. Adverse events were not usually persistent or difficult to manage.
## Left Ventricular Dysfunction Post Myocardial Infarction
- Adverse reactions related to Mavik occurring at a rate greater than that observed in placebo-treated patients with left ventricular dysfunction, are shown below. The incidences represent the experiences from the TRACE study. The follow-up time was between 24 and 50 months for this study.
- Clinical adverse experiences possibly or probably related or of uncertain relationship to therapy occurring in 0.3% to 1.0% (except as noted) of the patients treated with Mavik (with or without concomitant calcium ion antagonist or diuretic) in controlled or uncontrolled trials (N=1134) and less frequent, clinically significant events seen in clinical trials or post-marketing experience include (listed by body system):
## General Body Function
- Chest pain.
## Cardiovascular
- AV first degree block, bradycardia, edema, flushing, and palpitations.
## Central Nervous System
- Drowsiness, insomnia, paresthesia, vertigo.
## Dermatologic
- Pruritus, rash, pemphigus.
## Eye, Ear, Nose, Throat
- Epistaxis, throat inflammation, upper respiratory tract infection.
## Emotional, Mental, Sexual States
- Anxiety, impotence, decreased libido.
## Gastrointestinal
- Abdominal distention, abdominal pain/cramps, constipation, dyspepsia, diarrhea, vomiting, nausea.
## Hemopoietic
- Decreased leukocytes, decreased neutrophils.
## Metabolism and Endocrine
- Increased liver enzymes including SGPT (ALT).
## Musculoskeletal System
- Extremity pain, muscle cramps, gout.
## Pulmonary
- Dyspnea.
## Postmarketing
- The following adverse reactions were identified during post approval use of Mavik. 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.
## General Body Function
- Malaise, fever.
## Cardiovascular
- Myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, ventricular tachycardia, tachycardia, transient ischemic attack, arrhythmia.
## Central Nervous System
- Cerebral hemorrhage.
## Dermatologic
- Alopecia, sweating, Stevens-Johnson syndrome and toxic epidermal necrolysis.
## Emotional, Mental, Sexual States
- Hallucination, depression.
## Gastrointestinal
- Dry mouth, pancreatitis, jaundice and hepatitis.
## Hemopoietic
- Agranulocytosis, pancytopenia.
## Metabolism and Endocrine
- Increased SGOT (AST).
## Pulmonary
- Bronchitis.
## Renal and Urinary
- Renal failure.
## Clinical Laboratory Test Findings
## Hematology
Thrombocytopenia.
## Serum Electrolytes
- Hyponatremia.
## Creatinine and Blood Urea Nitrogen
- Increases in creatinine levels occurred in 1.1% of patients receiving Mavik alone and 7.3% of patients treated with Mavik, a calcium ion antagonist and a diuretic. Increases in blood urea nitrogen levels occurred in 0.6% of patients receiving Mavik alone and 1.4% of patients receiving Mavik, a calcium ion antagonist, and a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis.
## Liver Function Tests
- Occasional elevation of transaminases at the rate of 3X upper normals occurred in 0.8% of patients and persistent increase in bilirubin occurred in 0.2% of patients. Discontinuation for elevated liver enzymes occurred in 0.2% of patients.
## Other
- Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.
- Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Mavik and other agents that affect the RAS.
- Do not co-administer aliskiren with Mavik in patients with diabetes. Avoid use of aliskiren with Mavik in patients with renal impairment (GFR <60 ml/min).
## Concomitant Diuretic Therapy
- As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may experience an excessive reduction of blood pressure after initiation of therapy with Mavik. The possibility of exacerbation of hypotensive effects with Mavik may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Mavik. If it is not possible to discontinue the diuretic, the starting dose of trandolapril should be reduced.
## Agents Increasing Serum Potassium
- Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium.
## Antidiabetic Agents
- Concomitant use of ACE inhibitors and antidiabetic medicines (insulin or oral hypoglycemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycemia.
## Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
## Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving trandolapril and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs.
## Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Mavik.
## Other
- No clinically significant pharmacokinetic interaction has been found between trandolaprilat and food, cimetidine, digoxin, or furosemide.
- The anticoagulant effect of warfarin was not significantly changed by trandolapril.
- The hypotensive effect of certain inhalation anesthetics may be enhanced by ACE inhibitors including trandolapril
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Mavik, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Mavik for hypotension, oliguria, and hyperkalemia.
- Doses of 0.8 mg/kg/day (9.4 mg/m2/day) in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg woman.
- Trandolapril pharmacokinetics have been investigated in the elderly (> 65 years) and in both genders. The plasma concentration of trandolapril is increased in elderly hypertensive patients, but the plasma concentration of trandolaprilat and inhibition of ACE activity are similar in elderly and young hypertensive patients. The pharmacokinetics of trandolapril and trandolaprilat and inhibition of ACE activity are similar in male and female elderly hypertensive patients.
- The recommended initial dosage of Mavik for patients not receiving a diuretic is 1 mg once daily in non-black patients and 2 mg in black patients. Dosage should be adjusted according to the blood pressure response. Generally, dosage adjustments should be made at intervals of at least 1 week. Most patients have required dosages of 2 to 4 mg once daily. There is little clinical experience with doses above 8 mg.
- Patients inadequately treated with once-daily dosing at 4 mg may be treated with twice-daily dosing. If blood pressure is not adequately controlled with Mavik monotherapy, a diuretic may be added.
- In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Mavik. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with Mavik. Then, if blood pressure is not controlled with Mavik alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 0.5 mg Mavik should be used with careful medical supervision for several hours until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response.
- Concomitant administration of Mavik with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium.
- The recommended starting dose is 1 mg, once daily. Following the initial dose, all patients should be titrated (as tolerated) toward a target dose of 4 mg, once daily. If a 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.
- For patients with a creatinine clearance < 30 mL/min. or with hepatic cirrhosis, the recommended starting dose, based on clinical and pharmacokinetic data, is 0.5 mg daily. Patients should subsequently have their dosage titrated (as described above) to the optimal response.
- Laboratory determinations of serum levels of trandolapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of trandolapril overdose. No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH of the urine) might accelerate elimination of trandolapril and its metabolites. Trandolaprilat is removed by hemodialysis. Angiotensin II could presumably serve as a specific antagonist antidote in the setting of trandolapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of trandolapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat trandolapril overdose by infusion of normal saline solution.
- ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of trandolapril remains to be elucidated.
- While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, trandolapril exerts antihypertensive actions even in patients with low-renin hypertension. Mavik was an effective antihypertensive in all races studied. Both black patients (usually a predominantly low-renin group) and non-black patients responded to 2 to 4 mg of Mavik.
- M.W. = 430.54
- Melting Point = 125°C
- Trandolapril is a white or almost white powder that is soluble (> 100 mg/mL) in chloroform, dichloromethane, and methanol. Mavik tablets contain 1 mg, 2 mg, or 4 mg of trandolapril for oral administration. Each tablet also contains corn starch, croscarmellose sodium, hypromellose, iron oxide, lactose monohydrate, povidone, sodium stearyl fumarate.
# Metabolism and Excretion
- After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces. The extent of the absorbed dose which is biliary excreted has not been determined. Plasma concentrations (Cmax and AUC of trandolapril and Cmax of trandolaprilat) are dose proportional over the 1-4 mg range, but the AUC of trandolaprilat is somewhat less than dose proportional. In addition to trandolaprilat, at least 7 other metabolites have been found, principally glucuronides or deesterification products.
- Serum protein binding of trandolapril is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration.
- The volume of distribution of trandolapril is about 18 liters. Total plasma clearances of trandolapril and trandolaprilat after approximately 2 mg IV doses are about 52 liters/hour and 7 liters/hour respectively. Renal clearance of trandolaprilat varies from 1-4 liters/hour, depending on dose.
- Long-term studies were conducted with oral trandolapril administered by gavage to mice (78 weeks) and rats (104 and 106 weeks). No evidence of carcinogenic potential was seen in mice dosed up to 25 mg/kg/day (85 mg/m2/day) or rats dosed up to 8 mg/kg/day (60 mg/m2/day). These doses are 313 and 32 times (mice), and 100 and 23 times (rats) the maximum recommended human daily dose (MRHDD) of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg individual. The genotoxic potential of trandolapril was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic or clastogenic potential in these in vitro and in vivo assays.
- Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m2/day) of trandolapril, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively.
- A single 2-mg dose of Mavik produces 70 to 85% inhibition of plasma ACE activity at 4 hours with about 10% decline at 24 hours and about half the effect manifest at 8 days. Maximum ACE inhibition is achieved with a plasma trandolaprilat concentration of 2 ng/mL. ACE inhibition is a function of trandolaprilat concentration, not trandolapril concentration. The effect of trandolapril on exogenous angiotensin I was not measured.
## Hypertension
- Four placebo-controlled dose response studies were conducted using once-daily oral dosing of Mavik in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once-daily dose was 1 mg in non-black patients and 2 mg in black patients. Further decreases in trough supine diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing interval, but trough/peak ratios are well above 50% for all effective doses. There was a slightly greater effect on the diastolic pressure, but no difference on systolic pressure with b.i.d. dosing. During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Following 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once-daily doses of 2 to 4 mg lowered supine or standing systolic/diastolic blood pressure 24 hours after dosing by an average 7-10/4-5 mmHg below placebo responses in non-black patients. Once-daily doses of 2 to 4 mg lowered blood pressure 4-6/3-4 mmHg in black patients. Trough to peak ratios for effective doses ranged from 0.5 to 0.9. There were no differences in response between men and women, but responses were somewhat greater in patients under 60 than in patients over 60 years old. Abrupt withdrawal of Mavik has not been associated with a rapid increase in blood pressure.
- Administration of Mavik to patients with mild to moderate hypertension results in a reduction of supine, sitting and standing blood pressure to about the same extent without compensatory tachycardia.
- Symptomatic hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. Use of Mavik in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone, and the additional effect of trandolapril is similar to the effect of monotherapy.
## Heart Failure Post Myocardial Infarction or Left Ventricular Dysfunction Post Myocardial Infarction
- The Trandolapril Cardiac Evaluation (TRACE) Trial was a Danish, 27-center, double-blind, placebo controlled, parallel-group study of the effect of trandolapril on all-cause mortality in stable patients with echocardiographic evidence of left ventricular dysfunction 3 to 7 days after a myocardial infarction. Subjects with residual ischemia or overt heart failure were included. Patients tolerant of a test dose of 1 mg trandolapril were randomized to placebo (n=873) or trandolapril (n=876) and followed for 24 months. Among patients randomized to trandolapril, who began treatment on 1 mg, 62% were successfully titrated to a target dose of 4 mg once daily over a period of weeks. The use of trandolapril was associated with a 16% reduction in the risk of all-cause mortality (p=0.042), largely cardiovascular mortality. Trandolapril was also associated with a 20% reduction in the risk of progression of heart failure (p=0.047), defined by a time-to-first-event analysis of death attributed to heart failure, hospitalization for heart failure, or requirement for open-label ACE inhibitor for the treatment of heart failure. There was no significant effect of treatment on other end-points: subsequent hospitalization, incidence of recurrent myocardial infarction, exercise tolerance, ventricular function, ventricular dimensions, or NYHA class.
- The population in TRACE was entirely Caucasian and had less usage than would be typical in a U.S. population of other post-infarction interventions: 42% thrombolysis, 16% beta-adrenergic blockade, and 6.7% PTCA or CABG during the entire period of follow-up. Blood pressure control, especially in the placebo group, was poor: 47 to 53% of patients randomized to placebo and 32 to 40% of patients randomized to trandolapril had blood pressures > 140/95 at 90-day follow-up visits.
- 1 mg tablet - Salmon colored, round shaped, scored, compressed tablets, with the “a” logo on one side and code identification letters FT on the other side. NDC 0074-2278-13 - bottles of 100 NDC 0074-2278-11 - unit dose packs of 100
- 2 mg tablet - Yellow colored, round shaped, compressed tablets, with the “a” logo on one side and code identification letters FX on the other side. NDC 0074-2279-13 - bottles of 100 NDC 0074-2279-11 - unit dose packs of 100
- 4 mg tablet - Rose colored, round shaped, compressed tablets, with the “a” logo on one side and code identification letters FZ on the other side. NDC 0074-2280-13 - bottles of 100 NDC 0074-2280-11 - unit dose packs of 100
- Dispense in well-closed container with safety closure.
：- Angioedema, including laryngeal edema, may occur at any time during treatment with ACE inhibitors, including Mavik. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician.
- Symptomatic Hypotension
- Patients should be cautioned that light-headedness can occur, especially during the first days of Mavik therapy, and should be reported to a physician. If actual syncope occurs, patients should be told to stop taking the drug until they have consulted with their physician.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting, resulting in reduced fluid volume, may precipitate an excessive fall in blood pressure with the same consequences of light-headedness and possible syncope.
Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor that has a long duration of action.
- Hyperkalemia
- Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician.
- Neutropenia
- Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.
- Pregnancy
- Female patients of childbearing age should be told about the consequences of exposure to Mavik during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with Mavik is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
- ↑ Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S (2006). "Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials". Lancet. 368 (9535): 581–8. doi:10.1016/S0140-6736(06)69201-5. PMID 16905022.CS1 maint: Multiple names: authors list (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}
- ↑ Bauduceau B, Genès N, Chamontin B, Vaur L, Renault M, Etienne S et al. (1998) Ambulatory blood pressure and urinary albumin excretion in diabetic (non-insulin-dependent and insulin-dependent) hypertensive patients: relationships at baseline and after treatment by the angiotensin converting enzyme inhibitor trandolapril. Am J Hypertens 11 (9):1065-73. PMID: 9752891
- ↑ Nakamura T, Ushiyama C, Suzuki S, Hara M, Shimada N, Ebihara I et al. (2000) Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol Dial Transplant 15 (9):1379-83. PMID: 10978394
- ↑ Malik RA, Williamson S, Abbott C, Carrington AL, Iqbal J, Schady W et al. (1998) Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet 352 (9145):1978-81. DOI:10.1016/S0140-6736(98)02478-7 PMID: 9872248
- ↑ Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T (2003) Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361 (9352):117-24. DOI:10.1016/S0140-6736(03)12229-5 PMID: 12531578 | Trandolapril
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
### Hypertension
- Dosing Information（without diuretics)
- Recommended initial dosage(for non-black patients): 1 mg PO qd
- Recommended initial dosage(for black patients): 2 mg PO qd
- Generally, dosage adjustments should be made at intervals of at least 1 week
- Required dosage for most patients: 4-8 mg PO qd (4 mg PO bid if the inadequately treated)
- Dosing information (with diuretics)
- The diuretic should, if possible, be discontinued two to three days prior to beginning therapy with Mavik in case the occurrence of hypotension.
- If the blood pressure is not controlled with Mavik alone, diuretic therapy should be resumed.
- If the diuretic cannot be discontinued, an initial dose of 0.5 mg Mavik should be used with careful medical supervision for several hours until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response.
- Special notice: Concomitant administration of Mavik with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium.
### Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction
- Dosing information
- Recommended starting dosage: 1 mg PO qd
- Followed-by: 4 mg PO qd (If a 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.)
### Dosage Adjustment in Renal Impairment or Hepatic Cirrhosis
- Dosing information
- Initial dosage: 0.5 mg/day and have their dosage titrated to the optimal response.
### Acute ST segment elevation myocardial infarction
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA)
- Class of Recommendation: Class IIa
- Strength of Evidence: Level A
- Dosing Information/Recommendation
- Test dosageL: 0.5 mg/kg ; titrate up to 4 mg/day as tolerated.
### Prophylaxis treatment of Cardiovascular event risk
- Dosing information
- 4 mg/day[1]
- Dosing information
- 2-4 mg/day[2]
- 1 mg/day[3]
- 2 mg/day[4]
- Dosing information
- 1 mg PO qd-3 mg PO bid [5]
- Do not co-administer aliskiren with Mavik in patients with diabetes
- Presumably because angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including Mavik, may be subject to a variety of adverse reactions, some of them serious.
### Anaphylactoid Reactions During Desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.
### Anaphylactoid Reactions During Membrane Exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
### Head and Neck Angioedema
- In controlled trials ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients.
- Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including Mavik. Symptoms suggestive of angioedema or facial edema occurred in 0.13% of Mavik-treated patients. Two of the four cases were life-threatening and resolved without treatment or with medication (corticosteroids). Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with Mavik should be discontinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, emergency therapy, including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3 to 0.5 mL) should be promptly administered.
### Intestinal Angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
### Hypotension
- Mavik can cause symptomatic hypotension. Like other ACE inhibitors, Mavik has only rarely been associated with symptomatic hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been salt- or volume-depleted as a result of prolonged treatment with diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating treatment with Mavik. In controlled and uncontrolled studies, hypotension was reported as an adverse event in 0.6% of patients and led to discontinuations in 0.1% of patients.
- In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and rarely, with acute renal failure and death. In such patients, Mavik therapy should be started at the recommended dose under close medical supervision. These patients should be followed closely during the first 2 weeks of treatment and, thereafter, whenever the dosage of Mavik or diuretic is increased. Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease.
- If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal saline may be administered intravenously. A transient hypotensive response is not a contraindication to further doses; however, lower doses of Mavik or reduced concomitant diuretic therapy should be considered.
### Neutropenia/Agranulocytosis
- Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of trandolapril are insufficient to show that trandolapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.
### Hepatic Failure
- ACE inhibitors rarely have been associated with a syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice should discontinue the ACE inhibitor and receive appropriate medical follow-up.
### Fetal Toxicity
### Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Mavik as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Mavik, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Mavik for hypotension, oliguria, and hyperkalemia.
- Doses of 0.8 mg/kg/day (9.4 mg/m2/day) in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg woman.
### Precautions
### General
### Impaired Renal Function
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Mavik (trandolapril), may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
- Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when ACE inhibitors have been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or the ACE inhibitor may be required. Evaluation of hypertensive patients should always include assessment of renal function.
### Hyperkalemia and Potassium-sparing Diuretics
- In clinical trials, hyperkalemia (serum potassium > 6.00 mEq/L) occurred in approximately 0.4% of hypertensive patients receiving Mavik. In most cases, elevated serum potassium levels were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Mavik.
### Cough
- Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of a relationship to dose.
### Surgery/Anesthesia
- In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Mavik will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
- Headache and fatigue were all seen in more than 1% of Mavik-treated patients but were more frequently seen on placebo. Adverse events were not usually persistent or difficult to manage.
### Left Ventricular Dysfunction Post Myocardial Infarction
- Adverse reactions related to Mavik occurring at a rate greater than that observed in placebo-treated patients with left ventricular dysfunction, are shown below. The incidences represent the experiences from the TRACE study. The follow-up time was between 24 and 50 months for this study.
- Clinical adverse experiences possibly or probably related or of uncertain relationship to therapy occurring in 0.3% to 1.0% (except as noted) of the patients treated with Mavik (with or without concomitant calcium ion antagonist or diuretic) in controlled or uncontrolled trials (N=1134) and less frequent, clinically significant events seen in clinical trials or post-marketing experience include (listed by body system):
### General Body Function
- Chest pain.
### Cardiovascular
- AV first degree block, bradycardia, edema, flushing, and palpitations.
### Central Nervous System
- Drowsiness, insomnia, paresthesia, vertigo.
### Dermatologic
- Pruritus, rash, pemphigus.
### Eye, Ear, Nose, Throat
- Epistaxis, throat inflammation, upper respiratory tract infection.
### Emotional, Mental, Sexual States
- Anxiety, impotence, decreased libido.
### Gastrointestinal
- Abdominal distention, abdominal pain/cramps, constipation, dyspepsia, diarrhea, vomiting, nausea.
### Hemopoietic
- Decreased leukocytes, decreased neutrophils.
### Metabolism and Endocrine
- Increased liver enzymes including SGPT (ALT).
### Musculoskeletal System
- Extremity pain, muscle cramps, gout.
### Pulmonary
- Dyspnea.
### Postmarketing
- The following adverse reactions were identified during post approval use of Mavik. 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.
### General Body Function
- Malaise, fever.
### Cardiovascular
- Myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, ventricular tachycardia, tachycardia, transient ischemic attack, arrhythmia.
### Central Nervous System
- Cerebral hemorrhage.
### Dermatologic
- Alopecia, sweating, Stevens-Johnson syndrome and toxic epidermal necrolysis.
### Emotional, Mental, Sexual States
- Hallucination, depression.
### Gastrointestinal
- Dry mouth, pancreatitis, jaundice and hepatitis.
### Hemopoietic
- Agranulocytosis, pancytopenia.
### Metabolism and Endocrine
- Increased SGOT (AST).
### Pulmonary
- Bronchitis.
### Renal and Urinary
- Renal failure.
### Clinical Laboratory Test Findings
### Hematology
Thrombocytopenia.
### Serum Electrolytes
- Hyponatremia.
### Creatinine and Blood Urea Nitrogen
- Increases in creatinine levels occurred in 1.1% of patients receiving Mavik alone and 7.3% of patients treated with Mavik, a calcium ion antagonist and a diuretic. Increases in blood urea nitrogen levels occurred in 0.6% of patients receiving Mavik alone and 1.4% of patients receiving Mavik, a calcium ion antagonist, and a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis.
### Liver Function Tests
- Occasional elevation of transaminases at the rate of 3X upper normals occurred in 0.8% of patients and persistent increase in bilirubin occurred in 0.2% of patients. Discontinuation for elevated liver enzymes occurred in 0.2% of patients.
### Other
- Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.
- Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Mavik and other agents that affect the RAS.
- Do not co-administer aliskiren with Mavik in patients with diabetes. Avoid use of aliskiren with Mavik in patients with renal impairment (GFR <60 ml/min).
### Concomitant Diuretic Therapy
- As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may experience an excessive reduction of blood pressure after initiation of therapy with Mavik. The possibility of exacerbation of hypotensive effects with Mavik may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Mavik. If it is not possible to discontinue the diuretic, the starting dose of trandolapril should be reduced.
### Agents Increasing Serum Potassium
- Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium.
### Antidiabetic Agents
- Concomitant use of ACE inhibitors and antidiabetic medicines (insulin or oral hypoglycemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycemia.
### Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
### Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving trandolapril and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs.
### Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Mavik.
### Other
- No clinically significant pharmacokinetic interaction has been found between trandolaprilat and food, cimetidine, digoxin, or furosemide.
- The anticoagulant effect of warfarin was not significantly changed by trandolapril.
- The hypotensive effect of certain inhalation anesthetics may be enhanced by ACE inhibitors including trandolapril
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Mavik, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Mavik for hypotension, oliguria, and hyperkalemia.
- Doses of 0.8 mg/kg/day (9.4 mg/m2/day) in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg woman.
- Trandolapril pharmacokinetics have been investigated in the elderly (> 65 years) and in both genders. The plasma concentration of trandolapril is increased in elderly hypertensive patients, but the plasma concentration of trandolaprilat and inhibition of ACE activity are similar in elderly and young hypertensive patients. The pharmacokinetics of trandolapril and trandolaprilat and inhibition of ACE activity are similar in male and female elderly hypertensive patients.
- The recommended initial dosage of Mavik for patients not receiving a diuretic is 1 mg once daily in non-black patients and 2 mg in black patients. Dosage should be adjusted according to the blood pressure response. Generally, dosage adjustments should be made at intervals of at least 1 week. Most patients have required dosages of 2 to 4 mg once daily. There is little clinical experience with doses above 8 mg.
- Patients inadequately treated with once-daily dosing at 4 mg may be treated with twice-daily dosing. If blood pressure is not adequately controlled with Mavik monotherapy, a diuretic may be added.
- In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Mavik. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with Mavik. Then, if blood pressure is not controlled with Mavik alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 0.5 mg Mavik should be used with careful medical supervision for several hours until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response.
- Concomitant administration of Mavik with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium.
- The recommended starting dose is 1 mg, once daily. Following the initial dose, all patients should be titrated (as tolerated) toward a target dose of 4 mg, once daily. If a 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.
- For patients with a creatinine clearance < 30 mL/min. or with hepatic cirrhosis, the recommended starting dose, based on clinical and pharmacokinetic data, is 0.5 mg daily. Patients should subsequently have their dosage titrated (as described above) to the optimal response.
- Laboratory determinations of serum levels of trandolapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of trandolapril overdose. No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH of the urine) might accelerate elimination of trandolapril and its metabolites. Trandolaprilat is removed by hemodialysis. Angiotensin II could presumably serve as a specific antagonist antidote in the setting of trandolapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of trandolapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat trandolapril overdose by infusion of normal saline solution.
- ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of trandolapril remains to be elucidated.
- While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, trandolapril exerts antihypertensive actions even in patients with low-renin hypertension. Mavik was an effective antihypertensive in all races studied. Both black patients (usually a predominantly low-renin group) and non-black patients responded to 2 to 4 mg of Mavik.
- M.W. = 430.54
- Melting Point = 125°C
- Trandolapril is a white or almost white powder that is soluble (> 100 mg/mL) in chloroform, dichloromethane, and methanol. Mavik tablets contain 1 mg, 2 mg, or 4 mg of trandolapril for oral administration. Each tablet also contains corn starch, croscarmellose sodium, hypromellose, iron oxide, lactose monohydrate, povidone, sodium stearyl fumarate.
## Metabolism and Excretion
- After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces. The extent of the absorbed dose which is biliary excreted has not been determined. Plasma concentrations (Cmax and AUC of trandolapril and Cmax of trandolaprilat) are dose proportional over the 1-4 mg range, but the AUC of trandolaprilat is somewhat less than dose proportional. In addition to trandolaprilat, at least 7 other metabolites have been found, principally glucuronides or deesterification products.
- Serum protein binding of trandolapril is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration.
- The volume of distribution of trandolapril is about 18 liters. Total plasma clearances of trandolapril and trandolaprilat after approximately 2 mg IV doses are about 52 liters/hour and 7 liters/hour respectively. Renal clearance of trandolaprilat varies from 1-4 liters/hour, depending on dose.
- Long-term studies were conducted with oral trandolapril administered by gavage to mice (78 weeks) and rats (104 and 106 weeks). No evidence of carcinogenic potential was seen in mice dosed up to 25 mg/kg/day (85 mg/m2/day) or rats dosed up to 8 mg/kg/day (60 mg/m2/day). These doses are 313 and 32 times (mice), and 100 and 23 times (rats) the maximum recommended human daily dose (MRHDD) of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg individual. The genotoxic potential of trandolapril was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic or clastogenic potential in these in vitro and in vivo assays.
- Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m2/day) of trandolapril, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively.
- A single 2-mg dose of Mavik produces 70 to 85% inhibition of plasma ACE activity at 4 hours with about 10% decline at 24 hours and about half the effect manifest at 8 days. Maximum ACE inhibition is achieved with a plasma trandolaprilat concentration of 2 ng/mL. ACE inhibition is a function of trandolaprilat concentration, not trandolapril concentration. The effect of trandolapril on exogenous angiotensin I was not measured.
### Hypertension
- Four placebo-controlled dose response studies were conducted using once-daily oral dosing of Mavik in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once-daily dose was 1 mg in non-black patients and 2 mg in black patients. Further decreases in trough supine diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing interval, but trough/peak ratios are well above 50% for all effective doses. There was a slightly greater effect on the diastolic pressure, but no difference on systolic pressure with b.i.d. dosing. During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Following 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once-daily doses of 2 to 4 mg lowered supine or standing systolic/diastolic blood pressure 24 hours after dosing by an average 7-10/4-5 mmHg below placebo responses in non-black patients. Once-daily doses of 2 to 4 mg lowered blood pressure 4-6/3-4 mmHg in black patients. Trough to peak ratios for effective doses ranged from 0.5 to 0.9. There were no differences in response between men and women, but responses were somewhat greater in patients under 60 than in patients over 60 years old. Abrupt withdrawal of Mavik has not been associated with a rapid increase in blood pressure.
- Administration of Mavik to patients with mild to moderate hypertension results in a reduction of supine, sitting and standing blood pressure to about the same extent without compensatory tachycardia.
- Symptomatic hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. Use of Mavik in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone, and the additional effect of trandolapril is similar to the effect of monotherapy.
### Heart Failure Post Myocardial Infarction or Left Ventricular Dysfunction Post Myocardial Infarction
- The Trandolapril Cardiac Evaluation (TRACE) Trial was a Danish, 27-center, double-blind, placebo controlled, parallel-group study of the effect of trandolapril on all-cause mortality in stable patients with echocardiographic evidence of left ventricular dysfunction 3 to 7 days after a myocardial infarction. Subjects with residual ischemia or overt heart failure were included. Patients tolerant of a test dose of 1 mg trandolapril were randomized to placebo (n=873) or trandolapril (n=876) and followed for 24 months. Among patients randomized to trandolapril, who began treatment on 1 mg, 62% were successfully titrated to a target dose of 4 mg once daily over a period of weeks. The use of trandolapril was associated with a 16% reduction in the risk of all-cause mortality (p=0.042), largely cardiovascular mortality. Trandolapril was also associated with a 20% reduction in the risk of progression of heart failure (p=0.047), defined by a time-to-first-event analysis of death attributed to heart failure, hospitalization for heart failure, or requirement for open-label ACE inhibitor for the treatment of heart failure. There was no significant effect of treatment on other end-points: subsequent hospitalization, incidence of recurrent myocardial infarction, exercise tolerance, ventricular function, ventricular dimensions, or NYHA class.
- The population in TRACE was entirely Caucasian and had less usage than would be typical in a U.S. population of other post-infarction interventions: 42% thrombolysis, 16% beta-adrenergic blockade, and 6.7% PTCA or CABG during the entire period of follow-up. Blood pressure control, especially in the placebo group, was poor: 47 to 53% of patients randomized to placebo and 32 to 40% of patients randomized to trandolapril had blood pressures > 140/95 at 90-day follow-up visits.
- 1 mg tablet - Salmon colored, round shaped, scored, compressed tablets, with the “a” logo on one side and code identification letters FT on the other side. NDC 0074-2278-13 - bottles of 100 NDC 0074-2278-11 - unit dose packs of 100
- 2 mg tablet - Yellow colored, round shaped, compressed tablets, with the “a” logo on one side and code identification letters FX on the other side. NDC 0074-2279-13 - bottles of 100 NDC 0074-2279-11 - unit dose packs of 100
- 4 mg tablet - Rose colored, round shaped, compressed tablets, with the “a” logo on one side and code identification letters FZ on the other side. NDC 0074-2280-13 - bottles of 100 NDC 0074-2280-11 - unit dose packs of 100
- Dispense in well-closed container with safety closure.
：* Angioedema, including laryngeal edema, may occur at any time during treatment with ACE inhibitors, including Mavik. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician.
- Symptomatic Hypotension
- Patients should be cautioned that light-headedness can occur, especially during the first days of Mavik therapy, and should be reported to a physician. If actual syncope occurs, patients should be told to stop taking the drug until they have consulted with their physician.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting, resulting in reduced fluid volume, may precipitate an excessive fall in blood pressure with the same consequences of light-headedness and possible syncope.
Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor that has a long duration of action.
- Hyperkalemia
- Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician.
- Neutropenia
- Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.
- Pregnancy
- Female patients of childbearing age should be told about the consequences of exposure to Mavik during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with Mavik is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
- ↑ Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S (2006). "Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials". Lancet. 368 (9535): 581–8. doi:10.1016/S0140-6736(06)69201-5. PMID 16905022.CS1 maint: Multiple names: authors list (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}
- ↑ Bauduceau B, Genès N, Chamontin B, Vaur L, Renault M, Etienne S et al. (1998) Ambulatory blood pressure and urinary albumin excretion in diabetic (non-insulin-dependent and insulin-dependent) hypertensive patients: relationships at baseline and after treatment by the angiotensin converting enzyme inhibitor trandolapril. Am J Hypertens 11 (9):1065-73. PMID: 9752891
- ↑ Nakamura T, Ushiyama C, Suzuki S, Hara M, Shimada N, Ebihara I et al. (2000) Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol Dial Transplant 15 (9):1379-83. PMID: 10978394
- ↑ Malik RA, Williamson S, Abbott C, Carrington AL, Iqbal J, Schady W et al. (1998) Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet 352 (9145):1978-81. DOI:10.1016/S0140-6736(98)02478-7 PMID: 9872248
- ↑ Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T (2003) Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361 (9352):117-24. DOI:10.1016/S0140-6736(03)12229-5 PMID: 12531578 | https://www.wikidoc.org/index.php/Mavik | |
81ec40627aa5732f02f64506f2fbac059dc94441 | wikidoc | Max Delbrück | Max Delbrück
Max Ludwig Henning Delbrück (September 4, 1906 – March 9, 1981) was a German-American biophysicist and Nobel laureate.
# Biography
Max Delbrück was born in Berlin, Germany. His father was Hans Delbrück, a professor of history at the University of Berlin, and his mother was the granddaughter of Justus von Liebig.
Delbrück studied astrophysics, shifting towards theoretical physics, at the University of Göttingen. After receiving his Ph.D. in 1930, he traveled through England, Denmark, and Switzerland. He met Wolfgang Pauli and Niels Bohr, who got him interested in biology.
Delbrück went back to Berlin in 1932 as an assistant to Lise Meitner, who was collaborating with Otto Hahn on the results of irradiating uranium with neutrons. During this period he wrote a few papers, one of which turned out to be an important contribution on the scattering of gamma rays by a Coulomb field due to polarization of the vacuum produced by that field (1933). His conclusion proved to be theoretically sound but inapplicable to the case in point, but 20 years later Hans Bethe confirmed the phenomenon and named it "Delbrück scattering".
In 1937, he moved to the United States to pursue his interests in biology, taking up research in the Biology Division at Caltech on genetics of the fruit fly Drosophila melanogaster. While at Caltech Delbrück became acquainted with bacteria and their viruses (bacteriophage or 'phage'). In 1939, he co-authored a paper called The Growth of Bacteriophage with E.L. Ellis in which they demonstrated that viruses reproduce in "one step", rather than exponentially as cellular organisms do.
In 1941, he married Mary Bruce, with whom he had four children. Delbrück's brother Justus Delbrück, a lawyer, his sister Emmi Bonhoeffer and his brother-in-law Klaus Bonhoeffer (brother of the theologian, Dietrich Bonhoeffer) were in the German Resistance against the Nazi Regime. Klaus and Dietrich Bonhoeffer were executed in the last days of Hitler's Germany.
Delbrück remained in the US during World War II, teaching physics at Vanderbilt University in Nashville while pursuing his genetic research. In 1942, he and Salvador Luria of Indiana University demonstrated that bacterial resistance to virus infection is caused by random mutation and not adaptive change. This research, known as the Luria-Delbrück experiment, was also significant for its use of mathematics to make quantitative predictions for the results to be expected from alternative models. For that work, they were awarded the Nobel Prize in Physiology or Medicine in 1969, sharing it with Alfred Hershey. In the same year together with Salvador Luria he was awarded the Louisa Gross Horwitz Prize from Columbia University.
In 1947, Delbrück returned to Caltech as a professor of biology where he remained until 1977.
From the 1950s on, Delbrück applied biophysical methods to problems in sensory physiology rather than genetics. He also set up the institute for molecular genetics at the University of Cologne.
Delbrück was one of the most influential people in the movement of physical scientists into biology during the 20th century. Delbrück's thinking about the physical basis of life stimulated Erwin Schrödinger to write the highly influential book, What Is Life?. Schrödinger's book was an important influence on Francis Crick, James D. Watson and Maurice Wilkins who won a Nobel prize for the discovery of the DNA double helix. During the 1940s Delbrück developed a course in bacteriophage genetics at the Cold Spring Harbor Laboratory to encourage interest in the field. Delbrück's efforts to promote the "Phage Group" (exploring genetics by way of the viruses that infect bacteria) was important in the early development of molecular biology. On 26-27 August 2007, what would have been his 100th birthday celebration, Cold Spring Harbor Laboratory hosted a meeting of Delbrück's family members and friends to reminisce about the life and work of Delbrück. | Max Delbrück
Template:Infobox Scientist
Max Ludwig Henning Delbrück (September 4, 1906 – March 9, 1981) was a German-American biophysicist and Nobel laureate.
# Biography
Max Delbrück was born in Berlin, Germany. His father was Hans Delbrück, a professor of history at the University of Berlin, and his mother was the granddaughter of Justus von Liebig.
Delbrück studied astrophysics, shifting towards theoretical physics, at the University of Göttingen. After receiving his Ph.D. in 1930, he traveled through England, Denmark, and Switzerland. He met Wolfgang Pauli and Niels Bohr, who got him interested in biology.
Delbrück went back to Berlin in 1932 as an assistant to Lise Meitner, who was collaborating with Otto Hahn on the results of irradiating uranium with neutrons. During this period he wrote a few papers, one of which turned out to be an important contribution on the scattering of gamma rays by a Coulomb field due to polarization of the vacuum produced by that field (1933). His conclusion proved to be theoretically sound but inapplicable to the case in point, but 20 years later Hans Bethe confirmed the phenomenon and named it "Delbrück scattering".[1]
In 1937, he moved to the United States to pursue his interests in biology, taking up research in the Biology Division at Caltech on genetics of the fruit fly Drosophila melanogaster. While at Caltech Delbrück became acquainted with bacteria and their viruses (bacteriophage or 'phage'). In 1939, he co-authored a paper called The Growth of Bacteriophage with E.L. Ellis in which they demonstrated that viruses reproduce in "one step", rather than exponentially as cellular organisms do.
In 1941, he married Mary Bruce, with whom he had four children. Delbrück's brother Justus Delbrück, a lawyer, his sister Emmi Bonhoeffer and his brother-in-law Klaus Bonhoeffer (brother of the theologian, Dietrich Bonhoeffer) were in the German Resistance against the Nazi Regime. Klaus and Dietrich Bonhoeffer were executed in the last days of Hitler's Germany.
Delbrück remained in the US during World War II, teaching physics at Vanderbilt University in Nashville while pursuing his genetic research. In 1942, he and Salvador Luria of Indiana University demonstrated that bacterial resistance to virus infection is caused by random mutation and not adaptive change. This research, known as the Luria-Delbrück experiment, was also significant for its use of mathematics to make quantitative predictions for the results to be expected from alternative models. For that work, they were awarded the Nobel Prize in Physiology or Medicine in 1969, sharing it with Alfred Hershey.[2] In the same year together with Salvador Luria he was awarded the Louisa Gross Horwitz Prize from Columbia University.
In 1947, Delbrück returned to Caltech as a professor of biology where he remained until 1977.
From the 1950s on, Delbrück applied biophysical methods to problems in sensory physiology rather than genetics. He also set up the institute for molecular genetics at the University of Cologne.
Delbrück was one of the most influential people in the movement of physical scientists into biology during the 20th century. Delbrück's thinking about the physical basis of life stimulated Erwin Schrödinger to write the highly influential book, What Is Life?[3]. Schrödinger's book was an important influence on Francis Crick, James D. Watson and Maurice Wilkins who won a Nobel prize for the discovery of the DNA double helix[4]. During the 1940s Delbrück developed a course in bacteriophage genetics at the Cold Spring Harbor Laboratory to encourage interest in the field. Delbrück's efforts to promote the "Phage Group" (exploring genetics by way of the viruses that infect bacteria) was important in the early development of molecular biology. On 26-27 August 2007, what would have been his 100th birthday celebration, Cold Spring Harbor Laboratory hosted a meeting of Delbrück's family members and friends to reminisce about the life and work of Delbrück.[5] | https://www.wikidoc.org/index.php/Max_Delbr%C3%BCck | |
6a5a4ba4d12c7c75421268b433c83ad07ba54f57 | wikidoc | Mecamylamine | Mecamylamine
# Disclaimer
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# Overview
Mecamylamine is a autonomic ganglionic blocker that is FDA approved for the {{{indicationType}}} of moderately severe to severe essential hypertension and uncomplicated cases of malignant hypertension. Common adverse reactions include orthostatic hypotension, dizziness, lightheadedness, and fainting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Administration of Mecamylamine HCl after meals may cause a more gradual absorption and smoother control of excessively high blood pressure. The timing of doses in relation to meals should be consistent. Since the blood pressure response to antihypertensive drugs is increased in the early morning, the larger dose should be given at noontime and perhaps in the evening. The morning dose, as a rule, should be relatively small and in some instances may even be omitted.
- The initial regulation of dosage should be determined by blood pressure readings in the erect position at the time of maximal effect of the drug, as well as by other signs and symptoms of orthostatic hypotension.
- The effective maintenance dosage should be regulated by blood pressure readings in the erect position and by limitation of dosage to that which causes slight faintness or dizziness in this position. If the patient or a relative can use a sphygmomanometer, instructions may be given to reduce or omit a dose if readings fall below a designated level or if faintness or lightheadedness occurs. However, no change should be instituted without the knowledge of the physician.
- Close supervision and education of the patient, as well as critical adjustment of dosage, are essential to successful therapy.
- Other Antihypertensive Agents
- When Mecamylamine HCl is given with other antihypertensive drugs, the dosage of these other agents, as well as that of Mecamylamine HCl, should be reduced to avoid excessive hypotension. However, thiazides should be continued in their usual dosage, while that of Mecamylamine HCl is decreased by at least 50 percent.
- Dosing Information
- Initial Dosage: 2.5 mg PO bid
- This initial dosage should be modified by increments of one 2.5 mg tablet at intervals of not less than 2 days until the desired blood pressure response occurs (the criterion being a dosage just under that which causes signs of mild postural hypotension).
- Maintenance Dosage: 25 mg/day PO tid
- However, as little as 2.5 mg daily may be sufficient to control hypertension in some patients. A range of two to four or even more doses may be required in severe cases when smooth control is difficult to obtain. In severe or urgent cases, larger increments at smaller intervals may be needed. Partial tolerance may develop in certain patients, requiring an increase in the daily dosage of Mecamylamine HCl.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecamylamine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mecamylamine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecamylamine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mecamylamine in pediatric patients.
# Contraindications
- Mild, moderate, labile hypertension
- Mecamylamine HCl should not be used in mild, moderate, labile hypertension and may prove unsuitable in uncooperative patients.
- Coronary insufficiency or recent myocardial infarction
- It is contraindicated in coronary insufficiency or recent myocardial infarction.
- Uremia
- Mecamylamine HCl should be given with great discretion, if at all, when renal insufficiency is manifested by a rising or elevated BUN. The drug is contraindicated in uremia.
- Use of antibiotics and sulfonamides
- Patients receiving antibiotics and sulfonamides should generally not be treated with ganglionic blockers.
- Glaucoma
- Organic pyloric stenosis
- Hypersensitivity
# Warnings
- Mecamylamine, a secondary amine, readily penetrates into the brain and thus may produce central nervous system effects. Tremor, choreiform movements, mental aberrations, and convulsions may occur rarely. These have occurred most often when large doses of Mecamylamine HCl were used, especially in patients with cerebral or renal insufficiency.
- When ganglionic blockers or other potent antihypertensive drugs are discontinued suddenly, hypertensive levels return. In patients with malignant hypertension and others, this may occur abruptly and may cause fatal cerebral vascular accidents or acute congestive heart failure. When Mecamylamine HCl is withdrawn, this should be done gradually and other antihypertensive therapy usually must be substituted. On the other hand, the effects of Mecamylamine HCl sometimes may last from hours to days after therapy is discontinued.
### Precautions
- The patient's condition should be evaluated carefully, particularly as to renal and cardiovascular function. When renal, cerebral, or coronary blood flow is deficient, any additional impairment, which might result from added hypotension, must be avoided. The use of Mecamylamine HCl in patients with marked cerebral and coronary arteriosclerosis or after a recent cerebral accident requires caution.
- The action of Mecamylamine HCl may be potentiated by excessive heat, fever, infection, hemorrhage, pregnancy, anesthesia, surgery, vigorous exercise, other antihypertensive drugs, alcohol, and salt depletion as a result of diminished intake or increased excretion due to diarrhea, vomiting, excessive sweating, or diuretics.
- During therapy with Mecamylamine HCl, sodium intake should not be restricted but, if necessary, the dosage of the ganglionic blocker must be adjusted.
- Since urinary retention may occur in patients on ganglionic blockers, caution is required in patients with prostatic hypertrophy, bladder neck obstruction, and urethral stricture.
- Frequent loose bowel movements with abdominal distention and decreased borborygmi may be the first signs of paralytic ileus. If these are present, Mecamylamine HCl should be discontinued immediately and remedial steps taken.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Mecamylamine in the drug label.
## Postmarketing Experience
- The following adverse reactions have been reported and within each category are listed in order of decreasing severity.
Convulsions, choreiform movements, mental aberrations, tremor, and paresthesias
Orthostatic dizziness and syncope, postural hypotension.
Interstitial pulmonary edema and fibrosis.
Ileus, constipation (sometimes preceded by small, frequent liquid stools), vomiting, nausea, anorexia, glossitis and dryness of mouth.
Urinary retention, impotence, decreased libido.
Blurred vision, dilated pupils.
Weakness, fatigue, sedation.
# Drug Interactions
- Sulfonamides
- Patients receiving antibiotics and sulfonamides generally should not be treated with ganglionic blockers.
- Anesthesia, other antihypertensive drugs, and alcohol
- The action of Mecamylamine HCl may be potentiated by anesthesia, other antihypertensive drugs and alcohol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with Mecamylamine HCl. It is not known whether Mecamylamine HCl can cause fetal harm when given to a pregnant woman or can affect reproductive capacity. Mecamylamine HCl 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 Mecamylamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mecamylamine during labor and delivery.
### Nursing Mothers
- Because of the potential for serious adverse reactions in nursing infants from Mecamylamine HCl, 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
There is no FDA guidance on the use of Mecamylamine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Mecamylamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mecamylamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mecamylamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mecamylamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mecamylamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mecamylamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Mecamylamine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Mecamylamine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Signs of overdosage include: hypotension (which may progress to peripheral vascular collapse), postural hypotension, nausea, vomiting, diarrhea, constipation, paralytic ileus, urinary retention, dizziness, anxiety, dry mouth, mydriasis, blurred vision, or palpitations. A rise in intraocular pressure may occur.
- Pressor amines may be used to counteract excessive hypotension. Since patients being treated with ganglionic blockers are more than normally reactive to pressor amines, small doses of the latter are recommended to avoid excessive response.
- The oral LD50 of Mecamylamine HCl in the mouse is 92 mg/kg.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mecamylamine in the drug label.
# Pharmacology
## Mechanism of Action
- Mecamylamine HCl is a potent, oral antihypertension agent and ganglionic blocker, and is a secondary amine.
## Structure
- Mecamylamine HCl is N,2,3,3-tetramethyl-bicyclo heptan-2-amine hydrochloride. Its empirical formula is C11H21N - HCl and its structural formula is:
- It is a white, odorless, or practically odorless, crystalline powder, is highly stable, soluble in water and has a molecular weight of 203.75.
- Mecamylamine HCl is supplied as tablets for oral use, each containing 2.5 mg mecamylamine HCl. Inactive ingredients are calcium phosphate, D&C Yellow 10, FD&C Yellow 6, lactose, magnesium stearate, cornstarch, and talc.
## Pharmacodynamics
- Mecamylamine HCl reduces blood pressure in both normotensive and hypertensive individuals. It has a gradual onset of action (1/2 to 2 hours) and a long-lasting effect (usually 6 to 12 hours or more). A small oral dosage often produces a smooth and predictable reduction of blood pressure. Although this antihypertensive effect is predominantly orthostatic, the supine blood pressure is also significantly reduced.
## Pharmacokinetics
- Mecamylamine HCl is almost completely absorbed from the gastrointestinal tract, resulting in consistent lowering of blood pressure in most patients with hypertensive cardiovascular disease. Mecamylamine HCl is excreted slowly in the urine in the unchanged form. The rate of its renal elimination is influenced markedly by urinary pH. Alkalinization of the urine reduces, and acidification promotes, renal excretion of mecamylamine.
- Mecamylamine HCl crosses the blood-brain and placental barriers.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies in animals have not been performed to evaluate the effects upon fertility, mutagenic or carcinogenic potential of Mecamylamine HCl.
# Clinical Studies
There is limited information regarding Clinical Studies of Mecamylamine in the drug label.
# How Supplied
- Vecamyl are slightly yellow, round, compressed tablets, coded MP on one side and 2.5 on the other side. They are supplied as follows:
- Storage
## Storage
There is limited information regarding Mecamylamine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Mecamylamine HCl may cause dizziness, lightheadedness, or fainting, especially when rising from a lying or sitting position. This effect may be increased by alcoholic beverages, exercise, or during hot weather. Getting up slowly may help alleviate such a reaction.
# Precautions with Alcohol
- The action of Mecamylamine may be potentiated by alcohol.
- Mecamylamine may cause dizziness, lightheadedness, or fainting, especially when rising from a lying or sitting position. This effect may be increased by alcoholic beverages.
# Brand Names
- Vecamyl®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Mecamylamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
# Disclaimer
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# Overview
Mecamylamine is a autonomic ganglionic blocker that is FDA approved for the {{{indicationType}}} of moderately severe to severe essential hypertension and uncomplicated cases of malignant hypertension. Common adverse reactions include orthostatic hypotension, dizziness, lightheadedness, and fainting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Administration of Mecamylamine HCl after meals may cause a more gradual absorption and smoother control of excessively high blood pressure. The timing of doses in relation to meals should be consistent. Since the blood pressure response to antihypertensive drugs is increased in the early morning, the larger dose should be given at noontime and perhaps in the evening. The morning dose, as a rule, should be relatively small and in some instances may even be omitted.
- The initial regulation of dosage should be determined by blood pressure readings in the erect position at the time of maximal effect of the drug, as well as by other signs and symptoms of orthostatic hypotension.
- The effective maintenance dosage should be regulated by blood pressure readings in the erect position and by limitation of dosage to that which causes slight faintness or dizziness in this position. If the patient or a relative can use a sphygmomanometer, instructions may be given to reduce or omit a dose if readings fall below a designated level or if faintness or lightheadedness occurs. However, no change should be instituted without the knowledge of the physician.
- Close supervision and education of the patient, as well as critical adjustment of dosage, are essential to successful therapy.
- Other Antihypertensive Agents
- When Mecamylamine HCl is given with other antihypertensive drugs, the dosage of these other agents, as well as that of Mecamylamine HCl, should be reduced to avoid excessive hypotension. However, thiazides should be continued in their usual dosage, while that of Mecamylamine HCl is decreased by at least 50 percent.
- Dosing Information
- Initial Dosage: 2.5 mg PO bid
- This initial dosage should be modified by increments of one 2.5 mg tablet at intervals of not less than 2 days until the desired blood pressure response occurs (the criterion being a dosage just under that which causes signs of mild postural hypotension).
- Maintenance Dosage: 25 mg/day PO tid
- However, as little as 2.5 mg daily may be sufficient to control hypertension in some patients. A range of two to four or even more doses may be required in severe cases when smooth control is difficult to obtain. In severe or urgent cases, larger increments at smaller intervals may be needed. Partial tolerance may develop in certain patients, requiring an increase in the daily dosage of Mecamylamine HCl.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecamylamine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mecamylamine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecamylamine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mecamylamine in pediatric patients.
# Contraindications
- Mild, moderate, labile hypertension
- Mecamylamine HCl should not be used in mild, moderate, labile hypertension and may prove unsuitable in uncooperative patients.
- Coronary insufficiency or recent myocardial infarction
- It is contraindicated in coronary insufficiency or recent myocardial infarction.
- Uremia
- Mecamylamine HCl should be given with great discretion, if at all, when renal insufficiency is manifested by a rising or elevated BUN. The drug is contraindicated in uremia.
- Use of antibiotics and sulfonamides
- Patients receiving antibiotics and sulfonamides should generally not be treated with ganglionic blockers.
- Glaucoma
- Organic pyloric stenosis
- Hypersensitivity
# Warnings
- Mecamylamine, a secondary amine, readily penetrates into the brain and thus may produce central nervous system effects. Tremor, choreiform movements, mental aberrations, and convulsions may occur rarely. These have occurred most often when large doses of Mecamylamine HCl were used, especially in patients with cerebral or renal insufficiency.
- When ganglionic blockers or other potent antihypertensive drugs are discontinued suddenly, hypertensive levels return. In patients with malignant hypertension and others, this may occur abruptly and may cause fatal cerebral vascular accidents or acute congestive heart failure. When Mecamylamine HCl is withdrawn, this should be done gradually and other antihypertensive therapy usually must be substituted. On the other hand, the effects of Mecamylamine HCl sometimes may last from hours to days after therapy is discontinued.
### Precautions
- The patient's condition should be evaluated carefully, particularly as to renal and cardiovascular function. When renal, cerebral, or coronary blood flow is deficient, any additional impairment, which might result from added hypotension, must be avoided. The use of Mecamylamine HCl in patients with marked cerebral and coronary arteriosclerosis or after a recent cerebral accident requires caution.
- The action of Mecamylamine HCl may be potentiated by excessive heat, fever, infection, hemorrhage, pregnancy, anesthesia, surgery, vigorous exercise, other antihypertensive drugs, alcohol, and salt depletion as a result of diminished intake or increased excretion due to diarrhea, vomiting, excessive sweating, or diuretics.
- During therapy with Mecamylamine HCl, sodium intake should not be restricted but, if necessary, the dosage of the ganglionic blocker must be adjusted.
- Since urinary retention may occur in patients on ganglionic blockers, caution is required in patients with prostatic hypertrophy, bladder neck obstruction, and urethral stricture.
- Frequent loose bowel movements with abdominal distention and decreased borborygmi may be the first signs of paralytic ileus. If these are present, Mecamylamine HCl should be discontinued immediately and remedial steps taken.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Mecamylamine in the drug label.
## Postmarketing Experience
- The following adverse reactions have been reported and within each category are listed in order of decreasing severity.
Convulsions, choreiform movements, mental aberrations, tremor, and paresthesias
Orthostatic dizziness and syncope, postural hypotension.
Interstitial pulmonary edema and fibrosis.
Ileus, constipation (sometimes preceded by small, frequent liquid stools), vomiting, nausea, anorexia, glossitis and dryness of mouth.
Urinary retention, impotence, decreased libido.
Blurred vision, dilated pupils.
Weakness, fatigue, sedation.
# Drug Interactions
- Sulfonamides
- Patients receiving antibiotics and sulfonamides generally should not be treated with ganglionic blockers.
- Anesthesia, other antihypertensive drugs, and alcohol
- The action of Mecamylamine HCl may be potentiated by anesthesia, other antihypertensive drugs and alcohol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with Mecamylamine HCl. It is not known whether Mecamylamine HCl can cause fetal harm when given to a pregnant woman or can affect reproductive capacity. Mecamylamine HCl 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 Mecamylamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mecamylamine during labor and delivery.
### Nursing Mothers
- Because of the potential for serious adverse reactions in nursing infants from Mecamylamine HCl, 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
There is no FDA guidance on the use of Mecamylamine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Mecamylamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mecamylamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mecamylamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mecamylamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mecamylamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mecamylamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Mecamylamine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Mecamylamine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Signs of overdosage include: hypotension (which may progress to peripheral vascular collapse), postural hypotension, nausea, vomiting, diarrhea, constipation, paralytic ileus, urinary retention, dizziness, anxiety, dry mouth, mydriasis, blurred vision, or palpitations. A rise in intraocular pressure may occur.
- Pressor amines may be used to counteract excessive hypotension. Since patients being treated with ganglionic blockers are more than normally reactive to pressor amines, small doses of the latter are recommended to avoid excessive response.
- The oral LD50 of Mecamylamine HCl in the mouse is 92 mg/kg.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mecamylamine in the drug label.
# Pharmacology
## Mechanism of Action
- Mecamylamine HCl is a potent, oral antihypertension agent and ganglionic blocker, and is a secondary amine.
## Structure
- Mecamylamine HCl is N,2,3,3-tetramethyl-bicyclo [2.2.1] heptan-2-amine hydrochloride. Its empirical formula is C11H21N • HCl and its structural formula is:
- It is a white, odorless, or practically odorless, crystalline powder, is highly stable, soluble in water and has a molecular weight of 203.75.
- Mecamylamine HCl is supplied as tablets for oral use, each containing 2.5 mg mecamylamine HCl. Inactive ingredients are calcium phosphate, D&C Yellow 10, FD&C Yellow 6, lactose, magnesium stearate, cornstarch, and talc.
## Pharmacodynamics
- Mecamylamine HCl reduces blood pressure in both normotensive and hypertensive individuals. It has a gradual onset of action (1/2 to 2 hours) and a long-lasting effect (usually 6 to 12 hours or more). A small oral dosage often produces a smooth and predictable reduction of blood pressure. Although this antihypertensive effect is predominantly orthostatic, the supine blood pressure is also significantly reduced.
## Pharmacokinetics
- Mecamylamine HCl is almost completely absorbed from the gastrointestinal tract, resulting in consistent lowering of blood pressure in most patients with hypertensive cardiovascular disease. Mecamylamine HCl is excreted slowly in the urine in the unchanged form. The rate of its renal elimination is influenced markedly by urinary pH. Alkalinization of the urine reduces, and acidification promotes, renal excretion of mecamylamine.
- Mecamylamine HCl crosses the blood-brain and placental barriers.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies in animals have not been performed to evaluate the effects upon fertility, mutagenic or carcinogenic potential of Mecamylamine HCl.
# Clinical Studies
There is limited information regarding Clinical Studies of Mecamylamine in the drug label.
# How Supplied
- Vecamyl [Mecamylamine HCl Tablet USP] are slightly yellow, round, compressed tablets, coded MP on one side and 2.5 on the other side. They are supplied as follows:
- Storage
## Storage
There is limited information regarding Mecamylamine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Mecamylamine HCl may cause dizziness, lightheadedness, or fainting, especially when rising from a lying or sitting position. This effect may be increased by alcoholic beverages, exercise, or during hot weather. Getting up slowly may help alleviate such a reaction.
# Precautions with Alcohol
- The action of Mecamylamine may be potentiated by alcohol.
- Mecamylamine may cause dizziness, lightheadedness, or fainting, especially when rising from a lying or sitting position. This effect may be increased by alcoholic beverages.
# Brand Names
- Vecamyl®[1]
# Look-Alike Drug Names
- N/A[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mecamylamine | |
65cf0187f979f7e7dc0b381c7833af03e6ab94e1 | wikidoc | Medetomidine | Medetomidine
Medetomidine (active form medetomidine hydrochloride) is a synthetic drug used as both a surgical anesthetic and analgesic. It is a crystalline white alpha-two adrenergic agonist that can be administered as an intravenous drug solution with sterile water. It is currently approved for dogs in the United States, and distributed by Pfizer Animal Health under the product name Domitor.
It is often used in combinations with opioids (butorphanol, buprenorphine etc) as premedication (before a general anaesthetic) in healthy cats and dogs. It can be given by intramuscular injection (IM), subcutaneous injection (SI) or intravenous injection (II). When delivered intravenously, a significantly decreased dose is used. Some authors suggest a sublingual route is also effective.
Following administration, marked peripheral vasoconstriction and bradycardia are noted. Often the dosage of induction agents (i.e. propofol) may be drastically reduced, as may the volumes of anaesthetic gases (i.e. halothane, isoflurane, sevoflurane) used to maintain general anaesthesia.
It is sometimes used in combination with butorphanol and ketamine (given IM) to produce general anaesthesia for short periods in healthy but fractious felines that will not allow an intravenous induction agent to be given.
Medetomidine has also been used in combination with morphine (or methadone), lignocaine and ketamine in constant rate infusion analgesia in canines. It is often used in so called microdoses for this analgesic effect.
It's effects can be reversed using atipamezole (distributed as Antisedan by Pfizer).
# See Also
- Veterinary anesthesia | Medetomidine
Medetomidine (active form medetomidine hydrochloride) is a synthetic drug used as both a surgical anesthetic and analgesic. It is a crystalline white alpha-two adrenergic agonist that can be administered as an intravenous drug solution with sterile water. It is currently approved for dogs in the United States, and distributed by Pfizer Animal Health under the product name Domitor.
It is often used in combinations with opioids (butorphanol, buprenorphine etc) as premedication (before a general anaesthetic) in healthy cats and dogs. It can be given by intramuscular injection (IM), subcutaneous injection (SI) or intravenous injection (II). When delivered intravenously, a significantly decreased dose is used. Some authors suggest a sublingual route is also effective.
Following administration, marked peripheral vasoconstriction and bradycardia are noted. Often the dosage of induction agents (i.e. propofol) may be drastically reduced, as may the volumes of anaesthetic gases (i.e. halothane, isoflurane, sevoflurane) used to maintain general anaesthesia.
It is sometimes used in combination with butorphanol and ketamine (given IM) to produce general anaesthesia for short periods in healthy but fractious felines that will not allow an intravenous induction agent to be given.
Medetomidine has also been used in combination with morphine (or methadone), lignocaine and ketamine in constant rate infusion analgesia in canines. It is often used in so called microdoses for this analgesic effect.
It's effects can be reversed using atipamezole (distributed as Antisedan by Pfizer).
# See Also
- Veterinary anesthesia | https://www.wikidoc.org/index.php/Medetomidine | |
3b4fe95773c70fd823e5fb39ecc756291cce277c | wikidoc | Median nerve | Median nerve
The median nerve is a nerve that runs down the arm and forearm. It is one of the five main nerves originating from the brachial plexus.
The median nerve is formed from parts of the medial and lateral cords of the brachial plexus, and continues down the arm to enter the forearm with the brachial artery.
The median nerve is the only nerve that passes through the carpal tunnel, where it may be compressed to cause carpal tunnel syndrome.
# Course
## Course in the Upper Arm
After receiving inputs from both the lateral and medial cords of the brachial plexus, the median nerve courses with brachial artery on medial side of arm between biceps brachii and brachialis. At first lateral to the artery, it then crosses anteriorly to run medial to the artery in the distal arm and into the cubital fossa.
The median nerve gives off an articular branch in the upper arm as it passes the elbow joint.
## Course and Branches in the forearm
The median nerves arises from the cubital fossa and passes between the two heads of pronator teres. It then travels between flexor digitorum superficialis and flexor digitorum profundus before emerging between flexor digitorum superficialis and flexor carpi radialis.
The unbranched portion of the median nerve (which arises from the cubital fossa) innervates muscles of superficial and intermediate groups of the anterior compartment except flexor carpi ulnaris
The median nerve does give off two branches as it courses through the forearm:
- The anterior interosseous branch courses with the anterior interosseous artery and innervates all the muscles of the deep group of the anterior compartment of the forearm except the medial (ulnar) half of flexor digitorum profundus. Its ends with its innervation of pronator quadratus.
- The palmar cutaneous branch of the median nerve arises at distal part of the forearm. It supplies sensory innervation to the lateral aspect of the palmar skin (but not the digits).
The palmar cutaneous branch of the median nerve, which supplies the lateral aspect of the palmar skin arises proximal to the flexor retinaculum and passes superficial to it so does not pass through the carpal tunnel.
## Branches in the hand
The median nerve enters the hand through the carpal tunnel, deep to the flexor retinaculum along with the tendons of flexor digitorum superficialis, flexor digitorum profundus, and flexor pollicis longus.
From there it sends off several branches:
- 1. Recurrent branch to muscles of the thenar compartment (the recurrent branch is also called "the million dollar nerve")
- 2. Digital cutaneous branches to common palmar digital branch and proper palmar digital branch of the median nerve which supply the:
a) lateral (radial) three and a half digits on the palmar side
b) index, middle and ring finger on dorsum of the hand
- a) lateral (radial) three and a half digits on the palmar side
- b) index, middle and ring finger on dorsum of the hand
The median nerve supplies motor innervation to the first and second lumbricals.
# Innervation
## Upper Arm
No motor innervation, but it gives vascular branches to the wall of the brachial artery (sympathatic fibers).
## Forearm
It innervates most of the flexors in the forearm except flexor carpi ulnaris and the medial two digits of flexor digitorum profundus, which are supplied by the ulnar nerve.
Unbranched, the median nerves supplies the following muscles.
Superior Group:
- Pronator teres
- Flexor carpi radialis
- Palmaris longus
Intermediate Group:
- Flexor digitorum superficialis muscle
The anterior interosseus branch supplies the following muscles...
Deep group:
- lateral (radial) half of Flexor digitorum profundus
- Flexor pollicis longus
- Pronator quadratus
## Hand
In the hand, the median nerve supplies motor innervation to the 1st and 2nd lumbricals and the muscles of the thenar eminence of the hand by a recurrent thenar branch. The rest of the intrinsic muscles of the hand are supplied by the ulnar nerve.
The median nerve innervates the skin of the palmar side of the thumb, the index and middle finger, half the ring finger, and the nail bed of these fingers. The lateral part of the palm is supplied by the palmar cutaneous branch of the median nerve which leaves the nerve proximal to the wrist creases. This palmar cutaneous branch travels in a separate fascial groove adjacent to the flexor carpi radialis.
# Injury
Injury of median nerve at different levels cause different syndromes. Injury of this nerve at a level above elbow joint results in loss of pronation and a decrease in flexion of the hand at the wrist joint. In the hand, thenar muscles are paralysed and atrophy in time. Opposition and flexion movements of thumb are lost, and thumb and index finger are arrested in adduction and hyperextension position. This appearance of the hand is collectively referred as ape hand deformity. In addition, in palmar side of the hand sensation of lateral part of hand, first three fingers and lateral half of the fourth finger and in dorsal side sensation of distal ⅓ portions of first three fingers and lateral half of distal ⅓ portion of fourth finger is lost.
# Additional images
- Nervous system
- Cross-section through the middle of upper arm.
- Cross-section through the middle of the forearm.
- Transverse section across distal ends of radius and ulna.
- Transverse section across the wrist and digits.
- The brachial artery.
- Ulnar and radial arteries. Deep view.
- The right brachial plexus (infraclavicular portion) in the axillary fossa; viewed from below and in front.
- Cutaneous nerves of right upper extremity. Anterior view.
- Diagram of segmental distribution of the cutaneous nerves of the right upper extremity. Anterior view.
- Diagram of segmental distribution of the cutaneous nerves of the right upper extremity. Posterior view.
- Superficial palmar nerves.
- Deep palmar nerves.
- Front of right upper extremity, showing surface markings for bones, arteries, and nerves.
- Brachial plexus | Median nerve
Template:Infobox Nerve
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The median nerve is a nerve that runs down the arm and forearm. It is one of the five main nerves originating from the brachial plexus.
The median nerve is formed from parts of the medial and lateral cords of the brachial plexus, and continues down the arm to enter the forearm with the brachial artery.
The median nerve is the only nerve that passes through the carpal tunnel, where it may be compressed to cause carpal tunnel syndrome.
# Course
## Course in the Upper Arm
After receiving inputs from both the lateral and medial cords of the brachial plexus, the median nerve courses with brachial artery on medial side of arm between biceps brachii and brachialis. At first lateral to the artery, it then crosses anteriorly to run medial to the artery in the distal arm and into the cubital fossa.
The median nerve gives off an articular branch in the upper arm as it passes the elbow joint.
## Course and Branches in the forearm
The median nerves arises from the cubital fossa and passes between the two heads of pronator teres. It then travels between flexor digitorum superficialis and flexor digitorum profundus before emerging between flexor digitorum superficialis and flexor carpi radialis.
The unbranched portion of the median nerve (which arises from the cubital fossa) innervates muscles of superficial and intermediate groups of the anterior compartment except flexor carpi ulnaris
The median nerve does give off two branches as it courses through the forearm:
- The anterior interosseous branch courses with the anterior interosseous artery and innervates all the muscles of the deep group of the anterior compartment of the forearm except the medial (ulnar) half of flexor digitorum profundus. Its ends with its innervation of pronator quadratus.
- The palmar cutaneous branch of the median nerve arises at distal part of the forearm. It supplies sensory innervation to the lateral aspect of the palmar skin (but not the digits).
The palmar cutaneous branch of the median nerve, which supplies the lateral aspect of the palmar skin arises proximal to the flexor retinaculum and passes superficial to it so does not pass through the carpal tunnel.
## Branches in the hand
The median nerve enters the hand through the carpal tunnel, deep to the flexor retinaculum along with the tendons of flexor digitorum superficialis, flexor digitorum profundus, and flexor pollicis longus.
From there it sends off several branches:
- 1. Recurrent branch to muscles of the thenar compartment (the recurrent branch is also called "the million dollar nerve")
- 2. Digital cutaneous branches to common palmar digital branch and proper palmar digital branch of the median nerve which supply the:
a) lateral (radial) three and a half digits on the palmar side
b) index, middle and ring finger on dorsum of the hand
- a) lateral (radial) three and a half digits on the palmar side
- b) index, middle and ring finger on dorsum of the hand
The median nerve supplies motor innervation to the first and second lumbricals.
# Innervation
## Upper Arm
No motor innervation, but it gives vascular branches to the wall of the brachial artery (sympathatic fibers).
## Forearm
It innervates most of the flexors in the forearm except flexor carpi ulnaris and the medial two digits of flexor digitorum profundus, which are supplied by the ulnar nerve.
Unbranched, the median nerves supplies the following muscles.
Superior Group:
- Pronator teres
- Flexor carpi radialis
- Palmaris longus
Intermediate Group:
- Flexor digitorum superficialis muscle
The anterior interosseus branch supplies the following muscles...
Deep group:
- lateral (radial) half of Flexor digitorum profundus
- Flexor pollicis longus
- Pronator quadratus
## Hand
In the hand, the median nerve supplies motor innervation to the 1st and 2nd lumbricals and the muscles of the thenar eminence of the hand by a recurrent thenar branch. The rest of the intrinsic muscles of the hand are supplied by the ulnar nerve.
The median nerve innervates the skin of the palmar side of the thumb, the index and middle finger, half the ring finger, and the nail bed of these fingers. The lateral part of the palm is supplied by the palmar cutaneous branch of the median nerve which leaves the nerve proximal to the wrist creases. This palmar cutaneous branch travels in a separate fascial groove adjacent to the flexor carpi radialis.
# Injury
Injury of median nerve at different levels cause different syndromes. Injury of this nerve at a level above elbow joint results in loss of pronation and a decrease in flexion of the hand at the wrist joint. In the hand, thenar muscles are paralysed and atrophy in time. Opposition and flexion movements of thumb are lost, and thumb and index finger are arrested in adduction and hyperextension position. This appearance of the hand is collectively referred as ape hand deformity. In addition, in palmar side of the hand sensation of lateral part of hand, first three fingers and lateral half of the fourth finger and in dorsal side sensation of distal ⅓ portions of first three fingers and lateral half of distal ⅓ portion of fourth finger is lost.
# Additional images
- Nervous system
- Cross-section through the middle of upper arm.
- Cross-section through the middle of the forearm.
- Transverse section across distal ends of radius and ulna.
- Transverse section across the wrist and digits.
- The brachial artery.
- Ulnar and radial arteries. Deep view.
- The right brachial plexus (infraclavicular portion) in the axillary fossa; viewed from below and in front.
- Cutaneous nerves of right upper extremity. Anterior view.
- Diagram of segmental distribution of the cutaneous nerves of the right upper extremity. Anterior view.
- Diagram of segmental distribution of the cutaneous nerves of the right upper extremity. Posterior view.
- Superficial palmar nerves.
- Deep palmar nerves.
- Front of right upper extremity, showing surface markings for bones, arteries, and nerves.
- Brachial plexus
# External links
- Template:DukeOrtho
- Median+Nerve at the US National Library of Medicine Medical Subject Headings (MeSH)
- Template:KansasHandKinesiology
- Template:UMichAtlas - "Axilla, dissection, anterior view"
Template:Gray's
Template:Brachial plexus
Template:WikiDoc Sources
de:Nervus medianus
he:עצב התווך
lt:Vidurinis nervas
sv:Nervus medianus | https://www.wikidoc.org/index.php/Median_nerve | |
21c8e632a4387f77e1cb2355f11502e938579178 | wikidoc | Median plane | Median plane
# Overview
The median plane is a sagittal plane which bisects the body through the umbilicus.
It is one of the lines used to define the right upper quadrant of the human abdomen.
The midsternal line can be interpreted as a segment of the median plane. | Median plane
Template:Infobox Anatomy
# Overview
The median plane is a sagittal plane which bisects the body through the umbilicus.
It is one of the lines used to define the right upper quadrant of the human abdomen.
The midsternal line can be interpreted as a segment of the median plane.
Template:Anatomical planes
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Median_plane | |
1782abc5b30f08fe53f23c75d7f04b4565534883 | wikidoc | Medrogestone | Medrogestone
# Overview
Medrogestone (INN; trade names Colpro(ne) by Wyeth and Prothil by Solvay) is a progestin, a synthetic drug with similar effects as progesterone, a hormone involved in the menstrual cycle and pregnancy. As of 2010, it is no longer available in Germany or Austria.
# Indications
In the past, medrogestone was used in the treatment of endometrial cancer and in some regimens for breast cancer, and, in men, for benign prostatic hyperplasia. It still finds use in the treatment of amenorrhea and as the progestin component in certain forms of menopausal hormone replacement therapy.
# Contraindications
Intrahepatic cholestasis of pregnancy (acute or in history), vaginal bleeding of unknown origin, and severe diseases of the liver such as tumours are absolute contraindications for medrogestone. Relative contraindications include a history of jaundice or itching in pregnancy or gestational pemphigoid.
## Pregnancy and lactation
Medrogestone is contraindicated during pregnancy because progestogens are associated with risks for the foetus in animals and humans. Studies in pregnant rabbits have shown skeletal deformations under 3 mg medrogestone per kilogram body weight but not under 1 mg/kg. Typical therapeutic doses are between 0.1 and 0.25 mg/kg.
It is not known whether medrogestone passes into breast milk, but it is to be expected given its lipophilicity and studies with chemically related progestins.
# Adverse effects
Medrogestone seldom produces adverse effects, all of which are typical of progestogens. They include lack of appetite, nausea, headache, dizziness, and depression.
# Overdose
The acute toxicity of the drug is low. Overdose causes only harmless side-effects such as nausea and vaginal bleeding. The Template:LD50 has been found to range between 500 mg/kg in dogs and over 3000 mg/kg in rats. Chronic toxicity has been examined in animals, but nothing but the typical adverse effects of progestogens, and reduction of prostatic weight in Rhesus Monkeys, have been found. Accidental intake of the drug, including in children, is not dangerous.
# Chemical properties
Medrogestone is a steroid. More specifically, it is a derivative of pregna-4,6-diene structurally related to the progestin chlormadinone acetate and the antiandrogen cyproterone acetate. As is frequently found in other synthetic steroid hormones, medrogestone possesses a lipophilic group at position 6. However in contrast to chlormadinone acetate and cyproterone acetate or to fluocinolone that contain a chlorine or fluorine respectively at position 6, medrogestone contains a methyl substituent at this position. The methyl in position 17 is unusual for a steroid, as many such drugs carry an oxygen atom in that position.
# Pharmacology
## Pharmacokinetics
The drug is absorbed quickly and completely from the gut and reaches peak plasma concentrations after about one to four hours. Unlike many other steroids it binds neither to transcortin (corticosteroid-binding globulin, CBG, which binds progesterone nor to sex hormone-binding globulin (SHBG), but to albumin.Medrogestone itself cannot be excreted. The substance is hydroxylised and glucuronidised in the liver, and the resulting metabolites are eliminated via urine and faeces.
## Pharmacodynamics
The profile of medrogestone is similar to the natural hormone progesterone. It has pronounced progestogenic effects and opposes the proliferative effects of estrogen in the utereus, but lacks anabolic, androgenic, estrogenic and corticoid activity. In extremely high doses it is an androgen antagonist (in 2500-fold therapeutic doses) as well as an antigonadotropin.
# Interactions
Enzyme inducers such as barbiturates, phenylbutazone, phenytoin, ampicillin or tetracyclines are expected to reduce plasma concentrations of medrogestone, but no systematic research has been done. | Medrogestone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Medrogestone (INN; trade names Colpro(ne) by Wyeth and Prothil by Solvay) is a progestin, a synthetic drug with similar effects as progesterone, a hormone involved in the menstrual cycle and pregnancy. As of 2010, it is no longer available in Germany or Austria.
# Indications
In the past, medrogestone was used in the treatment of endometrial cancer and in some regimens for breast cancer, and, in men, for benign prostatic hyperplasia. It still finds use in the treatment of amenorrhea and as the progestin component in certain forms of menopausal hormone replacement therapy.
# Contraindications
Intrahepatic cholestasis of pregnancy (acute or in history), vaginal bleeding of unknown origin, and severe diseases of the liver such as tumours are absolute contraindications for medrogestone. Relative contraindications include a history of jaundice or itching in pregnancy or gestational pemphigoid.
## Pregnancy and lactation
Medrogestone is contraindicated during pregnancy because progestogens are associated with risks for the foetus in animals and humans. Studies in pregnant rabbits have shown skeletal deformations under 3 mg medrogestone per kilogram body weight but not under 1 mg/kg. Typical therapeutic doses are between 0.1 and 0.25 mg/kg.
It is not known whether medrogestone passes into breast milk, but it is to be expected given its lipophilicity and studies with chemically related progestins.
# Adverse effects
Medrogestone seldom produces adverse effects, all of which are typical of progestogens. They include lack of appetite, nausea, headache, dizziness, and depression.
# Overdose
The acute toxicity of the drug is low. Overdose causes only harmless side-effects such as nausea and vaginal bleeding. The Template:LD50 has been found to range between 500 mg/kg in dogs and over 3000 mg/kg in rats. Chronic toxicity has been examined in animals, but nothing but the typical adverse effects of progestogens, and reduction of prostatic weight in Rhesus Monkeys, have been found. Accidental intake of the drug, including in children, is not dangerous.
# Chemical properties
Medrogestone is a steroid. More specifically, it is a derivative of pregna-4,6-diene structurally related to the progestin chlormadinone acetate and the antiandrogen cyproterone acetate. As is frequently found in other synthetic steroid hormones, medrogestone possesses a lipophilic group at position 6. However in contrast to chlormadinone acetate and cyproterone acetate or to fluocinolone that contain a chlorine or fluorine respectively at position 6, medrogestone contains a methyl substituent at this position. The methyl in position 17 is unusual for a steroid, as many such drugs carry an oxygen atom in that position.
# Pharmacology
## Pharmacokinetics
The drug is absorbed quickly and completely from the gut and reaches peak plasma concentrations after about one to four hours. Unlike many other steroids it binds neither to transcortin (corticosteroid-binding globulin, CBG, which binds progesterone nor to sex hormone-binding globulin (SHBG), but to albumin.Medrogestone itself cannot be excreted. The substance is hydroxylised and glucuronidised in the liver, and the resulting metabolites are eliminated via urine and faeces.
## Pharmacodynamics
The profile of medrogestone is similar to the natural hormone progesterone. It has pronounced progestogenic effects and opposes the proliferative effects of estrogen in the utereus, but lacks anabolic, androgenic, estrogenic and corticoid activity. In extremely high doses it is an androgen antagonist (in 2500-fold therapeutic doses) as well as an antigonadotropin.
# Interactions
Enzyme inducers such as barbiturates, phenylbutazone, phenytoin, ampicillin or tetracyclines are expected to reduce plasma concentrations of medrogestone, but no systematic research has been done. | https://www.wikidoc.org/index.php/Medrogestone | |
1c9a7f799246351db6e3ce5a24f7a3201b589f9e | wikidoc | Ximelagatran | Ximelagatran
# Overview
Ximelagatran (Exanta® or Exarta®, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would not attempt to market ximelagatran after reports of hepatotoxicity (liver damage) during trials, and to discontinue its distribution in countries where the drug had been approved.
# Method of action
Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. It acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues through dealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).
# Uses
Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation such as stroke. The efficacy of ximelagatran for these indications had been well-documented (Eriksson et al 2003, Frances et al 2004, Schulman et al 2004).
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by vitamin K and heparin by protamine sulfate.
# Side-effects
Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzyme levels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications (AstraZeneca press release 2006). | Ximelagatran
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ximelagatran (Exanta® or Exarta®, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would not attempt to market ximelagatran after reports of hepatotoxicity (liver damage) during trials, and to discontinue its distribution in countries where the drug had been approved.
# Method of action
Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. It acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues through dealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).
# Uses
Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation such as stroke. The efficacy of ximelagatran for these indications had been well-documented (Eriksson et al 2003, Frances et al 2004, Schulman et al 2004).
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by vitamin K and heparin by protamine sulfate.
# Side-effects
Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzyme levels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications (AstraZeneca press release 2006). | https://www.wikidoc.org/index.php/Melagatran | |
ae1eb59cd4f6327a6bcbb9393ce9cae4daa2454a | wikidoc | Melanophilin | Melanophilin
Melanophilin is a carrier protein which in humans is encoded by the MLPH gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.
# Function
This gene encodes a member of the exophilin subfamily of Rab effector proteins. The protein forms a ternary complex with the small Ras-related GTPase Rab27A in its GTP-bound form and the motor protein myosin Va. A similar protein complex in mouse functions to tether pigment-producing organelles called melanosomes to the actin cytoskeleton in melanocytes, and is required for visible pigmentation in the hair and skin.
In melanocytic cells MLPH gene expression may be regulated by MITF.
# Clinical significance
A mutation in this gene results in Griscelli syndrome type 3, which is characterized by a silver-gray hair color and abnormal pigment distribution in the hair shaft.
Mutations in melanophilin cause the "dilute" coat color phenotype in dogs and cats. Variation in this gene appears to have been a target for recent natural selection in humans, and it has been hypothesized that this is due to a role in human pigmentation. | Melanophilin
Melanophilin is a carrier protein which in humans is encoded by the MLPH gene.[1][2] Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.
# Function
This gene encodes a member of the exophilin subfamily of Rab effector proteins. The protein forms a ternary complex with the small Ras-related GTPase Rab27A in its GTP-bound form and the motor protein myosin Va.[3] A similar protein complex in mouse functions to tether pigment-producing organelles called melanosomes to the actin cytoskeleton in melanocytes, and is required for visible pigmentation in the hair and skin.[4]
In melanocytic cells MLPH gene expression may be regulated by MITF.[5]
# Clinical significance
A mutation in this gene results in Griscelli syndrome type 3, which is characterized by a silver-gray hair color and abnormal pigment distribution in the hair shaft.
Mutations in melanophilin cause the "dilute" coat color phenotype in dogs[6] and cats.[7] Variation in this gene appears to have been a target for recent natural selection in humans, and it has been hypothesized that this is due to a role in human pigmentation.[8] | https://www.wikidoc.org/index.php/Melanophilin | |
e603f7bf0d80d48b3d025040090f63aeeeee80df | wikidoc | Men's skirts | Men's skirts
Men's skirts are skirts worn by men. The wearing of a skirt is conventionally, in North America and Europe, an expression of a female role. However, people have variously attempted to promote the wearing of skirts by men and to do away with this sex distinction, albeit with little general success and considerable cultural resistance
# Background
From the early Victorian period there was a decline in the wearing of bright colours and luxurious fabrics by men, with a definite preference for sobriety of dress. By the mid 20th Century orthodox Western male dress, especially business and semi-formal dress, was dominated by sober suits, plain shirts and ties.
In the 1960s there was widespread reaction against the accepted (North American and European) conventions of male and female dress. This unisex fashion movement aimed to eliminate the sartorial differences between men and women. In practice, it usually meant that women would wear male dress, i.e. shirts and trousers. Men rarely went as far in the adoption of traditionally female dress modes. The furthest that most men went in the 1960s in this regard were velvet trousers, flowered or frilled shirts and ties, and long hair.
In the 1980s, a few male celebrities dressed in skirts, and fashion designers such as Jean-Paul Gaultier, Giorgio Armani, John Galliano, Kenzo, Rei Kawakubo, and Yohji Yamamoto tried to promote the idea of men wearing skirts, but failed to popularize the idea. Male skirt wearing remains firmly linked with ideas of effeminacy.
# Metropolitan Museum of Art exhibition
In 2003, the Metropolitan Museum of Art displayed an exhibition, organized by Andrew Bolton and Harold Koda of the Museum's Costume Institute and sponsored by Gaultier, entitled Bravehearts: Men in Skirts. The idea of the exhibition was to explore how various groups and individuals (from hippies through pop stars to fashion designers) have promoted the idea of men wearing skirts as "the future of menswear". It displayed male skirts on mannequins, as if in the window of a department store, in several historical and cross-cultural contexts.
The exhibition display pointed out the lack of a "natural link" between an item of clothing and the masculinity of femininity of the wearer, mentioning the kilt as "one of the most potent, versatile, and enduring skirt forms often looked upon by fashion designers as a symbol of a natural, uninhibited, masculinity". It pointed out that fashion designers and male skirt-wearers employ the wearing of skirts for three purposes: to transgress conventional moral and social codes, to redefine the ideal of masculinity, and to inject novelty into male fashion. It linked the wearing of male skirts to youth movements and countercultural movements such as punk, grunge, and glam rock, and to pop music icons such as Boy George and Adrian Young.
Ellsworth eavesdropped on several visitors to the exhibition, noting that because of the exhibition's placement in a self-contained space accessed by a staircase at the far end of the Museum's first floor, the visitors were primarily self-selected as those who would be intrigued enough by such an idea in the first place to actually seek it out. According to her report, the reactions were wide-ranging, from the number of women who teased their male companions about whether they would ever consider wearing skirts (to which several men responded that they would) to the man who said "A caftan — after a shower or in the gym — can you imagine? 'Excuse me! Coming through!'". An adolescent girl rejected in disgust the notion that skirts were similar to the wide pants worn by hip-hop artists. Two elderly women called the idea "utterly ridiculous". One man, reading the exhibition's presentation on the subject of male skirt-wearing in cultures other than those in the North America and Europe, observed that "God! Three quarters of the world's population !".
The exhibition itself attempted to provoke visitors into considering how, historically, male dress codes have come to this point, and whether in fact a trend towards the wearing of skirts by men in the future actually exists. It attempted to raise challenging questions of how a simple item of dress connotes (in Ellsworth's words) "huge ramifications in meanings, behaviours, everyday life, senses of self and others, and configurations of insider and outsider".
# General Popularity
The wearing of skirts, kilts, or similar garments on an everyday basis by men in western cultures is, as of 2007, very much a minority movement.
Kilts, and derivatives of the garment remain popular. One manufacturer of contemporary kilt styles claims to sell over 12,000 such garments annually, resulting in over $2 million annually worth of sales, and has appeared at a major fashion show. According to a CNN correspondent: "At Seattle's Fremont Market, men are often seen sporting the Utilikilt" US News said in 2003 that "... the Seattle-made utilikilt, a rugged, everyday riff on traditional Scottish garb, has leapt from idea to over 10,000 sold in just three years, via the Web and word of mouth alone." "They've become a common sight around Seattle, especially in funkier neighborhoods and at the city's many alternative cultural events. They often are worn with chunky black boots." writes AP reporter Anne Kim. "I actually see more people wearing kilts in Seattle than I did when I lived in Scotland," one purchaser remarked in 2003.
In addition, since the mid-1990s a number of clothing companies have been established to sell skirts specifically designed for men. These include Macabi Skirt in the 1990s, Menintime in 1999 and Midas Clothing in 2002.
# Wicca and neo-paganism
In Wicca and neopaganism in the United States of America, men (just as women) are encouraged to question their traditional gender roles. Amongst other things this involves the wearing of skirts at festivals and sabbat celebrations, as ritual clothing (which Eilers equates to the "church clothes" worn by Christians on Sundays).
# Dance
In some western dance cultures, men commonly wear skirts and kilts. These include a broad range of professional dance productions where they may be worn to improve the artistic effect of the choreography, a style known as contra dance, where they are worn partly for ventilation and partly for the swirling movement, gay line dancing clubs where kilts are often worn, and revellers in Scottish night clubs where they are worn for ventilation and to express cultural identity.
# Outside of Western cultures
Outside of Western cultures, male clothing includes skirts and skirt-like garments. One common form is a single sheet of fabric folded and wrapped around the waist, such as the dhoti in India, and the Lungi and sarong in South/Southeast Asia. Some long robes also resemble a skirt or dress, including the Middle Eastern and North African caftan and djellaba.
# In fiction
One notable example of men wearing skirts in fiction is in early episodes of Star Trek: The Next Generation. The uniforms worn in the first and second season included a variant consisting of a short sleeved top, with attached skirt. This variant was seen worn by both male and female crew members. The Art of Star Trek explained that "the skirt design for men 'skant' was a logical development, given the total equality of the sexes presumed to exist in the 24th century." | Men's skirts
Template:Globalize
Men's skirts are skirts worn by men. The wearing of a skirt is conventionally, in North America and Europe, an expression of a female role. However, people have variously attempted to promote the wearing of skirts by men and to do away with this sex distinction, albeit with little general success[1] and considerable cultural resistance[2]
# Background
From the early Victorian period there was a decline in the wearing of bright colours and luxurious fabrics by men, with a definite preference for sobriety of dress.[3][4][5] By the mid 20th Century orthodox Western male dress, especially business and semi-formal dress, was dominated by sober suits, plain shirts and ties.
In the 1960s there was widespread reaction against the accepted (North American and European) conventions of male and female dress. This unisex fashion movement aimed to eliminate the sartorial differences between men and women. In practice, it usually meant that women would wear male dress, i.e. shirts and trousers. Men rarely went as far in the adoption of traditionally female dress modes. The furthest that most men went in the 1960s in this regard were velvet trousers, flowered or frilled shirts and ties, and long hair.[3]
In the 1980s, a few male celebrities dressed in skirts, and fashion designers such as Jean-Paul Gaultier, Giorgio Armani, John Galliano, Kenzo, Rei Kawakubo, and Yohji Yamamoto tried to promote the idea of men wearing skirts, but failed to popularize the idea. Male skirt wearing remains firmly linked with ideas of effeminacy.
# Metropolitan Museum of Art exhibition
In 2003, the Metropolitan Museum of Art displayed an exhibition, organized by Andrew Bolton and Harold Koda of the Museum's Costume Institute and sponsored by Gaultier, entitled Bravehearts: Men in Skirts. The idea of the exhibition was to explore how various groups and individuals (from hippies through pop stars to fashion designers) have promoted the idea of men wearing skirts as "the future of menswear". It displayed male skirts on mannequins, as if in the window of a department store, in several historical and cross-cultural contexts.[6]
The exhibition display pointed out the lack of a "natural link" between an item of clothing and the masculinity of femininity of the wearer, mentioning the kilt as "one of the most potent, versatile, and enduring skirt forms often looked upon by fashion designers as a symbol of a natural, uninhibited, masculinity". It pointed out that fashion designers and male skirt-wearers employ the wearing of skirts for three purposes: to transgress conventional moral and social codes, to redefine the ideal of masculinity, and to inject novelty into male fashion. It linked the wearing of male skirts to youth movements and countercultural movements such as punk, grunge, and glam rock, and to pop music icons such as Boy George and Adrian Young.[6]
Ellsworth eavesdropped on several visitors to the exhibition, noting that because of the exhibition's placement in a self-contained space accessed by a staircase at the far end of the Museum's first floor, the visitors were primarily self-selected as those who would be intrigued enough by such an idea in the first place to actually seek it out. According to her report, the reactions were wide-ranging, from the number of women who teased their male companions about whether they would ever consider wearing skirts (to which several men responded that they would) to the man who said "A caftan — after a shower or in the gym — can you imagine? 'Excuse me! Coming through!'". An adolescent girl rejected in disgust the notion that skirts were similar to the wide pants worn by hip-hop artists. Two elderly women called the idea "utterly ridiculous". One man, reading the exhibition's presentation on the subject of male skirt-wearing in cultures other than those in the North America and Europe, observed that "God! Three quarters of the world's population [wear skirts]!".[6]
The exhibition itself attempted to provoke visitors into considering how, historically, male dress codes have come to this point, and whether in fact a trend towards the wearing of skirts by men in the future actually exists. It attempted to raise challenging questions of how a simple item of dress connotes (in Ellsworth's words) "huge ramifications in meanings, behaviours, everyday life, senses of self and others, and configurations of insider and outsider".[6]
# General Popularity
The wearing of skirts, kilts, or similar garments on an everyday basis by men in western cultures is, as of 2007, very much a minority movement.
Kilts, and derivatives of the garment remain popular. One manufacturer of contemporary kilt styles claims to sell over 12,000 such garments annually,[7] resulting in over $2 million annually worth of sales, and has appeared at a major fashion show. [8] According to a CNN correspondent: "At Seattle's Fremont Market, men are often seen sporting the Utilikilt" [9] US News said in 2003 that "... the Seattle-made utilikilt, a rugged, everyday riff on traditional Scottish garb, has leapt from idea to over 10,000 sold in just three years, via the Web and word of mouth alone."[10] "They've become a common sight around Seattle, especially in funkier neighborhoods and at the city's many alternative cultural events. They often are worn with chunky black boots." writes AP reporter Anne Kim.[11] "I actually see more people wearing kilts in Seattle than I did when I lived in Scotland," one purchaser remarked in 2003.[12]
In addition, since the mid-1990s a number of clothing companies have been established to sell skirts specifically designed for men. These include Macabi Skirt in the 1990s, Menintime in 1999 and Midas Clothing in 2002.
# Wicca and neo-paganism
In Wicca and neopaganism in the United States of America, men (just as women) are encouraged to question their traditional gender roles. Amongst other things this involves the wearing of skirts at festivals and sabbat celebrations, as ritual clothing (which Eilers equates to the "church clothes" worn by Christians on Sundays).[13][14]
# Dance
In some western dance cultures, men commonly wear skirts and kilts. These include a broad range of professional dance productions where they may be worn to improve the artistic effect of the choreography[15], a style known as contra dance, where they are worn partly for ventilation and partly for the swirling movement[16], gay line dancing clubs where kilts are often worn[17], and revellers in Scottish night clubs where they are worn for ventilation and to express cultural identity.
# Outside of Western cultures
Outside of Western cultures, male clothing includes skirts and skirt-like garments[18]. One common form is a single sheet of fabric folded and wrapped around the waist, such as the dhoti in India, and the Lungi and sarong in South/Southeast Asia. Some long robes also resemble a skirt or dress, including the Middle Eastern and North African caftan and djellaba.
# In fiction
One notable example of men wearing skirts in fiction is in early episodes of Star Trek: The Next Generation. The uniforms worn in the first and second season included a variant consisting of a short sleeved top, with attached skirt. This variant was seen worn by both male and female crew members. The Art of Star Trek explained that "the skirt design for men 'skant' was a logical development, given the total equality of the sexes presumed to exist in the 24th century." | https://www.wikidoc.org/index.php/Men%27s_skirts | |
02ffcfcca58a350a859d621d86b680bc32369cce | wikidoc | Menstruation | Menstruation
# Overview
Menstruation is a phase of the menstrual cycle in which the uterine lining (endometrium) is shed. Menstrual cycles occur exclusively in humans and other great apes. The females of other mammalian species experience an estrus, in which the endometrium is reabsorbed by the animal at the end of its reproductive cycle.
# Characteristics
Eumenorrhea denotes normal, regular menstruation that lasts for a few days (usually 3 to 5 days, but anywhere from 2 to 7 days is considered normal).
The average blood loss during menstruation is 35 millilitres with 10-80 mL considered normal;
many females also notice shedding of the endometrium lining that appears as tissue mixed with the blood. An enzyme called plasmin — contained in the endometrium — tends to inhibit the blood from clotting. Because of this blood loss, females have higher dietary requirements for iron than do males to prevent iron deficiency. Many females experience uterine cramps, also referred to as dysmenorrhea, during this time. A vast industry has grown to provide drugs to aid in these cramps, as well as sanitary products to help manage menses.
# As part of the menstrual cycle
Menstruation is the most visible phase of the menstrual cycle. Menstrual cycles are counted from the first day of menstrual bleeding, because the onset of menstruation corresponds closely with the hormonal cycle.
The evolutionary impetus for menstruation remains somewhat unclear. Most mammals reabsorb the uterine lining during their oestral cycle. The ancient writer Hippocrates considered that menstruation was intended to cleanse the body of "evil humours", and modern evolutionary biologist Margie Profet contends that the primary function of menstruation is to remove sperm-borne pathogens from the uterus. In support of this theory, she has pointed to the relatively high levels of macrophages in menstrual blood. Anthropologist Beverly Strassmann has posited that the energy savings of not having to continuously maintain the uterine lining more than offsets the blood loss of menstruation. Currently, however, no single explanation of the evolutionary purpose of menstruation is accepted.
Beginning in 1971, some research suggested that menstrual cycles of co-habiting human females became synchronized. Anthropologists such as Desmond Morris and Chris Knight hypothesized that in hunter-gatherer societies, males would go on hunting journeys whilst the females of the tribe were menstruating, speculating that the females would not have been as receptive to sexual relations while menstruating. However, there is currently significant dispute as to whether menstrual synchrony exists.
# Culture and menstruation
Common usage refers to menstruation and menses as a period. Aside from its biological purpose, this bleeding serves as a sign that a woman has not become pregnant. (However, this cannot be taken as certainty, as sometimes there is some bleeding in early pregnancy, and some women have irregular cycles.) During the reproductive years, failure to menstruate may provide the first indication to a woman that she may have become pregnant. A woman might say that her "period is late" when an expected menstruation has not started and she might have become pregnant.
Many religions have menstruation-related traditions. These may be bans on certain actions during menstruation (such as intercourse in orthodox Judaism and Islam), or rituals to be performed at the end of each menses (such as the mikvah in Judaism and the ghusl in Islam). Some traditional societies sequester females in residences ("menstrual huts") that are reserved for that exclusive purpose until the end of their menstrual period.
## Physical experience
In many women, various intense sensations brought about by the involved hormones and by cramping of the uterus can precede or accompany menstruation. Stronger sensations may include significant menstrual pain (dysmenorrhea), abdominal pain, migraine headaches, depression, emotional sensitivity, feeling bloated, and changes in sex drive. Breast discomfort caused by premenstrual water retention or hormone fluctuation is very common. The sensations experienced vary from woman to woman and from cycle to cycle.
## Emotional reactions
Many women experience emotional side-effects. These range from the irritability popularly associated with Premenstrual Syndrome, to tiredness, or "weepiness" (i.e. tears of emotional closeness). A similar range of emotional effects and mood swings is associated with pregnancy.
## Flow
The normal menstrual flow follows a "crescendo-decrescendo" pattern; that is, it starts at a moderate level, increases somewhat, and then slowly tapers. Sudden heavy flows or amounts in excess of 80 mL (hypermenorrhea or menorrhagia) may stem from hormonal disturbance, uterine abnormalities, including uterine leiomyoma or cancer, and other causes. Doctors call the opposite phenomenon, of bleeding very little, hypomenorrhea.
## Duration
The typical woman bleeds for two to seven days at the beginning of each menstrual cycle.
Prolonged bleeding (metrorrhagia, also meno-metrorrhagia) no longer shows a clear interval pattern. Dysfunctional uterine bleeding refers to hormonally caused bleeding abnormalities, typically anovulation.
All these bleeding abnormalities need medical attention; they may indicate hormone imbalances, uterine fibroids, or other problems. As pregnant patients may bleed, a pregnancy test forms part of the evaluation of abnormal bleeding.
# Menstrual products
Most women use something to absorb or catch their menses. There are a number of different methods available.
Disposable items:
- Sanitary napkins (Sanitary towels) or pads - Somewhat rectangular pieces of material worn in the underwear to absorb menstrual flow, often with "wings," pieces that fold around the panties, and/or an adhesive backing to hold the pad in place. Disposable synthetic pads are made of wood pulp or synthetic products, usually with a plastic lining and bleached. Some sanitary napkins, particularly older styles, are held in place by a belt-like apparatus, instead of adhesive or wings.
- Tampons - Disposable cylinders of treated rayon/cotton blends or all-cotton fleece, usually bleached, that are inserted into the vagina to absorb menstrual flow.
- Padettes - Disposable wads of treated rayon/cotton blend fleece that are placed within the inner labia to absorb menstrual flow.
- Disposable menstrual cups -- A firm, flexible cup-shaped device worn inside the vagina to catch menstrual flow. Disposable cups are made of soft plastic.
Reusable items:
- Reusable cloth pads are made of cotton (often organic), terrycloth, or flannel, and may be handsewn (from material or reused old clothes and towels) or storebought.
- Menstrual cups - A firm, flexible bell-shaped device worn inside the vagina to catch menstrual flow. Reusable versions include rubber or silicone cups.
- Sea sponges - Natural sponges, worn internally like a tampon to absorb menstrual flow.
- Padded panties - Reuseable cloth (usually cotton) underwear with extra absorbent layers sewn in to absorb flow. (like Lunapads)
- Blanket, towel - (also known as a draw sheet) -- large reusable piece of cloth, most often used at night, placed between legs to absorb menstrual flow.
In addition to products to contain the menstrual flow, pharmaceutical companies likewise provide products — commonly non-steroidal anti-inflammatory drugs (NSAIDs) — to relieve menstrual cramps. Some herbs, such as dong quai, raspberry leaf and crampbark, are also claimed to relieve menstrual pain, however there is no documented scientific evidence. | Menstruation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
# Overview
Menstruation is a phase of the menstrual cycle in which the uterine lining (endometrium) is shed. Menstrual cycles occur exclusively in humans and other great apes.[1] The females of other mammalian species experience an estrus, in which the endometrium is reabsorbed by the animal at the end of its reproductive cycle.
# Characteristics
Eumenorrhea denotes normal, regular menstruation that lasts for a few days (usually 3 to 5 days, but anywhere from 2 to 7 days is considered normal).[2]
The average blood loss during menstruation is 35 millilitres with 10-80 mL considered normal;[3]
many females also notice shedding of the endometrium lining that appears as tissue mixed with the blood. An enzyme called plasmin — contained in the endometrium — tends to inhibit the blood from clotting. Because of this blood loss, females have higher dietary requirements for iron than do males to prevent iron deficiency. Many females experience uterine cramps, also referred to as dysmenorrhea, during this time. A vast industry has grown to provide drugs to aid in these cramps, as well as sanitary products to help manage menses.
# As part of the menstrual cycle
Menstruation is the most visible phase of the menstrual cycle. Menstrual cycles are counted from the first day of menstrual bleeding, because the onset of menstruation corresponds closely with the hormonal cycle.
The evolutionary impetus for menstruation remains somewhat unclear. Most mammals reabsorb the uterine lining during their oestral cycle. The ancient writer Hippocrates considered that menstruation was intended to cleanse the body of "evil humours", and modern evolutionary biologist Margie Profet contends that the primary function of menstruation is to remove sperm-borne pathogens from the uterus. In support of this theory, she has pointed to the relatively high levels of macrophages in menstrual blood. Anthropologist Beverly Strassmann has posited that the energy savings of not having to continuously maintain the uterine lining more than offsets the blood loss of menstruation. Currently, however, no single explanation of the evolutionary purpose of menstruation is accepted.[4]
Beginning in 1971, some research suggested that menstrual cycles of co-habiting human females became synchronized. Anthropologists such as Desmond Morris and Chris Knight hypothesized that in hunter-gatherer societies, males would go on hunting journeys whilst the females of the tribe were menstruating, speculating that the females would not have been as receptive to sexual relations while menstruating.[5][6] However, there is currently significant dispute as to whether menstrual synchrony exists.[7]
# Culture and menstruation
Common usage refers to menstruation and menses as a period. Aside from its biological purpose, this bleeding serves as a sign that a woman has not become pregnant. (However, this cannot be taken as certainty, as sometimes there is some bleeding in early pregnancy, and some women have irregular cycles.) During the reproductive years, failure to menstruate may provide the first indication to a woman that she may have become pregnant. A woman might say that her "period is late" when an expected menstruation has not started and she might have become pregnant.
Many religions have menstruation-related traditions. These may be bans on certain actions during menstruation (such as intercourse in orthodox Judaism and Islam), or rituals to be performed at the end of each menses (such as the mikvah in Judaism and the ghusl in Islam). Some traditional societies sequester females in residences ("menstrual huts") that are reserved for that exclusive purpose until the end of their menstrual period.
## Physical experience
Template:Seealso
In many women, various intense sensations brought about by the involved hormones and by cramping of the uterus can precede or accompany menstruation. Stronger sensations may include significant menstrual pain (dysmenorrhea), abdominal pain, migraine headaches, depression, emotional sensitivity, feeling bloated, and changes in sex drive. Breast discomfort caused by premenstrual water retention or hormone fluctuation is very common. The sensations experienced vary from woman to woman and from cycle to cycle.
## Emotional reactions
Many women experience emotional side-effects. These range from the irritability popularly associated with Premenstrual Syndrome, to tiredness, or "weepiness" (i.e. tears of emotional closeness). A similar range of emotional effects and mood swings is associated with pregnancy.
## Flow
The normal menstrual flow follows a "crescendo-decrescendo" pattern; that is, it starts at a moderate level, increases somewhat, and then slowly tapers. Sudden heavy flows or amounts in excess of 80 mL (hypermenorrhea or menorrhagia) may stem from hormonal disturbance, uterine abnormalities, including uterine leiomyoma or cancer, and other causes. Doctors call the opposite phenomenon, of bleeding very little, hypomenorrhea.
## Duration
The typical woman bleeds for two to seven days at the beginning of each menstrual cycle.
Prolonged bleeding (metrorrhagia, also meno-metrorrhagia) no longer shows a clear interval pattern. Dysfunctional uterine bleeding refers to hormonally caused bleeding abnormalities, typically anovulation.
All these bleeding abnormalities need medical attention; they may indicate hormone imbalances, uterine fibroids, or other problems. As pregnant patients may bleed, a pregnancy test forms part of the evaluation of abnormal bleeding.
# Menstrual products
Most women use something to absorb or catch their menses. There are a number of different methods available.
Disposable items:
- Sanitary napkins (Sanitary towels) or pads - Somewhat rectangular pieces of material worn in the underwear to absorb menstrual flow, often with "wings," pieces that fold around the panties, and/or an adhesive backing to hold the pad in place. Disposable synthetic pads are made of wood pulp or synthetic products, usually with a plastic lining and bleached. Some sanitary napkins, particularly older styles, are held in place by a belt-like apparatus, instead of adhesive or wings.
- Tampons - Disposable cylinders of treated rayon/cotton blends or all-cotton fleece, usually bleached, that are inserted into the vagina to absorb menstrual flow.
- Padettes - Disposable wads of treated rayon/cotton blend fleece that are placed within the inner labia to absorb menstrual flow.
- Disposable menstrual cups -- A firm, flexible cup-shaped device worn inside the vagina to catch menstrual flow. Disposable cups are made of soft plastic.
Reusable items:
- Reusable cloth pads are made of cotton (often organic), terrycloth, or flannel, and may be handsewn (from material or reused old clothes and towels) or storebought.
- Menstrual cups - A firm, flexible bell-shaped device worn inside the vagina to catch menstrual flow. Reusable versions include rubber or silicone cups.
- Sea sponges - Natural sponges, worn internally like a tampon to absorb menstrual flow.
- Padded panties - Reuseable cloth (usually cotton) underwear with extra absorbent layers sewn in to absorb flow. (like Lunapads)
- Blanket, towel - (also known as a draw sheet) -- large reusable piece of cloth, most often used at night, placed between legs to absorb menstrual flow.
In addition to products to contain the menstrual flow, pharmaceutical companies likewise provide products — commonly non-steroidal anti-inflammatory drugs (NSAIDs) — to relieve menstrual cramps. Some herbs, such as dong quai, raspberry leaf and crampbark, are also claimed to relieve menstrual pain, however there is no documented scientific evidence.[8] | https://www.wikidoc.org/index.php/Menses | |
528979ab92c24cde8d337c2032c5a9d01f4363c4 | wikidoc | Mental model | Mental model
A mental model is an explanation in someone's thought process for how something works in the real world. It is a kind of internal symbol or representation of external reality, hypothesized to play a major role in cognition and decision-making. Once formed, mental models may replace carefully considered analysis as a means of conserving time and energy. A simple example is the mental model of a wild animal as dangerous: upon encountering a raccoon or a snake, one who holds this model will likely retreat from the animal as if by reflex. Retreat is the result of the application of the mental model, and would probably not be the immediate reaction of one whose mental model of wild animals was formed solely from experience with similar stuffed toy animals, or who had not yet formed any mental models about wild raccoons or snakes.
The term is believed to have been originated by Kenneth Craik in his 1943 book The Nature of Explanation. After the early death of Craik in a bicycle accident, the idea was not elaborated on until much later. Before Craik, Georges-Henri Luquet had already developed this idea to some extent: in his seminal book Le dessin enfantin (Children's Drawings), published in 1927 by Alcan, Paris, he argued that children obviously construct internal models, a view that influenced, among others, Jean Piaget.
Two books, both titled Mental Models, appeared in 1983 . One was by Philip Johnson-Laird, a psychology professor at Princeton University. The other was a collection of articles edited by Dedre Gentner and Albert Stevens. The first line of this book helps explain the idea further: "One function of this chapter is to belabor the obvious; people's views of the world, of themselves, of their own capabilities, and of the tasks that they are asked to perform, or topics they are asked to learn, depend heavily on the conceptualizations that they bring to the task." See Mental Models (Gentner-Stevens book). Since then there has been much discussion and use of the idea in human computer interaction and usability by people such as Donald Norman and by Steve Krug in his book Don't Make Me Think. Walter Kintsch and Teun A. van Dijk, using the term situation model (in their book Strategies of Discourse Comprehension, 1983), showed the relevance of mental models for the production and comprehension of discourse.
# Researchers who study mental models
- Ruth Byrne
- Dedre Gentner
- Philip Johnson-Laird
- Stephen J. Payne, Internet Archive version
- Walter Kintsch
- Teun A. van Dijk
- Norbert M. Seel
# Software
- CONSIDEO MODELER
- STELLA / iThink
- VENSIM | Mental model
A mental model is an explanation in someone's thought process for how something works in the real world. It is a kind of internal symbol or representation of external reality, hypothesized to play a major role in cognition and decision-making. Once formed, mental models may replace carefully considered analysis as a means of conserving time and energy. A simple example is the mental model of a wild animal as dangerous: upon encountering a raccoon or a snake, one who holds this model will likely retreat from the animal as if by reflex. Retreat is the result of the application of the mental model, and would probably not be the immediate reaction of one whose mental model of wild animals was formed solely from experience with similar stuffed toy animals, or who had not yet formed any mental models about wild raccoons or snakes.
The term is believed to have been originated by Kenneth Craik in his 1943 book The Nature of Explanation. After the early death of Craik in a bicycle accident, the idea was not elaborated on until much later. Before Craik, Georges-Henri Luquet had already developed this idea to some extent: in his seminal book Le dessin enfantin (Children's Drawings), published in 1927 by Alcan, Paris, he argued that children obviously construct internal models, a view that influenced, among others, Jean Piaget.
Two books, both titled Mental Models, appeared in 1983 [1]. One was by Philip Johnson-Laird, a psychology professor at Princeton University. The other was a collection of articles edited by Dedre Gentner and Albert Stevens. The first line of this book helps explain the idea further: "One function of this chapter is to belabor the obvious; people's views of the world, of themselves, of their own capabilities, and of the tasks that they are asked to perform, or topics they are asked to learn, depend heavily on the conceptualizations that they bring to the task." See Mental Models (Gentner-Stevens book). Since then there has been much discussion and use of the idea in human computer interaction and usability by people such as Donald Norman and by Steve Krug in his book Don't Make Me Think. Walter Kintsch and Teun A. van Dijk, using the term situation model (in their book Strategies of Discourse Comprehension, 1983), showed the relevance of mental models for the production and comprehension of discourse.
# Researchers who study mental models
- Ruth Byrne
- Dedre Gentner
- Philip Johnson-Laird
- Stephen J. Payne, Internet Archive version
- Walter Kintsch
- Teun A. van Dijk
- Norbert M. Seel
# Software
- CONSIDEO MODELER
- STELLA / iThink
- VENSIM | https://www.wikidoc.org/index.php/Mental_model | |
e404cb7b7f566a2542a80f1562b3924bed170e20 | wikidoc | Mesna (oral) | Mesna (oral)
# 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
Mesna (oral) is a cytoprotective agent that is FDA approved for the prophylaxis of ifosfamide-induced hemorrhagic cystitis. Common adverse reactions include nausea, vomiting, constipation, leukopenia, fatigue, fever, anorexia, thrombocytopenia, anemia, granulocytopenia, diarrhea, asthenia, abdominal pain, headache, alopecia, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- MESNEX may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of MESNEX tablets as outlined below.
- MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. MESNEX tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of MESNEX is 100% of the ifosfamide dose. The recommended dosing schedule is outlined in Table 2.
- The efficacy and safety of this ratio of intravenous and oral MESNEX has not been established as being effective for daily doses of ifosfamide higher than 2 g/m2.
- Patients who vomit within two hours of taking oral MESNEX should repeat the dose or receive intravenous MESNEX.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American Society of Clinical Oncology
- Class of Recommendation: Class IIb
- Strength of Evidence: Category B
- Dosing Information
- In the setting on stem cell transplantation, forced/saline diuresis or saline diuresis plus mesna is recommended.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mesna (oral) in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Mesna (oral) in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mesna (oral) in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mesna (oral) in pediatric patients.
# Contraindications
- MESNEX is contraindicated in patients known to be hypersensitive to MESNEX or to any of the excipients.
# Warnings
### Precautions
- Hypersensitivity Reactions
- MESNEX may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue MESNEX and provide supportive care.
- Dermatologic Toxicity
- Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions, consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. MESNEX may cause skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema, periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several months of exposure. Discontinue MESNEX and provide supportive care.
- Benzyl Alcohol Toxicity
- Benzyl alcohol, a preservative in MESNEX, has been associated with serious adverse reactions and death (including gasping syndrome) in neonates, premature, and low-birth weight infants. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Consider the combined daily metabolic load of benzyl alcohol from all sources when prescribing MESNEX (10.4 mg benzyl alcohol per mL). Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Monitor patients for signs or symptoms of toxicity. Avoid use in neonates, premature, and low-birth weight infants.
- Laboratory Test Interferences
- False-Positive Urine Tests for Ketone Bodies
- A false positive test for urinary ketones may arise in patients treated with MESNEX when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet color that intensifies).
- False-Negative Tests for Enzymatic CPK Activity
- MESNEX may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use a thiol compound (e.g., N-acetylcysteine) for CPK reactiviation. This may result in a falsely low CPK level.
- False-Positive Tests for Ascorbic Acid
- MESNEX may cause false-positive reactions in Tillman’s reagent-based urine screening tests for ascorbic acid.
- Use in Patients with a History of Adverse Reactions to Thiol Compounds
- MESNEX is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Hypersensitivity reactions to MESNEX and to amifostine, another thiol compound, have been reported. It is not clear whether patients who experienced an adverse reaction to a thiol compound are at increased risk for a hypersensitivity reaction to MESNEX.
# 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.
- MESNEX adverse reaction data are available from four Phase 1 studies in which single intravenous doses of 600-1200 mg MESNEX Injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers and single oral doses of 600-2400 mg of MESNEX Tablets were administered to a total of 82 healthy volunteers. The most frequently reported side effects (observed in two or more healthy volunteers) for healthy volunteers receiving single doses of MESNEX Injection alone were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, and coughing. In two Phase 1 multiple-dose studies where healthy volunteers received MESNEX Tablets alone or intravenous MESNEX followed by repeated doses of MESNEX Tablets, flatulence and rhinitis were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of intravenous MESNEX.
- Additional adverse reactions in healthy volunteers receiving MESNEX alone included injection site reactions, abdominal pain/colic, epigastric pain/burning, mucosal irritation, lightheadedness, back pain, arthralgia, myalgia, conjunctivitis, nasal congestion, rigors, paresthesia, photophobia, fatigue, lymphadenopathy, extremity pain, malaise, chest pain, dysuria, pleuritic pain, dry mouth, dyspnea, and hyperhidrosis. In healthy volunteers, MESNEX was commonly associated with a rapid (within 24 hours) decrease in lymphocyte count, which was generally reversible within one week of administration.
- Because MESNEX is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to MESNEX from those caused by the concomitantly administered cytotoxic agents.
- Adverse reactions reasonably associated with MESNEX administered intravenously and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in Table 3.
## Postmarketing Experience
- The following adverse reactions have been reported in the postmarketing experience of patients receiving MESNEX in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse reactions which may be due to MESNEX from those caused by the concomitantly administered cytotoxic agents. Because these reactions are reported from a population of unknown size, precise estimates of frequency cannot be made.
Hypertension
Dysgeusia
Hepatitis
Convulsion
Hemoptysis
# Drug Interactions
- No clinical drug interaction studies have been conducted with MESNEX.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no studies of MESNEX in pregnant women. Reproduction studies performed in rats and rabbits at oral doses approximately 10 times the maximum recommended total daily intravenous-oral-oral human dose on a body surface area basis (1000 mg/kg in rabbits and 2000 mg/kg in rats) revealed no evidence of harm to the fetus due to mesna. The incidence of malformations in human pregnancies has not been established for MESNEX. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations and 15 to 20% for pregnancy loss. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy 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 Mesna (oral) in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mesna (oral) during labor and delivery.
### Nursing Mothers
- It is not known whether mesna or dimesna is excreted in human milk. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from MESNEX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of MESNEX in pediatric patients have not been established. MESNEX contains benzyl alcohol (10.4 mg benzyl alcohol per mL) which has been associated with serious adverse reactions and death in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis and gasping respirations) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates, premature, and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
### Geriatic Use
- Clinical studies of MESNEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The ratio of ifosfamide to MESNEX should remain unchanged.
### Gender
There is no FDA guidance on the use of Mesna (oral) with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mesna (oral) with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mesna (oral) in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mesna (oral) in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mesna (oral) in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mesna (oral) in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when MESNEX is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.
# IV Compatibility
There is limited information regarding IV Compatibility of Mesna (oral) in the drug label.
# Overdosage
## Acute Overdose
- There is no known antidote for MESNEX.
- In a clinical trial, 11 patients received intravenous MESNEX 10 mg/kg to 66 mg/kg per day for 3 to 5 days. Patients also received ifosfamide or cyclophosphamide. Adverse reactions included nausea, vomiting, diarrhea and fever. An increased rate of these adverse reactions has also been found in oxazaphosphorine-treated patients receiving ≥80 mg MESNEX per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.
- Postmarketing, administration of 4.5 g to 6.9 g of MESNEX resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mesna (oral) in the drug label.
# Pharmacology
## Mechanism of Action
- Mesna reacts chemically with the urotoxic ifosfamide metabolites, acrolein and 4-hydroxy-ifosfamide, resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder.
## Structure
- MESNEX is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active ingredient, mesna, is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2 and a molecular weight of 164.18. Its structural formula is as follows:
- HS–CH2–CH2SO3–Na+
- MESNEX (mesna) injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multidose vials for intravenous administration. MESNEX injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. MESNEX Injection multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of 7.5-8.5.
- MESNEX (mesna) tablets are white, oblong, scored biconvex film-coated tablets with the imprint M4. They contain 400 mg mesna. The excipients are calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Mesna (oral) in the drug label.
## Pharmacokinetics
- Absorption
- Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses.
- Food does not affect the urinary availability of orally administered MESNEX.
- Distribution
- Mean apparent volume of distribution (Vd) for mesna is 0.652 ± 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water).
- Metabolism
- Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Plasma concentrations of mesna exceed those of dimesna after oral or intravenous administration.
- Excretion
- Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.
## Nonclinical Toxicology
- No long-term studies in animals have been performed to evaluate the carcinogenic potential of mesna.
- Mesna was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.
- No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies (≤ 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on a body surface area basis.
# Clinical Studies
- Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At a dose of 1.2 g/m2 ifosfamide administered daily for 5 days, 16 to 26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC per hpf or macrohematuria) (Studies 1, 2, and 3). In contrast, none of the patients who received mesna injection together with this dose of ifosfamide developed hematuria (Studies 3 and 4). In two randomized studies, (Studies 5 and 6), higher doses of ifosfamide, from 2 g/m2 to 4 g/m2 administered for 3 to 5 days, produced hematuria in 31 to 100% of the patients. When MESNEX was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.
- Clinical studies comparing recommended intravenous and oral MESNEX dosing regimens demonstrated incidences of grade 3 to 4 hematuria of <5%. Study 7 was an open label, randomized, two-way crossover study comparing three intravenous doses with an initial intravenous dose followed by two oral doses of MESNEX in patients with cancer treated with ifosfamide at a dose of 1.2 g/m2 to 2.0 g/m2 for 3 to 5 days. Study 8 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 5 days. In both studies, development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing hematuria in each of these studies is presented in Table 5.
# How Supplied
- MESNEX (mesna) injection 100 mg/mL
- NDC 0338-1305-01 1 g Multidose Vial, Box of 1 vial of 10 mL
- NDC 0338-1305-03 1 g Multidose Vial, Box of 10 vials of 10 mL
- Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).
- MESNEX (mesna) tablets
- NDC 67108-3565-9 400 mg scored tablets packaged in box of 10 tablets
- Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).
## Storage
There is limited information regarding Mesna (oral) Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to discontinue MESNEX and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction, including systemic anaphylactic reactions occur.
- Advise the patient to take MESNEX at the exact time and in the exact amount as prescribed. Advise the patient to contact their healthcare provider if they vomit within 2 hours of taking oral MESNEX, or if they miss a dose of oral MESNEX.
- MESNEX does not prevent hemorrhagic cystitis in all patients nor does it prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide. Advise the patient to report to their healthcare provider if his/her urine has turned a pink or red color.
- Advise the patient to drink 1 to 2 liters of fluid each day during MESNEX therapy.
- Advise the patient that Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions have occurred with MESNEX. Advise the patient to report to their healthcare provider if signs and symptoms of these syndromes occur.
# Precautions with Alcohol
- Alcohol-Mesna (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MESNEX®
# Look-Alike Drug Names
- mesna® — mesalamine®
# Drug Shortage Status
# Price | Mesna (oral)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
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# Overview
Mesna (oral) is a cytoprotective agent that is FDA approved for the prophylaxis of ifosfamide-induced hemorrhagic cystitis. Common adverse reactions include nausea, vomiting, constipation, leukopenia, fatigue, fever, anorexia, thrombocytopenia, anemia, granulocytopenia, diarrhea, asthenia, abdominal pain, headache, alopecia, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- MESNEX may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of MESNEX tablets as outlined below.
- MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. MESNEX tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of MESNEX is 100% of the ifosfamide dose. The recommended dosing schedule is outlined in Table 2.
- The efficacy and safety of this ratio of intravenous and oral MESNEX has not been established as being effective for daily doses of ifosfamide higher than 2 g/m2.
- Patients who vomit within two hours of taking oral MESNEX should repeat the dose or receive intravenous MESNEX.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American Society of Clinical Oncology
- Class of Recommendation: Class IIb
- Strength of Evidence: Category B
- Dosing Information
- In the setting on stem cell transplantation, forced/saline diuresis or saline diuresis plus mesna is recommended.[1]
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mesna (oral) in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Mesna (oral) in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mesna (oral) in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mesna (oral) in pediatric patients.
# Contraindications
- MESNEX is contraindicated in patients known to be hypersensitive to MESNEX or to any of the excipients.
# Warnings
### Precautions
- Hypersensitivity Reactions
- MESNEX may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue MESNEX and provide supportive care.
- Dermatologic Toxicity
- Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions, consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. MESNEX may cause skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema, periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several months of exposure. Discontinue MESNEX and provide supportive care.
- Benzyl Alcohol Toxicity
- Benzyl alcohol, a preservative in MESNEX, has been associated with serious adverse reactions and death (including gasping syndrome) in neonates, premature, and low-birth weight infants. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Consider the combined daily metabolic load of benzyl alcohol from all sources when prescribing MESNEX (10.4 mg benzyl alcohol per mL). Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Monitor patients for signs or symptoms of toxicity. Avoid use in neonates, premature, and low-birth weight infants.
- Laboratory Test Interferences
- False-Positive Urine Tests for Ketone Bodies
- A false positive test for urinary ketones may arise in patients treated with MESNEX when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet color that intensifies).
- False-Negative Tests for Enzymatic CPK Activity
- MESNEX may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use a thiol compound (e.g., N-acetylcysteine) for CPK reactiviation. This may result in a falsely low CPK level.
- False-Positive Tests for Ascorbic Acid
- MESNEX may cause false-positive reactions in Tillman’s reagent-based urine screening tests for ascorbic acid.
- Use in Patients with a History of Adverse Reactions to Thiol Compounds
- MESNEX is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Hypersensitivity reactions to MESNEX and to amifostine, another thiol compound, have been reported. It is not clear whether patients who experienced an adverse reaction to a thiol compound are at increased risk for a hypersensitivity reaction to MESNEX.
# 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.
- MESNEX adverse reaction data are available from four Phase 1 studies in which single intravenous doses of 600-1200 mg MESNEX Injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers and single oral doses of 600-2400 mg of MESNEX Tablets were administered to a total of 82 healthy volunteers. The most frequently reported side effects (observed in two or more healthy volunteers) for healthy volunteers receiving single doses of MESNEX Injection alone were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, and coughing. In two Phase 1 multiple-dose studies where healthy volunteers received MESNEX Tablets alone or intravenous MESNEX followed by repeated doses of MESNEX Tablets, flatulence and rhinitis were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of intravenous MESNEX.
- Additional adverse reactions in healthy volunteers receiving MESNEX alone included injection site reactions, abdominal pain/colic, epigastric pain/burning, mucosal irritation, lightheadedness, back pain, arthralgia, myalgia, conjunctivitis, nasal congestion, rigors, paresthesia, photophobia, fatigue, lymphadenopathy, extremity pain, malaise, chest pain, dysuria, pleuritic pain, dry mouth, dyspnea, and hyperhidrosis. In healthy volunteers, MESNEX was commonly associated with a rapid (within 24 hours) decrease in lymphocyte count, which was generally reversible within one week of administration.
- Because MESNEX is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to MESNEX from those caused by the concomitantly administered cytotoxic agents.
- Adverse reactions reasonably associated with MESNEX administered intravenously and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in Table 3.
## Postmarketing Experience
- The following adverse reactions have been reported in the postmarketing experience of patients receiving MESNEX in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse reactions which may be due to MESNEX from those caused by the concomitantly administered cytotoxic agents. Because these reactions are reported from a population of unknown size, precise estimates of frequency cannot be made.
Hypertension
Dysgeusia
Hepatitis
Convulsion
Hemoptysis
# Drug Interactions
- No clinical drug interaction studies have been conducted with MESNEX.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no studies of MESNEX in pregnant women. Reproduction studies performed in rats and rabbits at oral doses approximately 10 times the maximum recommended total daily intravenous-oral-oral human dose on a body surface area basis (1000 mg/kg in rabbits and 2000 mg/kg in rats) revealed no evidence of harm to the fetus due to mesna. The incidence of malformations in human pregnancies has not been established for MESNEX. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations and 15 to 20% for pregnancy loss. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy 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 Mesna (oral) in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mesna (oral) during labor and delivery.
### Nursing Mothers
- It is not known whether mesna or dimesna is excreted in human milk. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from MESNEX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of MESNEX in pediatric patients have not been established. MESNEX contains benzyl alcohol (10.4 mg benzyl alcohol per mL) which has been associated with serious adverse reactions and death in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis and gasping respirations) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates, premature, and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
### Geriatic Use
- Clinical studies of MESNEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The ratio of ifosfamide to MESNEX should remain unchanged.
### Gender
There is no FDA guidance on the use of Mesna (oral) with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mesna (oral) with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mesna (oral) in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mesna (oral) in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mesna (oral) in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mesna (oral) in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when MESNEX is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.
# IV Compatibility
There is limited information regarding IV Compatibility of Mesna (oral) in the drug label.
# Overdosage
## Acute Overdose
- There is no known antidote for MESNEX.
- In a clinical trial, 11 patients received intravenous MESNEX 10 mg/kg to 66 mg/kg per day for 3 to 5 days. Patients also received ifosfamide or cyclophosphamide. Adverse reactions included nausea, vomiting, diarrhea and fever. An increased rate of these adverse reactions has also been found in oxazaphosphorine-treated patients receiving ≥80 mg MESNEX per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.
- Postmarketing, administration of 4.5 g to 6.9 g of MESNEX resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mesna (oral) in the drug label.
# Pharmacology
## Mechanism of Action
- Mesna reacts chemically with the urotoxic ifosfamide metabolites, acrolein and 4-hydroxy-ifosfamide, resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder.
## Structure
- MESNEX is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active ingredient, mesna, is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2 and a molecular weight of 164.18. Its structural formula is as follows:
- HS–CH2–CH2SO3–Na+
- MESNEX (mesna) injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multidose vials for intravenous administration. MESNEX injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. MESNEX Injection multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of 7.5-8.5.
- MESNEX (mesna) tablets are white, oblong, scored biconvex film-coated tablets with the imprint M4. They contain 400 mg mesna. The excipients are calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Mesna (oral) in the drug label.
## Pharmacokinetics
- Absorption
- Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses.
- Food does not affect the urinary availability of orally administered MESNEX.
- Distribution
- Mean apparent volume of distribution (Vd) for mesna is 0.652 ± 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water).
- Metabolism
- Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Plasma concentrations of mesna exceed those of dimesna after oral or intravenous administration.
- Excretion
- Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.
## Nonclinical Toxicology
- No long-term studies in animals have been performed to evaluate the carcinogenic potential of mesna.
- Mesna was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.
- No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies (≤ 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on a body surface area basis.
# Clinical Studies
- Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At a dose of 1.2 g/m2 ifosfamide administered daily for 5 days, 16 to 26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC per hpf or macrohematuria) (Studies 1, 2, and 3). In contrast, none of the patients who received mesna injection together with this dose of ifosfamide developed hematuria (Studies 3 and 4). In two randomized studies, (Studies 5 and 6), higher doses of ifosfamide, from 2 g/m2 to 4 g/m2 administered for 3 to 5 days, produced hematuria in 31 to 100% of the patients. When MESNEX was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.
- Clinical studies comparing recommended intravenous and oral MESNEX dosing regimens demonstrated incidences of grade 3 to 4 hematuria of <5%. Study 7 was an open label, randomized, two-way crossover study comparing three intravenous doses with an initial intravenous dose followed by two oral doses of MESNEX in patients with cancer treated with ifosfamide at a dose of 1.2 g/m2 to 2.0 g/m2 for 3 to 5 days. Study 8 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 5 days. In both studies, development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing hematuria in each of these studies is presented in Table 5.
# How Supplied
- MESNEX (mesna) injection 100 mg/mL
- NDC 0338-1305-01 1 g Multidose Vial, Box of 1 vial of 10 mL
- NDC 0338-1305-03 1 g Multidose Vial, Box of 10 vials of 10 mL
- Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).
- MESNEX (mesna) tablets
- NDC 67108-3565-9 400 mg scored tablets packaged in box of 10 tablets
- Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).
## Storage
There is limited information regarding Mesna (oral) Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to discontinue MESNEX and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction, including systemic anaphylactic reactions occur.
- Advise the patient to take MESNEX at the exact time and in the exact amount as prescribed. Advise the patient to contact their healthcare provider if they vomit within 2 hours of taking oral MESNEX, or if they miss a dose of oral MESNEX.
- MESNEX does not prevent hemorrhagic cystitis in all patients nor does it prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide. Advise the patient to report to their healthcare provider if his/her urine has turned a pink or red color.
- Advise the patient to drink 1 to 2 liters of fluid each day during MESNEX therapy.
- Advise the patient that Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions have occurred with MESNEX. Advise the patient to report to their healthcare provider if signs and symptoms of these syndromes occur.
# Precautions with Alcohol
- Alcohol-Mesna (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MESNEX®[2]
# Look-Alike Drug Names
- mesna® — mesalamine®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mesna_(oral) | |
1ca89d7f15ee65419c0f997055ba2ecbc4359277 | wikidoc | Mesoridazine | Mesoridazine
# Overview
Mesoridazine (Serentil) is a piperidine neuroleptic drug belonging to the class of drugs called phenothiazines, used in the treatment of schizophrenia. It is a metabolite of thioridazine. The drug's name is derived from the methylsulfoxy and piperidine functional groups in its chemical structure.
It has central antiadrenergic, antidopaminergic, antiserotonergic and weak muscarinic anticholinergic effects.
Serious side effects include akathisia, tardive dyskinesia and the potentially fatal neuroleptic malignant syndrome.
Mesoridazine was withdrawn from the United States market in 2004 due to dangerous side effects, namely irregular heart beat and QT-prolongation of the electrocardiogram.
It currently appears to be unavailable worldwide.
# Chemistry
Mesoridazine (10--2-(methylsufinyl)phenothiazine) is synthesized by an analogous scheme to that seen already for thioridazine.
However, it is also synthesized by alkylating the acidic form of 2-methylthiophenothiazine -methylsulfonylphenothiazine- using 2-(2-chloroethyl)-1-methylpiperidine. 2-methylthiophenothiazine is initially acylated at the nitrogen atom using acetic anhydride, giving 10-acetyl-2-methylthiophenothiazine. The resulting acetyl derivative is further oxidized by hydrogen peroxide into 10-acetyl-2-methylsulfonylpenothiazine. Deacylation of this product in potassium carbonate methanol solution gives 2-methylsulfanylphenothiazine, which is alkylated by 2-(2-chlorethyl)-1-methylpiperidine in the presence of sodamide, affording the desired mesoridazine. | Mesoridazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Mesoridazine (Serentil) is a piperidine neuroleptic drug belonging to the class of drugs called phenothiazines, used in the treatment of schizophrenia. It is a metabolite of thioridazine. The drug's name is derived from the methylsulfoxy and piperidine functional groups in its chemical structure.
It has central antiadrenergic, antidopaminergic, antiserotonergic and weak muscarinic anticholinergic effects.
Serious side effects include akathisia, tardive dyskinesia and the potentially fatal neuroleptic malignant syndrome.
Mesoridazine was withdrawn from the United States market in 2004 due to dangerous side effects, namely irregular heart beat and QT-prolongation of the electrocardiogram.[1]
It currently appears to be unavailable worldwide.
# Chemistry
Mesoridazine (10-[2-(1-methyl-2-piperidyl)ethyl]-2-(methylsufinyl)phenothiazine) is synthesized by an analogous scheme to that seen already for thioridazine.
However, it is also synthesized by alkylating the acidic form of 2-methylthiophenothiazine -methylsulfonylphenothiazine- using 2-(2-chloroethyl)-1-methylpiperidine. 2-methylthiophenothiazine is initially acylated at the nitrogen atom using acetic anhydride, giving 10-acetyl-2-methylthiophenothiazine. The resulting acetyl derivative is further oxidized by hydrogen peroxide into 10-acetyl-2-methylsulfonylpenothiazine. Deacylation of this product in potassium carbonate methanol solution gives 2-methylsulfanylphenothiazine, which is alkylated by 2-(2-chlorethyl)-1-methylpiperidine in the presence of sodamide, affording the desired mesoridazine. | https://www.wikidoc.org/index.php/Mesoridazine | |
bce4f965c222b0d0da029c9afe2d5236f727c6ee | wikidoc | Metabolomics | Metabolomics
# Overview
Metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind" - specifically, the study of their small-molecule metabolite profiles. The metabolome represents the collection of all metabolites in a biological organism, which are the end products of its gene expression. Thus, while mRNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling can give an instantaneous snapshot of the physiology of that cell. One of the challenges of systems biology is to integrate proteomic, transcriptomic, and metabolomic information to give a more complete picture of living organisms.
# Metabolome
Metabolome refers to the complete set of small-molecule metabolites (such as metabolic intermediates, hormones and other signalling molecules, and secondary metabolites) to be found within a biological sample, such as a single organism. The word was coined in analogy with transcriptomics and proteomics; like the transcriptome and the proteome, the metabolome is dynamic, changing from second to second. Although the metabolome can be defined readily enough, it is not currently possible to analyse the entire range of metabolites by a single analytical method. In January 2007, scientists at the University of Alberta and the University of Calgary completed the first draft of the human metabolome. They catalogued approximately 2500 metabolites, 1200 drugs and 3500 food components that can be found in the human body, as reported in the literature. This information, available at the Human Metabolome Database (HMDB is available at: www.hmdb.ca.) and based on analysis of information available in the current the scientific literature, is far from complete.
In contrast, much more is known about the metabolomes of other organisms, especially of plants, where over 50,000 metabolites have been characterized from the plant kingdom, and many thousands of metabolites have been identified and/or characterized from single plants. Metabolomics in today's world carries on its shoulders the huge responsibility of providing a detailed description of metabolic pathways and their workings, whether they be in humans, animals, or the plants we both eat and admire.
# Metabolites
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in the normal growth, development, and reproduction. A secondary metabolite is not directly involved in those processes, but usually has important ecological function. Examples include antibiotics and pigments.
The metabolome forms a large network of metabolic reactions, where outputs from one enzymatic chemical reaction are inputs to other chemical reactions. Such systems have been described as hypercycles.
# Metabonomics
Metabonomics is defined as "the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification". This approach originated at Imperial College London and has been used in toxicology, disease diagnosis and a number of other fields.
There has been some disagreement over the exact differences between 'metabolomics' and 'metabonomics', although the term 'metabolomics' is more commonly used. The difference between the two terms is not related to choice of analytical platform: although metabonomics is more associated with NMR spectroscopy and metabolomics with mass spectrometry-based techniques, this is simply because of usages amongst different groups that have popularized the different terms. While there is still no absolute agreement, there is a growing consensus that the difference resides in the fact that 'metabolomics' places a greater emphasis on comprehensive metabolic profiling, regardless of species investigated, while 'metabonomics' is used to describe multiple (but not necessarily comprehensive) metabolic changes caused by a biological perturbation. The term 'metabonomics' is rarely used to describe research not directly related to human disease or nutrition. In practice, within the field of human disease research there is still a large degree of overlap in the way both terms are used, and they are often in effect synonymous.
# History
Metabolic biochemists have arguably been 'doing metabolomics' for decades. The chromatographic separation techniques that made the initial detection of metabolites possible were developed in the late 1960's, which marks the technical origin of the field.
The development of metabolomics began in 1970 by Arthur Robinson investigating Pauling's ideas as to whether biological variability could be explained on the basis of far wider ranges of nutritional requirements than what was generally recognized. In analyzing the "messy" chromatographic patterns of urine from vitamin B6-loaded subjects, Robinson realized that the patterns of hundreds or thousands of chemical constituents in urine contained much useful information.
Although it was not called metabolomics, the first paper devoted to this topic was titled, “Quantitative Analysis of Urine Vapor and Breath by Gas-Liquid Partition Chromatography”, by Robinson and Pauling in 1971 and published in the Proceedings of the National Academy of Sciences. Since then, Robinson has had nineteen more papers published on the quantitative patterns of metabolites in body fluids (see below). Robinson and colleagues have identified several diseases, conditions, and physiological age based on this data. It was his expectation that body fluid analysis can be optimized to make a low cost, information-rich, medically-relevant means of measuring metabolically-driven changes in functional state, even when the chemical constituents are all in the “normal range”.
The core idea that Robinson conceived is that information-rich data that reflects the functional status of a complex biological system resides in the quantitative and qualitative pattern of metabolites in body fluids. Twenty years later, others began to realize the value of this approach, and interest in this has mushroomed. The name metabolomics was coined in the 1990s (the first paper using the word metabolome is Oliver, S. G., Winson, M. K., Kell, D. B. & Baganz, F. (1998). Systematic functional analysis of the yeast genome. Trends Biotechnol. 16, 373-378), and in 2004 a society was formed to promote its study. Many of the bioanalytical methods used for metabolomics have been adapted (or in some cases simply adopted) from existing biochemical techniques. What sets metabolomics apart from strictly analytical chemistry-based analyses is the scope of the work. Three characteristics common to metabolomic research are:
- Effort is made to profile metabolites with as little bias as is possible towards a specific metabolite or group of metabolites. Nevertheless, all profiling approaches require extraction of metabolites from biological tissues, and will therefore be biased due to solvent properties. This holds true, but is reduced, even if multiple solvent systems are used.
- Large numbers of metabolites are profiled at the same time, instead of being analyzed one by one.
- Relationships between the metabolites are characterized, currently mostly by multivariate methods, although other data analysis tools are being developed.
The field of metabolomics exploded in the early 2000s, particularly as a result of efforts by researchers from the Max Planck Institute for Plant Physiology, in Golm, Germany, under the direction of Prof. Dr. Lothar Willmitzer. Their research, while still more appropriately called 'metabolite profiling' because they analyzed only hundreds of compounds and not the entire complement of the plant cell, set the framework for metabolomics-scale investigations. Their review articles promoting the field and its potential applications to agriculture, medicine, and other fields in the biological sciences, definitely had a strong stimulatory effect on the field as a whole.
On January 23rd, 2007, the Human Metabolome Project, led by Dr. David Wishart of the University of Alberta, Canada, completed the first draft of the human metabolome, consisting of a database of approximately 2500 metabolites, 1200 drugs and 3500 food components. Similar projects have been underway in several plant species, most notably Medicago truncatula and Arabidopsis thaliana for several years.
# Analytical technologies
There are four important issues to be addressed for metabolite analysis: 1. Efficient and unbiased extraction of metabolites from biological tissues. 2. Separation of the analytes, usually by chromatography. Electrophoresis, particularly capillary electrophoresis, is also used. 3. Detection of the analytes, following separation by chromatographic or other methods. 4. Identification and quantification of the analytes.
## Separation methods
- Gas chromatography, especially when interfaced with mass spectrometry (GC-MS), is one of the most widely used and powerful methods. It offers very high chromatographic resolution, but requires chemical derivatization for many biomolecules: only volatile chemicals can be analysed without derivatization. (Some modern instruments allow '2D' chromatography, using a short polar column after the main analytical column, which increases the resolution still further.) Some large and polar metabolites cannot be analysed by GC.
- High performance liquid chromatography (HPLC). Compared to GC, HPLC has lower chromatographic resolution, but it does have the advantage that a much wider range of analytes can potentially be measured.
- Capillary electrophoresis (CE). So far, there are only a relatively small number of publications on use of CE for metabolite profiling. This will no doubt change, as there are a number of advantages of CE: it has a higher theoretical separation efficiency than HPLC, and is suitable for use with a wider range of metabolite classes than is GC. As for all electrophoretic techniques, it is most appropriate for charged analytes.
## Detection methods
- Mass spectrometry (MS) is used to identify and to quantify metabolites after separation by GC, HPLC, or CE. GC-MS is the most 'natural' combination of the three, and was the first to be developed. In addition, mass spectral fingerprint libraries exist or can be developed that allow identification of a metabolite according to its fragmentation pattern. MS is both sensitive (although, particularly for HPLC-MS, sensitivity is more of an issue as it is affected by the charge on the metabolite, and can be subject to ion suppression artifacts) and can be very specific. There are also a number of studies which use MS as a stand-alone technology: the sample is infused directly into the mass spectrometer with no prior separation, and the MS serves to both separate and to detect metabolites.
- Nuclear magnetic resonance (NMR) spectroscopy. NMR is the only detection technique which does not rely on separation of the analytes, and the sample can thus be recovered for further analyses. All kinds of small molecule metabolites can be measured simultaneously - in this sense, NMR is close to being a universal detector. Practically, however, it is relatively insensitive compared to mass spectrometry-based techniques; additionally, NMR spectra can be very difficult to interpret for complex mixtures.
- Other techniques. MS and NMR are by far the two leading technologies for metabolomics. Other methods of detection that have been used include electrochemical detection (coupled to HPLC) and radiolabel (when combined with thin-layer chromatography).
# Key applications
- Toxicity assessment/toxicology. Metabolic profiling (especially of urine or blood plasma samples) can be used to detect the physiological changes caused by toxic insult of a chemical (or mixture of chemicals). In many cases, the observed changes can be related to specific syndromes, e.g. a specific lesion in liver or kidney. This is of particular relevance to pharmaceutical companies wanting to test the toxicity of potential drug candidates: if a compound can be eliminated before it reaches clinical trials on the grounds of adverse toxicity, it saves the enormous expense of the trials.
- Functional genomics. Metabolomics can be an excellent tool for determining the phenotype caused by a genetic manipulation, such as gene deletion or insertion. Sometimes this can be a sufficient goal in itself -- for instance, to detect any phenotypic changes in a genetically-modified plant intended for human or animal consumption. More exciting is the prospect of predicting the function of unknown genes by comparison with the metabolic perturbations caused by deletion/insertion of known genes. Such advances are most likely to come from model organisms such as Saccharomyces cerevisiae and Arabidopsis thaliana.
- Nutrigenomics is a generalised term which links genomics, transcriptomics, proteomics and metabolomics to human nutrition. In general a metabolome in a given body fluid is influenced by endogenous factors such as age, sex, body composition and genetics as well as underlying pathologies. The large bowel microflora are also a very significant potential confounder of metabolic profiles and could be classified as either an endogenous or exogenous factor. The main exogenous factors are diet and drugs. Diet can then be broken down to nutrients and non- nutrients. Metabolomics is one means to determine a biological endpoint, or metabolic fingerprint, which reflects the balance of all these forces on an individual's metabolism. | Metabolomics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind" - specifically, the study of their small-molecule metabolite profiles.[1] The metabolome represents the collection of all metabolites in a biological organism, which are the end products of its gene expression. Thus, while mRNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling can give an instantaneous snapshot of the physiology of that cell. One of the challenges of systems biology is to integrate proteomic, transcriptomic, and metabolomic information to give a more complete picture of living organisms.
# Metabolome
Metabolome refers to the complete set of small-molecule metabolites (such as metabolic intermediates, hormones and other signalling molecules, and secondary metabolites) to be found within a biological sample, such as a single organism.[2] The word was coined in analogy with transcriptomics and proteomics; like the transcriptome and the proteome, the metabolome is dynamic, changing from second to second. Although the metabolome can be defined readily enough, it is not currently possible to analyse the entire range of metabolites by a single analytical method. In January 2007, scientists at the University of Alberta and the University of Calgary completed the first draft of the human metabolome. They catalogued approximately 2500 metabolites, 1200 drugs and 3500 food components that can be found in the human body, as reported in the literature.[3] This information, available at the Human Metabolome Database (HMDB is available at: www.hmdb.ca.) and based on analysis of information available in the current the scientific literature, is far from complete.
In contrast, much more is known about the metabolomes of other organisms, especially of plants, where over 50,000 metabolites have been characterized from the plant kingdom, and many thousands of metabolites have been identified and/or characterized from single plants. Metabolomics in today's world carries on its shoulders the huge responsibility of providing a detailed description of metabolic pathways and their workings, whether they be in humans, animals, or the plants we both eat and admire.
# Metabolites
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in the normal growth, development, and reproduction. A secondary metabolite is not directly involved in those processes, but usually has important ecological function. Examples include antibiotics and pigments.
The metabolome forms a large network of metabolic reactions, where outputs from one enzymatic chemical reaction are inputs to other chemical reactions. Such systems have been described as hypercycles.
# Metabonomics
Metabonomics is defined as "the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification". This approach originated at Imperial College London and has been used in toxicology, disease diagnosis and a number of other fields.[4]
There has been some disagreement over the exact differences between 'metabolomics' and 'metabonomics', although the term 'metabolomics' is more commonly used. The difference between the two terms is not related to choice of analytical platform: although metabonomics is more associated with NMR spectroscopy and metabolomics with mass spectrometry-based techniques, this is simply because of usages amongst different groups that have popularized the different terms. While there is still no absolute agreement, there is a growing consensus that the difference resides in the fact that 'metabolomics' places a greater emphasis on comprehensive metabolic profiling, regardless of species investigated, while 'metabonomics' is used to describe multiple (but not necessarily comprehensive) metabolic changes caused by a biological perturbation. The term 'metabonomics' is rarely used to describe research not directly related to human disease or nutrition. In practice, within the field of human disease research there is still a large degree of overlap in the way both terms are used, and they are often in effect synonymous.
# History
Metabolic biochemists have arguably been 'doing metabolomics' for decades. The chromatographic separation techniques that made the initial detection of metabolites possible were developed in the late 1960's, which marks the technical origin of the field. [5]
The development of metabolomics began in 1970 by Arthur Robinson investigating Pauling's ideas as to whether biological variability could be explained on the basis of far wider ranges of nutritional requirements than what was generally recognized. In analyzing the "messy" chromatographic patterns of urine from vitamin B6-loaded subjects, Robinson realized that the patterns of hundreds or thousands of chemical constituents in urine contained much useful information.
Although it was not called metabolomics, the first paper devoted to this topic was titled, “Quantitative Analysis of Urine Vapor and Breath by Gas-Liquid Partition Chromatography”, by Robinson and Pauling in 1971 and published in the Proceedings of the National Academy of Sciences. Since then, Robinson has had nineteen more papers published on the quantitative patterns of metabolites in body fluids (see below). Robinson and colleagues have identified several diseases, conditions, and physiological age based on this data. It was his expectation that body fluid analysis can be optimized to make a low cost, information-rich, medically-relevant means of measuring metabolically-driven changes in functional state, even when the chemical constituents are all in the “normal range”.
The core idea that Robinson conceived is that information-rich data that reflects the functional status of a complex biological system resides in the quantitative and qualitative pattern of metabolites in body fluids. Twenty years later, others began to realize the value of this approach, and interest in this has mushroomed. The name metabolomics was coined in the 1990s (the first paper using the word metabolome is Oliver, S. G., Winson, M. K., Kell, D. B. & Baganz, F. (1998). Systematic functional analysis of the yeast genome. Trends Biotechnol. 16, 373-378), and in 2004 a society was formed to promote its study. Many of the bioanalytical methods used for metabolomics have been adapted (or in some cases simply adopted) from existing biochemical techniques. What sets metabolomics apart from strictly analytical chemistry-based analyses is the scope of the work. Three characteristics common to metabolomic research are:
- Effort is made to profile metabolites with as little bias as is possible towards a specific metabolite or group of metabolites. Nevertheless, all profiling approaches require extraction of metabolites from biological tissues, and will therefore be biased due to solvent properties. This holds true, but is reduced, even if multiple solvent systems are used.
- Large numbers of metabolites are profiled at the same time, instead of being analyzed one by one.
- Relationships between the metabolites are characterized, currently mostly by multivariate methods, although other data analysis tools are being developed.
The field of metabolomics exploded in the early 2000s, particularly as a result of efforts by researchers from the Max Planck Institute for Plant Physiology, in Golm, Germany, under the direction of Prof. Dr. Lothar Willmitzer. Their research, while still more appropriately called 'metabolite profiling' because they analyzed only hundreds of compounds and not the entire complement of the plant cell, set the framework for metabolomics-scale investigations. Their review articles promoting the field and its potential applications to agriculture, medicine, and other fields in the biological sciences, definitely had a strong stimulatory effect on the field as a whole.
On January 23rd, 2007, the Human Metabolome Project, led by Dr. David Wishart of the University of Alberta, Canada, completed the first draft of the human metabolome, consisting of a database of approximately 2500 metabolites, 1200 drugs and 3500 food components. Similar projects have been underway in several plant species, most notably Medicago truncatula and Arabidopsis thaliana for several years.
# Analytical technologies
There are four important issues to be addressed for metabolite analysis: 1. Efficient and unbiased extraction of metabolites from biological tissues. 2. Separation of the analytes, usually by chromatography. Electrophoresis, particularly capillary electrophoresis, is also used. 3. Detection of the analytes, following separation by chromatographic or other methods. 4. Identification and quantification of the analytes.
## Separation methods
- Gas chromatography, especially when interfaced with mass spectrometry (GC-MS), is one of the most widely used and powerful methods. It offers very high chromatographic resolution, but requires chemical derivatization for many biomolecules: only volatile chemicals can be analysed without derivatization. (Some modern instruments allow '2D' chromatography, using a short polar column after the main analytical column, which increases the resolution still further.) Some large and polar metabolites cannot be analysed by GC.
- High performance liquid chromatography (HPLC). Compared to GC, HPLC has lower chromatographic resolution, but it does have the advantage that a much wider range of analytes can potentially be measured.
- Capillary electrophoresis (CE). So far, there are only a relatively small number of publications on use of CE for metabolite profiling. This will no doubt change, as there are a number of advantages of CE: it has a higher theoretical separation efficiency than HPLC, and is suitable for use with a wider range of metabolite classes than is GC. As for all electrophoretic techniques, it is most appropriate for charged analytes.
## Detection methods
- Mass spectrometry (MS) is used to identify and to quantify metabolites after separation by GC, HPLC, or CE. GC-MS is the most 'natural' combination of the three, and was the first to be developed. In addition, mass spectral fingerprint libraries exist or can be developed that allow identification of a metabolite according to its fragmentation pattern. MS is both sensitive (although, particularly for HPLC-MS, sensitivity is more of an issue as it is affected by the charge on the metabolite, and can be subject to ion suppression artifacts) and can be very specific. There are also a number of studies which use MS as a stand-alone technology: the sample is infused directly into the mass spectrometer with no prior separation, and the MS serves to both separate and to detect metabolites.
- Nuclear magnetic resonance (NMR) spectroscopy. NMR is the only detection technique which does not rely on separation of the analytes, and the sample can thus be recovered for further analyses. All kinds of small molecule metabolites can be measured simultaneously - in this sense, NMR is close to being a universal detector. Practically, however, it is relatively insensitive compared to mass spectrometry-based techniques; additionally, NMR spectra can be very difficult to interpret for complex mixtures.
- Other techniques. MS and NMR are by far the two leading technologies for metabolomics. Other methods of detection that have been used include electrochemical detection (coupled to HPLC) and radiolabel (when combined with thin-layer chromatography).
# Key applications
- Toxicity assessment/toxicology. Metabolic profiling (especially of urine or blood plasma samples) can be used to detect the physiological changes caused by toxic insult of a chemical (or mixture of chemicals). In many cases, the observed changes can be related to specific syndromes, e.g. a specific lesion in liver or kidney. This is of particular relevance to pharmaceutical companies wanting to test the toxicity of potential drug candidates: if a compound can be eliminated before it reaches clinical trials on the grounds of adverse toxicity, it saves the enormous expense of the trials.
- Functional genomics. Metabolomics can be an excellent tool for determining the phenotype caused by a genetic manipulation, such as gene deletion or insertion. Sometimes this can be a sufficient goal in itself -- for instance, to detect any phenotypic changes in a genetically-modified plant intended for human or animal consumption. More exciting is the prospect of predicting the function of unknown genes by comparison with the metabolic perturbations caused by deletion/insertion of known genes. Such advances are most likely to come from model organisms such as Saccharomyces cerevisiae and Arabidopsis thaliana.
- Nutrigenomics is a generalised term which links genomics, transcriptomics, proteomics and metabolomics to human nutrition. In general a metabolome in a given body fluid is influenced by endogenous factors such as age, sex, body composition and genetics as well as underlying pathologies. The large bowel microflora are also a very significant potential confounder of metabolic profiles and could be classified as either an endogenous or exogenous factor. The main exogenous factors are diet and drugs. Diet can then be broken down to nutrients and non- nutrients. Metabolomics is one means to determine a biological endpoint, or metabolic fingerprint, which reflects the balance of all these forces on an individual's metabolism.[6] | https://www.wikidoc.org/index.php/Metabolites | |
8b45f0d2eebef743c716b0d31fa40357fee1b7b8 | wikidoc | Methacholine | Methacholine
# 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
Methacholine is a non-selective muscarinic receptor agonist that is FDA approved for the diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma. Common adverse reactions include headache, throat irritation, Iightheadedness and itching.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Indications
- Methacholine chloride powder for inhalation is indicated for the diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma.
## Dosage
- Before methacholine chloride powder for inhalation Inhalation challenge is begun, baseline pulmonary function tests must be performed. A subject to be challenged must have an FEV1 of at least 70% of the predicted value.
- The target level for a positive challenge is a 20% reduction in the FEV1 compared with the baseline value after inhalation of the control sodium chloride solution (Note: Use the same diluent that the methacholine powder has been reconstituted with for the baseline spirometry). This target value should be calculated and recorded before methacholine challenge is started.
- Dilutions: (Note: Do not inhale powder. Do not handle this material if you have asthma or hay fever.) All dilutions should be made with 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0) using sterile, empty USP Type I borosilcate glass vials. After adding the sodium chloride solution, shake each vial to obtain a clear solution (Note: When preparing dilutions, use only the same kind of diluent to prepare all concentrations).
- Dilutions A through D should be stored at 36° to 46°F (2° to 8°C) in a refrigerator and can be stored for not more than 2 weeks. . After this time, discard the vials and prepare new dilutions. Freezing does not affect the stability of dilutions A through D. Vial E must be prepared on the day of challenge.
- A Sterile bacterial-retentive filter (porosity 0.22µm) should be used when transferring a solution from each vial (at least 2mL) to a nebulizer.
- Procedure: A standardized procedure for inhalation has been developed.
- The challenge is performed by giving a subject ascending serial concentrations of methacholine. At each concentration, five breaths are administered by a nebulizer that permits intermittent delivery time of 0.6 seconds by a breath-actuated timing device (dosimeter).
- At each of five inhalations of a serial concentration, the subject begins at functional residual capacity (FRC) and slowly and completely inhales the dose delivered. Within 5 minutes, FEV1 values are determined. The procedure ends either when there is a 20% or greater reduction in FEV1 compared with the baseline sodium chloride solution value (i.e., a positive response) or if 188.88 total cumulative units has been administered (see table below) and the FEV1 has been reduced by 14% or less (i.e., a negative response). If there is a reduction of 15% to 19% in the FEV1 compared with baseline, either the challenge may be repeated at that concentration or a higher concentration may be given as long as the dosage administered does not result in total cumulative units exceeding 188.88.
- The following is a suggested schedule for the administration of methacholine (methacholine chloride powder for inhalation) challenge. Cumulative units are calculated by multiplying the number of breaths by the concentration administered.
- An inhaled beta-agonist may be administered after methacholine challenge to expedite the return of the FEV1 to baseline and to relieve the discomfort of the subject. Most patients revert to normal pulmonary function within 5 minutes following bronchodilators or within 30 to 45 minutes without any bronchodilator.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Methacholine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Methacholine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and efficacy of methacholine inhalation challenge have not been established in children below the age of 5 years.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Methacholine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Methacholine in pediatric patients.
# Contraindications
- Methacholine chloride powder for inhalation is contraindicated in patients with known hypersensitivity to this drug or to other parasympathomimetic agents.
- Repeated administration of methacholine by inhalation other than on the day that a patient undergoes challenge with increasing doses is contraindicated.
- Inhalation challenge should not be performed in patients receiving any beta-adrenergic blocking agent because in such patients responses to methacholine chloride can be exaggerated or prolonged, and may not respond as readily to accepted modalities of treatment.
# Warnings
## Precations
### General
- Administration of methacholine chloride powder for inhalation to patients with epilepsy, cardiovascular disease accompanied by bradycardia, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other condition that could be adversely affected by a cholinergic agent should be undertaken only if the physician feels benefit to the individual outweighs the potential risks.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions associated with 153 inhaled methacholine chloride challenges include one occurrence each of headache, throat irritation, Iightheadedness and itching.
- Methacholine chloride powder for inhalation is to be administered only by inhalation. When administered orally or by injection, methacholine chloride is reported to be associated with nausea and vomiting, substernal pain or pressure, hypotension,fainting and transient complete heart block.
## Postmarketing Experience
- There is limited information regarding postmarketing experience.
# Drug Interactions
- There is limited information regarding Drug Interactions.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with methacholine chloride. It is not known whether methacholine chloride can cause fetal harm when administered to a pregnant patient or affect reproductive capacity. Methacholine chloride should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methacholine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Methacholine during labor and delivery.
### Nursing Mothers
- Methacholine inhalation challenge should not be administered to a nursing mother since it is not known whether methacholine chloride when inhaled is excreted in breast milk.
### Pediatric Use
- The safety and efficacy of methacholine inhalation challenge have not been established in children below the age of 5 years.
### Geriatic Use
There is no FDA guidance on the use of Methacholine in geriatric settings.
### Gender
There is no FDA guidance on the use of Methacholine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Methacholine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Methacholine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Methacholine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methacholine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Methacholine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Respiratory (inhalation)
### Monitoring
There is limited information regarding drug monitoring
# IV Compatibility
- There is limited information regarding IV Compatibility.
# Overdosage
- Methacholine chloride powder for inhalation is to be administered only by inhalation. When administered orally or by injection, overdosage with methacholine chloride can result in a syncopal reaction, with cardiac arrest and loss of consciousness. Serious toxic reactions should be treated with 0.5 mg to 1 mg of atropine sulfate, administered IM or IV.
- The acute (24 hour) oral LD50 of methacholine chloride and related compounds is 1100 mg/kg in the mouse and 750 mg/kg in the rat.
- Cynomolgus monkeys were exposed to a 2% (20 mg/mL) aerosol of methacholine chloride in acute (10 minute) and subchronic (7 day) inhalation toxicity studies. In the former study, animals exposed to the aerosol for up to 10 minutes demonstrated an increase in respiratory rate and decrease in tidal volume after 30 seconds. These changes peaked at 2 minutes and were followed by a rise in pulmonary resistance and a decrease in compliance. Pulmonary function returned to normal 20 to 25 minutes after exposure ended. In the 7 day study, monkeys were given daily inhalations equivalent to the maximum and roughly five times the maximum standard human dose. Although the typical pulmonary response/ recovery sequence was observed, distinct changes in airway resistance were noted at the end of the study. These changes were not rapidly reversed in the maximum equivalent standard dose group, which was observed for 9 weeks.
# Pharmacology
## Mechanism of Action
- Methacholine chloride is the ß-methyl homolog of acetylcholine and differs from the latter primarily in its greater duration and selectivity of action. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation.
- Bronchoconstriction occurs when the vagus nerve is stimulated and acetylcholine is released from the nerve endings. Muscle constriction is essentially confined to the local site of release because acetylcholine is rapidly inactivated by acetylcholinesterase.
- Compared with acetylcholine, methacholine chloride is more slowly hydrolyzed by acetylcholinesterase and is almost totally resistant to inactivation by nonspecific cholinesterase or pseudocholinesterase. When a sodium chloride solution containing methacholine chloride is inhaled, subjects with asthma are markedly more sensitive to methacholine-induced bronchoconstriction than are healthy subjects. This difference in response is the pharmacologic basis for the methacholine (methacholine chloride powder for inhalation) inhalation diagnostic challenge. However, it should be recognized that methacholine challenge may occasionally be positive after influenza, upper respiratory infections or immunizations, in very young or very old patients, or in patients with chronic lung disease (cystic fibrosis, sarcoidosis, tuberculosis, chronic obstructive pulmonary disease). The challenge may also be positive in patients with allergic rhinitis without asthma, in smokers, in patients after exposure to air pollutants, or in patients who have had or will in the future develop asthma.
## Structure
- Methacholine chloride powder for inhalation is a parasympathomimetic (cholinergic)) bronchoconstrictor agent to be administered in solution only, by inhalation, for diagnostic purposes. Each 20 mL vial contains 100 mg and each 50 mL vial contains 1600 mg of methacholine chloride powder which is to be reconstituted with 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0).
- Chemically, methacholine chloride (the active ingredient) is 1-propanaminium, 2-(acetyloxy)N,N,N, - trimethyl,-chloride. It is a white to practically white deliquescent compound, soluble in water. Methacholine chloride has an empirical formula of C8H18ClN02, a calculated molecular weight of 195.69, and the following structural formula:
## Pharmacodynamics
There is limited information regarding Methacholine Pharmacodynamics in the drug label.
## Pharmacokinetics
- There are no pharmacokinetic data available on methacholine chloride.
## Nonclinical Toxicology
- There have been no studies with methacholine chloride that would permit an evaluation of its carcinogenic or mutagenic potential or of its effect on fertility.
# Clinical Studies
- There is limited information regarding Clinical Studies.
# How Supplied
- 20mL amber vial containing 100mg methacholine chloride powder which is to be reconstituted with 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0) – boxes of 6 (NDC 64281-100-06).
- 50 mL amber vials containing 1600 mg of methacholine chloride powder which is to be reconstituted with 0.9% sodium chloride injection or with 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0) – single vial per box (NDC 64281-100-16).
## Storage
- Store the powder at 59° to 86°F (15° to 30°C). Refrigerate the reconstituted solutions (dilutions A-D) at 36° to 46°F (2° to 8°C) for not more than 2 weeks. Dilution E must be prepared on the day of the challenge.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- To assure the safe and effective use of Provocholine® inhalation challenge, the following instructions and information should be given to patients:
- Patients should be instructed regarding symptoms that may occur as a result of the test and how such symptoms can be managed.
- Female patient should inform her physician if she is pregnant, or the date of her last onset of menses, or the date and result of her last pregnancy test.
# Precautions with Alcohol
- Alcohol-Methacholine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PROVOCHOLINE®
# Look-Alike Drug Names
- There is limited information regarding Look-Alike Drug Names.
# Drug Shortage Status
# Price | Methacholine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, 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
Methacholine is a non-selective muscarinic receptor agonist that is FDA approved for the diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma. Common adverse reactions include headache, throat irritation, Iightheadedness and itching.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Indications
- Methacholine chloride powder for inhalation is indicated for the diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma.
## Dosage
- Before methacholine chloride powder for inhalation Inhalation challenge is begun, baseline pulmonary function tests must be performed. A subject to be challenged must have an FEV1 of at least 70% of the predicted value.
- The target level for a positive challenge is a 20% reduction in the FEV1 compared with the baseline value after inhalation of the control sodium chloride solution (Note: Use the same diluent that the methacholine powder has been reconstituted with for the baseline spirometry). This target value should be calculated and recorded before methacholine challenge is started.
- Dilutions: (Note: Do not inhale powder. Do not handle this material if you have asthma or hay fever.) All dilutions should be made with 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0) using sterile, empty USP Type I borosilcate glass vials. After adding the sodium chloride solution, shake each vial to obtain a clear solution (Note: When preparing dilutions, use only the same kind of diluent to prepare all concentrations).
- Dilutions A through D should be stored at 36° to 46°F (2° to 8°C) in a refrigerator and can be stored for not more than 2 weeks. [The unreconstituted powder should be stored at 59°F to 86°F (15° to 30°C)]. After this time, discard the vials and prepare new dilutions. Freezing does not affect the stability of dilutions A through D. Vial E must be prepared on the day of challenge.
- A Sterile bacterial-retentive filter (porosity 0.22µm) should be used when transferring a solution from each vial (at least 2mL) to a nebulizer.
- Procedure: A standardized procedure for inhalation has been developed.
- The challenge is performed by giving a subject ascending serial concentrations of methacholine. At each concentration, five breaths are administered by a nebulizer that permits intermittent delivery time of 0.6 seconds by a breath-actuated timing device (dosimeter).
- At each of five inhalations of a serial concentration, the subject begins at functional residual capacity (FRC) and slowly and completely inhales the dose delivered. Within 5 minutes, FEV1 values are determined. The procedure ends either when there is a 20% or greater reduction in FEV1 compared with the baseline sodium chloride solution value (i.e., a positive response) or if 188.88 total cumulative units has been administered (see table below) and the FEV1 has been reduced by 14% or less (i.e., a negative response). If there is a reduction of 15% to 19% in the FEV1 compared with baseline, either the challenge may be repeated at that concentration or a higher concentration may be given as long as the dosage administered does not result in total cumulative units exceeding 188.88.
- The following is a suggested schedule for the administration of methacholine (methacholine chloride powder for inhalation) challenge. Cumulative units are calculated by multiplying the number of breaths by the concentration administered.
- An inhaled beta-agonist may be administered after methacholine challenge to expedite the return of the FEV1 to baseline and to relieve the discomfort of the subject. Most patients revert to normal pulmonary function within 5 minutes following bronchodilators or within 30 to 45 minutes without any bronchodilator.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Methacholine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Methacholine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and efficacy of methacholine inhalation challenge have not been established in children below the age of 5 years.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Methacholine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Methacholine in pediatric patients.
# Contraindications
- Methacholine chloride powder for inhalation is contraindicated in patients with known hypersensitivity to this drug or to other parasympathomimetic agents.
- Repeated administration of methacholine by inhalation other than on the day that a patient undergoes challenge with increasing doses is contraindicated.
- Inhalation challenge should not be performed in patients receiving any beta-adrenergic blocking agent because in such patients responses to methacholine chloride can be exaggerated or prolonged, and may not respond as readily to accepted modalities of treatment.
# Warnings
## Precations
### General
- Administration of methacholine chloride powder for inhalation to patients with epilepsy, cardiovascular disease accompanied by bradycardia, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other condition that could be adversely affected by a cholinergic agent should be undertaken only if the physician feels benefit to the individual outweighs the potential risks.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions associated with 153 inhaled methacholine chloride challenges include one occurrence each of headache, throat irritation, Iightheadedness and itching.
- Methacholine chloride powder for inhalation is to be administered only by inhalation. When administered orally or by injection, methacholine chloride is reported to be associated with nausea and vomiting, substernal pain or pressure, hypotension,fainting and transient complete heart block.
## Postmarketing Experience
- There is limited information regarding postmarketing experience.
# Drug Interactions
- There is limited information regarding Drug Interactions.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with methacholine chloride. It is not known whether methacholine chloride can cause fetal harm when administered to a pregnant patient or affect reproductive capacity. Methacholine chloride should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methacholine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Methacholine during labor and delivery.
### Nursing Mothers
- Methacholine inhalation challenge should not be administered to a nursing mother since it is not known whether methacholine chloride when inhaled is excreted in breast milk.
### Pediatric Use
- The safety and efficacy of methacholine inhalation challenge have not been established in children below the age of 5 years.
### Geriatic Use
There is no FDA guidance on the use of Methacholine in geriatric settings.
### Gender
There is no FDA guidance on the use of Methacholine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Methacholine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Methacholine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Methacholine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methacholine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Methacholine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Respiratory (inhalation)
### Monitoring
There is limited information regarding drug monitoring
# IV Compatibility
- There is limited information regarding IV Compatibility.
# Overdosage
- Methacholine chloride powder for inhalation is to be administered only by inhalation. When administered orally or by injection, overdosage with methacholine chloride can result in a syncopal reaction, with cardiac arrest and loss of consciousness. Serious toxic reactions should be treated with 0.5 mg to 1 mg of atropine sulfate, administered IM or IV.
- The acute (24 hour) oral LD50 of methacholine chloride and related compounds is 1100 mg/kg in the mouse and 750 mg/kg in the rat.
- Cynomolgus monkeys were exposed to a 2% (20 mg/mL) aerosol of methacholine chloride in acute (10 minute) and subchronic (7 day) inhalation toxicity studies. In the former study, animals exposed to the aerosol for up to 10 minutes demonstrated an increase in respiratory rate and decrease in tidal volume after 30 seconds. These changes peaked at 2 minutes and were followed by a rise in pulmonary resistance and a decrease in compliance. Pulmonary function returned to normal 20 to 25 minutes after exposure ended. In the 7 day study, monkeys were given daily inhalations equivalent to the maximum and roughly five times the maximum standard human dose. Although the typical pulmonary response/ recovery sequence was observed, distinct changes in airway resistance were noted at the end of the study. These changes were not rapidly reversed in the maximum equivalent standard dose group, which was observed for 9 weeks.
# Pharmacology
## Mechanism of Action
- Methacholine chloride is the ß-methyl homolog of acetylcholine and differs from the latter primarily in its greater duration and selectivity of action. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation.
- Bronchoconstriction occurs when the vagus nerve is stimulated and acetylcholine is released from the nerve endings. Muscle constriction is essentially confined to the local site of release because acetylcholine is rapidly inactivated by acetylcholinesterase.
- Compared with acetylcholine, methacholine chloride is more slowly hydrolyzed by acetylcholinesterase and is almost totally resistant to inactivation by nonspecific cholinesterase or pseudocholinesterase. When a sodium chloride solution containing methacholine chloride is inhaled, subjects with asthma are markedly more sensitive to methacholine-induced bronchoconstriction than are healthy subjects. This difference in response is the pharmacologic basis for the methacholine (methacholine chloride powder for inhalation) inhalation diagnostic challenge. However, it should be recognized that methacholine challenge may occasionally be positive after influenza, upper respiratory infections or immunizations, in very young or very old patients, or in patients with chronic lung disease (cystic fibrosis, sarcoidosis, tuberculosis, chronic obstructive pulmonary disease). The challenge may also be positive in patients with allergic rhinitis without asthma, in smokers, in patients after exposure to air pollutants, or in patients who have had or will in the future develop asthma.
## Structure
- Methacholine chloride powder for inhalation is a parasympathomimetic (cholinergic)) bronchoconstrictor agent to be administered in solution only, by inhalation, for diagnostic purposes. Each 20 mL vial contains 100 mg and each 50 mL vial contains 1600 mg of methacholine chloride powder which is to be reconstituted with 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0).
- Chemically, methacholine chloride (the active ingredient) is 1-propanaminium, 2-(acetyloxy)N,N,N, - trimethyl,-chloride. It is a white to practically white deliquescent compound, soluble in water. Methacholine chloride has an empirical formula of C8H18ClN02, a calculated molecular weight of 195.69, and the following structural formula:
## Pharmacodynamics
There is limited information regarding Methacholine Pharmacodynamics in the drug label.
## Pharmacokinetics
- There are no pharmacokinetic data available on methacholine chloride.
## Nonclinical Toxicology
- There have been no studies with methacholine chloride that would permit an evaluation of its carcinogenic or mutagenic potential or of its effect on fertility.
# Clinical Studies
- There is limited information regarding Clinical Studies.
# How Supplied
- 20mL amber vial containing 100mg methacholine chloride powder which is to be reconstituted with 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0) – boxes of 6 (NDC 64281-100-06).
- 50 mL amber vials containing 1600 mg of methacholine chloride powder which is to be reconstituted with 0.9% sodium chloride injection or with 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0) – single vial per box (NDC 64281-100-16).
## Storage
- Store the powder at 59° to 86°F (15° to 30°C). Refrigerate the reconstituted solutions (dilutions A-D) at 36° to 46°F (2° to 8°C) for not more than 2 weeks. Dilution E must be prepared on the day of the challenge.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- To assure the safe and effective use of Provocholine® inhalation challenge, the following instructions and information should be given to patients:
- Patients should be instructed regarding symptoms that may occur as a result of the test and how such symptoms can be managed.
- Female patient should inform her physician if she is pregnant, or the date of her last onset of menses, or the date and result of her last pregnancy test.
# Precautions with Alcohol
- Alcohol-Methacholine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PROVOCHOLINE®[1]
# Look-Alike Drug Names
- There is limited information regarding Look-Alike Drug Names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Metacholine | |
87235d9466fb283b8e4a38028c6c5dd3fa35e5a5 | wikidoc | Metanauplius | Metanauplius
Metanauplius is an early larval stage of some crustaceans such as krill. It follows the nauplius stage.
In sac-spawningTemplate:Fn krill, there is an intermediary phase called pseudometanauplius, a newly hatched form distinguished from older metanauplii by its extremely short abdomen. In some species, this form is not considered a separate developmental stage as it develops into a metanauplius without molting; in other species such as Nyctiphanes couchii, it can be separated from the metanauplius stage by the molt of a very thin cuticle soon after hatching.
Broadcast-spawning species of krill do not have a pseudometanauplius stage. They generally hatch in the nauplius 1 stage, but recently have been discovered to hatch sometimes as metanauplius or even as calyptopis stages.
# Footnotes | Metanauplius
Metanauplius is an early larval stage of some crustaceans such as krill. It follows the nauplius stage.
In sac-spawningTemplate:Fn krill, there is an intermediary phase called pseudometanauplius, a newly hatched form distinguished from older metanauplii by its extremely short abdomen. In some species, this form is not considered a separate developmental stage as it develops into a metanauplius without molting; in other species such as Nyctiphanes couchii, it can be separated from the metanauplius stage by the molt of a very thin cuticle soon after hatching.[1]
Broadcast-spawning species of krill do not have a pseudometanauplius stage. They generally hatch in the nauplius 1 stage, but recently have been discovered to hatch sometimes as metanauplius or even as calyptopis stages.[2]
# Footnotes
Template:Fnb There are two kinds of spawning mechanisms in krill. Females of broadcast spawning species just release the fertilized eggs into the water, where they sink, disperse, and are on their own. In sac-spawning species, the female carries the eggs with her attached to its rearmost pairs of thoracopods until they hatch. | https://www.wikidoc.org/index.php/Metanauplius | |
20ae1cd66aee33a0d0f3ed2e9d80233e323772c9 | wikidoc | Methsuximide | Methsuximide
# 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
Methsuximide is an anticonvulsant that is FDA approved for the treatment of absence seizures that are refractory to other drugs. Common adverse reactions include weight loss, abdominal pain, constipation, diarrhea, epigastric pain,loss of appetite, nausea, vomiting
ataxia, dizziness and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Indications
- Methsuximide is indicated for the control of absence seizures (petit mal) that are refractory to other drugs.
## Dosage
- Optimum dosage of methsuximide must be determined by trial. A suggested dosage schedule is 300 mg per day for the first week. If required, dosage may be increased thereafter at weekly intervals by 300 mg per day for the three weeks following to a daily dosage of 1.2 g. Because therapeutic effect and tolerance vary among patients, therapy with methsuximide must be individualized according to the response of each patient. Optimal dosage is that amount of methsuximide which is barely sufficient to control seizures so that side effects may be kept to a minimum.
- Methsuximide may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence (petit mal).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Methsuximide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Methsuximide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-labeled indications and dosage information of Methsuximide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Methsuximide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Methsuximide in pediatric patients.
# Contraindications
- Methsuximide should not be used in patients with a history of hypersensitivity to succinimides.
# Warnings
### Blood dyscrasias
- Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of succinimides; therefore, periodic blood counts should be performed. Should signs and/or symptoms of infection (eg, sore throat, fever) develop, blood counts should be considered at that point.
### Effects on Liver
- It has been reported that succinimides have produced morphological and functional changes in animal liver. For this reason, methsuximide should be administered with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug.
### Systemic Lupus Erythematosus
- Cases of systemic lupus erythematosus have been reported with the use of succinimides. The physician should be alert to this possibility.
### Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including methsuximide, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing methsuximide or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
## Precautions
### General
- It is recommended that the physician withdraw the drug slowly on the appearance of unusual depression, aggressiveness, or other behavioral alterations.
- As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status.
- Methsuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients.
### Information for Patients
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking methsuximide. Instruct patients to take methsuximide only as prescribed.
- Methsuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly. Patients taking methsuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen.
- Patients should be instructed to promptly contact their physician if they develop signs and/or symptoms suggesting an infection (eg, sore throat, fever).
- ADVICE TO THE PHARMACIST AND PATIENT: Since methsuximide has a relatively low melting temperature (124° F), storage conditions which may promote high temperatures (closed cars, delivery vans, or storage near steam pipes) should be avoided. Do not dispense or use capsules that are not full or in which contents have melted. Effectiveness may be reduced. Protect from excessive heat (104° F).
- Patients, their caregivers, and families should be counseled that AEDs, including methsuximide, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.
# Adverse Reactions
## Clinical Trials Experience
- Gastrointestinal System: Gastrointestinal symptoms occur frequently and have included nausea or vomiting, anorexia, diarrhea, weight loss, epigastric and abdominal pain, and constipation.
- Hemopoietic System: Hemopoietic complications associated with the administration of methsuximide have included eosinophilia, leukopenia, monocytosis, and pancytopenia with or without bone marrow suppression.
- Nervous System: Neurologic and sensory reactions reported during therapy with methsuximide have included drowsiness, ataxia or dizziness, irritability and nervousness, headache, blurred vision, photophobia, hiccups, and insomnia. Drowsiness, ataxia, and dizziness have been the most frequent side effects noted. Psychologic abnormalities have included confusion, instability, mental slowness, depression, hypochondriacal behavior, and aggressiveness. There have been rare reports of psychosis, suicidal behavior, and auditory hallucinations.
- Integumentary System: Dermatologic manifestations which have occurred with the administration of methsuximide have included urticaria, Stevens-Johnson syndrome, and pruritic erythematous rashes.
- Cardiovascular: Hyperemia.
- Genitourinary System: Proteinuria, microscopic hematuria.
- Body as a Whole: Periorbital edema.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience.
# Drug Interactions
- Since methsuximide may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg, methsuximide may increase the plasma concentrations of phenytoin and phenobarbital).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.
- The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, eg, genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
- The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methsuximide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Methsuximide during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Methsuximide in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Methsuximide in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Methsuximide in geriatric settings.
### Gender
There is no FDA guidance on the use of Methsuximide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Methsuximide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Methsuximide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Methsuximide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methsuximide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Methsuximide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral.
### Monitoring
- There is limited information regarding drug monitoring.
# IV Compatibility
- There is limited information regarding IV Compatibility.
# Overdosage
- Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. Methsuximide poisoning may follow a biphasic course. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. It is believed that an active metabolite of methsuximide, N-desmethylmethsuximide, is responsible for this biphasic profile. It is important to follow plasma levels of N-desmethylmethsuximide in methsuximide poisonings. Levels greater than 40 µg/mL have caused toxicity, and coma has been seen at levels of 150 µg/mL.
### Treatment
- Treatment should include emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Charcoal hemoperfusion may be useful in removing the N-desmethyl metabolite of methsuximide. Forced diuresis and exchange transfusions are ineffective.
# Pharmacology
## Mechanism of Action
- Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence seizures (petit mal). The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.
## Structure
- Methsuximide is an anticonvulsant succinimide, chemically designated as N,2-Dimethyl-2-phenylsuccinimide, with the following structural formula:
- Each Celontin capsule contains 300 mg methsuximide, USP. Also contains starch, NF. The capsule contains colloidal silicon dioxide, NF; D&C yellow No. 10; FD&C yellow No. 6; gelatin, NF; and sodium lauryl sulfate, NF.
## Pharmacodynamics
- There is limited information regarding pharmacodynamics.
## Pharmacokinetics
- There is limited information regarding pharmacokinetics.
## Nonclinical Toxicology
- There is limited information regarding nonclinical toxicology.
# Clinical Studies
- There is limited information regarding Clinical Studies.
# How Supplied
- N 0071-0525-24 (P-D 525)–Celontin Capsules, #1 capsule each containing 300 mg methsuximide; bottles of 100.
## Storage
- Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) .
- Protect from light and moisture. Protect from excessive heat 40°C (104°F).
# Images
## Drug Images
## Package and Label Display Panel
Pfizer
ALWAYS DISPENSE WITH MEDICATION GUIDE
NDC 0071-0525-24
Celontin®
(Methsuximide Capsules, USP)
300 mg
100 Capsules
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Methsuximide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CELONTIN ®
# Look-Alike Drug Names
There is limited information regarding Methsuximide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Methsuximide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, 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
Methsuximide is an anticonvulsant that is FDA approved for the treatment of absence seizures that are refractory to other drugs. Common adverse reactions include weight loss, abdominal pain, constipation, diarrhea, epigastric pain,loss of appetite, nausea, vomiting
ataxia, dizziness and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Indications
- Methsuximide is indicated for the control of absence seizures (petit mal) that are refractory to other drugs.
## Dosage
- Optimum dosage of methsuximide must be determined by trial. A suggested dosage schedule is 300 mg per day for the first week. If required, dosage may be increased thereafter at weekly intervals by 300 mg per day for the three weeks following to a daily dosage of 1.2 g. Because therapeutic effect and tolerance vary among patients, therapy with methsuximide must be individualized according to the response of each patient. Optimal dosage is that amount of methsuximide which is barely sufficient to control seizures so that side effects may be kept to a minimum.
- Methsuximide may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence (petit mal).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Methsuximide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Methsuximide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-labeled indications and dosage information of Methsuximide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Methsuximide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Methsuximide in pediatric patients.
# Contraindications
- Methsuximide should not be used in patients with a history of hypersensitivity to succinimides.
# Warnings
### Blood dyscrasias
- Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of succinimides; therefore, periodic blood counts should be performed. Should signs and/or symptoms of infection (eg, sore throat, fever) develop, blood counts should be considered at that point.
### Effects on Liver
- It has been reported that succinimides have produced morphological and functional changes in animal liver. For this reason, methsuximide should be administered with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug.
### Systemic Lupus Erythematosus
- Cases of systemic lupus erythematosus have been reported with the use of succinimides. The physician should be alert to this possibility.
### Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including methsuximide, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing methsuximide or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
## Precautions
### General
- It is recommended that the physician withdraw the drug slowly on the appearance of unusual depression, aggressiveness, or other behavioral alterations.
- As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status.
- Methsuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients.
### Information for Patients
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking methsuximide. Instruct patients to take methsuximide only as prescribed.
- Methsuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly. Patients taking methsuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen.
- Patients should be instructed to promptly contact their physician if they develop signs and/or symptoms suggesting an infection (eg, sore throat, fever).
- ADVICE TO THE PHARMACIST AND PATIENT: Since methsuximide has a relatively low melting temperature (124° F), storage conditions which may promote high temperatures (closed cars, delivery vans, or storage near steam pipes) should be avoided. Do not dispense or use capsules that are not full or in which contents have melted. Effectiveness may be reduced. Protect from excessive heat (104° F).
- Patients, their caregivers, and families should be counseled that AEDs, including methsuximide, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.
# Adverse Reactions
## Clinical Trials Experience
- Gastrointestinal System: Gastrointestinal symptoms occur frequently and have included nausea or vomiting, anorexia, diarrhea, weight loss, epigastric and abdominal pain, and constipation.
- Hemopoietic System: Hemopoietic complications associated with the administration of methsuximide have included eosinophilia, leukopenia, monocytosis, and pancytopenia with or without bone marrow suppression.
- Nervous System: Neurologic and sensory reactions reported during therapy with methsuximide have included drowsiness, ataxia or dizziness, irritability and nervousness, headache, blurred vision, photophobia, hiccups, and insomnia. Drowsiness, ataxia, and dizziness have been the most frequent side effects noted. Psychologic abnormalities have included confusion, instability, mental slowness, depression, hypochondriacal behavior, and aggressiveness. There have been rare reports of psychosis, suicidal behavior, and auditory hallucinations.
- Integumentary System: Dermatologic manifestations which have occurred with the administration of methsuximide have included urticaria, Stevens-Johnson syndrome, and pruritic erythematous rashes.
- Cardiovascular: Hyperemia.
- Genitourinary System: Proteinuria, microscopic hematuria.
- Body as a Whole: Periorbital edema.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience.
# Drug Interactions
- Since methsuximide may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg, methsuximide may increase the plasma concentrations of phenytoin and phenobarbital).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.
- The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, eg, genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
- The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methsuximide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Methsuximide during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Methsuximide in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Methsuximide in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Methsuximide in geriatric settings.
### Gender
There is no FDA guidance on the use of Methsuximide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Methsuximide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Methsuximide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Methsuximide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methsuximide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Methsuximide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral.
### Monitoring
- There is limited information regarding drug monitoring.
# IV Compatibility
- There is limited information regarding IV Compatibility.
# Overdosage
- Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. Methsuximide poisoning may follow a biphasic course. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. It is believed that an active metabolite of methsuximide, N-desmethylmethsuximide, is responsible for this biphasic profile. It is important to follow plasma levels of N-desmethylmethsuximide in methsuximide poisonings. Levels greater than 40 µg/mL have caused toxicity, and coma has been seen at levels of 150 µg/mL.
### Treatment
- Treatment should include emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Charcoal hemoperfusion may be useful in removing the N-desmethyl metabolite of methsuximide. Forced diuresis and exchange transfusions are ineffective.
# Pharmacology
## Mechanism of Action
- Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence seizures (petit mal). The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.
## Structure
- Methsuximide is an anticonvulsant succinimide, chemically designated as N,2-Dimethyl-2-phenylsuccinimide, with the following structural formula:
- Each Celontin capsule contains 300 mg methsuximide, USP. Also contains starch, NF. The capsule contains colloidal silicon dioxide, NF; D&C yellow No. 10; FD&C yellow No. 6; gelatin, NF; and sodium lauryl sulfate, NF.
## Pharmacodynamics
- There is limited information regarding pharmacodynamics.
## Pharmacokinetics
- There is limited information regarding pharmacokinetics.
## Nonclinical Toxicology
- There is limited information regarding nonclinical toxicology.
# Clinical Studies
- There is limited information regarding Clinical Studies.
# How Supplied
- N 0071-0525-24 (P-D 525)–Celontin Capsules, #1 capsule each containing 300 mg methsuximide; bottles of 100.
## Storage
- Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].
- Protect from light and moisture. Protect from excessive heat 40°C (104°F).
# Images
## Drug Images
## Package and Label Display Panel
Pfizer
ALWAYS DISPENSE WITH MEDICATION GUIDE
NDC 0071-0525-24
Celontin®
(Methsuximide Capsules, USP)
300 mg
100 Capsules
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Methsuximide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CELONTIN ®[1]
# Look-Alike Drug Names
There is limited information regarding Methsuximide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Methsuximide | |
d4751f90ed3adb14126cf6a8ce18ad2ecb920eb7 | wikidoc | Methyl group | Methyl group
# Overview
In chemistry, a methyl group is a hydrophobic alkyl functional group derived from methane CH4). It has the formula -CH3 and is very often abbreviated as -Me in the structure of a molecule. This hydrocarbon unit can be found in many organic compounds. It is customarily written as H3C when on the left of a bond; for example, ethane is represented as H3C-CH3.
Methyl groups can be incorporated in organic compounds by an SN2 reaction on iodomethane, or by the reaction of methyl lithium or MeMgCl with a carbon atom that is substituted with a leaving group.
# Reactivity
The introduction of methyl groups as new substituents in a compound usually increases the lipophilicity of the compound and reduces its water solubility. It should improve the ease of absorption of the analogue into a biological membrane but will make its release from biological membranes into the aqueous media more difficult. The incorporation of a methyl group can have one of three general effects on the rate of metabolism of an analogue:
- an increased rate of metabolism due to oxidation of the methyl group
- an increase in the rate of metabolism due to demethylation by the transfer of the methyl group to another compound, or a reduction of the analogue.
Chemically, the reactivity of a methyl group depends partially on what it is attached to. For example, when a methyl group is part of an alkane, it is extremely unreactive and resists all but the strongest of acids, bases, oxidizing agents, and reducing agents. However, in the compound toluene, C6H5CH3, the methyl group is considerably more reactive due to the electron donating abilities of the ring.Electrophilic reagents are then able to attack the methyl group; for example, oxidation with permanganate converts the methyl group to carboxyl (-COOH), which produces benzoic acid.
# Methyl radical
The methyl radical is the substance CH3 on its own, with an unpaired electron. Though it readily dimerizes to ethane, it is stable enough (unlike atomic hydrogen) to be observed as a dilute gas. It can be produced by thermal decomposition of certain compounds, especially those with a -N=N- linkage, which lose the extremely stable dinitrogen molecule on heating. | Methyl group
# Overview
In chemistry, a methyl group is a hydrophobic alkyl functional group derived from methane CH4). It has the formula -CH3 and is very often abbreviated as -Me in the structure of a molecule. This hydrocarbon unit can be found in many organic compounds. It is customarily written as H3C when on the left of a bond; for example, ethane is represented as H3C-CH3.
Methyl groups can be incorporated in organic compounds by an SN2 reaction on iodomethane, or by the reaction of methyl lithium or MeMgCl with a carbon atom that is substituted with a leaving group.
# Reactivity
The introduction of methyl groups as new substituents in a compound usually increases the lipophilicity of the compound and reduces its water solubility. It should improve the ease of absorption of the analogue into a biological membrane but will make its release from biological membranes into the aqueous media more difficult. The incorporation of a methyl group can have one of three general effects on the rate of metabolism of an analogue:
- an increased rate of metabolism due to oxidation of the methyl group
- an increase in the rate of metabolism due to demethylation by the transfer of the methyl group to another compound, or a reduction of the analogue.
Chemically, the reactivity of a methyl group depends partially on what it is attached to. For example, when a methyl group is part of an alkane, it is extremely unreactive and resists all but the strongest of acids, bases, oxidizing agents, and reducing agents. However, in the compound toluene, C6H5CH3, the methyl group is considerably more reactive due to the electron donating abilities of the ring.Electrophilic reagents are then able to attack the methyl group; for example, oxidation with permanganate converts the methyl group to carboxyl (-COOH), which produces benzoic acid.
# Methyl radical
The methyl radical is the substance CH3 on its own, with an unpaired electron. Though it readily dimerizes to ethane, it is stable enough (unlike atomic hydrogen) to be observed as a dilute gas. It can be produced by thermal decomposition of certain compounds, especially those with a -N=N- linkage, which lose the extremely stable dinitrogen molecule on heating. | https://www.wikidoc.org/index.php/Methyl | |
b209055933bde11b8f2eeca87c797305ff69de7c | wikidoc | Methyldopate | Methyldopate
# 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
Methyldopate is an antihypertensive agent that is FDA approved for the treatment of hypertension, when parenteral medication is indicated. Common adverse reactions include drowsiness, sedation, headache and asthenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Hypertension, when parenteral medication is indicated. The treatment of hypertensive crises may be initiated with Methyldopate HCl Injection.
### Dosing Information
- Methyldopate HCl Injection when given intravenously in effective doses, causes a decline in blood pressure that may begin in four to six hours and last 10 to 16 hours after injection.
- Add the desired dose of Methyldopate HCl Injection to 100 mL of Dextrose Injection 5%, USP. Alternatively the desired dose may be given in 5% dextrose in water in a concentration of 100 mg/10 mL. Give this intravenous infusion slowly over a period of 30 to 60 minutes.
- The usual adult dosage intravenously is 250 mg to 500 mg at six hour intervals as required. The maximum recommended intravenous dose is 1 gram every six hours.
- When control has been obtained, oral therapy with tablets may be substituted for intravenous therapy, starting with the same dosage schedule used for the parenteral route. The effectiveness and anticipated responses are described in the circular for tablets.
- Since methyldopate has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.
- Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 grams of methyldopa daily.
- Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methyldopate in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methyldopate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosing Information
- The recommended daily dosage is 20 to 40 mg/kg of body weight in divided doses every six hours. The maximum dosage is 65 mg/kg or 3 grams daily, whichever is less. When the blood pressure is under control, continue with oral therapy using tablets in the same dosage as for the parenteral route.
- 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 (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methyldopate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methyldopate in pediatric patients.
# Contraindications
- Methyldopate hydrochloride is contraindicated in patients:
- with active hepatic disease, such as acute hepatitis and active cirrhosis.
- with liver disorders previously associated with methyldopa therapy
- with hypersensitivity to any component of this product, including sulfites
- on therapy with monoamine oxidase (MAO) inhibitors.
# Warnings
- It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy. The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed. Read this section carefully to understand these reactions.
- With prolonged methyldopa therapy, 10 to 20 percent of patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is at daily dosage of 1 gram or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a positive direct Coombs test may develop hemolytic anemia.
- Prior existence or development of a positive direct Coombs test is not in itself a contraindication to use of methyldopa. If a positive Coombs test develops during methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test there is less often a positive indirect Coombs test which may interfere with cross matching of blood.
- Before treatment is started, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.
- If Coombs-positive hemolytic anemia occurs, the cause may be methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be considered. If the hemolytic anemia is related to methyldopa, the drug should not be reinstituted.
- When methyldopa causes Coombs positivity alone or with hemolytic anemia, the red cell is usually coated with gamma globulin of the lgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after methyldopa is stopped.
- Should the need for transfusion arise in a patient receiving methyldopa, both a direct and indirect Coombs test should be performed. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.
- Occasionally, fever has occurred within the first three weeks of methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin and prothrombin time. Jaundice, with or without fever, may occur with onset usually within the first two to three months of therapy. In some patients the findings are consistent with those of cholestasis. In others the findings are consistent with hepatitis and hepatocellular injury.
- Rarely fatal hepatic necrosis has been reported after use of methyldopa. These hepatic changes may represent hypersensitivity reactions. Periodic determination of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.
- Rarely, a reversible reduction of the white blood cell count with a primary effect on the granulocytes has been seen. The granulocyte count returned promptly to normal on discontinuance of the drug. Rare cases of granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred rarely.
- Contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
### PRECAUTIONS
- Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction.
- Some patients taking methyldopa experience clinical edema or weight gain which may be controlled by use of a diuretic. Methyldopa should not be continued if edema progresses or signs of heart failure appear.
- A paradoxical pressor response has been reported with intravenous administration of Methyldopate HCl Injection.
- Hypertension has recurred occasionally after dialysis in patients given methyldopa because the drug is removed by this procedure.
- Rarely involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.
# Adverse Reactions
## Clinical Trials Experience
- Sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. Headache, asthenia, or weakness may be noted as early and transient symptoms. However, significant adverse effects due to methyldopa have been infrequent and this agent usually is well tolerated.
- The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.
- Aggravation of angina pectoris, congestive heart failure, prolonged carotid sinus hypersensitivity, paradoxical pressor response with intravenous use, orthostatic hypotension (decrease daily dosage), edema and weight gain, bradycardia.
- Pancreatitis, colitis, vomiting, diarrhea, sialadenitis, sore or ``black′′ tongue, nausea, constipation, distension, flatus, dryness of mouth.
- Hyperprolactinemia.
- Bone marrow depression, leukopenia, granulocytopenia, thrombocytopenia, hemolytic anemia; positive tests for antinuclear antibody, LE cells, and rheumatoid factor, positive Coombs tests.
- Liver disorders including hepatitis, jaundice, abnormal liver function test
- Myocarditis, pericarditis, vasculitis, lupus-like syndrome, drug-related fever, eosinophilia.
- Parkinsonism, Bell's palsy, decreased mental acuity, choreoathetotic movements, symptoms of cerebrovascular insufficiency, psychic disturbances including nightmares and reversible mild psychoses or depression, headache, sedation, asthenia or weakness, dizziness, lightheadedness, paresthesias.
- Rise in BUN
- Arthralgia, with or without joint swelling; myalgia.
- Nasal stuffiness.
- Toxic epidermal necrolysis, rash.
- Amenorrhea, breast enlargement, gynecomastia, lactation, impotence, decreased libido.
## Postmarketing Experience
There is limited information regarding Methyldopate Postmarketing Experience in the drug label.
# Drug Interactions
### Laboratory Tests
- Blood count, Coombs test, and liver function tests are recommended before initiating therapy and at periodic intervals.
### Drug Interactions
- When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy.
- Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.
- When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations.
- Monoamine oxidase (MAO) inhibitors
### Drug/Laboratory Test Interactions
- Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported.
- Since methyldopa causes fluorescence in urine samples at the same wavelengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Methyldopate HCl. It is also not known whether Methyldopate HCl can affect reproduction capacity or can cause fetal harm when given to a pregnant woman. Methyldopate HCl should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methyldopate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Methyldopate during labor and delivery.
### Nursing Mothers
- Methyldopa appears in breast milk. Therefore, caution should be exercised when methyldopa is given to a nursing woman.
### Pediatric Use
- There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Methyldopate in geriatric settings.
### Gender
There is no FDA guidance on the use of Methyldopate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Methyldopate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Methyldopate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Methyldopate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methyldopate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Methyldopate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Injection, solution
### Monitoring
There is limited information regarding Methyldopate Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Methyldopate and IV administrations.
# Overdosage
- Acute overdosage may produce acute hypotension with other responses attributable to brain and gastrointestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, lightheadedness, constipation, distention, flatus, diarrhea, nausea, vomiting).
- In the event of overdosage, symptomatic and supportive measures should be employed. Management includes special attention to cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity.
- Sympathomimetic drugs may be indicated.
- The acute intravenous LD50 of Methyldopate HCl in the mouse is 321 mg/kg.
# Pharmacology
There is limited information regarding Methyldopate Pharmacology in the drug label.
## Mechanism of Action
- Methyldopate, an antihypertensive agent, is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methyl-norepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.
- Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.
- Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.
- Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.
- Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.
## Structure
- Methyldopate HCl Injection, USP, is an antihypertensive agent for intravenous use. Sterile, nonpyrogenic.
- Methyldopate hydrochloride is the ethyl ester of methyldopa, supplied as the hydrochloride salt with a molecular weight of 275.73. Methyldopate hydrochloride is more soluble and stable in solution than methyldopa and is the preferred form for intravenous use.
- The molecular formula for Methyldopate hydrochloride is C12H17NO4·HCl and the structural formula is:
## Pharmacodynamics
There is limited information regarding Methyldopate Pharmacodynamics in the drug label.
## Pharmacokinetics
- Methyldopate hydrochloride is the ethyl ester of methyldopa hydrochloride and possesses the same pharmacologic attributes.
- Methyldopa is extensively metabolized. The known urinary metabolites are ∝-methyldopa mono-0-sulfate; 3-0-methyl-∝-methyldopa; 3,4-dihydroxyphenylacetone; ∝-methyldopamine; 3-0-methyl-∝-methyldopamine and their conjugates.
- Following intravenous administration of methyldopate hydrochloride a decrease in blood pressure may occur in four to six hours and last 10 to 16 hours.
- Approximately 49 percent of the dose of methyldopate hydrochloride is excreted in the urine as methyldopa and its mono-0-sulfate. The renal clearance of methyldopa following methyldopate hydrochloride is about 156 mL/min in normal subjects and is diminished in renal insufficiency. Following methyldopate hydrochloride injection the plasma half-life of methyldopa is 90-127 minutes. Approximately 17 percent of a dose of methyldopate hydrochloride given to normal subjects appears in plasma as free methyldopa.
- Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of a tumorigenic effect was seen when methyldopa was given for two years to mice at doses up to 1800 mg/kg/day or to rats at doses up to 240 mg/kg/day (30 and 4 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body weight; 2.5 and 0.6 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg).
- Methyldopa was not mutagenic in the Ames Test and did not increase chromosomal aberration or sister chromatic exchanges in Chinese hamster ovary cells. These in vitro studies were carried out both with and without exogenous metabolic activation.
- Fertility was unaffected when methyldopa was given to male and female rats at 100 mg/kg/day (1.7 times the maximum daily human dose when compared on the basis of body weight; 0.2 times the maximum daily human dose when compared on the basis of body surface area). Methyldopa decreased sperm count, sperm motility, the number of late spermatids and the male fertility index when given to male rats at 200 and 400 mg/kg/day (3.3 and 6.7 times the maximum daily human dose when compared on the basis of body weight; 0.5 and 1 times the maximum daily human dose when compared on the basis of body surface area).
- Long-term studies in animals have not been performed to evaluate the carcinogenic potential of methyldopate hydrochloride; nor have evaluations of this ester's mutagenic potential or potential to affect fertility been carried out.
# Clinical Studies
There is limited information regarding Methyldopate Clinical Studies in the drug label.
# How Supplied
Methyldopate HCl Injection, USP 250 mg/5 mL (50 mg/mL).
NDC 0517-8905-10 5 mL Single Dose Vial Boxes of 10
Rx Only
IN8905
Rev. 11/05
MG #7604
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
## Storage
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CONTAINER
NDC 0517-8905-10
METHYLDOPATE HCl
INJECTION, USP
250 mg/5 mL (50 mg/mL)
5 mL SINGLE DOSE VIAL
FOR IV USE AFTER DILUTION
Rx Only
AMERICAN REGENT, INC.
SHIRLEY, NY 11967
### PRINCIPAL DISPLAY PANEL – Carton
METHYLDOPATE HCl
INJECTION, USP
250 mg/5 mL (50 mg/mL)
NDC 0517-8905-10
10 x 5 mL
SINGLE DOSE VIALS
FOR INTRAVENOUS USE AFTER DILUTION
Rx Only
Each mL contains: Methyldopate HCl 50 mg, Citric Acid (Anhydrous) 5 mg, Edetate Disodium 0.5 mg, Monothioglycerol 2 mg, Water for Injection q.s. Methylparaben 1.5 mg and Propylparaben 0.2 mg added as preservatives, Sodium Bisulfite 3.2 mg added as an antioxidant. pH adjusted with Sodium Hydroxide and/or Hydrochloric Acid.
DISCARD UNUSED PORTION.
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) (See USP Controlled Room Temperature).
Directions for Use: See Package Insert.
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
Rev. 11/05
# Patient Counseling Information
There is limited information regarding Methyldopate Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Methyldopate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Methyldopate Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Methyldopate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Methyldopate
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
Methyldopate is an antihypertensive agent that is FDA approved for the treatment of hypertension, when parenteral medication is indicated. Common adverse reactions include drowsiness, sedation, headache and asthenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Hypertension, when parenteral medication is indicated. The treatment of hypertensive crises may be initiated with Methyldopate HCl Injection.
### Dosing Information
- Methyldopate HCl Injection when given intravenously in effective doses, causes a decline in blood pressure that may begin in four to six hours and last 10 to 16 hours after injection.
- Add the desired dose of Methyldopate HCl Injection to 100 mL of Dextrose Injection 5%, USP. Alternatively the desired dose may be given in 5% dextrose in water in a concentration of 100 mg/10 mL. Give this intravenous infusion slowly over a period of 30 to 60 minutes.
- The usual adult dosage intravenously is 250 mg to 500 mg at six hour intervals as required. The maximum recommended intravenous dose is 1 gram every six hours.
- When control has been obtained, oral therapy with tablets may be substituted for intravenous therapy, starting with the same dosage schedule used for the parenteral route. The effectiveness and anticipated responses are described in the circular for tablets.
- Since methyldopate has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.
- Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 grams of methyldopa daily.
- Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methyldopate in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methyldopate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosing Information
- The recommended daily dosage is 20 to 40 mg/kg of body weight in divided doses every six hours. The maximum dosage is 65 mg/kg or 3 grams daily, whichever is less. When the blood pressure is under control, continue with oral therapy using tablets in the same dosage as for the parenteral route.
- 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 (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methyldopate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methyldopate in pediatric patients.
# Contraindications
- Methyldopate hydrochloride is contraindicated in patients:
- with active hepatic disease, such as acute hepatitis and active cirrhosis.
- with liver disorders previously associated with methyldopa therapy
- with hypersensitivity to any component of this product, including sulfites
- on therapy with monoamine oxidase (MAO) inhibitors.
# Warnings
- It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy. The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed. Read this section carefully to understand these reactions.
- With prolonged methyldopa therapy, 10 to 20 percent of patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is at daily dosage of 1 gram or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a positive direct Coombs test may develop hemolytic anemia.
- Prior existence or development of a positive direct Coombs test is not in itself a contraindication to use of methyldopa. If a positive Coombs test develops during methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test there is less often a positive indirect Coombs test which may interfere with cross matching of blood.
- Before treatment is started, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.
- If Coombs-positive hemolytic anemia occurs, the cause may be methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be considered. If the hemolytic anemia is related to methyldopa, the drug should not be reinstituted.
- When methyldopa causes Coombs positivity alone or with hemolytic anemia, the red cell is usually coated with gamma globulin of the lgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after methyldopa is stopped.
- Should the need for transfusion arise in a patient receiving methyldopa, both a direct and indirect Coombs test should be performed. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.
- Occasionally, fever has occurred within the first three weeks of methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin and prothrombin time. Jaundice, with or without fever, may occur with onset usually within the first two to three months of therapy. In some patients the findings are consistent with those of cholestasis. In others the findings are consistent with hepatitis and hepatocellular injury.
- Rarely fatal hepatic necrosis has been reported after use of methyldopa. These hepatic changes may represent hypersensitivity reactions. Periodic determination of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.
- Rarely, a reversible reduction of the white blood cell count with a primary effect on the granulocytes has been seen. The granulocyte count returned promptly to normal on discontinuance of the drug. Rare cases of granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred rarely.
- Contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
### PRECAUTIONS
- Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction.
- Some patients taking methyldopa experience clinical edema or weight gain which may be controlled by use of a diuretic. Methyldopa should not be continued if edema progresses or signs of heart failure appear.
- A paradoxical pressor response has been reported with intravenous administration of Methyldopate HCl Injection.
- Hypertension has recurred occasionally after dialysis in patients given methyldopa because the drug is removed by this procedure.
- Rarely involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.
# Adverse Reactions
## Clinical Trials Experience
- Sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. Headache, asthenia, or weakness may be noted as early and transient symptoms. However, significant adverse effects due to methyldopa have been infrequent and this agent usually is well tolerated.
- The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.
- Aggravation of angina pectoris, congestive heart failure, prolonged carotid sinus hypersensitivity, paradoxical pressor response with intravenous use, orthostatic hypotension (decrease daily dosage), edema and weight gain, bradycardia.
- Pancreatitis, colitis, vomiting, diarrhea, sialadenitis, sore or ``black′′ tongue, nausea, constipation, distension, flatus, dryness of mouth.
- Hyperprolactinemia.
- Bone marrow depression, leukopenia, granulocytopenia, thrombocytopenia, hemolytic anemia; positive tests for antinuclear antibody, LE cells, and rheumatoid factor, positive Coombs tests.
- Liver disorders including hepatitis, jaundice, abnormal liver function test
- Myocarditis, pericarditis, vasculitis, lupus-like syndrome, drug-related fever, eosinophilia.
- Parkinsonism, Bell's palsy, decreased mental acuity, choreoathetotic movements, symptoms of cerebrovascular insufficiency, psychic disturbances including nightmares and reversible mild psychoses or depression, headache, sedation, asthenia or weakness, dizziness, lightheadedness, paresthesias.
- Rise in BUN
- Arthralgia, with or without joint swelling; myalgia.
- Nasal stuffiness.
- Toxic epidermal necrolysis, rash.
- Amenorrhea, breast enlargement, gynecomastia, lactation, impotence, decreased libido.
## Postmarketing Experience
There is limited information regarding Methyldopate Postmarketing Experience in the drug label.
# Drug Interactions
### Laboratory Tests
- Blood count, Coombs test, and liver function tests are recommended before initiating therapy and at periodic intervals.
### Drug Interactions
- When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy.
- Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.
- When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations.
- Monoamine oxidase (MAO) inhibitors
### Drug/Laboratory Test Interactions
- Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported.
- Since methyldopa causes fluorescence in urine samples at the same wavelengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Methyldopate HCl. It is also not known whether Methyldopate HCl can affect reproduction capacity or can cause fetal harm when given to a pregnant woman. Methyldopate HCl should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methyldopate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Methyldopate during labor and delivery.
### Nursing Mothers
- Methyldopa appears in breast milk. Therefore, caution should be exercised when methyldopa is given to a nursing woman.
### Pediatric Use
- There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Methyldopate in geriatric settings.
### Gender
There is no FDA guidance on the use of Methyldopate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Methyldopate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Methyldopate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Methyldopate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methyldopate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Methyldopate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Injection, solution
### Monitoring
There is limited information regarding Methyldopate Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Methyldopate and IV administrations.
# Overdosage
- Acute overdosage may produce acute hypotension with other responses attributable to brain and gastrointestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, lightheadedness, constipation, distention, flatus, diarrhea, nausea, vomiting).
- In the event of overdosage, symptomatic and supportive measures should be employed. Management includes special attention to cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity.
- Sympathomimetic drugs [e.g., levarterenol, epinephrine, ARAMINE* (Metaraminol Bitartrate, MSD)] may be indicated.
- The acute intravenous LD50 of Methyldopate HCl in the mouse is 321 mg/kg.
# Pharmacology
There is limited information regarding Methyldopate Pharmacology in the drug label.
## Mechanism of Action
- Methyldopate, an antihypertensive agent, is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methyl-norepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.
- Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.
- Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.
- Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.
- Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.
## Structure
- Methyldopate HCl Injection, USP, is an antihypertensive agent for intravenous use. Sterile, nonpyrogenic.
- Methyldopate hydrochloride [levo-3-(3,4-dihydroxyphenyl)-2-methylalanine, ethyl ester hydrochloride] is the ethyl ester of methyldopa, supplied as the hydrochloride salt with a molecular weight of 275.73. Methyldopate hydrochloride is more soluble and stable in solution than methyldopa and is the preferred form for intravenous use.
- The molecular formula for Methyldopate hydrochloride is C12H17NO4·HCl and the structural formula is:
## Pharmacodynamics
There is limited information regarding Methyldopate Pharmacodynamics in the drug label.
## Pharmacokinetics
- Methyldopate hydrochloride is the ethyl ester of methyldopa hydrochloride and possesses the same pharmacologic attributes.
- Methyldopa is extensively metabolized. The known urinary metabolites are ∝-methyldopa mono-0-sulfate; 3-0-methyl-∝-methyldopa; 3,4-dihydroxyphenylacetone; ∝-methyldopamine; 3-0-methyl-∝-methyldopamine and their conjugates.
- Following intravenous administration of methyldopate hydrochloride a decrease in blood pressure may occur in four to six hours and last 10 to 16 hours.
- Approximately 49 percent of the dose of methyldopate hydrochloride is excreted in the urine as methyldopa and its mono-0-sulfate. The renal clearance of methyldopa following methyldopate hydrochloride is about 156 mL/min in normal subjects and is diminished in renal insufficiency. Following methyldopate hydrochloride injection the plasma half-life of methyldopa is 90-127 minutes. Approximately 17 percent of a dose of methyldopate hydrochloride given to normal subjects appears in plasma as free methyldopa.
- Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of a tumorigenic effect was seen when methyldopa was given for two years to mice at doses up to 1800 mg/kg/day or to rats at doses up to 240 mg/kg/day (30 and 4 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body weight; 2.5 and 0.6 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg).
- Methyldopa was not mutagenic in the Ames Test and did not increase chromosomal aberration or sister chromatic exchanges in Chinese hamster ovary cells. These in vitro studies were carried out both with and without exogenous metabolic activation.
- Fertility was unaffected when methyldopa was given to male and female rats at 100 mg/kg/day (1.7 times the maximum daily human dose when compared on the basis of body weight; 0.2 times the maximum daily human dose when compared on the basis of body surface area). Methyldopa decreased sperm count, sperm motility, the number of late spermatids and the male fertility index when given to male rats at 200 and 400 mg/kg/day (3.3 and 6.7 times the maximum daily human dose when compared on the basis of body weight; 0.5 and 1 times the maximum daily human dose when compared on the basis of body surface area).
- Long-term studies in animals have not been performed to evaluate the carcinogenic potential of methyldopate hydrochloride; nor have evaluations of this ester's mutagenic potential or potential to affect fertility been carried out.
# Clinical Studies
There is limited information regarding Methyldopate Clinical Studies in the drug label.
# How Supplied
Methyldopate HCl Injection, USP 250 mg/5 mL (50 mg/mL).
NDC 0517-8905-10 5 mL Single Dose Vial Boxes of 10
Rx Only
IN8905
Rev. 11/05
MG #7604
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
## Storage
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CONTAINER
NDC 0517-8905-10
METHYLDOPATE HCl
INJECTION, USP
250 mg/5 mL (50 mg/mL)
5 mL SINGLE DOSE VIAL
FOR IV USE AFTER DILUTION
Rx Only
AMERICAN REGENT, INC.
SHIRLEY, NY 11967
### PRINCIPAL DISPLAY PANEL – Carton
METHYLDOPATE HCl
INJECTION, USP
250 mg/5 mL (50 mg/mL)
NDC 0517-8905-10
10 x 5 mL
SINGLE DOSE VIALS
FOR INTRAVENOUS USE AFTER DILUTION
Rx Only
Each mL contains: Methyldopate HCl 50 mg, Citric Acid (Anhydrous) 5 mg, Edetate Disodium 0.5 mg, Monothioglycerol 2 mg, Water for Injection q.s. Methylparaben 1.5 mg and Propylparaben 0.2 mg added as preservatives, Sodium Bisulfite 3.2 mg added as an antioxidant. pH adjusted with Sodium Hydroxide and/or Hydrochloric Acid.
DISCARD UNUSED PORTION.
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) (See USP Controlled Room Temperature).
Directions for Use: See Package Insert.
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
Rev. 11/05
# Patient Counseling Information
There is limited information regarding Methyldopate Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Methyldopate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Methyldopate Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Methyldopate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Methyldopate | |
936f67fc7480e2aae6dd220c2b1c92832b21eb8c | wikidoc | Methysergide | Methysergide
# Overview
Methysergide (1-methyl-D-lysergic acid butanolamide or UML-491) is a prescription drug formerly used for prophylaxis of cluster headaches/migraine headaches, but is no longer recommended due to retroperitoneal/retropulmonary fibrosis.
# Medical uses
Methysergide is used to treat headaches such as migraine and other recurrent throbbing headaches. Methysergide is one of the most effective medications for the prevention of migraine, but not for the treatment of an acute attack.
It is also used in carcinoid syndrome to treat severe diarrhea. It may also be used in the treatment of serotonin syndrome.
# Side effects
It has a known side effect, retroperitoneal fibrosis, which is severe, although uncommon. Other severe but uncommon side effects include pleural fibrosis, and subendocardial fibrosis.
In addition, there is an increased risk of left-sided cardiac valve dysfunction.
# Pharmacology
Methysergide interacts with serotonin (5-HT) receptors. Its therapeutic effect in migraine prophylaxis has been associated with its antagonism at the 5-HT2B receptor.
Furthermore, it is an antagonist at the 5-HT2C receptor, while at the 5-HT1A receptor it serves as a partial agonist. It is known to have partial agonist effects on some of the other 5-HT receptors as well. Methysergide is metabolised into methylergometrine in humans, which is responsible for its psychedelic effects.
# History
Methysergide was approved by the U.S. Food and Drug Administration (FDA) in 1962.
Novartis withdrew it from the U.S. market after taking over Sandoz, but currently lists it as a product.
# Synthesis | Methysergide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Methysergide (1-methyl-D-lysergic acid butanolamide or UML-491) is a prescription drug formerly used for prophylaxis of cluster headaches/migraine headaches, but is no longer recommended due to retroperitoneal/retropulmonary fibrosis.
# Medical uses
Methysergide is used to treat headaches such as migraine and other recurrent throbbing headaches.[1] Methysergide is one of the most effective[2] medications for the prevention of migraine, but not for the treatment of an acute attack.
It is also used in carcinoid syndrome to treat severe diarrhea.[1] It may also be used in the treatment of serotonin syndrome.[3]
# Side effects
It has a known side effect, retroperitoneal fibrosis,[4] which is severe, although uncommon. Other severe but uncommon side effects include pleural fibrosis, and subendocardial fibrosis.
In addition, there is an increased risk of left-sided cardiac valve dysfunction.[2][5]
# Pharmacology
Methysergide interacts with serotonin (5-HT) receptors. Its therapeutic effect in migraine prophylaxis has been associated with its antagonism at the 5-HT2B receptor.[6]
Furthermore, it is an antagonist at the 5-HT2C receptor, while at the 5-HT1A receptor it serves as a partial agonist.[7][8][9] It is known to have partial agonist effects on some of the other 5-HT receptors as well.[10] Methysergide is metabolised into methylergometrine in humans, which is responsible for its psychedelic effects.[11]
# History
Methysergide was approved by the U.S. Food and Drug Administration (FDA) in 1962.
Novartis withdrew it from the U.S. market after taking over Sandoz, but currently lists it as a product.[citation needed]
# Synthesis | https://www.wikidoc.org/index.php/Methysergide | |
e3c63ce0266b576dc094c9429061e81835588999 | wikidoc | Metipranolol | Metipranolol
# 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
Metipranolol is a non-selective beta-adrenergic receptor blocking agent that is FDA approved for the treatment of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma.. Common adverse reactions include Burning sensation in eye, Blurred vision, Conjunctivitis, Blepharitis, photophobia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Metipranolol ophthalmic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma.
### Dosage
- The recommended dose is one drop of metipranolol ophthalmic solution in the affected eye(s) twice a day.
- If the patient's IOP is not at a satisfactory level on this regimen, use of more frequent administration or a larger dose of metipranolol ophthalmic solution is not known to be of benefit. Concomitant therapy to lower intraocular pressure can be instituted.
- In clinical trials, metipranolol ophthalmic solution was safely used during concomitant therapy with pilocarpine, epinephrine, or acetazolamide.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metipranolol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metipranolol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Metipranolol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metipranolol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metipranolol in pediatric patients.
# Contraindications
- Hypersensitivity to any component of this product.
- Metipranolol ophthalmic solution is contraindicated in patients with bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease; symptomatic sinus bradycardia; greater than a first degree atrioventricular block; cardiogenic shock; or overt cardiac failure.
# Warnings
- As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. Thus, the same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely, death in association with cardiac failure, have been reported following topical application of beta-adrenergic blocking agents .
- Since metipranolol ophthalmic solution had a minor effect on heart rate and blood pressure in clinical studies, caution should be observed in treating patients with a history of cardiac failure. Treatment with metipranolol ophthalmic solution should be discontinued at the first evidence of cardiac failure.
- Metipranolol ophthalmic solution, or other beta-blockers, should not, in general, be administered to patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity. However, if the drug is necessary in such patients, then it should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2 receptors.
### Precautions
- Because of potential effects of beta-adrenergic receptor blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with metipranolol ophthalmic solution, alternative therapy should be considered.
- Some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents in patients undergoing elective surgery. If necessary during surgery, the effects of beta-adrenergic receptor blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.
- While metipranolol ophthalmic solution has demonstrated a low potential for systemic effect, it should be used with caution in patients with diabetes (especially labile diabetes) because of possible masking of signs and symptoms of acute hypoglycemia.
- Beta-adrenergic receptor blocking agents may mask certain signs and symptoms of hyperthyroidism, and their abrupt withdrawal might precipitate a thyroid storm.
- Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).
- Risk of anaphylactic reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, the use of metipranolol ophthalmic solution has been associated with transient local discomfort.
- Other ocular adverse reactions, such as abnormal vision, blepharitis, blurred vision, browache, conjunctivitis, edema, eyelid dermatitis, photophobia, tearing, and uveitis have been reported in small numbers of patients.
- Other systemic adverse reactions, such as allergic reaction, angina, anxiety, arthritis, asthenia, atrial fibrillation, bradycardia, bronchitis, coughing, depression, dizziness, dyspnea, epistaxis, headache, hypertension, myalgia, myocardial infarct, nausea, nervousness, palpitation, rash, rhinitis, and somnolence have also been reported in small numbers of patients.
## Postmarketing Experience
There is limited information regarding Metipranolol Postmarketing Experience in the drug label.
# Drug Interactions
- Metipranolol ophthalmic solution should be used with caution in patients who are receiving a beta-adrenergic blocking agent orally, because of the potential for additive effects on systemic beta-blockade.
- Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or bradycardia.
- Caution should be used in the coadministration of beta-adrenergic receptor blocking agents, such as metipranolol, and oral or intravenous calcium channel antagonists, because of possible precipitation of left ventricular failure, and hypotension. In patients with impaired cardiac function, who are receiving calcium channel antagonists, coadministration should be avoided.
- The concomitant use of beta-adrenergic receptor blocking agents with digitalis and calcium channel antagonists may have additive effects, prolonging atrioventricular conduction time.
- Caution should be used in patients using concomitant adrenergic psychotropic drugs.
- Ocular: In patients with angle-closure glaucoma, the immediate treatment objective is to re-open the angle by constriction of the pupil with a miotic agent. Metipranolol ophthalmic solution has little or no effect on the pupil, therefore, when it is used to reduce intraocular pressure in angle-closure glaucoma, it should be used only with concomitant administration of a miotic agent.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- No drug related effects were reported for the segment II teratology study in fetal rats after administration, during organogenesis, to dams of up to 50 mg/kg/day. Metipranolol ophthalmic solution has been shown to increase fetal resorption, fetal death, and delayed development when administered orally to rabbits at 50 mg/kg/day during organogenesis.
- There are no adequate and well-controlled studies in pregnant women. Metipranolol ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
- It is not known whether metipranolol ophthalmic solution is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when metipranolol ophthalmic solution is administered in nursing women
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
- Ophthalmic
### Monitoring
There is limited information regarding Monitoring of Metipranolol in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Metipranolol and IV administrations.
# Overdosage
- No information is available on overdosage of metipranolol ophthalmic solution in humans. The symptoms which might be expected with an overdose of a systemically administered beta-adrenergic receptor blocking agent are bradycardia, hypotension and acute cardiac failure.
# Pharmacology
## Mechanism of Action
- Metipranolol blocks beta1 and beta2 (non-selective) adrenergic receptors. It does not have significant intrinsic sympathomimetic activity, and has only weak local anesthetic (membrane-stabilizing) and myocardial depressant activity.
- Orally administered beta-adrenergic blocking agents reduce cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor antagonists may inhibit the sympathetic stimulatory effect necessary to maintain adequate cardiac output.
- Beta-adrenergic receptor blockade in the bronchi and bronchioles may result in significantly increased airway resistance from unopposed para-sympathetic activity. Such an effect is potentially dangerous in patients with asthma or other bronchospastic conditions
## Structure
- Metipranolol ophthalmic solution 0.3% is a sterile solution that contains metipranolol, a non-selective beta-adrenergic receptor blocking agent. Metipranolol is a white, odorless, crystalline powder. The chemical name of metipranolol is (±)-1-(4-Hydroxy-2, 3,5-trimethylphenoxy)-3-(isopropylamino)-2-propanol-4-acetate.
- The chemical structural of metipranolol is:
- Each mL of metipranolol ophthalmic solution, for ophthalmic administration, contains 3 mg metipranolol. INACTIVES: povidone, glycerol, hydrochloric acid, sodium chloride, edetate disodium, and purified water. Sodium Hydroxide may be added to adjust pH. PRESERVATIVE ADDED: Benzalkonium chloride 0.004%. DM-00
## Pharmacodynamics
(Description)
## Pharmacokinetics
- Metipranolol when applied topically in the eye, has the action of reducing elevated as well as normal intraocular pressure (IOP), whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.
- The primary mechanism of the ocular hypotensive action of metipranolol is most likely due to reduction in aqueous humor production. A slight increase in outflow may be an additional mechanism. Metipranolol reduces IOP with little or no effect on pupil size or accommodation.
- In controlled studies of patients with intraocular pressure greater than 24 mmHg at baseline, metipranolol ophthalmic solution reduced the average intraocular pressure approximately 20 - 26%.
- The onset of action of metipranolol ophthalmic solution, as measured by a reduction in intraocular pressure, occurs within 30 minutes after a single administration. The maximum effect occurs at about 2 hours. A reduction in intraocular pressure can be demonstrated 24 hours after a single dose. Clinical studies in patients with glaucoma treated for up to two years indicate that an intraocular pressure lowering effect is maintained.
### ANIMAL PHARMACOLOGY
- In rabbits administered metipranolol in one eye at 2 to 4 fold increased concentrations, multi-focal interstitial nephritis was observed in male animals, and lympho-hystiocytic and heterophilic interstitial pneumonia was observed in female animals. The clinical relevance of these findings is unknown.
## Nonclinical Toxicology
- Lifetime studies with metipranolol have been conducted in mice at oral doses of 5, 50 and 100 mg/kg/day and in rats at oral doses of up to 70 mg/kg/day. Metipranolol demonstrated no carcinogenic effect. In the mouse study, female animals receiving the low, but not the intermediate or high dose, had an increased number of pulmonary adenomas. The significance of this observation is unknown. In a variety of in vitro and in vivo bacterial and mammalian cell assays, metipranolol was nonmutagenic.
- Reproduction and fertility studies of metipranolol in rats and mice showed no adverse effect on male fertility at oral doses of up to 50 mg/kg/day, and female fertility at oral doses of up to 25 mg/kg/day.
# Clinical Studies
There is limited information regarding Metipranolol Clinical Studies in the drug label.
# How Supplied
- Metipranolol ophthalmic solution 0.3% is supplied in a plastic bottle with a controlled drop tip and a white plastic screw-top cap as follows:
## Storage
- Store at controlled room temperature, 15°-30°C (59°-86°F). Replace cap immediately after use.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 61314-447-10 Rx Only
FALCON PHARMACEUTICALS®
Metipranolol
Ophthalmic
Solution
10 mL STERILE
AFFILIATE OF
ALCON LABORATORIES, INC
QUALITY RX
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be instructed to avoid allowing the tip of the dispensing containers to contact the eye or surrounding structures. Patients should be advised that metipranolol contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following metipranolol administration.
# Precautions with Alcohol
Alcohol-Metipranolol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Optipranolol®
# Look-Alike Drug Names
There is limited information regarding Metipranolol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Metipranolol
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
Metipranolol is a non-selective beta-adrenergic receptor blocking agent that is FDA approved for the treatment of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma.. Common adverse reactions include Burning sensation in eye, Blurred vision, Conjunctivitis, Blepharitis, photophobia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Metipranolol ophthalmic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma.
### Dosage
- The recommended dose is one drop of metipranolol ophthalmic solution in the affected eye(s) twice a day.
- If the patient's IOP is not at a satisfactory level on this regimen, use of more frequent administration or a larger dose of metipranolol ophthalmic solution is not known to be of benefit. Concomitant therapy to lower intraocular pressure can be instituted.
- In clinical trials, metipranolol ophthalmic solution was safely used during concomitant therapy with pilocarpine, epinephrine, or acetazolamide.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metipranolol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metipranolol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Metipranolol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metipranolol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metipranolol in pediatric patients.
# Contraindications
- Hypersensitivity to any component of this product.
- Metipranolol ophthalmic solution is contraindicated in patients with bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease; symptomatic sinus bradycardia; greater than a first degree atrioventricular block; cardiogenic shock; or overt cardiac failure.
# Warnings
- As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. Thus, the same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely, death in association with cardiac failure, have been reported following topical application of beta-adrenergic blocking agents .
- Since metipranolol ophthalmic solution had a minor effect on heart rate and blood pressure in clinical studies, caution should be observed in treating patients with a history of cardiac failure. Treatment with metipranolol ophthalmic solution should be discontinued at the first evidence of cardiac failure.
- Metipranolol ophthalmic solution, or other beta-blockers, should not, in general, be administered to patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity. However, if the drug is necessary in such patients, then it should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2 receptors.
### Precautions
- Because of potential effects of beta-adrenergic receptor blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with metipranolol ophthalmic solution, alternative therapy should be considered.
- Some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents in patients undergoing elective surgery. If necessary during surgery, the effects of beta-adrenergic receptor blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.
- While metipranolol ophthalmic solution has demonstrated a low potential for systemic effect, it should be used with caution in patients with diabetes (especially labile diabetes) because of possible masking of signs and symptoms of acute hypoglycemia.
- Beta-adrenergic receptor blocking agents may mask certain signs and symptoms of hyperthyroidism, and their abrupt withdrawal might precipitate a thyroid storm.
- Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).
- Risk of anaphylactic reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, the use of metipranolol ophthalmic solution has been associated with transient local discomfort.
- Other ocular adverse reactions, such as abnormal vision, blepharitis, blurred vision, browache, conjunctivitis, edema, eyelid dermatitis, photophobia, tearing, and uveitis have been reported in small numbers of patients.
- Other systemic adverse reactions, such as allergic reaction, angina, anxiety, arthritis, asthenia, atrial fibrillation, bradycardia, bronchitis, coughing, depression, dizziness, dyspnea, epistaxis, headache, hypertension, myalgia, myocardial infarct, nausea, nervousness, palpitation, rash, rhinitis, and somnolence have also been reported in small numbers of patients.
## Postmarketing Experience
There is limited information regarding Metipranolol Postmarketing Experience in the drug label.
# Drug Interactions
- Metipranolol ophthalmic solution should be used with caution in patients who are receiving a beta-adrenergic blocking agent orally, because of the potential for additive effects on systemic beta-blockade.
- Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or bradycardia.
- Caution should be used in the coadministration of beta-adrenergic receptor blocking agents, such as metipranolol, and oral or intravenous calcium channel antagonists, because of possible precipitation of left ventricular failure, and hypotension. In patients with impaired cardiac function, who are receiving calcium channel antagonists, coadministration should be avoided.
- The concomitant use of beta-adrenergic receptor blocking agents with digitalis and calcium channel antagonists may have additive effects, prolonging atrioventricular conduction time.
- Caution should be used in patients using concomitant adrenergic psychotropic drugs.
- Ocular: In patients with angle-closure glaucoma, the immediate treatment objective is to re-open the angle by constriction of the pupil with a miotic agent. Metipranolol ophthalmic solution has little or no effect on the pupil, therefore, when it is used to reduce intraocular pressure in angle-closure glaucoma, it should be used only with concomitant administration of a miotic agent.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- No drug related effects were reported for the segment II teratology study in fetal rats after administration, during organogenesis, to dams of up to 50 mg/kg/day. Metipranolol ophthalmic solution has been shown to increase fetal resorption, fetal death, and delayed development when administered orally to rabbits at 50 mg/kg/day during organogenesis.
- There are no adequate and well-controlled studies in pregnant women. Metipranolol ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
- It is not known whether metipranolol ophthalmic solution is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when metipranolol ophthalmic solution is administered in nursing women
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
- Ophthalmic
### Monitoring
There is limited information regarding Monitoring of Metipranolol in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Metipranolol and IV administrations.
# Overdosage
- No information is available on overdosage of metipranolol ophthalmic solution in humans. The symptoms which might be expected with an overdose of a systemically administered beta-adrenergic receptor blocking agent are bradycardia, hypotension and acute cardiac failure.
# Pharmacology
## Mechanism of Action
- Metipranolol blocks beta1 and beta2 (non-selective) adrenergic receptors. It does not have significant intrinsic sympathomimetic activity, and has only weak local anesthetic (membrane-stabilizing) and myocardial depressant activity.
- Orally administered beta-adrenergic blocking agents reduce cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor antagonists may inhibit the sympathetic stimulatory effect necessary to maintain adequate cardiac output.
- Beta-adrenergic receptor blockade in the bronchi and bronchioles may result in significantly increased airway resistance from unopposed para-sympathetic activity. Such an effect is potentially dangerous in patients with asthma or other bronchospastic conditions
## Structure
- Metipranolol ophthalmic solution 0.3% is a sterile solution that contains metipranolol, a non-selective beta-adrenergic receptor blocking agent. Metipranolol is a white, odorless, crystalline powder. The chemical name of metipranolol is (±)-1-(4-Hydroxy-2, 3,5-trimethylphenoxy)-3-(isopropylamino)-2-propanol-4-acetate.
- The chemical structural of metipranolol is:
- Each mL of metipranolol ophthalmic solution, for ophthalmic administration, contains 3 mg metipranolol. INACTIVES: povidone, glycerol, hydrochloric acid, sodium chloride, edetate disodium, and purified water. Sodium Hydroxide may be added to adjust pH. PRESERVATIVE ADDED: Benzalkonium chloride 0.004%. DM-00
## Pharmacodynamics
(Description)
## Pharmacokinetics
- Metipranolol when applied topically in the eye, has the action of reducing elevated as well as normal intraocular pressure (IOP), whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.
- The primary mechanism of the ocular hypotensive action of metipranolol is most likely due to reduction in aqueous humor production. A slight increase in outflow may be an additional mechanism. Metipranolol reduces IOP with little or no effect on pupil size or accommodation.
- In controlled studies of patients with intraocular pressure greater than 24 mmHg at baseline, metipranolol ophthalmic solution reduced the average intraocular pressure approximately 20 - 26%.
- The onset of action of metipranolol ophthalmic solution, as measured by a reduction in intraocular pressure, occurs within 30 minutes after a single administration. The maximum effect occurs at about 2 hours. A reduction in intraocular pressure can be demonstrated 24 hours after a single dose. Clinical studies in patients with glaucoma treated for up to two years indicate that an intraocular pressure lowering effect is maintained.
### ANIMAL PHARMACOLOGY
- In rabbits administered metipranolol in one eye at 2 to 4 fold increased concentrations, multi-focal interstitial nephritis was observed in male animals, and lympho-hystiocytic and heterophilic interstitial pneumonia was observed in female animals. The clinical relevance of these findings is unknown.
## Nonclinical Toxicology
- Lifetime studies with metipranolol have been conducted in mice at oral doses of 5, 50 and 100 mg/kg/day and in rats at oral doses of up to 70 mg/kg/day. Metipranolol demonstrated no carcinogenic effect. In the mouse study, female animals receiving the low, but not the intermediate or high dose, had an increased number of pulmonary adenomas. The significance of this observation is unknown. In a variety of in vitro and in vivo bacterial and mammalian cell assays, metipranolol was nonmutagenic.
- Reproduction and fertility studies of metipranolol in rats and mice showed no adverse effect on male fertility at oral doses of up to 50 mg/kg/day, and female fertility at oral doses of up to 25 mg/kg/day.
# Clinical Studies
There is limited information regarding Metipranolol Clinical Studies in the drug label.
# How Supplied
- Metipranolol ophthalmic solution 0.3% is supplied in a plastic bottle with a controlled drop tip and a white plastic screw-top cap as follows:
## Storage
- Store at controlled room temperature, 15°-30°C (59°-86°F). Replace cap immediately after use.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 61314-447-10 Rx Only
FALCON PHARMACEUTICALS®
Metipranolol
Ophthalmic
Solution
0.3%
10 mL STERILE
AFFILIATE OF
ALCON LABORATORIES, INC
QUALITY RX
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be instructed to avoid allowing the tip of the dispensing containers to contact the eye or surrounding structures. Patients should be advised that metipranolol contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following metipranolol administration.
# Precautions with Alcohol
Alcohol-Metipranolol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Optipranolol®[1]
# Look-Alike Drug Names
There is limited information regarding Metipranolol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Metipranolol | |
3a1c4a1c3bfce1248d9e012d6ba99c05267374e1 | wikidoc | Microsurgery | Microsurgery
# Overview
Microsurgery is a general term for surgery requiring an operating microscope. The most obvious developments have been procedures developed to allow anastomosis of successively smaller blood vessels and nerves (typically 1 mm in diameter) which have allowed transfer of tissue from one part of the body to another and re-attachment of severed parts. Although microsurgery is used mostly by plastic surgery, microsurgical techniques are utilized by all specialties today, especially those involved in reconstructive surgery such as: General surgery, orthopedic surgery, gynecological surgery, otolaryngology, Maxillofacial surgery, and pediatric surgery.
# History
The advances in the techniques and technology that popularized microsurgery began in the early 1960s. The first microvascular surgery, using a microscope to aid in the repair of blood vessels, was described by vascular surgeon, Jules Jacobson, of the University of Vermont in 1960. Using an operating microscope, he performed coupling of vessels as small as 1.4 mm and coined the term "microsurgery." Hand surgeons Kleinert and Kasdan performed the first revascularization of a partial digital amputation in 1963.
Nakayama, a Japanese cardiothoracic surgeon, reported the first true series of microsurgical free-tissue transfers using vascularized intestinal segments to the neck for esophageal reconstruction after cancer resections using 3-4mm vessels.
Contemporary reconstructive microsurgery was introduced by an American plastic surgeon, Dr. Harry J. Buncke. In 1964, Buncke reported a rabbit ear replantation, famously using a garage as a lab/operating theatre and home-made instruments.
This was the first report of successfully using blood vessels 1 millimeter in size. In 1966, Buncke used microsurgery to transplant a primate's great toe to its hand.
During the late sixties and early 1970s, plastic surgeons ushered in many new microsurgical innovations that were previously unimaginable. The first human microsurgical transplantation of the great toe (big toe) to thumb was performed in April 1968 by Mr. John Cobbett, in England. In Australia work by Dr. Ian Taylor saw new techniques developed to reconstruct head and neck cancer defects with living bone from the hip or the fibula.
Although primarily developed and used by plastic surgeons, a number of surgical specialties now use microsurgical techniques. Otolaryngologists (ear, nose, and throat doctors) perform microsurgery on structures of the inner ear or the vocal cords. Maxillofacial surgeons and Otolaryngologists use microsurgical techniques when reconstructing head and neck cancer patients. Cataract surgery, corneal transplants, and treatment of conditions like glaucoma are performed by ophthalmologists. Urologists and gynecologists can frequently now reverse vasectomies and tubal ligations to restore fertility.
# Free tissue transfer
Free tissue transfer is a surgical reconstructive procedure using microsurgery. A region of "donor" tissue is selected that can be isolated on a feeding artery and vein; this tissue is usually a composite of several tissue types (e.g., skin, muscle, fat, bone). Common donor regions include the rectus abdominis muscle, latissimus dorsi muscle, fibula, and radial forearm bone and skin lateral arm skin. The composite tissue is transferred (moved as a free flap of tissue) to the region on the patient requiring reconstruction (e.g., mandible after oral cancer resection, breast after cancer resection, traumatic tissue loss, congenital tissue absence). The vessels that supply the free flap are anastomosed with microsurgery to matching vessels (artery and vein) in the reconstructive site. The procedure was first done in the early 1970s and has become a popular "one-stage" (single operation) procedure for many surgical reconstructive applications.
- Traumatic foot/ankle soft tissue wound from motor vehicle accident
Traumatic foot/ankle soft tissue wound from motor vehicle accident
- Anterio-lateral thigh flap free-tissue transfer reconstruction
Anterio-lateral thigh flap free-tissue transfer reconstruction
# Replantation
Replantation is the reattachment of a completely detached body part. Fingers and thumbs are the commonest but the ear, scalp, nose, arm and penis have all been replanted. Generally replantation involves restoring blood flow through arteries and veins, restoring the bony skeleton and connecting tendons and nerves as required.
Initially, when the techniques were developed to make replantation possible, success was defined in terms of a survival of the amputated part alone. However, as more experience was gained in this field, surgeons specializing in replantation began to understand that survival of the amputated piece was not enough to ensure success of the replant. In this way, functional demands of the amputated specimen became paramount in guiding which amputated pieces should and should not be replanted. Additional concerns about the patients ability to tolerate the long rehabilitation process that is necessary after replantation both on physical and psychological levels also became important. So, when fingers are amputated, for instance, a replantation surgeon must seriously consider the contribution of the finger to the overall function of the hand. In this way, every attempt will be made to salvage an amputated thumb, since a great deal of hand function is dependent on the thumb, while an index finger or small finger may not be replanted, depending on the individual needs of the patient and the ability of the patient to tolerate a long surgery and a long course of rehabilitation.
However, if an amputated specimen is not able to be replanted to its original location entirely, this does not mean that the specimen is unreplantable. In fact, replantation surgeons have learned that only a piece or a portion may be necessary to obtain a functional result, or especially in the case of multply amputated fingers, a finger or fingers may be transposed to a more useful location to obtain a more functional result. This concept is called "spare parts" surgery.
# Transplantation
Microsurgical techniques have played a crucial role in the development of transplantation immunological research because it allowed the use of rodents models, which are more appropriate for transplantation research (there are more reagents, monoclonal antibodies, knockout animals, and other immunological tool for mice and rats than other species). Before it was introduced, transplant immunology was studied in rodents using the skin transplantation model, which is limited by the fact it is not vascularized. Thus, microsurgery represents the link between surgery and transplant immunological research.
The first microsurgical experiments (porto-caval anastomosis in the rat) were performed by Dr. Sun Lee (pioneer of microsurgery) at the University of Pittsburgh in 1958. After a short time, many models of organ tranplants in rat and mice have been established. Today, virtually every rat or mouse organ can be transplanted with relative high success rate.
Microsurgery was also important to develop new techniques of transplantation, that would be later performed in humans. In addition, it allows reconstruction of small arteries in clinical organ transplantation (e.g. accessory arteries in cadaver liver transplantation, polar arteries in renal transplantation and in living liver donor transplantation).
# Links
E-Medicine Microsurgery Principles
Microsurgeon.org History of Microsurgery | Microsurgery
Editor-In-Chief: Michel C. Samson, M.D., FRCSC, FACS [1]
# Overview
Microsurgery is a general term for surgery requiring an operating microscope. The most obvious developments have been procedures developed to allow anastomosis of successively smaller blood vessels and nerves (typically 1 mm in diameter) which have allowed transfer of tissue from one part of the body to another and re-attachment of severed parts. Although microsurgery is used mostly by plastic surgery, microsurgical techniques are utilized by all specialties today, especially those involved in reconstructive surgery such as: General surgery, orthopedic surgery, gynecological surgery, otolaryngology, Maxillofacial surgery, and pediatric surgery.
# History
The advances in the techniques and technology that popularized microsurgery began in the early 1960s. The first microvascular surgery, using a microscope to aid in the repair of blood vessels, was described by vascular surgeon, Jules Jacobson, of the University of Vermont in 1960. Using an operating microscope, he performed coupling of vessels as small as 1.4 mm and coined the term "microsurgery."[2] Hand surgeons Kleinert and Kasdan performed the first revascularization of a partial digital amputation in 1963.[1]
Nakayama, a Japanese cardiothoracic surgeon, reported the first true series of microsurgical free-tissue transfers using vascularized intestinal segments to the neck for esophageal reconstruction after cancer resections using 3-4mm vessels. [2]
Contemporary reconstructive microsurgery was introduced by an American plastic surgeon, Dr. Harry J. Buncke. In 1964, Buncke reported a rabbit ear replantation, famously using a garage as a lab/operating theatre and home-made instruments.[3]
This was the first report of successfully using blood vessels 1 millimeter in size. In 1966, Buncke used microsurgery to transplant a primate's great toe to its hand.[4]
During the late sixties and early 1970s, plastic surgeons ushered in many new microsurgical innovations that were previously unimaginable. The first human microsurgical transplantation of the great toe (big toe) to thumb was performed in April 1968 by Mr. John Cobbett, in England. [5] In Australia work by Dr. Ian Taylor [6] saw new techniques developed to reconstruct head and neck cancer defects with living bone from the hip or the fibula.
Although primarily developed and used by plastic surgeons, a number of surgical specialties now use microsurgical techniques. Otolaryngologists (ear, nose, and throat doctors) perform microsurgery on structures of the inner ear or the vocal cords. Maxillofacial surgeons and Otolaryngologists use microsurgical techniques when reconstructing head and neck cancer patients. Cataract surgery, corneal transplants, and treatment of conditions like glaucoma are performed by ophthalmologists. Urologists and gynecologists can frequently now reverse vasectomies and tubal ligations to restore fertility.
# Free tissue transfer
Free tissue transfer is a surgical reconstructive procedure using microsurgery. A region of "donor" tissue is selected that can be isolated on a feeding artery and vein; this tissue is usually a composite of several tissue types (e.g., skin, muscle, fat, bone). Common donor regions include the rectus abdominis muscle, latissimus dorsi muscle, fibula, and radial forearm bone and skin lateral arm skin. The composite tissue is transferred (moved as a free flap of tissue) to the region on the patient requiring reconstruction (e.g., mandible after oral cancer resection, breast after cancer resection, traumatic tissue loss, congenital tissue absence). The vessels that supply the free flap are anastomosed with microsurgery to matching vessels (artery and vein) in the reconstructive site. The procedure was first done in the early 1970s and has become a popular "one-stage" (single operation) procedure for many surgical reconstructive applications.
- Traumatic foot/ankle soft tissue wound from motor vehicle accident
Traumatic foot/ankle soft tissue wound from motor vehicle accident
- Anterio-lateral thigh flap free-tissue transfer reconstruction
Anterio-lateral thigh flap free-tissue transfer reconstruction
# Replantation
Replantation is the reattachment of a completely detached body part. Fingers and thumbs are the commonest but the ear, scalp, nose, arm and penis have all been replanted. Generally replantation involves restoring blood flow through arteries and veins, restoring the bony skeleton and connecting tendons and nerves as required.
Initially, when the techniques were developed to make replantation possible, success was defined in terms of a survival of the amputated part alone. However, as more experience was gained in this field, surgeons specializing in replantation began to understand that survival of the amputated piece was not enough to ensure success of the replant. In this way, functional demands of the amputated specimen became paramount in guiding which amputated pieces should and should not be replanted. Additional concerns about the patients ability to tolerate the long rehabilitation process that is necessary after replantation both on physical and psychological levels also became important. So, when fingers are amputated, for instance, a replantation surgeon must seriously consider the contribution of the finger to the overall function of the hand. In this way, every attempt will be made to salvage an amputated thumb, since a great deal of hand function is dependent on the thumb, while an index finger or small finger may not be replanted, depending on the individual needs of the patient and the ability of the patient to tolerate a long surgery and a long course of rehabilitation.
However, if an amputated specimen is not able to be replanted to its original location entirely, this does not mean that the specimen is unreplantable. In fact, replantation surgeons have learned that only a piece or a portion may be necessary to obtain a functional result, or especially in the case of multply amputated fingers, a finger or fingers may be transposed to a more useful location to obtain a more functional result. This concept is called "spare parts" surgery.
# Transplantation
Microsurgical techniques have played a crucial role in the development of transplantation immunological research because it allowed the use of rodents models, which are more appropriate for transplantation research (there are more reagents, monoclonal antibodies, knockout animals, and other immunological tool for mice and rats than other species). Before it was introduced, transplant immunology was studied in rodents using the skin transplantation model, which is limited by the fact it is not vascularized. Thus, microsurgery represents the link between surgery and transplant immunological research.
The first microsurgical experiments (porto-caval anastomosis in the rat) were performed by Dr. Sun Lee (pioneer of microsurgery) at the University of Pittsburgh in 1958. After a short time, many models of organ tranplants in rat and mice have been established. Today, virtually every rat or mouse organ can be transplanted with relative high success rate.
Microsurgery was also important to develop new techniques of transplantation, that would be later performed in humans. In addition, it allows reconstruction of small arteries in clinical organ transplantation (e.g. accessory arteries in cadaver liver transplantation, polar arteries in renal transplantation and in living liver donor transplantation).
# Links
E-Medicine Microsurgery Principles
Microsurgeon.org History of Microsurgery | https://www.wikidoc.org/index.php/Microsurgery | |
ca315db545c040f464904e1ceb33316abf02b4cc | wikidoc | Tunica media | Tunica media
The tunica media (or just media) is the middle layer of an artery or vein.
# Artery
It is made up of smooth muscle cells and elastic tissue. It lies between the tunica intima on the inside and the tunica adventitia on the outside.
The middle coat (tunica media) is distinguished from the inner by its color and by the transverse arrangement of its fibers.
- In the smaller arteries it consists principally of plain muscle fibers in fine bundles, arranged in lamellæ and disposed circularly around the vessel. These lamellæ vary in number according to the size of the vessel; the smallest arteries having only a single layer, and those slightly larger three or four layers. It is to this coat that the thickness of the wall of the artery is mainly due.
- In the larger arteries, as the iliac, femoral, and carotid, elastic fibers unite to form lamellæ which alternate with the layers of muscular fibers; these lamellæ are united to one another by elastic fibers which pass between the muscular bundles, and are connected with the fenestrated membrane of the inner coat.
- In the largest arteries, as the aorta and brachiocephalic , the amount of elastic tissue is very considerable; in these vessels a few bundles of white connective tissue also have been found in the middle coat. The muscle fiber cells are about 50μ in length and contain well-marked, rod-shaped nuclei, which are often slightly curved.
# Vein
The middle coat is composed of a thick layer of connective tissue with elastic fibers, intermixed, in some veins, with a transverse layer of muscular tissue.
The white fibrous element is in considerable excess, and the elastic fibers are in much smaller proportion in the veins than in the arteries.
# Additional images
- Vein
- Anatomy of the arterial wall
- Section of a medium-sized artery. | Tunica media
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The tunica media (or just media) is the middle layer of an artery or vein.[1]
# Artery
It is made up of smooth muscle cells and elastic tissue. It lies between the tunica intima on the inside and the tunica adventitia on the outside.
The middle coat (tunica media) is distinguished from the inner by its color and by the transverse arrangement of its fibers.
- In the smaller arteries it consists principally of plain muscle fibers in fine bundles, arranged in lamellæ and disposed circularly around the vessel. These lamellæ vary in number according to the size of the vessel; the smallest arteries having only a single layer[2], and those slightly larger three or four layers. It is to this coat that the thickness of the wall of the artery is mainly due.
- In the larger arteries, as the iliac, femoral, and carotid, elastic fibers unite to form lamellæ which alternate with the layers of muscular fibers; these lamellæ are united to one another by elastic fibers which pass between the muscular bundles, and are connected with the fenestrated membrane of the inner coat.
- In the largest arteries, as the aorta[3] and brachiocephalic , the amount of elastic tissue is very considerable; in these vessels a few bundles of white connective tissue also have been found in the middle coat. The muscle fiber cells are about 50μ in length and contain well-marked, rod-shaped nuclei, which are often slightly curved.
# Vein
The middle coat is composed of a thick layer of connective tissue with elastic fibers, intermixed, in some veins, with a transverse layer of muscular tissue. [4]
The white fibrous element is in considerable excess, and the elastic fibers are in much smaller proportion in the veins than in the arteries.
# Additional images
- Vein
- Anatomy of the arterial wall
- Section of a medium-sized artery. | https://www.wikidoc.org/index.php/Middle_coat | |
a0b4dc12f36c07a3078db4f91fe1ced12a0141b3 | wikidoc | Milk thistle | Milk thistle
Milk thistles are thistles of the genus Silybum Adans., flowering plants of the daisy family (Asteraceae). They are native to the Mediterranean regions of Europe, North Africa and the Middle East. Whilst health uses mostly for chronic liver disease have been traditionally claimed for the plant, increasing research is being undertaken on this and other possible medical uses.
# Description and classification
Members of this genus grow as annual or biennial plants. The erect stem is tall, branched and furrowed but not spiny. The large, alternate leaves are waxy-lobed, toothed and thorny, as in other genera of thistle. The lower leaves are cauline (attached to the stem without petiole). The upper leaves have a clasping base. They have large, disc-shaped pink-to-purple, rarely white, solitary flower heads at the end of the stem. The flowers consist of tubular florets. The phyllaries under the flowers occur in many rows, with the outer row with spine-tipped lobes and apical spines. The fruit is a black achene with a white pappus.
Only two species are currently classified in this genus:
- Silybum eburneum Coss. & Dur., known as the Silver Milk Thistle, Elephant Thistle, or Ivory Thistle
Silybum eburneum Coss. & Dur. var. hispanicum
- Silybum eburneum Coss. & Dur. var. hispanicum
- Silybum marianum (L.) Gaertner, the Blessed Milk Thistle, which has a large number of other common names, such as Variegated Thistle.
The two species hybridise naturally, the hybrid being known as Silybum × gonzaloi Cantó , Sánchez Mata & Rivas Mart. (S. eburneum var. hispanicum x S. marianum)
A number of other plants have been classified in this genus in the past but have since been relocated elsewhere in the light of additional research.
S. marianum is by far the more widely known species. It is believed to give some remedy for liver diseases (e.g. viral hepatitis) and an extract, silymarin, is used in medicine. The adverse effect of the medicinal use of milk thistle is loose stools.
# Health benefits
Milk thistles have been reported to have protective effects on the liver and to improve its function. They are typically used to treat liver cirrhosis, chronic hepatitis (liver inflammation), and gallbladder disorders. The active compound in Milk thistle credited with this effect is "silymarin", and is typically administered in amount ranging from 200-500mg per day (common Milk Thistle supplements have an 80% standardized extract of silymarin). Increasing research is being carried out into its possible medical uses and the mechanisms of such effects.. However, a previous literature review using only studies with both double-blind and placebo protocols concluded that milk thistle and its derivatives "does not seem to significantly influence the course of patients with alcoholic and/or hepatitis B or C liver diseases."
Treatment claims also include:
- Lowering cholesterol levels
- Reducing insulin resistance in people with type 2 diabetes who also have cirrhosis
- Reducing the growth of cancer cells in breast, cervical, and prostate cancers.
- Milk thistle is also used in many products claiming to reduce the effects of a hangover.
- Milk thistle can also be found as an ingredient in some energy drinks like the AriZona Beverage Company Green Tea energy drink and Rockstar Energy Drink. | Milk thistle
Milk thistles are thistles of the genus Silybum Adans., flowering plants of the daisy family (Asteraceae). They are native to the Mediterranean regions of Europe, North Africa and the Middle East. Whilst health uses mostly for chronic liver disease have been traditionally claimed for the plant, increasing research is being undertaken on this and other possible medical uses.[1]
# Description and classification
Members of this genus grow as annual or biennial plants. The erect stem is tall, branched and furrowed but not spiny. The large, alternate leaves are waxy-lobed, toothed and thorny, as in other genera of thistle. The lower leaves are cauline (attached to the stem without petiole). The upper leaves have a clasping base. They have large, disc-shaped pink-to-purple, rarely white, solitary flower heads at the end of the stem. The flowers consist of tubular florets. The phyllaries under the flowers occur in many rows, with the outer row with spine-tipped lobes and apical spines. The fruit is a black achene with a white pappus.
Only two species are currently classified in this genus:
- Silybum eburneum Coss. & Dur., known as the Silver Milk Thistle, Elephant Thistle, or Ivory Thistle
Silybum eburneum Coss. & Dur. var. hispanicum
- Silybum eburneum Coss. & Dur. var. hispanicum
- Silybum marianum (L.) Gaertner, the Blessed Milk Thistle, which has a large number of other common names, such as Variegated Thistle.
The two species hybridise naturally, the hybrid being known as Silybum × gonzaloi Cantó , Sánchez Mata & Rivas Mart. (S. eburneum var. hispanicum x S. marianum)
A number of other plants have been classified in this genus in the past but have since been relocated elsewhere in the light of additional research.
S. marianum is by far the more widely known species. It is believed to give some remedy for liver diseases (e.g. viral hepatitis) and an extract, silymarin, is used in medicine. The adverse effect of the medicinal use of milk thistle is loose stools.
# Health benefits
Milk thistles have been reported to have protective effects on the liver and to improve its function. They are typically used to treat liver cirrhosis, chronic hepatitis (liver inflammation), and gallbladder disorders. The active compound in Milk thistle credited with this effect is "silymarin", and is typically administered in amount ranging from 200-500mg per day (common Milk Thistle supplements have an 80% standardized extract of silymarin). Increasing research is being carried out into its possible medical uses and the mechanisms of such effects.[1]. However, a previous literature review using only studies with both double-blind and placebo protocols concluded that milk thistle and its derivatives "does not seem to significantly influence the course of patients with alcoholic and/or hepatitis B or C liver diseases."[2]
Treatment claims also include:
- Lowering cholesterol levels
- Reducing insulin resistance in people with type 2 diabetes who also have cirrhosis
- Reducing the growth of cancer cells in breast, cervical, and prostate cancers.[3]
- Milk thistle is also used in many products claiming to reduce the effects of a hangover.
- Milk thistle can also be found as an ingredient in some energy drinks like the AriZona Beverage Company Green Tea energy drink and Rockstar Energy Drink. | https://www.wikidoc.org/index.php/Milk_thistle | |
879aa029a56ac6365e49e8c7ab8d89e09ab19f95 | wikidoc | Mind control | Mind control
Mind control (not to be confused with "brainwashing") refers to a broad range of psychological tactics able to subvert an individual's control of his own thinking, behavior, emotions, or decisions. The concept is closely related to hypnosis, but differs in practical approach.
There are a number of controversial issues regarding mind control and the methods by which control might be attained (either direct or more subtle) are the focus of study among psychologists, neuroscientists, and sociologists.
The question of mind control has been discussed in relation to religion, politics, prisoners of war, totalitarianism, black operations, neural cell manipulation, cults, terrorism, torture, parental alienation, and even battered person syndrome.
Mind control as a legal defense tactic (see also temporary insanity) was rejected by the court in the case of Patty Hearst, and in several court cases involving New Religious Movements.
Also, questions of mind control are regarding ethical questions linked to the subject of free will.
# Theoretical models and methods
## Lifton thought reform model
In his 1961 book Thought Reform and the Psychology of Totalism: A Study of "Brainwashing" in China, psychiatrist Robert Jay Lifton, M.D., describes eight coercive methods which, he says, are able to change the minds of individuals without their knowledge and were used with this purpose on prisoners of war in Korea and China. These include:
- Milieu Control. This involves the control of information and communication both within the environment and, ultimately, within the individual, resulting in a significant degree of isolation from society at large.
- Mystical Manipulation. There is manipulation of experiences that appear spontaneous but in fact were planned and orchestrated by the group or its leaders in order to demonstrate divine authority or spiritual advancement or some special gift or talent that will then allow the leader to reinterpret events, scripture, and experiences as he or she wishes.
- Demand for Purity. The world is viewed as black and white and the members are constantly exhorted to conform to the ideology of the group and strive for perfection. The induction of guilt and/or shame is a powerful control device used here.
- Confession. Sins, as defined by the group, are to be confessed either to a personal monitor or publicly to the group. There is no confidentiality; members' "sins," "attitudes," and "faults" are discussed and exploited by the leaders.
- Sacred Science. The group's doctrine or ideology is considered to be the ultimate Truth, beyond all questioning or dispute. Truth is not to be found outside the group. The leader, as the spokesperson for God or for all humanity, is likewise above criticism.
- Loading the Language. The group interprets or uses words and phrases in new ways so that often the outside world does not understand. This jargon consists of thought-terminating clichés, which serve to alter members' thought processes to conform to the group's way of thinking.
- Doctrine over person. Member's personal experiences are subordinated to the sacred science and any contrary experiences must be denied or reinterpreted to fit the ideology of the group.
- Dispensing of existence. The group has the prerogative to decide who has the right to exist and who does not. This is usually not literal but means that those in the outside world are not saved, unenlightened, unconscious and they must be converted to the group's ideology. If they do not join the group or are critical of the group, then they must be rejected by the members. Thus, the outside world loses all credibility. In conjunction, should any member leave the group, he or she must be rejected also.
In his 1999 book Destroying the world to save it: Aum Shinrikyo, Apocalyptic Violence and the New Global Terrorism, he concluded that thought reform was possible without violence or physical coercion.
Robert W. Ford, a British radio operator who worked in Tibet in the 50's, spent 5 years in Chinese jails. He published a book entitled "Captured in Tibet", describing and analyzing thought reform to which he was harshly subjected.
## William Sargant's theories on mind control
William Sargant connected Pavlov’s findings to the ways people learned and internalized belief systems. Conditioned behavior patterns could be changed by stimulated stresses beyond a dog’s capacity for response, in essence causing a breakdown. This could also be caused by intense signals, longer than normal waiting periods, rotating positive and negative signals and changing a dog’s physical condition, as through illness. Depending on the dog’s initial personality, this could possibly cause a new belief system to be held tenaciously. Sargant also connected Pavlov’s findings to the mechanisms of brain-washing in religion and politics.
"Though men are not dogs, they should humbly try to remember how much they resemble dogs in their brain functions, and not boast themselves as demigods. They are gifted with religious and social apprehensions, and they are gifted with the power of reason; but all these faculties are physiologically entailed to the brain. Therefore the brain should not be abused by having forced upon it any religious or political mystique that stunts the reason, or any form of crude rationalism that stunts the religious sense." (p. 274)
## Margaret Singer's conditions for mind control
Psychologist Margaret Singer describes in her book Cults in our Midst six conditions which she says would create an atmosphere in which thought reform is possible. Singer states that these conditions involve no need for physical coercion or violence.
- Keep the person unaware of what is going on and how he is being changed a step at a time.
Potential new members are led, step by step, through a behavioral-change program without being aware of the final agenda or full content of the group. The goal may be to make them deployable agents for the leadership, to get them to buy more courses, or get them to make a deeper commitment, depending on the leader's aim and desires.
- Potential new members are led, step by step, through a behavioral-change program without being aware of the final agenda or full content of the group. The goal may be to make them deployable agents for the leadership, to get them to buy more courses, or get them to make a deeper commitment, depending on the leader's aim and desires.
- Control the person's social and/or physical environment; especially control the person's time.
Through various methods, newer members are kept busy and led to think about the group and its content during as much of their waking time as possible.
- Through various methods, newer members are kept busy and led to think about the group and its content during as much of their waking time as possible.
- Systematically create a sense of powerlessness in the person.
This is accomplished by getting members away from their normal social support group for a period of time and into an environment where the majority of people are already group members.
The members serve as models of the attitudes and behaviors of the group and speak an in-group language.
Strip members of their main occupation (quit jobs, drop out of school) or source of income or have them turn over their income (or the majority of) to the group.
Once stripped of your usual support network, your confidence in your own perception erodes.
As your sense of powerlessness increases, your good judgment and understanding of the world are diminished. (ordinary view of reality is destabilized)
As group attacks your previous worldview, it causes you distress and inner confusion; yet you are not allowed to speak about this confusion or object to it -- leadership suppresses questions and counters resistance.
This process is sped up if you are kept tired -- the cult will keep you constantly busy.
- This is accomplished by getting members away from their normal social support group for a period of time and into an environment where the majority of people are already group members.
- The members serve as models of the attitudes and behaviors of the group and speak an in-group language.
- Strip members of their main occupation (quit jobs, drop out of school) or source of income or have them turn over their income (or the majority of) to the group.
- Once stripped of your usual support network, your confidence in your own perception erodes.
- As your sense of powerlessness increases, your good judgment and understanding of the world are diminished. (ordinary view of reality is destabilized)
- As group attacks your previous worldview, it causes you distress and inner confusion; yet you are not allowed to speak about this confusion or object to it -- leadership suppresses questions and counters resistance.
- This process is sped up if you are kept tired -- the cult will keep you constantly busy.
- Manipulate a system of rewards, punishments and experiences in such a way as to inhibit behavior that reflects the person's former social identity.
Manipulation of experiences can be accomplished through various methods of trance induction, including leaders using such techniques as paced speaking patterns, guided imagery, chanting, long prayer sessions or lectures, and lengthy meditation sessions.
Your old beliefs and patterns of behavior are defined as irrelevant or evil. Leadership wants these old patterns eliminated, so the member must suppress them.
Members get positive feedback for conforming to the group's beliefs and behaviors and negative feedback for old beliefs and behavior.
- Manipulation of experiences can be accomplished through various methods of trance induction, including leaders using such techniques as paced speaking patterns, guided imagery, chanting, long prayer sessions or lectures, and lengthy meditation sessions.
- Your old beliefs and patterns of behavior are defined as irrelevant or evil. Leadership wants these old patterns eliminated, so the member must suppress them.
- Members get positive feedback for conforming to the group's beliefs and behaviors and negative feedback for old beliefs and behavior.
- Manipulate a system of rewards, punishments, and experiences in order to promote learning the group's ideology or belief system and group-approved behaviors.
Good behavior, demonstrating an understanding and acceptance of the group's beliefs, and compliance are rewarded while questioning, expressing doubts or criticizing are met with disapproval, redress and possible rejection. If one expresses a question, he or she is made to feel that there is something inherently wrong with them to be questioning.
The only feedback members get is from the group, they become totally dependent upon the rewards given by those who control the environment.
Members must learn varying amounts of new information about the beliefs of the group and the behaviors expected by the group.
The more complicated and filled with contradictions the new system is and the more difficult it is to learn, the more effective the conversion process will be.
Esteem and affection from peers is very important to new recruits. Approval comes from having the new member's behaviors and thought patterns conform to the models (members). Members' relationship with peers is threatened whenever they fail to learn or display new behaviors. Over time, the easy solution to the insecurity generated by the difficulties of learning the new system is to inhibit any display of doubts -- new recruits simply acquiesce, affirm and act as if they do understand and accept the new ideology.
- Good behavior, demonstrating an understanding and acceptance of the group's beliefs, and compliance are rewarded while questioning, expressing doubts or criticizing are met with disapproval, redress and possible rejection. If one expresses a question, he or she is made to feel that there is something inherently wrong with them to be questioning.
- The only feedback members get is from the group, they become totally dependent upon the rewards given by those who control the environment.
- Members must learn varying amounts of new information about the beliefs of the group and the behaviors expected by the group.
- The more complicated and filled with contradictions the new system is and the more difficult it is to learn, the more effective the conversion process will be.
- Esteem and affection from peers is very important to new recruits. Approval comes from having the new member's behaviors and thought patterns conform to the models (members). Members' relationship with peers is threatened whenever they fail to learn or display new behaviors. Over time, the easy solution to the insecurity generated by the difficulties of learning the new system is to inhibit any display of doubts -- new recruits simply acquiesce, affirm and act as if they do understand and accept the new ideology.
- Put forth a closed system of logic and an authoritarian structure that permits no feedback and refuses to be modified except by leadership approval or executive order.
The group has a top-down, pyramid structure. The leaders must have verbal ways of never losing.
Members are not allowed to question, criticize or complain -- if they do, the leaders allege that the member is defective -- not the organization or the beliefs.
The individual is always wrong -- the system, its leaders and its belief are always right.
Conversion or remolding of the individual member happens in a closed system. As members learn to modify their behavior in order to be accepted in this closed system, they change -- begin to speak the language -- which serves to further isolate them from their prior beliefs and behaviors.
- The group has a top-down, pyramid structure. The leaders must have verbal ways of never losing.
- Members are not allowed to question, criticize or complain -- if they do, the leaders allege that the member is defective -- not the organization or the beliefs.
- The individual is always wrong -- the system, its leaders and its belief are always right.
- Conversion or remolding of the individual member happens in a closed system. As members learn to modify their behavior in order to be accepted in this closed system, they change -- begin to speak the language -- which serves to further isolate them from their prior beliefs and behaviors.
A report on brainwashing and mind control presented by an American Psychological Association (APA) task force known as the APA Taskforce on Deceptive and Indirect Techniques of Persuasion and Control (DIMPAC), chaired by Singer, was rejected in 1987 by the APA's Board of Social and Ethical Responsibility for Psychology (BSERP) as lacking "the scientific rigor and evenhanded critical approach necessary for APA imprimatur." and cautioned the task force members to "not distribute or publicize the report without indicating that the report was unacceptable to the Board."
In 2001, Alberto Amitrani and Raffaella Di Marzio, from the Roman seat of the Group for Research and Information about Sects (GRIS) published an article in which they assert that the rejection of the report should not be construed as a rejection of the theories of thought reform and mind control as applied to New Religious Movements, and that the rejection by one division of the APA does not represent the whole association. They quote a personal e-mail from Benjamin Zablocki, professor of sociology, from 1997 in which Zablocki told the authors "many people have been misled about the true position of the APA and the ASA with regard to brainwashing", and that the APA urged scholars to do more research on the matter. They also write that they have reason to believe that the APA still considers "psychological coercion" to be a phenomenon worth investigating, and not a notion rejected by the scientific community. They also write "Otherwise, why would people such as Margaret Singer, Michael Langone, and others considered to be 'anti-cultists' contribute to APA Conventions and be respected in other prestigious professional bodies as well?"
Writing in 1999, research and forensic psychologist Dick Anthony noted that the removal of Singer's brainwashing concept from the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) "would seem to indicate that the American Psychiatric Association, like the American Psychological Association, the American Sociological Association and the Society for the Scientific Study of Religion, has repudiated Singer's cultic brainwashing theory because of its unscientific character." Anthony also noted that Singer's testimony had also been repeatedly excluded from American legal trials.
## Steven Hassan's BITE model
In his book Releasing the Bonds: Empowering People to Think for Themselves, mental health counselor and exit counselor Steven Hassan describes his mind-control model, "BITE". "BITE" stands for "Behavior, Information, Thoughts, and Emotions." The model has a basis on the works of Singer and Lifton, and on the cognitive dissonance theory of Leon Festinger.
In the book, Hassan describes the components of the BITE model:
- Behavior Control
Regulation of individual’s physical reality
Major time commitment required for indoctrination sessions and group rituals
Need to ask permission for major decisions
Need to report thoughts, feelings, and activities to superiors
Rewards and punishments (behavior modification techniques positive and negative)
Individualism discouraged; "group think" prevails
Rigid rules and regulations
Need for obedience and dependency
- Regulation of individual’s physical reality
- Major time commitment required for indoctrination sessions and group rituals
- Need to ask permission for major decisions
- Need to report thoughts, feelings, and activities to superiors
- Rewards and punishments (behavior modification techniques positive and negative)
- Individualism discouraged; "group think" prevails
- Rigid rules and regulations
- Need for obedience and dependency
- Information Control
Use of deception
Access to non cult sources of information minimized or discouraged
Compartmentalization of information; Outsider vs. Insider doctrines
Spying on other members is encouraged
Extensive use of cult generated information and propaganda
Unethical use of confession
- Use of deception
- Access to non cult sources of information minimized or discouraged
- Compartmentalization of information; Outsider vs. Insider doctrines
- Spying on other members is encouraged
- Extensive use of cult generated information and propaganda
- Unethical use of confession
- Thought Control
Need to internalize the group’s doctrine as "Truth"
Use of "loaded" language (for example, “thought terminating clichés"). Words are the tools we use to think with. These "special" words constrict rather than expand understanding, and can even stop thoughts altogether. They function to reduce complexities of experience into trite, platitudinous "buzz words."
Only "good" and "proper" thoughts are encouraged.
Use of hypnotic techniques to induce altered mental states
Manipulation of memories and implantation of false memories
Use of thought stopping techniques, which shut down "reality testing" by stopping "negative" thoughts and allowing only "good" thoughts
Rejection of rational analysis, critical thinking, constructive criticism. No critical questions about leader, doctrine, or policy seen as legitimate.
No alternative belief systems viewed as legitimate, good, or useful
- Need to internalize the group’s doctrine as "Truth"
- Use of "loaded" language (for example, “thought terminating clichés"). Words are the tools we use to think with. These "special" words constrict rather than expand understanding, and can even stop thoughts altogether. They function to reduce complexities of experience into trite, platitudinous "buzz words."
- Only "good" and "proper" thoughts are encouraged.
- Use of hypnotic techniques to induce altered mental states
- Manipulation of memories and implantation of false memories
- Use of thought stopping techniques, which shut down "reality testing" by stopping "negative" thoughts and allowing only "good" thoughts
- Rejection of rational analysis, critical thinking, constructive criticism. No critical questions about leader, doctrine, or policy seen as legitimate.
- No alternative belief systems viewed as legitimate, good, or useful
- Emotional Control
Manipulate and narrow the range of a person’s feelings
Make the person feel that if there are ever any problems, it is always their fault, never the leader’s or the group’s
Excessive use of guilt
Excessive use of fear
Extremes of emotional highs and lows
Ritual and often public confession of "sins"
Phobia indoctrination: inculcating irrational fears about ever leaving the group or even questioning the leader’s authority. The person under mind control cannot visualize a positive, fulfilled future without being in the group.
- Manipulate and narrow the range of a person’s feelings
- Make the person feel that if there are ever any problems, it is always their fault, never the leader’s or the group’s
- Excessive use of guilt
- Excessive use of fear
- Extremes of emotional highs and lows
- Ritual and often public confession of "sins"
- Phobia indoctrination: inculcating irrational fears about ever leaving the group or even questioning the leader’s authority. The person under mind control cannot visualize a positive, fulfilled future without being in the group.
Hassan writes that cults recruit and retain members through a three-step process which he refers to as "unfreezing," "changing," and "refreezing". This involves the use of an extensive array of various techniques, including systematic deception, behavior modification, withholding of information, and emotionally intense persuasion techniques (such as the induction of phobias), which he collectively terms mind control.
He describes these steps as follows:
- Unfreezing: the process of breaking a person down
- Changing: the indoctrination process
- Refreezing: the process of reinforcing the new identity
In Releasing the Bonds he also writes "I suspect that most cult groups use informal hypnotic techniques to induce trance states. They tend to use what are called "naturalistic" hypnotic techniques. Practicing meditation to shut down thinking, chanting a phrase repetitively for hours, or reciting affirmations are all powerful ways to promote spiritual growth. But they can also be used unethically, as methods for mind control indoctrination."
Hassan, after taking part in a number of deprogrammings in the late 1970s, states that he is no longer involved in this practice. and which eventually became completely illegal except in the case of minors.
In Releasing the Bonds, Hassan describes an approach that he calls the "Strategic Interaction Approach" (SIA) in order to help cult members leave their groups, and in order to help them recover from the psychological damage that they have incurred. The approach is non-coercive and the person being treated is free to discontinue it at any time. He writes: "The goal of the SIA is to help the loved one recover his full faculties; to restore the creative, interdependent adult who fully understands what has happened to him; who has digested and integrated the experience and is better and stronger from the experience."
In 1998 the Enquete Commission issued its report on "So-called Sects and Psychogroups" in Germany. Reviewing Hassan's BITE model, the report said that:
Thus, the milieu control identified by Hassan, consisting of behavioural control, mental control, emotional control and information control cannot, in every case and as a matter of principle, be characterised as "manipulative". Control of these areas of action is an inevitable component of social interactions in a group or community. The social control that is always associated with intense commitment to a group must therefore be clearly distinguished from the exertion of intentional, methodical influence for the express purpose of manipulation.
## Mind Control and the Battered Person Syndrome
A very different explanation of the control some groups have over their members is by associating it with Battered person syndrome and Stockholm syndrome. This has been done by psychologists Teresa Ramirez Boulette, Ph.D. and Susan M. Andersen, Ph.D.
## Social psychology tactics
A contemporary view of mind control sees it as an intensified and persistent use of well researched social psychology principles like compliance, conformity, persuasion, dissonance, reactance, framing or emotional manipulation.
One of the most notable proponents of such theories is social psychologist Philip Zimbardo, former president of the American Psychological Association:
In Influence, Science and Practice, social psychologist Robert Cialdini argues that mind control is possible through the covert exploitation of the unconscious rules that underlie and facilitate healthy human social interactions. He states that common social rules can be used to prey upon the unwary, and he titles them as follows:
- "Reciprocation: The Old Give and Take...and Take"
- "Commitment and Consistency: Hobgoblins of the Mind"
- "Social Proof: Truths Are Us"
- "Liking: The Friendly Thief"
- "Authority: Directed Deference"
- "Scarcity: The Rule of the Few"
Using these six broad categories, he offers specific examples of both mild and extreme mind control (both one on one and in groups), notes the conditions under which each social rule is most easily exploited for false ends, and offers suggestions on how to resist such methods.
## Social psychological conditioning by Stahelski
Writing in the Journal of Homeland Security, a publication of the ANSER Institute for Homeland Security, Anthony Stahelski identifies five phases of social psychological conditioning which he calls cult-like conditioning techniques employed by terrorist groups: :
- Depluralization: stripping away all other group member identities
- Self-deindividuation: stripping away each member’s personal identity
- Other-deindividuation: stripping away the personal identities of enemies
- Dehumanization: identifying enemies as subhuman or nonhuman
- Demonization: identifying enemies as evil
## Subliminal advertising
Subliminal advertising was proposed around 1960 as a means for organized mass control of human behavior. The allegations has since then fallen out of the common debate, because there are few reports that subliminal advertising has any real effect in the way advertisers may wish.
# Cults and mind control controversies
Some of the mind control models discussed above have been related to religious and non-religious cults (for debates regarding what is a cult, see the article). There is debate among scholars, members of new religious movements, and cult critics whether or not mind control is applied either in general or by any particular group.
## Scholarly points of view
While the majority of scholars in the study of religion reject theories of mind control (e.g., Massimo Introvigne and J. Gordon Melton), it is often accepted in psychology and psychiatry (e.g., Margaret Singer, Michael Langone, and Philip Zimbardo) and in sociology the opinions are divided (e.g., David G. Bromley and Anson Shupe contra, Stephen A. Kent and Benjamin Zablocki pro). Most scholars have either a decided contra or a decided pro opinion; there are few who advocate a moderate point of view.
James T. (Jim) Richardson, professor of Sociology and Judicial Studies at the University of Nevada, writes in his "Brainwashing" Claims and Minority Religions Outside the United States: Cultural Diffusion of a Questionable Concept in the Legal Arena that, while heavy on theory, the mind control model is light on evidence:
James Richardson, also states that if the NRMs had access to powerful brainwashing techniques, one would expect that NRMs would have high growth rates, while in fact most have not had notable success in recruitment. Most adherents participate for only a short time, and the success in retaining members has been limited. In addition, Thomas Robbins, Eileen Barker, Newton Maloney, Massimo Introvigne, John Hall, Lorne Dawson, Anson Shupe, David G. Bromley, Gordon Melton, Marc Galanter, Saul Levine and other scholars researching NRMs have argued and established to the satisfaction of courts and relevant professional associations and scientific communities that there exists no scientific theory, generally accepted and based upon methodologically sound research, that supports the brainwashing theories as advanced by the anti-cult movement.
Sociologist Benjamin Zablocki sees strong indicators of mind control in some NRMs and suggests that the concept should be researched without bias:
Sociologists David Bromley and Anson Shupe consider the idea that "cults" are brainwashing American youth to be "implausible".. Sociology professor Stephen A. Kent published several articles where he discusses practices of NRMs as regards to brainwashing
In 1984 the American Psychological Association (APA) requested Margaret Singer, the main proponent of mind control theories, to set up a working group called the APA taskforce on Deceptive and Indirect Techniques of Persuasion and Control (DIMPAC).
In 1987 the DIMPAC committee submitted its final report to the Board of Social and Ethical Responsibility for Psychology of the APA. On May 11, 1987 the Board rejected the report. In the rejection memo it is stated:
"Finally, after much consideration, BSERP does not believe that we have sufficient information available to guide us in taking a position on this issue.".
There are two interpretations of this rejection: one side (e.g. Amitrani and di Marzio 2000 and Zablocki 2001) see it as no position on the issue of brainwashing, the other (e.g. Introvigne 1997) sees it as rejecting all brainwashing theories.
Philip Zimbardo, who teaches a course on the "The psychology of mind control" at Stanford University, wrote that "Several participants challenged our profession to form a task force on extreme forms of influence, asserting that the underlying issues inform discourses on terrorist recruiting, on destructive cults versus new religious movements, on social-political-'therapy' cults and on human malleability or resiliency when confronted by authority power."
Recently, there are indications that some members of both sides are willing to start a dialog as, for example, in the 2001 book "Misunderstanding Cults: Searching for Objectivity in a Controversial Field". Additionally, professor of Sociology Eileen Barker was invited to speak at the 2002 yearly conference of the International Cultic Studies Association. And J. Gordon Melton and Douglas Cowan were invited to speak at a conference sponsored by the Evangelical Ministries to New Religions.
## Mind control, exit counseling, and deprogramming
Opponents of some new religious movements have accused them of being cults that coerce recruits to join (and members to remain) by using strong influence over members that is instilled and maintained by manipulation (see also Anti-cult movement, Opposition to cults and new religious movements and Christian countercult movement). Such opponents frequently advocate exit counseling as necessary to free the cult member from mind control. The practice of coercive deprogramming has practically ceased. (Kent & Szimhart, 2002)
Opponents of deprogramming generally regard it as an even worse violation of personal autonomy than any loss of free will attributable to the recruiting tactics of new religious movements. These people complain that targets of deprogramming are being deceived, denied due process, and forced to endure more intense manipulation than that encountered during their previous group membership.
Steven Hassan, who began his career as a deprogrammer, criticizes deprogramming in his book Releasing the Bonds: Empowering People to Think for Themselves. He writes that "Deprogramming has many drawbacks. I have met dozens of people who were successfully deprogrammed but, to this day, experience psychological trauma as a result of the method. These people were glad to be released from the grip of cult programming but were not happy about the method used to help them."
## Mind control and recruitment rates
Eileen Barker states that out of one thousand people persuaded by the Moonies to attend one of their overnight programs in 1979, 90% had no further involvement. Only 8% joined for more than one week and less than 4% remained members by 1981, two years later.
Tyler Hendricks, former president of the Unification Church, estimates that approximately 100,000 people "moved into" the Unification Church as full-time members from the 1970s to the 1990s. Membership in the church was 8,600 in 2004 (counting only those who joined as adults and excluding the children of members). This is an attrition rate of 93%.
Billy Graham, one of the most prominent evangelists of the last century had only an average of 1% of the attendants of his evangelizations heed the altar call at all. Follow-up work after evangelizations shows that only 10% of the people responding to an altar call actually do join a church. Therefore successful Christian evangelizations resulted in a longterm success rate of 0.1%, as compared to the 4% of Barker's observation. And these 0.1% do not become full-time missionaries as in the Unification Church. (Langone, 1993).
## Mind control and faith
The American Civil Liberties Union (ACLU) published a statement in 1977 related to brainwashing and mind control. In this statement the ACLU opposed certain methods "depriving people of the free exercise of religion". The ACLU also rejected (under certain conditions) the idea that claims of the use of 'brainwashing' or of 'mind control' should overcome the free exercise of religion.
Leon Festinger based his theory of the cognitive dissonance, a component of Hassan's Mind Control model, on his observation that the faith of most members of a UFO cult was unshattered by failed prophecy. .
Barrett who is affiliated with CESNUR and Eileen Barker, whom some anti-cult activists consider cult apologists, wrote that logical arguments are irrelevant when trying to persuade some members to leave a movement due to the certainty that they have about their faith, which he sees as not confined to cults, but also occurring in some forms of mainstream religion. He also wrote that some members do not leave the movement even though they realize that things are wrong. See also Leaving a cult.
## Counter-cult movement and mind control
In the Christian counter-cult movement there are several commentators who refute mind control as a factor in cult membership, and membership in both Christian and non-Christian cults as a spiritual or theological issue.
In an article by the evangelical Christian writers Bob and Gretchen Passantino, first appearing in Cornerstone magazine, titled Overcoming The Bondage Of Victimization: A Critical Evaluation of Cult Mind Control Theories they challenge the validity of mind control theories and the alleged "victimization" by mind-control, and assert in their conclusion:
In a rebuttal to the Passantino's article, a protagonist of the counter-cult movement, Paul R. Martin, Ph.D. et al. in his Overcoming the Bondage of Revictimization: A Rational/Empirical Defense of Thought Reform, (first appeared in Cultic Studies Journal 15/2 1998), writes:
# Legal issues
Some persons have claimed a "brainwashing defense" for crimes committed while purportedly under mind control. In the cases of Patty Hearst, Steven Fishman and Lee Boyd Malvo the court rejected such defenses.
Also in the court cases against members of Aum Shinrikyo regarding the 1995 sarin gas attack on the Tokyo subway system the mind control defense was not a mitigating factor.
Starting from the Fishman case (1990) (where a defendant accused of commercial fraud raised as a defense that he was not fully responsible since he was under the mind control of Scientology) American courts consistently rejected testimonies about mind control and manipulation, stating that these were not part of accepted mainline science according to the Frye Standard (Anthony & Robbins 1992: 5-29). Margaret Singer and her associate Richard Ofshe filed suits against the American Psychological Association) (APA) and the American Sociological Association (ASA) (who had supported APA's 1987 statement) but they lost in 1993 and 1994.
The Frye standard has since been replaced by the Daubert standard and there have been to court cases where testimonies about mind control have been examined according to the Daubert standard.
Some Civil suits where mind control was an issue, were, though, more effective:
In the case of Wollersheim v. Church of Scientology of California the court states church practices had been conducted in a coercive environment and so were not protected by religious freedom guarantees. Wollersheim was finally awarded $8 million in damages. (California appellate court, 2nd district, 7th division, Wollersheim v. Church of Scientology of California, Civ. No. B023193 Cal. Super. (1986)
"During trial, Wollersheim's experts testified Scientology's "auditing" and "disconnect" practices constituted "brainwashing" and "thought reform" akin to what the Chinese and North Koreans practiced on American prisoners of war. A religious practice which takes place in the context of this level of coercion has less religious value than one the recipient engages in voluntarily. Even more significantly, it poses a greater threat to society to have coerced religious practices inflicted on its citizens." "Using its position as religious leader, the 'church' and its agents coerced Wollersheim into continuing auditing even though his sanity was repeatedly threatened by this practice... Thus there is adequate proof the religious practice in this instance caused real harm to the individual and the appellant's outrageous conduct caused that harm... 'Church' practices conducted in a coercive environment are not qualified to be voluntary religious practices entitled to first amendment religious freedom guarantees"
In 1993 the European Court of Human Rights upheld the right of a Greek Jehovah's Witness Minos Kokkinakis, who had been sentenced to prison and a fine for proselytizing, to spread his faith, though the court sought to define what it regarded as acceptable ways of sharing one's faith. However, in a dissenting judgment, two judges argued that Kokkinakis and his wife had applied "unacceptable psychological techniques" akin to brainwashing. KOKKINAKIS v. GREECE (14307/88) ECHR 20 (25 May 1993)
# Mind control against children in Parental Alienation
Stanley Clawar and Brynne Rivlin have claimed in Children Held Hostage: Dealing with Programmed and Brainwashed Children that many forms of mind control are used in Parental alienation by one parent against the other parent using both parents' children as unwitting weapons. This use of devastating mind control is often detrimental to children and follows them into adulthood by creating a chronic condition which the authors have named Parental Alienation Syndrome. (It should be noted that there is no medical or psychological recognition of PAS as an actual syndrome, and that the use of this term serves to reify the age-old practice of one parent turning the child against the other). The authors claim the mind control used in Parental Alienation often permanently damages or destroys the target parent's bonds with his or her children. While this is undoubtedly true in some cases, in others, the alienating parent may be in fact protecting the child from an abusive or inadequate parent. These kinds of disputes are complex and the use of a simplistic term such as PAS can distract from the uniqueness of each situation.
The parental alienation syndrome is not currently considered a syndrome in the DSM-IV and the American Psychological Association officially takes no position on "the purported syndrome."
It has been stated that the parental alienation syndrome should not be admitted in court, due to evidentiary and causation problems with its theory and due to the dangerous feeling of reliability and believability in this self-published theory.
# Mind control in fiction and popular culture
Despite, or because being a serious topic in itself, mind control have attracted a large interest in the eyes of the popular culture, since, by the same logic as in conspiration theories, it may make the plot believable and more exciting. | Mind control
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Mind control (not to be confused with "brainwashing") refers to a broad range of psychological tactics able to subvert an individual's control of his own thinking, behavior, emotions, or decisions. The concept is closely related to hypnosis[citation needed][dubious – discuss], but differs in practical approach.
There are a number of controversial issues regarding mind control and the methods by which control might be attained (either direct or more subtle) are the focus of study among psychologists, neuroscientists, and sociologists.
The question of mind control has been discussed in relation to religion, politics, prisoners of war, totalitarianism, black operations, neural cell manipulation, cults, terrorism, torture, parental alienation, and even battered person syndrome.
Mind control as a legal defense tactic (see also temporary insanity) was rejected by the court in the case of Patty Hearst, and in several court cases involving New Religious Movements.
Also, questions of mind control are regarding ethical questions linked to the subject of free will.[citation needed]
# Theoretical models and methods
## Lifton thought reform model
In his 1961 book Thought Reform and the Psychology of Totalism: A Study of "Brainwashing" in China, psychiatrist Robert Jay Lifton, M.D., describes eight coercive methods which, he says, are able to change the minds of individuals without their knowledge and were used with this purpose on prisoners of war in Korea and China. These include:[1]
- Milieu Control. This involves the control of information and communication both within the environment and, ultimately, within the individual, resulting in a significant degree of isolation from society at large.
- Mystical Manipulation. There is manipulation of experiences that appear spontaneous but in fact were planned and orchestrated by the group or its leaders in order to demonstrate divine authority or spiritual advancement or some special gift or talent that will then allow the leader to reinterpret events, scripture, and experiences as he or she wishes.
- Demand for Purity. The world is viewed as black and white and the members are constantly exhorted to conform to the ideology of the group and strive for perfection. The induction of guilt and/or shame is a powerful control device used here.
- Confession. Sins, as defined by the group, are to be confessed either to a personal monitor or publicly to the group. There is no confidentiality; members' "sins," "attitudes," and "faults" are discussed and exploited by the leaders.
- Sacred Science. The group's doctrine or ideology is considered to be the ultimate Truth, beyond all questioning or dispute. Truth is not to be found outside the group. The leader, as the spokesperson for God or for all humanity, is likewise above criticism.
- Loading the Language. The group interprets or uses words and phrases in new ways so that often the outside world does not understand. This jargon consists of thought-terminating clichés, which serve to alter members' thought processes to conform to the group's way of thinking.
- Doctrine over person. Member's personal experiences are subordinated to the sacred science and any contrary experiences must be denied or reinterpreted to fit the ideology of the group.
- Dispensing of existence. The group has the prerogative to decide who has the right to exist and who does not. This is usually not literal but means that those in the outside world are not saved, unenlightened, unconscious and they must be converted to the group's ideology. If they do not join the group or are critical of the group, then they must be rejected by the members. Thus, the outside world loses all credibility. In conjunction, should any member leave the group, he or she must be rejected also.
In his 1999 book Destroying the world to save it: Aum Shinrikyo, Apocalyptic Violence and the New Global Terrorism, he concluded that thought reform was possible without violence or physical coercion.
Robert W. Ford, a British radio operator who worked in Tibet in the 50's, spent 5 years in Chinese jails. He published a book entitled "Captured in Tibet", describing and analyzing thought reform to which he was harshly subjected.[2]
## William Sargant's theories on mind control
William Sargant connected Pavlov’s findings to the ways people learned and internalized belief systems. Conditioned behavior patterns could be changed by stimulated stresses beyond a dog’s capacity for response, in essence causing a breakdown. This could also be caused by intense signals, longer than normal waiting periods, rotating positive and negative signals and changing a dog’s physical condition, as through illness. Depending on the dog’s initial personality, this could possibly cause a new belief system to be held tenaciously. Sargant also connected Pavlov’s findings to the mechanisms of brain-washing in religion and politics.[3]
"Though men are not dogs, they should humbly try to remember how much they resemble dogs in their brain functions, and not boast themselves as demigods. They are gifted with religious and social apprehensions, and they are gifted with the power of reason; but all these faculties are physiologically entailed to the brain. Therefore the brain should not be abused by having forced upon it any religious or political mystique that stunts the reason, or any form of crude rationalism that stunts the religious sense." (p. 274)[3]
## Margaret Singer's conditions for mind control
Psychologist Margaret Singer describes in her book Cults in our Midst six conditions which she says would create an atmosphere in which thought reform is possible. Singer states that these conditions involve no need for physical coercion or violence.[4]
- Keep the person unaware of what is going on and how he is being changed a step at a time.
Potential new members are led, step by step, through a behavioral-change program without being aware of the final agenda or full content of the group. The goal may be to make them deployable agents for the leadership, to get them to buy more courses, or get them to make a deeper commitment, depending on the leader's aim and desires.
- Potential new members are led, step by step, through a behavioral-change program without being aware of the final agenda or full content of the group. The goal may be to make them deployable agents for the leadership, to get them to buy more courses, or get them to make a deeper commitment, depending on the leader's aim and desires.
- Control the person's social and/or physical environment; especially control the person's time.
Through various methods, newer members are kept busy and led to think about the group and its content during as much of their waking time as possible.
- Through various methods, newer members are kept busy and led to think about the group and its content during as much of their waking time as possible.
- Systematically create a sense of powerlessness in the person.
This is accomplished by getting members away from their normal social support group for a period of time and into an environment where the majority of people are already group members.
The members serve as models of the attitudes and behaviors of the group and speak an in-group language.
Strip members of their main occupation (quit jobs, drop out of school) or source of income or have them turn over their income (or the majority of) to the group.
Once stripped of your usual support network, your confidence in your own perception erodes.
As your sense of powerlessness increases, your good judgment and understanding of the world are diminished. (ordinary view of reality is destabilized)
As group attacks your previous worldview, it causes you distress and inner confusion; yet you are not allowed to speak about this confusion or object to it -- leadership suppresses questions and counters resistance.
This process is sped up if you are kept tired -- the cult will keep you constantly busy.
- This is accomplished by getting members away from their normal social support group for a period of time and into an environment where the majority of people are already group members.
- The members serve as models of the attitudes and behaviors of the group and speak an in-group language.
- Strip members of their main occupation (quit jobs, drop out of school) or source of income or have them turn over their income (or the majority of) to the group.
- Once stripped of your usual support network, your confidence in your own perception erodes.
- As your sense of powerlessness increases, your good judgment and understanding of the world are diminished. (ordinary view of reality is destabilized)
- As group attacks your previous worldview, it causes you distress and inner confusion; yet you are not allowed to speak about this confusion or object to it -- leadership suppresses questions and counters resistance.
- This process is sped up if you are kept tired -- the cult will keep you constantly busy.
- Manipulate a system of rewards, punishments and experiences in such a way as to inhibit behavior that reflects the person's former social identity.
Manipulation of experiences can be accomplished through various methods of trance induction, including leaders using such techniques as paced speaking patterns, guided imagery, chanting, long prayer sessions or lectures, and lengthy meditation sessions.
Your old beliefs and patterns of behavior are defined as irrelevant or evil. Leadership wants these old patterns eliminated, so the member must suppress them.
Members get positive feedback for conforming to the group's beliefs and behaviors and negative feedback for old beliefs and behavior.
- Manipulation of experiences can be accomplished through various methods of trance induction, including leaders using such techniques as paced speaking patterns, guided imagery, chanting, long prayer sessions or lectures, and lengthy meditation sessions.
- Your old beliefs and patterns of behavior are defined as irrelevant or evil. Leadership wants these old patterns eliminated, so the member must suppress them.
- Members get positive feedback for conforming to the group's beliefs and behaviors and negative feedback for old beliefs and behavior.
- Manipulate a system of rewards, punishments, and experiences in order to promote learning the group's ideology or belief system and group-approved behaviors.
Good behavior, demonstrating an understanding and acceptance of the group's beliefs, and compliance are rewarded while questioning, expressing doubts or criticizing are met with disapproval, redress and possible rejection. If one expresses a question, he or she is made to feel that there is something inherently wrong with them to be questioning.
The only feedback members get is from the group, they become totally dependent upon the rewards given by those who control the environment.
Members must learn varying amounts of new information about the beliefs of the group and the behaviors expected by the group.
The more complicated and filled with contradictions the new system is and the more difficult it is to learn, the more effective the conversion process will be.
Esteem and affection from peers is very important to new recruits. Approval comes from having the new member's behaviors and thought patterns conform to the models (members). Members' relationship with peers is threatened whenever they fail to learn or display new behaviors. Over time, the easy solution to the insecurity generated by the difficulties of learning the new system is to inhibit any display of doubts -- new recruits simply acquiesce, affirm and act as if they do understand and accept the new ideology.
- Good behavior, demonstrating an understanding and acceptance of the group's beliefs, and compliance are rewarded while questioning, expressing doubts or criticizing are met with disapproval, redress and possible rejection. If one expresses a question, he or she is made to feel that there is something inherently wrong with them to be questioning.
- The only feedback members get is from the group, they become totally dependent upon the rewards given by those who control the environment.
- Members must learn varying amounts of new information about the beliefs of the group and the behaviors expected by the group.
- The more complicated and filled with contradictions the new system is and the more difficult it is to learn, the more effective the conversion process will be.
- Esteem and affection from peers is very important to new recruits. Approval comes from having the new member's behaviors and thought patterns conform to the models (members). Members' relationship with peers is threatened whenever they fail to learn or display new behaviors. Over time, the easy solution to the insecurity generated by the difficulties of learning the new system is to inhibit any display of doubts -- new recruits simply acquiesce, affirm and act as if they do understand and accept the new ideology.
- Put forth a closed system of logic and an authoritarian structure that permits no feedback and refuses to be modified except by leadership approval or executive order.
The group has a top-down, pyramid structure. The leaders must have verbal ways of never losing.
Members are not allowed to question, criticize or complain -- if they do, the leaders allege that the member is defective -- not the organization or the beliefs.
The individual is always wrong -- the system, its leaders and its belief are always right.
Conversion or remolding of the individual member happens in a closed system. As members learn to modify their behavior in order to be accepted in this closed system, they change -- begin to speak the language -- which serves to further isolate them from their prior beliefs and behaviors.
- The group has a top-down, pyramid structure. The leaders must have verbal ways of never losing.
- Members are not allowed to question, criticize or complain -- if they do, the leaders allege that the member is defective -- not the organization or the beliefs.
- The individual is always wrong -- the system, its leaders and its belief are always right.
- Conversion or remolding of the individual member happens in a closed system. As members learn to modify their behavior in order to be accepted in this closed system, they change -- begin to speak the language -- which serves to further isolate them from their prior beliefs and behaviors.
A report on brainwashing and mind control presented by an American Psychological Association (APA) task force known as the APA Taskforce on Deceptive and Indirect Techniques of Persuasion and Control (DIMPAC), chaired by Singer, was rejected in 1987 by the APA's Board of Social and Ethical Responsibility for Psychology (BSERP) as lacking "the scientific rigor and evenhanded critical approach necessary for APA imprimatur." and cautioned the task force members to "not distribute or publicize the report without indicating that the report was unacceptable to the Board."[5]
In 2001, Alberto Amitrani and Raffaella Di Marzio, from the Roman seat of the Group for Research and Information about Sects (GRIS) published an article in which they assert that the rejection of the report should not be construed as a rejection of the theories of thought reform and mind control as applied to New Religious Movements, and that the rejection by one division of the APA does not represent the whole association. They quote a personal e-mail from Benjamin Zablocki, professor of sociology, from 1997 in which Zablocki told the authors "many people have been misled about the true position of the APA and the ASA with regard to brainwashing", and that the APA urged scholars to do more research on the matter. They also write that they have reason to believe that the APA still considers "psychological coercion" to be a phenomenon worth investigating, and not a notion rejected by the scientific community. They also write "Otherwise, why would people such as Margaret Singer, Michael Langone, and others considered to be 'anti-cultists' contribute to APA Conventions and be respected in other prestigious professional bodies as well?"[6]
Writing in 1999, research and forensic psychologist Dick Anthony noted that the removal of Singer's brainwashing concept from the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) "would seem to indicate that the American Psychiatric Association, like the American Psychological Association, the American Sociological Association and the Society for the Scientific Study of Religion, has repudiated Singer's cultic brainwashing theory because of its unscientific character." Anthony also noted that Singer's testimony had also been repeatedly excluded from American legal trials.[7]
## Steven Hassan's BITE model
In his book Releasing the Bonds: Empowering People to Think for Themselves, mental health counselor and exit counselor Steven Hassan describes his mind-control model, "BITE". "BITE" stands for "Behavior, Information, Thoughts, and Emotions." The model has a basis on the works of Singer and Lifton, and on the cognitive dissonance theory of Leon Festinger.[8]
In the book, Hassan describes the components of the BITE model:[8]
- Behavior Control
Regulation of individual’s physical reality
Major time commitment required for indoctrination sessions and group rituals
Need to ask permission for major decisions
Need to report thoughts, feelings, and activities to superiors
Rewards and punishments (behavior modification techniques positive and negative)
Individualism discouraged; "group think" prevails
Rigid rules and regulations
Need for obedience and dependency
- Regulation of individual’s physical reality
- Major time commitment required for indoctrination sessions and group rituals
- Need to ask permission for major decisions
- Need to report thoughts, feelings, and activities to superiors
- Rewards and punishments (behavior modification techniques positive and negative)
- Individualism discouraged; "group think" prevails
- Rigid rules and regulations
- Need for obedience and dependency
- Information Control
Use of deception
Access to non cult sources of information minimized or discouraged
Compartmentalization of information; Outsider vs. Insider doctrines
Spying on other members is encouraged
Extensive use of cult generated information and propaganda
Unethical use of confession
- Use of deception
- Access to non cult sources of information minimized or discouraged
- Compartmentalization of information; Outsider vs. Insider doctrines
- Spying on other members is encouraged
- Extensive use of cult generated information and propaganda
- Unethical use of confession
- Thought Control
Need to internalize the group’s doctrine as "Truth"
Use of "loaded" language (for example, “thought terminating clichés"). Words are the tools we use to think with. These "special" words constrict rather than expand understanding, and can even stop thoughts altogether. They function to reduce complexities of experience into trite, platitudinous "buzz words."
Only "good" and "proper" thoughts are encouraged.
Use of hypnotic techniques to induce altered mental states
Manipulation of memories and implantation of false memories
Use of thought stopping techniques, which shut down "reality testing" by stopping "negative" thoughts and allowing only "good" thoughts
Rejection of rational analysis, critical thinking, constructive criticism. No critical questions about leader, doctrine, or policy seen as legitimate.
No alternative belief systems viewed as legitimate, good, or useful
- Need to internalize the group’s doctrine as "Truth"
- Use of "loaded" language (for example, “thought terminating clichés"). Words are the tools we use to think with. These "special" words constrict rather than expand understanding, and can even stop thoughts altogether. They function to reduce complexities of experience into trite, platitudinous "buzz words."
- Only "good" and "proper" thoughts are encouraged.
- Use of hypnotic techniques to induce altered mental states
- Manipulation of memories and implantation of false memories
- Use of thought stopping techniques, which shut down "reality testing" by stopping "negative" thoughts and allowing only "good" thoughts
- Rejection of rational analysis, critical thinking, constructive criticism. No critical questions about leader, doctrine, or policy seen as legitimate.
- No alternative belief systems viewed as legitimate, good, or useful
- Emotional Control
Manipulate and narrow the range of a person’s feelings
Make the person feel that if there are ever any problems, it is always their fault, never the leader’s or the group’s
Excessive use of guilt
Excessive use of fear
Extremes of emotional highs and lows
Ritual and often public confession of "sins"
Phobia indoctrination: inculcating irrational fears about ever leaving the group or even questioning the leader’s authority. The person under mind control cannot visualize a positive, fulfilled future without being in the group.
- Manipulate and narrow the range of a person’s feelings
- Make the person feel that if there are ever any problems, it is always their fault, never the leader’s or the group’s
- Excessive use of guilt
- Excessive use of fear
- Extremes of emotional highs and lows
- Ritual and often public confession of "sins"
- Phobia indoctrination: inculcating irrational fears about ever leaving the group or even questioning the leader’s authority. The person under mind control cannot visualize a positive, fulfilled future without being in the group.
Hassan writes that cults recruit and retain members through a three-step process which he refers to as "unfreezing," "changing," and "refreezing". This involves the use of an extensive array of various techniques, including systematic deception, behavior modification, withholding of information, and emotionally intense persuasion techniques (such as the induction of phobias), which he collectively terms mind control.
He describes these steps as follows:[9]
- Unfreezing: the process of breaking a person down
- Changing: the indoctrination process
- Refreezing: the process of reinforcing the new identity
In Releasing the Bonds he also writes "I suspect that most cult groups use informal hypnotic techniques to induce trance states. They tend to use what are called "naturalistic" hypnotic techniques. Practicing meditation to shut down thinking, chanting a phrase repetitively for hours, or reciting affirmations are all powerful ways to promote spiritual growth. But they can also be used unethically, as methods for mind control indoctrination."[8]
Hassan, after taking part in a number of deprogrammings in the late 1970s, states that he is no longer involved in this practice.[10] and which eventually became completely illegal except in the case of minors.[citation needed]
In Releasing the Bonds, Hassan describes an approach that he calls the "Strategic Interaction Approach" (SIA) in order to help cult members leave their groups, and in order to help them recover from the psychological damage that they have incurred. The approach is non-coercive and the person being treated is free to discontinue it at any time. He writes: "The goal of the SIA is to help the loved one recover his full faculties; to restore the creative, interdependent adult who fully understands what has happened to him; who has digested and integrated the experience and is better and stronger from the experience."[11]
In 1998 the Enquete Commission issued its report on "So-called Sects and Psychogroups" in Germany. Reviewing Hassan's BITE model, the report said that:[12]
Thus, the milieu control identified by Hassan, consisting of behavioural control, mental control, emotional control and information control cannot, in every case and as a matter of principle, be characterised as "manipulative". Control of these areas of action is an inevitable component of social interactions in a group or community. The social control that is always associated with intense commitment to a group must therefore be clearly distinguished from the exertion of intentional, methodical influence for the express purpose of manipulation.
## Mind Control and the Battered Person Syndrome
A very different explanation of the control some groups have over their members is by associating it with Battered person syndrome and Stockholm syndrome. This has been done by psychologists Teresa Ramirez Boulette, Ph.D. and Susan M. Andersen, Ph.D.
## Social psychology tactics
A contemporary view of mind control sees it as an intensified and persistent use of well researched social psychology principles like compliance, conformity, persuasion, dissonance, reactance, framing or emotional manipulation.
One of the most notable proponents of such theories is social psychologist Philip Zimbardo, former president of the American Psychological Association:
In Influence, Science and Practice, social psychologist Robert Cialdini argues that mind control is possible through the covert exploitation of the unconscious rules that underlie and facilitate healthy human social interactions. He states that common social rules can be used to prey upon the unwary, and he titles them as follows:
- "Reciprocation: The Old Give and Take...and Take"
- "Commitment and Consistency: Hobgoblins of the Mind"
- "Social Proof: Truths Are Us"
- "Liking: The Friendly Thief"
- "Authority: Directed Deference"
- "Scarcity: The Rule of the Few"
Using these six broad categories, he offers specific examples of both mild and extreme mind control (both one on one and in groups), notes the conditions under which each social rule is most easily exploited for false ends, and offers suggestions on how to resist such methods.
## Social psychological conditioning by Stahelski
Writing in the Journal of Homeland Security, a publication of the ANSER Institute for Homeland Security, Anthony Stahelski identifies five phases of social psychological conditioning which he calls cult-like conditioning techniques employed by terrorist groups: [Stahelski, 2004]:
- Depluralization: stripping away all other group member identities
- Self-deindividuation: stripping away each member’s personal identity
- Other-deindividuation: stripping away the personal identities of enemies
- Dehumanization: identifying enemies as subhuman or nonhuman
- Demonization: identifying enemies as evil
## Subliminal advertising
Subliminal advertising was proposed around 1960 as a means for organized mass control of human behavior. The allegations has since then fallen out of the common debate, because there are few reports that subliminal advertising has any real effect in the way advertisers may wish.
# Cults and mind control controversies
Some of the mind control models discussed above have been related to religious and non-religious cults (for debates regarding what is a cult, see the article). There is debate among scholars, members of new religious movements, and cult critics whether or not mind control is applied either in general or by any particular group.
## Scholarly points of view
While the majority of scholars in the study of religion reject theories of mind control (e.g., Massimo Introvigne and J. Gordon Melton), it is often accepted in psychology and psychiatry[citation needed] (e.g., Margaret Singer, Michael Langone, and Philip Zimbardo) and in sociology the opinions are divided (e.g., David G. Bromley and Anson Shupe contra, Stephen A. Kent and Benjamin Zablocki pro). Most scholars have either a decided contra or a decided pro opinion; there are few who advocate a moderate point of view.[citation needed]
James T. (Jim) Richardson, professor of Sociology and Judicial Studies at the University of Nevada, writes in his "Brainwashing" Claims and Minority Religions Outside the United States: Cultural Diffusion of a Questionable Concept in the Legal Arena that, while heavy on theory, the mind control model is light on evidence:
James Richardson, also states that if the NRMs had access to powerful brainwashing techniques, one would expect that NRMs would have high growth rates, while in fact most have not had notable success in recruitment. Most adherents participate for only a short time, and the success in retaining members has been limited. In addition, Thomas Robbins, Eileen Barker, Newton Maloney, Massimo Introvigne, John Hall, Lorne Dawson, Anson Shupe, David G. Bromley, Gordon Melton, Marc Galanter, Saul Levine and other scholars researching NRMs have argued and established to the satisfaction of courts and relevant professional associations and scientific communities that there exists no scientific theory, generally accepted and based upon methodologically sound research, that supports the brainwashing theories as advanced by the anti-cult movement. [15]
Sociologist Benjamin Zablocki sees strong indicators of mind control in some NRMs and suggests that the concept should be researched without bias:
Sociologists David Bromley and Anson Shupe consider the idea that "cults" are brainwashing American youth to be "implausible".[14]. Sociology professor Stephen A. Kent published several articles where he discusses practices of NRMs as regards to brainwashing [16] [17]
In 1984 the American Psychological Association (APA) requested Margaret Singer, the main proponent of mind control theories, to set up a working group called the APA taskforce on Deceptive and Indirect Techniques of Persuasion and Control (DIMPAC).
In 1987 the DIMPAC committee submitted its final report to the Board of Social and Ethical Responsibility for Psychology of the APA. On May 11, 1987 the Board rejected the report. In the rejection memo [18] it is stated:
"Finally, after much consideration, BSERP does not believe that we have sufficient information available to guide us in taking a position on this issue.".
There are two interpretations of this rejection: one side (e.g. Amitrani and di Marzio 2000 and Zablocki 2001) see it as no position on the issue of brainwashing, the other (e.g. Introvigne 1997) sees it as rejecting all brainwashing theories.
Philip Zimbardo, who teaches a course on the "The psychology of mind control" at Stanford University, wrote that "Several participants [in a presentation called 'Cults of Hatred'] challenged our profession to form a task force on extreme forms of influence, asserting that the underlying issues inform discourses on terrorist recruiting, on destructive cults versus new religious movements, on social-political-'therapy' cults and on human malleability or resiliency when confronted by authority power."[19]
Recently, there are indications that some members of both sides are willing to start a dialog as, for example, in the 2001 book "Misunderstanding Cults: Searching for Objectivity in a Controversial Field". Additionally, professor of Sociology Eileen Barker was invited to speak at the 2002 yearly conference of the International Cultic Studies Association. And J. Gordon Melton and Douglas Cowan were invited to speak at a conference sponsored by the Evangelical Ministries to New Religions.
## Mind control, exit counseling, and deprogramming
Opponents of some new religious movements have accused them of being cults that coerce recruits to join (and members to remain) by using strong influence over members that is instilled and maintained by manipulation (see also Anti-cult movement, Opposition to cults and new religious movements and Christian countercult movement). Such opponents frequently advocate exit counseling as necessary to free the cult member from mind control. The practice of coercive deprogramming has practically ceased. (Kent & Szimhart, 2002)
Opponents of deprogramming generally regard it as an even worse violation of personal autonomy than any loss of free will attributable to the recruiting tactics of new religious movements. These people complain that targets of deprogramming are being deceived, denied due process, and forced to endure more intense manipulation than that encountered during their previous group membership.
Steven Hassan, who began his career as a deprogrammer, criticizes deprogramming in his book Releasing the Bonds: Empowering People to Think for Themselves. He writes that "Deprogramming has many drawbacks. I have met dozens of people who were successfully deprogrammed but, to this day, experience psychological trauma as a result of the method. These people were glad to be released from the grip of cult programming but were not happy about the method used to help them."[20]
## Mind control and recruitment rates
Eileen Barker states that out of one thousand people persuaded by the Moonies [Unification Church] to attend one of their overnight programs in 1979, 90% had no further involvement. Only 8% joined for more than one week and less than 4% remained members by 1981, two years later.[14]
Tyler Hendricks, former president of the Unification Church, estimates that approximately 100,000 people "moved into" the Unification Church as full-time members from the 1970s to the 1990s. Membership in the church was 8,600 in 2004 (counting only those who joined as adults and excluding the children of members). This is an attrition rate of 93%.
Billy Graham, one of the most prominent evangelists of the last century had only an average of 1% of the attendants of his evangelizations heed the altar call at all. Follow-up work after evangelizations shows that only 10% of the people responding to an altar call actually do join a church. Therefore successful Christian evangelizations resulted in a longterm success rate of 0.1%, as compared to the 4% of Barker's observation. And these 0.1% do not become full-time missionaries as in the Unification Church. (Langone, 1993).
## Mind control and faith
The American Civil Liberties Union (ACLU) published a statement in 1977 related to brainwashing and mind control. In this statement the ACLU opposed certain methods "depriving people of the free exercise of religion". The ACLU also rejected (under certain conditions) the idea that claims of the use of 'brainwashing' or of 'mind control' should overcome the free exercise of religion. [21]
Leon Festinger based his theory of the cognitive dissonance, a component of Hassan's Mind Control model, on his observation that the faith of most members of a UFO cult was unshattered by failed prophecy. [22].
Barrett who is affiliated with CESNUR and Eileen Barker, whom some anti-cult activists consider cult apologists, wrote that logical arguments are irrelevant when trying to persuade some members to leave a movement due to the certainty that they have about their faith, which he sees as not confined to cults, but also occurring in some forms of mainstream religion. He also wrote that some members do not leave the movement even though they realize that things are wrong. See also Leaving a cult.
## Counter-cult movement and mind control
In the Christian counter-cult movement there are several commentators who refute mind control as a factor in cult membership, and membership in both Christian and non-Christian cults as a spiritual or theological issue.
In an article by the evangelical Christian writers Bob and Gretchen Passantino, first appearing in Cornerstone magazine, titled Overcoming The Bondage Of Victimization: A Critical Evaluation of Cult Mind Control Theories they challenge the validity of mind control theories and the alleged "victimization" by mind-control, and assert in their conclusion:
In a rebuttal to the Passantino's article, a protagonist of the counter-cult movement, Paul R. Martin, Ph.D. et al. in his Overcoming the Bondage of Revictimization: A Rational/Empirical Defense of Thought Reform, (first appeared in Cultic Studies Journal 15/2 1998), writes:
# Legal issues
Some persons have claimed a "brainwashing defense" for crimes committed while purportedly under mind control. In the cases of Patty Hearst, Steven Fishman and Lee Boyd Malvo the court rejected such defenses.
Also in the court cases against members of Aum Shinrikyo regarding the 1995 sarin gas attack on the Tokyo subway system the mind control defense was not a mitigating factor.
Starting from the Fishman case (1990) (where a defendant accused of commercial fraud raised as a defense that he was not fully responsible since he was under the mind control of Scientology) American courts consistently rejected testimonies about mind control and manipulation, stating that these were not part of accepted mainline science according to the Frye Standard (Anthony & Robbins 1992: 5-29). Margaret Singer and her associate Richard Ofshe filed suits against the American Psychological Association) (APA) and the American Sociological Association (ASA) (who had supported APA's 1987 statement) but they lost in 1993 and 1994.[25]
The Frye standard has since been replaced by the Daubert standard and there have been to court cases where testimonies about mind control have been examined according to the Daubert standard.
Some Civil suits where mind control was an issue, were, though, more effective:
In the case of Wollersheim v. Church of Scientology of California the court states church practices had been conducted in a coercive environment and so were not protected by religious freedom guarantees. Wollersheim was finally awarded $8 million in damages. (California appellate court, 2nd district, 7th division, Wollersheim v. Church of Scientology of California, Civ. No. B023193 Cal. Super. (1986)
"During trial, Wollersheim's experts testified Scientology's "auditing" and "disconnect" practices constituted "brainwashing" and "thought reform" akin to what the Chinese and North Koreans practiced on American prisoners of war. A religious practice which takes place in the context of this level of coercion has less religious value than one the recipient engages in voluntarily. Even more significantly, it poses a greater threat to society to have coerced religious practices inflicted on its citizens." "Using its position as religious leader, the 'church' and its agents coerced Wollersheim into continuing auditing even though his sanity was repeatedly threatened by this practice... Thus there is adequate proof the religious practice in this instance caused real harm to the individual and the appellant's outrageous conduct caused that harm... 'Church' practices conducted in a coercive environment are not qualified to be voluntary religious practices entitled to first amendment religious freedom guarantees" [3]
In 1993 the European Court of Human Rights upheld the right of a Greek Jehovah's Witness Minos Kokkinakis, who had been sentenced to prison and a fine for proselytizing, to spread his faith, though the court sought to define what it regarded as acceptable ways of sharing one's faith. However, in a dissenting judgment, two judges argued that Kokkinakis and his wife had applied "unacceptable psychological techniques" akin to brainwashing. KOKKINAKIS v. GREECE (14307/88) [1993] ECHR 20 (25 May 1993) [4]
# Mind control against children in Parental Alienation
Stanley Clawar and Brynne Rivlin have claimed in Children Held Hostage: Dealing with Programmed and Brainwashed Children that many forms of mind control are used in Parental alienation by one parent against the other parent using both parents' children as unwitting weapons. This use of devastating mind control is often detrimental to children and follows them into adulthood by creating a chronic condition which the authors have named Parental Alienation Syndrome. (It should be noted that there is no medical or psychological recognition of PAS as an actual syndrome, and that the use of this term serves to reify the age-old practice of one parent turning the child against the other). The authors claim the mind control used in Parental Alienation often permanently damages or destroys the target parent's bonds with his or her children. While this is undoubtedly true in some cases, in others, the alienating parent may be in fact protecting the child from an abusive or inadequate parent. These kinds of disputes are complex and the use of a simplistic term such as PAS can distract from the uniqueness of each situation.
The parental alienation syndrome is not currently considered a syndrome in the DSM-IV and the American Psychological Association officially takes no position on "the purported syndrome." [26]
It has been stated that the parental alienation syndrome should not be admitted in court, due to evidentiary and causation problems with its theory and due to the dangerous feeling of reliability and believability in this self-published theory. [27]
# Mind control in fiction and popular culture
Despite, or because being a serious topic in itself, mind control have attracted a large interest in the eyes of the popular culture, since, by the same logic as in conspiration theories, it may make the plot believable and more exciting. | https://www.wikidoc.org/index.php/Mind_control | |
d05ba8ec9fbe28e50ea56382aea59b2f4ff3ec6c | wikidoc | Mineral acid | Mineral acid
- Acid-base extraction
- Acid-base reaction
- Acid dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
edit
A mineral acid is an acid derived by chemical reaction from inorganic minerals, as opposed to organic acids. Examples include:
- Hydrochloric acid
- Nitric acid
- Phosphoric acid
- Sulfuric acid
- Boric acid
- Hydrofluoric acid
# Characteristics
Mineral acids range from acids of great strength (example: sulfuric acid) to very weak (boric acid). As mineral acid molecules tend to consist of only a few atoms, of which many are polar, they tend to be very soluble in water, and insoluble in organic solvents. Mineral acids are very important to chemical procedures.
These acids are most often used in large-scale industries. Dilute solution of hydrochloric acid is used for removing the deposits from inside the boilers. However, precautions are taken to prevent the corrosion of the boiler by the acid. This process is known as de-scaling. Therefore, large quantities of these acids, especially sulfuric acid, nitric acid and hydrochloric acid are manufactured for commercial use in huge plants.
ar:حمض معدني
de:Mineralsäuren
th:กรดอนินทรีย์ | Mineral acid
- Acid-base extraction
- Acid-base reaction
- Acid dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
edit
A mineral acid is an acid derived by chemical reaction from inorganic minerals, as opposed to organic acids. Examples include:
- Hydrochloric acid
- Nitric acid
- Phosphoric acid
- Sulfuric acid
- Boric acid
- Hydrofluoric acid
# Characteristics
Mineral acids range from acids of great strength (example: sulfuric acid) to very weak (boric acid). As mineral acid molecules tend to consist of only a few atoms, of which many are polar, they tend to be very soluble in water, and insoluble in organic solvents. Mineral acids are very important to chemical procedures.
These acids are most often used in large-scale industries. Dilute solution of hydrochloric acid is used for removing the deposits from inside the boilers. However, precautions are taken to prevent the corrosion of the boiler by the acid. This process is known as de-scaling. Therefore, large quantities of these acids, especially sulfuric acid, nitric acid and hydrochloric acid are manufactured for commercial use in huge plants.
ar:حمض معدني
de:Mineralsäuren
th:กรดอนินทรีย์
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Mineral_acid | |
b74bbbaf2a6818397e81406840482c89da20496e | wikidoc | Mirror image | Mirror image
A mirror image is a mirror based duplicate of a single image.
# In Geometry
## In two dimensions
In geometry, the Mirror Image of an object or two-dimensional figure is the virtual image formed by reflection in a plane mirror; it is of the same size as the original object, yet different, unless the object or figure has reflection symmetry (also known as a P-symmetry).
If a point of an object has coordinates (x, y,z) then the image of this point (as reflected from the mirror in y, z plane) has coordinates (-x, y,z) - so mirror reflection is a reversal of the coordinate axis perpendicular to the mirror's surface. Thus, a mirror image does not have reversed right and left (or up and down), but rather reversed front and back.
Two-dimensional mirror images can be seen in the reflections of mirrors or other reflecting surfaces, or on a printed surface seen inside out.
## In three dimensions
The concept of mirror image can be extended to three-dimensional objects, including the inside parts, even if they are not transparent. The term then relates to structural as well as visual aspects. This is also called enantiomer or enantiomorph.
A mirror image appears three-dimensional if the observer moves. This is because the relative position of objects changes as the observer's perspective changes.
Looking through a mirror from different positions (but necessarily with the point of observation restricted to the halfspace on one side of the mirror) is like looking at the 3D mirror image of space; without further mirrors only the mirror image of the halfspace before the mirror is relevant; if there is another mirror, the mirror image of the other halfspace is too.
# Uses
A text is sometimes deliberately displayed in mirror image, in order to be read through a mirror. Emergency vehicles such as ambulances or fire engines use mirror images in order to be read from a driver's rear-view mirror. Some movie theaters also use a Rear Window Captioning System to assist individuals with hearing impairments watching the film.
# Systems of mirrors
In the case of two mirrors, in planes at an angle α, looking through both from the sector which is the intersection of the two halfspaces, is like looking at a version of the world rotated by an angle of 2α; the points of observations and directions of looking for which this applies correspond to those for looking through a frame like that of the first mirror, and a frame at the mirror image with respect to the first plane, of the second mirror. If the mirrors have vertical edges then the left edge of the field of view is the plane through the right edge of the first mirror and the edge of the second mirror which is on the right when looked at directly, but on the left in the mirror image.
In the case of two parallel mirrors, looking through both once is like looking at a version of the world which is translated by twice the distance between the mirrors, in the direction perpendicular to them, away from the observer. Since the plane of the mirror in which one looks directly is beyond that of the other mirror, one always looks at an oblique angle, and the translation just mentioned has not only a component away from the observer, but also one in a perpendicular direction. The translated view can also be described by a translation of the observer in opposite direction. For example, with a vertical periscope, the shift of the world is away from the observer and down, both by the length of the periscope, but it is more practical to consider the equivalent shift of the observer: up, and backward. | Mirror image
Template:Cleanup
A mirror image is a mirror based duplicate of a single image.
# In Geometry
## In two dimensions
In geometry, the Mirror Image of an object or two-dimensional figure is the virtual image formed by reflection in a plane mirror; it is of the same size as the original object, yet different, unless the object or figure has reflection symmetry (also known as a P-symmetry).
If a point of an object has coordinates (x, y,z) then the image of this point (as reflected from the mirror in y, z plane) has coordinates (-x, y,z) - so mirror reflection is a reversal of the coordinate axis perpendicular to the mirror's surface. Thus, a mirror image does not have reversed right and left (or up and down), but rather reversed front and back.
Two-dimensional mirror images can be seen in the reflections of mirrors or other reflecting surfaces, or on a printed surface seen inside out.
## In three dimensions
The concept of mirror image can be extended to three-dimensional objects, including the inside parts, even if they are not transparent. The term then relates to structural as well as visual aspects. This is also called enantiomer or enantiomorph.
A mirror image appears three-dimensional if the observer moves. This is because the relative position of objects changes as the observer's perspective changes.[1]
Looking through a mirror from different positions (but necessarily with the point of observation restricted to the halfspace on one side of the mirror) is like looking at the 3D mirror image of space; without further mirrors only the mirror image of the halfspace before the mirror is relevant; if there is another mirror, the mirror image of the other halfspace is too.
# Uses
A text is sometimes deliberately displayed in mirror image, in order to be read through a mirror. Emergency vehicles such as ambulances or fire engines use mirror images in order to be read from a driver's rear-view mirror. Some movie theaters also use a Rear Window Captioning System to assist individuals with hearing impairments watching the film.
# Systems of mirrors
In the case of two mirrors, in planes at an angle α, looking through both from the sector which is the intersection of the two halfspaces, is like looking at a version of the world rotated by an angle of 2α; the points of observations and directions of looking for which this applies correspond to those for looking through a frame like that of the first mirror, and a frame at the mirror image with respect to the first plane, of the second mirror. If the mirrors have vertical edges then the left edge of the field of view is the plane through the right edge of the first mirror and the edge of the second mirror which is on the right when looked at directly, but on the left in the mirror image.
In the case of two parallel mirrors, looking through both once is like looking at a version of the world which is translated by twice the distance between the mirrors, in the direction perpendicular to them, away from the observer. Since the plane of the mirror in which one looks directly is beyond that of the other mirror, one always looks at an oblique angle, and the translation just mentioned has not only a component away from the observer, but also one in a perpendicular direction. The translated view can also be described by a translation of the observer in opposite direction. For example, with a vertical periscope, the shift of the world is away from the observer and down, both by the length of the periscope, but it is more practical to consider the equivalent shift of the observer: up, and backward. | https://www.wikidoc.org/index.php/Mirror_image | |
594c975ea0779b3900c3b5e7f4c7dc1647e3709c | wikidoc | Missing data | Missing data
Slide Set: File:Missing Data.pdf
# Overview
In statistics missing data refers to the absence of registered data for a given variable. Missing data is frequent in clinical research. It is an important source of bias, reducing the consistency (precision or reproducibility) of the study. It can have an important effect on the conclusion of the study potentially leading to invalid results drawn from the data.
# Classification of missing data
Missing data can be classified depending on the relationship with the independent or dependent (outcome) variables in 3 categories:
- Missing completely at random (MCAR)
- Missing at random (MAR)
- Missing not at random (MNAR)
## Missing completely at random (MCAR)
It is independent of observed and non-observed data, therefore not related to the independent variables or the outcome.
Examples:
- Loss of study files
- Equipment malfunctioned
- Weather was terrible
- Data not entered correctly
## Missing at random (MAR)
It is not related to the outcome but is related to the independent variables (for example age, race, gender).
It is important to clarify that so it does not correspond to the general notion of 'random'; the probability of a value being missing generally depends on the observed values (independent variables) not on the missing values.
May influence if the independent variable is related to the outcome.
Example: Old patients dropping out from an intervention due to physical condition (walking to the center for follow up), which does not relate to the outcome.
## Missing not at random (MNAR)
It is is related to the outcome. It is considered the worst type of missing data because the dropouts are is related to the therapy or intervention under investigation.
There is a pattern of missing data which is related to unobserved data making impossible to use other values from the dataset to predict the missing values.
Example: Respondents with high income less likely to report income.
# Missing values
Missing values could be due to:
- Withdrawal of consent
- Loss of follow up
- Discontinuation study drug due to:
- Adverse effect
- Lack of efficacy
- Death due to:
- Cause-specific (auto accident)
- Composite outcome (AIDS-defining illness)
- Related to outcome of interest
# Handling missing data
- Complete Case Analysis - CCA (Listwise Deletion)
- Available Case Analysis
- Weighted Complete Case Analysis
- Single Imputation (replacement of missing values)
## Complete case analysis (CCA)
Analyzes only subjects who completed the study.
Advantages:
- Does not require manipulating the data
Disadvantages:
- Decrease of study power: increasing type II error
- Biased results: the dropout rate increases the risk of imbalanced groups
## Available Case Analysis
Special case of Complete Case Analysis, where all or part of the data is used depending on the given analysis.
Example: Incomplete cases used for baseline analysis, NOT used for outcome analysis.
## Weighted Complete Case Analysis
Used in surveys, gives weights for responses based on likelihood of response.
## Single Imputation
- Mean/Median Substitution Method
- Last Observation Carried Forward (LOCF)
- Regression Substitution Method
- Stochastic Regression imputation
- Increased Random Variability Method
- Worst Case Scenario Method
- Baseline Carried Forward Method
- Hot and Cold Deck Imputation
## Mean Substitution
Impute the missing data using the mean of the non-missing values.
Advantages:
- Simple
- Potential to reduce bias by using all study data to estimate response for missing subjects
Disadvantages:
- Significantly decreased standard deviation (variance)
- Increased Type I error
- Overestimation
## Last Observation Carried Forward (LOCF)
Impute the missing data with the value of the last observation with available data.
Advantages:
- Only imputation method accepted by FDA
- It is very simple
- Includes all subjects (ITT analysis)
- Mimics real life scenarios (as many patients in real clinical practice are not compliant to the treatment)
Disadvantages:
- Can lead to biased estimates (as it is based on the assumption that the patients after dropping out would either not improve or continue to get better), which can also decrease the power of a study.
## Regression Substitution
Build a regression model with baseline characteristics as predictors of the outcome using the available data. Then use the model to predict the outcome for patients with missing values.
Advantages:
- Has the potential to reduce bias by using all date to estimate the response for missing subject
Disadvantages:
- Requires a special statistics software
## Increased Random Variability
Use statistical software to generate a set of random values for the outcome and then replace missing data by randomly selecting values from this set.
Advantages:
- Potential to reduce bias by using all study data to estimate response for missing subjects
Disadvantages:
- Complicated statistical model (specific training)
- Not commonly used
- Might be questioned by reviewers
## Worst Case Scenario
Replace the missing data with the worse possible outcome.
Advantage:
- If the results are positive, they can be trusted.
Disadvantage:
- It cannot be used in studies in which a high number of dropouts
## Baseline Carried Forward
Assume that all participants with missing data resume their baseline status.
Replace missing data with the baseline data from each patient.
Advantages:
- Simple
Disadvantages:
- It might underestimate the effects of treatment (type II error)
## Hot and Cold Deck Imputation
Replaces individual missing data items with reported data from another person or household with similar characteristics
- Hot: a missing case is replaced with a case with similar characteristics
- Cold: deck (another dataset)
## Multiple Imputations
Each missing value will be replaced by a simulated value (done several times 3-10 times)
Advantage:
- Has a standard deviation and standard error closer to the one obtained with a complete sample
Disadvantage:
- Incorporate missing data uncertainty
## Multiple likelihood
Use the available values in order to find parameter estimate, which would be the best fit to the already observed data.
Disadvantages:
- Does not impute missing data but use the known characteristic of the individual to better estimate the unknown parameters of the incomplete variable
- Need to find the most appropriate variable to use
# Missing Data Prevention
Although methods can help to analyze as valid as possible dataset with missing data – best to prevent missing data:
- Run-in phase
- Enrichment design - selecting best responders
- Flexible dose (titration) studies
- Selection of target population who will respond to treatment, knowing the population
- Add on design
- Adding endpoints
- Reducing follow-up periods
- Allow rescue medication
- Define outcomes that can be defined without participant visit (for instance, death)
- Randomized withdrawal to define long-term efficacy
- Sending letters to subjects to motivate follow up protecting confidentially | Missing data
Template:Missing data, Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Gonzalo Romero, M.D.[2]
Slide Set: File:Missing Data.pdf
# Overview
In statistics missing data refers to the absence of registered data for a given variable. Missing data is frequent in clinical research. It is an important source of bias, reducing the consistency (precision or reproducibility) of the study. It can have an important effect on the conclusion of the study potentially leading to invalid results drawn from the data.
# Classification of missing data
Missing data can be classified depending on the relationship with the independent or dependent (outcome) variables in 3 categories:
- Missing completely at random (MCAR)
- Missing at random (MAR)
- Missing not at random (MNAR)
## Missing completely at random (MCAR)
It is independent of observed and non-observed data, therefore not related to the independent variables or the outcome.
Examples:
- Loss of study files
- Equipment malfunctioned
- Weather was terrible
- Data not entered correctly
## Missing at random (MAR)
It is not related to the outcome but is related to the independent variables (for example age, race, gender).
It is important to clarify that so it does not correspond to the general notion of 'random'; the probability of a value being missing generally depends on the observed values (independent variables) not on the missing values.
May influence if the independent variable is related to the outcome.
Example: Old patients dropping out from an intervention due to physical condition (walking to the center for follow up), which does not relate to the outcome.
## Missing not at random (MNAR)
It is is related to the outcome. It is considered the worst type of missing data because the dropouts are is related to the therapy or intervention under investigation.
There is a pattern of missing data which is related to unobserved data making impossible to use other values from the dataset to predict the missing values.
Example: Respondents with high income less likely to report income.
# Missing values
Missing values could be due to:
- Withdrawal of consent
- Loss of follow up
- Discontinuation study drug due to:
- Adverse effect
- Lack of efficacy
- Death due to:
- Cause-specific (auto accident)
- Composite outcome (AIDS-defining illness)
- Related to outcome of interest
# Handling missing data
- Complete Case Analysis - CCA (Listwise Deletion)
- Available Case Analysis
- Weighted Complete Case Analysis
- Single Imputation (replacement of missing values)
## Complete case analysis (CCA)
Analyzes only subjects who completed the study.
Advantages:
- Does not require manipulating the data
Disadvantages:
- Decrease of study power: increasing type II error
- Biased results: the dropout rate increases the risk of imbalanced groups
## Available Case Analysis
Special case of Complete Case Analysis, where all or part of the data is used depending on the given analysis.
Example: Incomplete cases used for baseline analysis, NOT used for outcome analysis.
## Weighted Complete Case Analysis
Used in surveys, gives weights for responses based on likelihood of response.
## Single Imputation
- Mean/Median Substitution Method
- Last Observation Carried Forward (LOCF)
- Regression Substitution Method
- Stochastic Regression imputation
- Increased Random Variability Method
- Worst Case Scenario Method
- Baseline Carried Forward Method
- Hot and Cold Deck Imputation
## Mean Substitution
Impute the missing data using the mean of the non-missing values.
Advantages:
- Simple
- Potential to reduce bias by using all study data to estimate response for missing subjects
Disadvantages:
- Significantly decreased standard deviation (variance)
- Increased Type I error
- Overestimation
## Last Observation Carried Forward (LOCF)
Impute the missing data with the value of the last observation with available data.
Advantages:
- Only imputation method accepted by FDA
- It is very simple
- Includes all subjects (ITT analysis)
- Mimics real life scenarios (as many patients in real clinical practice are not compliant to the treatment)
Disadvantages:
- Can lead to biased estimates (as it is based on the assumption that the patients after dropping out would either not improve or continue to get better), which can also decrease the power of a study.
## Regression Substitution
Build a regression model with baseline characteristics as predictors of the outcome using the available data. Then use the model to predict the outcome for patients with missing values.
Advantages:
- Has the potential to reduce bias by using all date to estimate the response for missing subject
Disadvantages:
- Requires a special statistics software
## Increased Random Variability
Use statistical software to generate a set of random values for the outcome and then replace missing data by randomly selecting values from this set.
Advantages:
- Potential to reduce bias by using all study data to estimate response for missing subjects
Disadvantages:
- Complicated statistical model (specific training)
- Not commonly used
- Might be questioned by reviewers
## Worst Case Scenario
Replace the missing data with the worse possible outcome.
Advantage:
- If the results are positive, they can be trusted.
Disadvantage:
- It cannot be used in studies in which a high number of dropouts
## Baseline Carried Forward
Assume that all participants with missing data resume their baseline status.
Replace missing data with the baseline data from each patient.
Advantages:
- Simple
Disadvantages:
- It might underestimate the effects of treatment (type II error)
## Hot and Cold Deck Imputation
Replaces individual missing data items with reported data from another person or household with similar characteristics
- Hot: a missing case is replaced with a case with similar characteristics
- Cold: deck (another dataset)
## Multiple Imputations
Each missing value will be replaced by a simulated value (done several times 3-10 times)
Advantage:
- Has a standard deviation and standard error closer to the one obtained with a complete sample
Disadvantage:
- Incorporate missing data uncertainty
## Multiple likelihood
Use the available values in order to find parameter estimate, which would be the best fit to the already observed data.
Disadvantages:
- Does not impute missing data but use the known characteristic of the individual to better estimate the unknown parameters of the incomplete variable
- Need to find the most appropriate variable to use
# Missing Data Prevention
Although methods can help to analyze as valid as possible dataset with missing data – best to prevent missing data:
- Run-in phase
- Enrichment design - selecting best responders
- Flexible dose (titration) studies
- Selection of target population who will respond to treatment, knowing the population
- Add on design
- Adding endpoints
- Reducing follow-up periods
- Allow rescue medication
- Define outcomes that can be defined without participant visit (for instance, death)
- Randomized withdrawal to define long-term efficacy
- Sending letters to subjects to motivate follow up protecting confidentially | https://www.wikidoc.org/index.php/Missing_data | |
f610037475b80f65bf745e976c66f34273870ff8 | wikidoc | Mithridatism | Mithridatism
# Overview
Mithridatism is the practice of protecting oneself against a poison by gradually self-administering non-lethal amounts. The word derives from Mithridates VI, the King of Pontus, who so feared being poisoned that he regularly ingested small doses, aiming to develop immunity. Having been defeated by Pompey, legend has it that Mithridates tried to commit suicide using poison but failed because of his immunity and so had to resort to having a mercenary run him through with his sword.
Generally, there is no practical purpose or favorable cost/benefit ratio for performing mithridatism except for people like zoo handlers, researchers, and circus artists who deal closely with venomous animals. Mithridatization has been tried with success in Australia and Brazil and total immunity has been achieved even to multiple bites of extremely venomous cobras and pit vipers. Bill Haast successfully immunized himself to a number of species of venomous snakes.
# In fiction
Mithridatism has been used as a plot device in novels, films, and TV shows including, among others, Alexandre Dumas, père's The Count of Monte Cristo; Yoshiaki Kawajiri's Ninja Scroll; Agatha Christie's The Mysterious Affair at Styles; William Goldman's The Princess Bride (and the movie of the same name); and Frisky Dingo.
# In poetry
A.E. Housman's "Terence, this is stupid stuff" (originally published in A Shropshire Lad) invokes mithridatism as a metaphor for the benefit that serious poetry brings to the reader. The final section is a poetic rendition of the Mithridates legend. | Mithridatism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Mithridatism is the practice of protecting oneself against a poison by gradually self-administering non-lethal amounts. The word derives from Mithridates VI, the King of Pontus, who so feared being poisoned that he regularly ingested small doses, aiming to develop immunity. Having been defeated by Pompey, legend has it that Mithridates tried to commit suicide using poison but failed because of his immunity and so had to resort to having a mercenary run him through with his sword.
Generally, there is no practical purpose or favorable cost/benefit ratio for performing mithridatism except for people like zoo handlers, researchers, and circus artists who deal closely with venomous animals. Mithridatization has been tried with success in Australia and Brazil and total immunity has been achieved even to multiple bites of extremely venomous cobras and pit vipers. Bill Haast successfully immunized himself to a number of species of venomous snakes.
# In fiction
Mithridatism has been used as a plot device in novels, films, and TV shows including, among others, Alexandre Dumas, père's The Count of Monte Cristo; Yoshiaki Kawajiri's Ninja Scroll; Agatha Christie's The Mysterious Affair at Styles; William Goldman's The Princess Bride (and the movie of the same name); and Frisky Dingo.
# In poetry
A.E. Housman's "Terence, this is stupid stuff" (originally published in A Shropshire Lad) invokes mithridatism as a metaphor for the benefit that serious poetry brings to the reader. The final section is a poetic rendition of the Mithridates legend.
# External links
- A Shropshire Lad LXII: "Terence, this is stupid stuff"
bg:Митридатизация
de:Mithridatisation
el:Μιθριδατισμός
Template:Jb1
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Mithridatism | |
649f0ad9d8d1327609e5f3f31feceb4cc7cc3161 | wikidoc | Mitoferrin-1 | Mitoferrin-1
Mitoferrin-1 (Mfrn1) is a 38 kDa protein that is encoded by the SLC25A37 gene in humans. It is a member of the Mitochondrial carrier (MC) Superfamily, however, its metal cargo makes it distinct from other members of this family. Mfrn1 plays a key role in mitochondrial iron homeostasis as an iron transporter, importing ferrous iron from the intermembrane space of the mitochondria to the mitochondrial matrix for the biosynthesis of heme groups and Fe-S clusters. This process is tightly regulated, given the redox potential of Mitoferrin’s iron cargo. Mfrn1 is paralogous to Mitoferrin-2 (Mfrn2), a 39 kDa protein encoded by the SLC25A28 gene in humans. Mfrn1 is highly expressed in differentiating erythroid cells and in other tissues at low levels, while Mfrn2 is expressed ubiquitously in non-erythroid tissues.
# Function
The molecular details of iron trafficking for heme and Iron-sulfur cluster synthesis are still unclear, however, Mitoferrin-1 has been shown to form oligomeric complexes with the ATP-binding cassette transporter ABCB10 and Ferrochelatase (or protoporphyrin ferrochelatase). Furthermore, ABC10 binding enhances the stability and functionality of Mfrn1, suggesting that transcriptional and post-translational mechanisms further regulate cellular and mitochondrial iron homeostasis.
Recombinant Mfrn1 in vitro has micromolar affinity for the following first-row transition metals: iron (II), manganese (II), cobalt (II), and nickel (II). Mfrn1 iron transport was reconstituted in proteoliposomes, where the protein was also able to transport manganese, cobalt, copper, and zinc, yet it discriminated against nickel, despite the aforementioned affinity. Notably, Mfrn1 appears to transport free iron ions as opposed to any sort of chelated iron complex. Additionally, Mfrn1 selects against divalent alkali ions.
Mfrn1 and its paralog Mfrn2 have complementary functionalities, though the precise relationship is still uncertain. For example, heme production is restored by expression of Mfrn2 in cells silenced for Mfrn1 and by ectopic expression of Mfrn1 in nonerythroid cells silenced for Mfrn2, where Mfrn1 accumulates due to an increased protein half-life. In contrast, ectopic expression of Mfrn2 failed to restore heme product in erythroid cells silenced for Mfrn1 because Mfrn2 was unable to accumulate in mitochondria.
# Clinical Significance
Mitoferrin-1 has been implicated in diseases associated with defective iron homeostasis, resulting in iron or porphyrin imbalances. Abnormal Mfrn1 expression, for example, may contribute to Erythropoietic protoporphyria, a porphyrin disease linked to mutations in the Ferrochelatase enzyme. Selective deletion of Mfrn1 in adult mice led to severe anemia rather than porphyria likely because Iron-responsive element-binding protein (specifically IRE-BP1) transcriptionally regulates porphyrin biogenesis, inhibiting it in the absence of Mfrn1.
Mfrn1 has also been implicated in depression and Myelin Displastic syndrome.
# Animal Studies
The importance of Mitoferrins in heme and Fe-S cluster biosynthesis was first discovered in the anemic zebrafish mutant frascati. Studies in mice revealed that total deletion of Mfrn1 resulted in embryonic lethality, while selective deletion in adults caused severe anemia as stated above. Expression mouse Mfrn1 rescued knockout zebrafish, indicating that the gene is highly evolutionarily conserved. The transcription factor, GATA-1, directly regulates Mfrn1 expression in zebrafish via distal cis-regulatory Mfrn1 elements. In C. elegans, reduced Mfrn1 expression results in abnormal development and increased lifespans of roughly 50-80%. | Mitoferrin-1
Mitoferrin-1 (Mfrn1) is a 38 kDa protein[1] that is encoded by the SLC25A37 gene in humans.[2][3] It is a member of the Mitochondrial carrier (MC) Superfamily, however, its metal cargo makes it distinct from other members of this family. Mfrn1 plays a key role in mitochondrial iron homeostasis as an iron transporter, importing ferrous iron from the intermembrane space of the mitochondria to the mitochondrial matrix for the biosynthesis of heme groups and Fe-S clusters.[4] This process is tightly regulated, given the redox potential of Mitoferrin’s iron cargo. Mfrn1 is paralogous to Mitoferrin-2 (Mfrn2), a 39 kDa protein encoded by the SLC25A28 gene in humans.[1] Mfrn1 is highly expressed in differentiating erythroid cells and in other tissues at low levels, while Mfrn2 is expressed ubiquitously in non-erythroid tissues.[5][1]
# Function
The molecular details of iron trafficking for heme and Iron-sulfur cluster synthesis are still unclear, however, Mitoferrin-1 has been shown to form oligomeric complexes with the ATP-binding cassette transporter ABCB10 and Ferrochelatase (or protoporphyrin ferrochelatase).[6] Furthermore, ABC10 binding enhances the stability and functionality of Mfrn1, suggesting that transcriptional and post-translational mechanisms further regulate cellular and mitochondrial iron homeostasis.[7]
Recombinant Mfrn1 in vitro has micromolar affinity for the following first-row transition metals: iron (II), manganese (II), cobalt (II), and nickel (II).[8] Mfrn1 iron transport was reconstituted in proteoliposomes, where the protein was also able to transport manganese, cobalt, copper, and zinc, yet it discriminated against nickel, despite the aforementioned affinity.[8] Notably, Mfrn1 appears to transport free iron ions as opposed to any sort of chelated iron complex.[8] Additionally, Mfrn1 selects against divalent alkali ions.[8]
Mfrn1 and its paralog Mfrn2 have complementary functionalities, though the precise relationship is still uncertain. For example, heme production is restored by expression of Mfrn2 in cells silenced for Mfrn1 and by ectopic expression of Mfrn1 in nonerythroid cells silenced for Mfrn2, where Mfrn1 accumulates due to an increased protein half-life.[9] In contrast, ectopic expression of Mfrn2 failed to restore heme product in erythroid cells silenced for Mfrn1 because Mfrn2 was unable to accumulate in mitochondria.[10]
# Clinical Significance
Mitoferrin-1 has been implicated in diseases associated with defective iron homeostasis, resulting in iron or porphyrin imbalances.[11] Abnormal Mfrn1 expression, for example, may contribute to Erythropoietic protoporphyria,[12] a porphyrin disease linked to mutations in the Ferrochelatase enzyme.[12] Selective deletion of Mfrn1 in adult mice led to severe anemia rather than porphyria[13] likely because Iron-responsive element-binding protein (specifically IRE-BP1) transcriptionally regulates porphyrin biogenesis, inhibiting it in the absence of Mfrn1.[5]
Mfrn1 has also been implicated in depression[14] and Myelin Displastic syndrome.[15]
# Animal Studies
The importance of Mitoferrins in heme and Fe-S cluster biosynthesis was first discovered in the anemic zebrafish mutant frascati.[2] Studies in mice revealed that total deletion of Mfrn1 resulted in embryonic lethality, while selective deletion in adults caused severe anemia as stated above.[16] Expression mouse Mfrn1 rescued knockout zebrafish, indicating that the gene is highly evolutionarily conserved.[17] The transcription factor, GATA-1, directly regulates Mfrn1 expression in zebrafish via distal cis-regulatory Mfrn1 elements.[18] In C. elegans, reduced Mfrn1 expression results in abnormal development and increased lifespans of roughly 50-80%.[19] | https://www.wikidoc.org/index.php/Mitoferrin-1 | |
7b460f36f5e3cbe46b2588c75e4f108052a26373 | wikidoc | Mitoxantrone | Mitoxantrone
# 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
Mitoxantrone is an antineoplastic agent that is FDA approved for the treatment of multiple sclerosis, pain related to advanced hormone-refractory prostate cancer, and acute nonlymphocytic leukemia (ANLL). There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, diarrhea, inflammatory disease of mucous membrane, nausea, vomiting, decreased hemoglobin, decreased lymphocyte count, decreased white blood cell count, leukopenia, liver function tests abnormal, headache, urinary tract infectious disease, and disorder of menstruation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dosage of Mitoxantrone Injection, USP is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of Mitoxantrone Injection, USP and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with Mitoxantrone Injection, USP. Mitoxantrone Injection, USP should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥ 140 mg/m2. Complete blood counts, including platelets, should be monitored prior to each course of Mitoxantrone Injection, USP and in the event that signs or symptoms of infection develop. Mitoxantrone Injection, USP generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3. Liver function tests should also be monitored prior to each course. Mitoxantrone Injection, USP therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Mitoxantrone Injection, USP clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.
- Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Mitoxantrone Injection, USP.
- Based on data from two Phase 3 comparative trials of mitoxantrone injection plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days.
- For induction, the recommended dosage is 12 mg/m2 of Mitoxantrone Injection daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1 to 7.
- Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. Mitoxantrone Injection should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.
- If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.
- Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1 to 5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mitoxantrone in adult patients.
### Non–Guideline-Supported Use
- MitoXANTRONE 80 mg/m(2) on day 3.
- MitoXANTRONE 60 milligrams/square meter (mg/m(2)).
- LOW-DOSE mitoXANTRONE 8 milligrams (mg)/square meter intravenously every four weeks.
- MitoXANTRONE 12 milligrams/square meter (mg/m(2)) up to a maximum of 14 mg/m(2).
- MitoXANTRONE 10 milligrams.
- MitoXANTRONE 10 mg/m(2) on day 1 (30 min infusion).
- MitoXANTRONE 14 milligrams/square meter intravenously every 3 weeks (30 minute IV infusion).
- MitoXANTRONE initial doses of 14 milligrams/square meter intravenously every three weeks, increasing by 2 milligrams/square meter every second course in the absence of significant myelotoxicity.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Mitoxantrone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mitoxantrone in pediatric patients.
### Non–Guideline-Supported Use
- MitoXANTRONE given in a dose of 18 milligrams/square meter as an intravenous infusion every 3 weeks.
# Contraindications
- Mitoxantrone Injection, USP is contraindicated in patients who have demonstrated prior hypersensitivity to it.
# Warnings
- Patients with pre-existing myelosuppression as the result of prior drug therapy should not receive mitoxantrone unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression.
- The safety of Mitoxantrone Injection, USP (concentrate) in patients with hepatic insufficiency is not established.
- Safety for use by routes other than intravenous administration has not been established.
- Mitoxantrone is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection.
- Mitoxantrone must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction.
- Topoisomerase II inhibitors, including mitoxantrone, have been associated with the development of secondary acute myeloid leukemia and myelosuppression.
- Cardiac Effects
- Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of mitoxantrone therapy in such patients should be determined before starting therapy.
- Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with mitoxantrone. Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with pre-existing cardiovascular disease. Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy. Cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%.
- Multiple Sclerosis
- Changes in cardiac function may occur in patients with multiple sclerosis treated with mitoxantrone. In one controlled trial (Study 1, see CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving mitoxantrone, one receiving a 5 mg/m2 dose and the other receiving the 12 mg/m2 dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m2, who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial. There were no reports of congestive heart failure in either controlled trial.
- MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of mitoxantrone therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Mitoxantrone should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m2. MS patients should have yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.
- Leukemia
- Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for ANLL. In first-line comparative trials of mitoxantrone + cytarabine vs. daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease.
- Hormone-Refractory Prostate Cancer
- Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with mitoxantrone. In a randomized comparative trial of mitoxantrone plus low-dose prednisone vs. low-dose prednisone, 7 of 128 patients (5.5 %) treated with mitoxantrone had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total mitoxantrone dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2.
- Among 112 patients evaluable for safety on the mitoxantrone + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total mitoxantrone doses administered to these patients is not available.
- Pregnancy
- Mitoxantrone may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal growth retardation at doses ≥ 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses ≥ 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.
- Secondary Leukemia
- Mitoxantrone therapy increases the risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.
- In a study of patients with prostate cancer, acute myeloid leukemia occurred in 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years follow-up.
- In a prospective, open-label, tolerability and safety monitoring study of mitoxantrone treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with mitoxantrone and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia.
- In 1774 patients with breast cancer who received mitoxantrone concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related acute myeloid leukemia was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated with mitoxantrone, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years.
- Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. Mitoxantrone is an anthracenedione, a related drug. The occurrence of secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.
- Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections.
### Precautions
- Therapy with mitoxantrone should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation.
- Systemic infections should be treated concomitantly with or just prior to commencing therapy with mitoxantrone.
# Adverse Reactions
## Clinical Trials Experience
- Mitoxantrone has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received mitoxantrone in combination with corticosteroids.
- In Study 1, the proportion of patients who discontinued treatment due to an adverse event was 9.7% (n = 6) in the 12 mg/m2 mitoxantrone arm (leukopenia, depression, decreased LV function, bone pain and emesis, renal failure, and one discontinuation to prevent future complications from repeated urinary tract infections) compared to 3.1% (n = 2) in the placebo arm (hepatitis and myocardial infarction). The following clinical adverse experiences were significantly more frequent in the mitoxantrone groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea.
- Table 4a summarizes clinical adverse events of all intensities occurring in ≥5% of patients in either dose group of mitoxantrone and that were numerically greater on drug than on placebo in Study 1. The majority of these events were of mild to moderate intensity, and nausea was the only adverse event that occurred with severe intensity in more than one patient (three patients in the 12 mg/m2 group). Of note, alopecia consisted of mild hair thinning.
- Two of the 127 patients treated with mitoxantrone in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m2 did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study.
- The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m2 group, and 81% for the 12 mg/m2 group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m2 patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m2 patients (tonsillitis, urinary tract infection , endometritis).
- Table 4b summarizes laboratory abnormalities that occurred in ≥ 5% of patients in either mitoxantrone dose group, and that were numerically more frequent than in the placebo group.
- There was no difference among treatment groups in the incidence or severity of hemorrhagic events.
- In Study 2, mitoxantrone was administered once a month. Clinical adverse events most frequently reported in the mitoxantrone group included amenorrhea (53% of female patients), alopecia (33% of patients), nausea (29% of patients), and asthenia (24% of patients). Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 5% of patients in the mitoxantrone group and numerically more frequent than in the control group.
- Leukopenia and neutropenia were reported in the M + MP group (see Table 5b). Neutropenia occurred within 3 weeks after mitoxantrone administration and was always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the M + MP group and in 3 of 21 patients in the MP group; none of these required hospitalization. There was no difference among treatment groups in the incidence or severity of hemorrhagic events. There were no withdrawals from Study 2 for safety reasons.
- Mitoxantrone has been studied in approximately 600 patients with acute nonlymphocytic leukemia (ANLL). Table 6 represents the adverse reaction experience in the large U.S. comparative study of mitoxantrone + cytarabine vs. daunorubicin + cytarabine. Experience in the large international study was similar. A much wider experience in a variety of other tumor types revealed no additional important reactions other than cardiomyopathy. It should be appreciated that the listed adverse reaction categories include overlapping clinical symptoms related to the same condition, e.g., dyspnea, cough and pneumonia. In addition, the listed adverse reactions cannot all necessarily be attributed to chemotherapy as it is often impossible to distinguish effects of the drug and effects of the underlying disease. It is clear, however, that the combination of mitoxantrone + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression.
- Table 6 summarizes adverse reactions occurring in patients treated with mitoxantrone + cytarabine in comparison with those who received daunorubicin + cytarabine for therapy of ANLL in a large multicenter randomized prospective U.S. trial.
- Adverse reactions are presented as major categories and selected examples of clinically significant subcategories.
- Detailed safety information is available for a total of 353 patients with hormone-refractory prostate cancer treated with mitoxantrone, including 274 patients who received mitoxantrone in combination with corticosteroids.
- Table 7 summarizes adverse reactions of all grades occurring in ≥ 5% of patients in Trial CCI-NOV22.
Hypotension, urticaria, dyspnea, and rashes have been reported occasionally. Anaphylaxis/anaphylactoid reactions have been reported rarely.
Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discoloration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of the infusion.
Topoisomerase II inhibitors, including mitoxantrone, in combination with other antineoplastic agents or alone, have been associated with the development of acute leukemia.
Myelosuppression is rapid in onset and is consistent with the requirement to produce significant marrow hypoplasia in order to achieve a response in acute leukemia. The incidences of infection and bleeding seen in the U.S. trial are consistent with those reported for other standard induction regimens.
In a randomized study where dose escalation was required for neutrophil counts greater than 1000/mm3, Grade 4 neutropenia (ANC < 500 /mm3) was observed in 54% of patients treated with mitoxantrone + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m2, Grade 4 neutropenia in 23% of patients treated with mitoxantrone + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving mitoxantrone + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm3 were noted in 4% and 3% of patients receiving mitoxantrone + corticosteroids on these trials, and there was one patient death on mitoxantrone + hydrocortisone due to intracranial hemorrhage after a fall.
Nausea and vomiting occurred acutely in most patients and may have contributed to reports of dehydration, but were generally mild to moderate and could be controlled through the use of antiemetics. Stomatitis/mucositis occurred within 1 week of therapy.
Congestive heart failure, tachycardia, EKG changes including arrhythmias, chest pain, and asymptomatic decreases in left ventricular ejection fraction have occurred (see WARNINGS).
Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included mitoxantrone.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Mitoxantrone in the drug label.
# Drug Interactions
- Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.
- Following concurrent administration of mitoxantrone with corticosteroids, no evidence of drug interactions has been observed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mitoxantrone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mitoxantrone during labor and delivery.
### Nursing Mothers
- Mitoxantrone is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breastfeeding should be discontinued before starting treatment.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Multiple Sclerosis
- Clinical studies of mitoxantrone did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- Hormone-Refractory Prostate Cancer
- One hundred forty-six patients aged 65 and over and 52 younger patients (<65 years) have been treated with mitoxantrone in controlled clinical studies. These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out.
- Acute Nonlymphocytic Leukemia
- Although definitive studies with mitoxantrone have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly. Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy.
### Gender
There is no FDA guidance on the use of Mitoxantrone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mitoxantrone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mitoxantrone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mitoxantrone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mitoxantrone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mitoxantrone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Mitoxantrone in the drug label.
# IV Compatibility
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
- The dose of mitoxantrone should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). Mitoxantrone Injection, USP (concentrate) may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE.
- Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that mitoxantrone not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted Mitoxantrone Injection, USP (concentrate) should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE.
- Care in the administration of mitoxantrone will reduce the chance of extravasation. Mitoxantrone should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes. MITOXANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritus, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of mitoxantrone extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.
- Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
# Overdosage
## Acute Overdose
- There is no known specific antidote for mitoxantrone. Accidental overdoses have been reported. Four patients receiving 140 to 180 mg/m2 as a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression.
- Although patients with severe renal failure have not been studied, mitoxantrone is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mitoxantrone in the drug label.
# Pharmacology
## Mechanism of Action
- Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
- Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL-2.
## Structure
- Mitoxantrone Injection, USP (concentrate) is a synthetic antineoplastic anthracenedione for intravenous use. It is supplied as a concentrate that MUST BE DILUTED PRIOR TO INJECTION. The concentrate is a sterile, nonpyrogenic, dark blue aqueous solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with the following inactive ingredients: sodium chloride (0.800% w/v), sodium acetate (0.005% w/v), acetic acid (0.046% w/v), and water for injection. The solution has a pH of 3.0 to 4.5 and contains 0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical name is 1,4-dihydroxy-5,8-bisethyl]amino]-9,10- anthracenedione dihydrochloride and the structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Mitoxantrone in the drug label.
## Pharmacokinetics
- Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of mitoxantrone can be characterized by a three-compartment model. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours).
- Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2.
- Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.
- In patients administered 15 to 90 mg/m2 of mitoxantrone intravenously, there is a linear relationship between dose and the area under the concentration-time curve (AUC).
- Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 to 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.
- Metabolism and Elimination
- Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates. The pathways leading to the metabolism of mitoxantrone have not been elucidated.
- Special Populations
- Gender
- The effect of gender on mitoxantrone pharmacokinetics is unknown.
- Geriatric
- In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3 L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 for non-elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively.
- Pediatric
- Mitoxantrone pharmacokinetics in the pediatric population are unknown.
- Race
- The effect of race on mitoxantrone pharmacokinetics is unknown.
- Renal Impairment
- Mitoxantrone pharmacokinetics in patients with renal impairment are unknown.
- Hepatic Impairment
- Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with mitoxantrone. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required.
- Drug Interactions
- In vitro drug interaction studies have demonstrated that mitoxantrone did not inhibit CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4 across a broad concentration range. The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity.
- Pharmacokinetic studies of the interaction of mitoxantrone with concomitantly administered medications in humans have not been performed. The pathways leading to the metabolism of mitoxantrone have not been elucidated. To date, postmarketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.
## Nonclinical Toxicology
- Carcinogenesis
- Intravenous treatment of rats and mice, once every 21 days for 24 months, with mitoxantrone resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m2 basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m2 basis). Intravenous treatment of rats, once every 21 days for 12 months with mitoxantrone resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m2 basis).
- Mutagenesis
- Mitoxantrone was clastogenic in the in vivo rat bone marrow assay. Mitoxantrone was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. Mitoxantrone was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma).
# Clinical Studies
- The safety and efficacy of mitoxantrone in multiple sclerosis were assessed in two randomized, multicenter clinical studies.
- One randomized, controlled study (Study 1) was conducted in patients with secondary progressive or progressive relapsing multiple sclerosis. Patients in this study demonstrated significant neurological disability based on the Kurtzke Expanded Disability Status Scale (EDSS). The EDSS is an ordinal scale with 0.5 point increments ranging from 0.0 to 10.0 (increasing score indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 4.5 to 7.5 points). Patients in this study had experienced a mean deterioration in EDSS of about 1.6 points over the 18 months prior to enrollment.
- Patients were randomized to receive placebo, 5 mg/m2 mitoxantrone, or 12 mg/m2 mitoxantrone administered IV every 3 months for 2 years. High-dose methylprednisolone was administered to treat relapses. The intent-to-treat analysis cohort consisted of 188 patients; 149 completed the 2-year study. Patients were evaluated every 3 months, and clinical outcome was determined after 24 months. In addition, a subset of patients was assessed with magnetic resonance imaging (MRI) at baseline, Month 12, and Month 24. Neurologic assessments and MRI reviews were performed by evaluators blinded to study drug and clinical outcome, although the diagnosis of relapse and the decision to treat relapses with steroids were made by unblinded treating physicians. A multivariate analysis of five clinical variables (EDSS, Ambulation Index , number of relapses requiring treatment with steroids, months to first relapse needing treatment with steroids, and Standard Neurological Status ) was used to determine primary efficacy. The AI is an ordinal scale ranging from 0 to 9 in one point increments to define progressive ambulatory impairment. The SNS provides an overall measure of neurologic impairment and disability, with scores ranging from 0 (normal neurologic examination) to 99 (worst possible score).
- Results of Study 1 are summarized in Table 1.
- A second randomized, controlled study (Study 2) evaluated mitoxantrone in combination with methylprednisolone (MP) and was conducted in patients with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. All patients had experienced at least two relapses with sequelae or neurological deterioration within the previous 12 months. The average deterioration in EDSS was 2.2 points during the previous 12 months. During the screening period, patients were treated with two monthly doses of 1 g of IV MP and underwent monthly MRI scans. Only patients who developed at least one new Gd-enhancing MRI lesion during the 2-month screening period were eligible for randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV MP alone (n=21) or ~12 mg/m2 of IV mitoxantrone plus 1 g of IV MP (n=21) (M+MP) for 6 months. Patients were evaluated monthly, and study outcome was determined after 6 months. The primary measure of effectiveness in this study was a comparison of the proportion of patients in each treatment group who developed no new Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel. Additional outcomes were measured, including EDSS and number of relapses, but all clinical measures in this trial were assessed by an unblinded treating physician. Five patients, all in the MP alone arm, failed to complete the study due to lack of efficacy.
- The results of this trial are displayed in Table 2.
- A multicenter Phase 2 trial of mitoxantrone and low-dose prednisone (M + P) was conducted in 27 symptomatic patients with hormone-refractory prostate cancer. Using NPCP (National Prostate Cancer Project) criteria for disease response, there was one partial responder and 12 patients with stable disease. However, nine patients or 33% achieved a palliative response defined on the basis of reduction in analgesic use or pain intensity.
- These findings led to the initiation of a randomized multicenter trial (CCI-NOV22) comparing the effectiveness of (M + P) to low-dose prednisone alone (P). Eligible patients were required to have metastatic or locally advanced disease that had progressed on standard hormonal therapy, a castrate serum testosterone level, and at least mild pain at study entry. Mitoxantrone was administered at a dose of 12 mg/m2 by short IV infusion every 3 weeks. Prednisone was administered orally at a dose of 5 mg twice a day. Patients randomized to the prednisone arm were crossed over to the M + P arm if they progressed or if they were not improved after a minimum of 6 weeks of therapy with prednisone alone.
- A total of 161 patients were randomized, 80 to the M + P arm and 81 to the P arm. The median mitoxantrone dose administered was 12 mg/m2 per cycle. The median cumulative mitoxantrone dose administered was 73 mg/m2 (range of 12 to 212 mg/m2).
- A primary palliative response (defined as a 2-point decrease in pain intensity in a 6-point pain scale, associated with stable analgesic use, and lasting a minimum of 6 weeks) was achieved in 29% of patients randomized to M + P compared to 12% of patients randomized to P alone (p = 0.011). Two responders left the study after meeting primary response criterion for two consecutive cycles. For the purposes of this analysis, these two patients were assigned a response duration of zero days. A secondary palliative response was defined as a 50% or greater decrease in analgesic use, associated with stable pain intensity, and lasting a minimum of 6 weeks. An overall palliative response (defined as primary plus secondary responses) was achieved in 38% of patients randomized to M + P compared to 21% of patients randomized to P (p = 0.025).
- The median duration of primary palliative response for patients randomized to M + P was 7.6 months compared to 2.1 months for patients randomized to P alone (p = 0.0009). The median duration of overall palliative response for patients randomized to M + P was 5.6 months compared to 1.9 months for patients randomized to P alone (p = 0.0004).
- Time to progression was defined as a 1-point increase in pain intensity, or a > 25% increase in analgesic use, or evidence of disease progression on radiographic studies, or requirement for radiotherapy. The median time to progression for all patients randomized to M + P was 4.4 months compared to 2.3 months for all patients randomized to P alone (p = 0.0001). Median time to death was 11.3 months for all patients on the M + P arm compared to 10.8 months for all patients on P alone (p = 0.2324).
- Forty-eight patients on the P arm crossed over to receive M + P. Of these, thirty patients had progressed on P, while 18 had stable disease on P. The median cycle of crossover was 5 cycles (range of 2 to 16 cycles). Time trends for pain intensity prior to crossover were significantly worse for patients who crossed over than for those who remained on P alone (p = 0.012). Nine patients (19%) demonstrated a palliative response on M + P after crossover. The median time to death for patients who crossed over to M + P was 12.7 months.
- The clinical significance of a fall in prostate-specific antigen (PSA) concentrations after chemotherapy is unclear. On the CCI-NOV22 trial, a PSA fall of 50% or greater for two consecutive follow-up assessments after baseline was reported in 33% of all patients randomized to the M + P arm and 9% of all patients randomized to the P arm. These findings should be interpreted with caution since PSA responses were not defined prospectively. A number of patients were inevaluable for response, and there was an imbalance between treatment arms in the numbers of evaluable patients. In addition, PSA reduction did not correlate precisely with palliative response, the primary efficacy endpoint of this study. For example, among the 26 evaluable patients randomized to the M + P arm who had a ≥50% reduction in PSA, only 13 had a primary palliative response. Also, among 42 evaluable patients on this arm who did not have this reduction in PSA, 8 nonetheless had a primary palliative response.
- Investigators at Cancer and Leukemia Group B (CALGB) conducted a Phase 3 comparative trial of mitoxantrone plus hydrocortisone (M + H) versus hydrocortisone alone (H) in patients with hormone-refractory prostate cancer (CALGB 9182). Eligible patients were required to have metastatic disease that had progressed despite at least one hormonal therapy. Progression at study entry was defined on the basis of progressive symptoms, increases in measurable or osseous disease, or rising PSA levels. Mitoxantrone was administered intravenously at a dose of 14 mg/m2 every 21 days and hydrocortisone was administered orally at a daily dose of 40 mg. A total of 242 subjects were randomized, 119 to the M + H arm and 123 to the H arm. There were no differences in survival between the two arms, with a median of 11.1 months in the M + H arm and 12 months in the H arm (p = 0.3298).
- Using NPCP criteria for response, partial responses were achieved in 10 patients (8.4%) randomized to the M+ H arm compared with 2 patients (1.6%) randomized to the H arm (p = 0.018). The median time to progression, defined by NPCP criteria, for patients randomized to the M + H arm was 7.3 months compared to 4.1 months for patients randomized to H alone (p = 0.0654).
- Approximately 60% of patients on each arm required analgesics at baseline. Analgesic use was measured in this study using a 5-point scale. The best percent change from baseline in mean analgesic use was -17% for 61 patients with available data on the M + H arm, compared with +17% for 61 patients on H alone (p = 0.014). A time trend analysis for analgesic use in individual patients also showed a trend favoring the M + H arm over H alone but was not statistically significant.
- Pain intensity was measured using the Symptom Distress Scale (SDS) Pain Item 2 (a 5-point scale). The best percent change from baseline in mean pain intensity was -14% for 37 patients with available data on the M + H arm, compared with +8% for 38 patients on H alone (p = 0.057). A time trend analysis for pain intensity in individual patients showed no difference between treatment arms.
- In two large randomized multicenter trials, remission induction therapy for acute nonlymphocytic leukemia (ANLL) with mitoxantrone 12 mg/m2 daily for 3 days as a 10-minute intravenous infusion and cytarabine 100 mg/m2 for 7 days given as a continuous 24-hour infusion was compared with daunorubicin 45 mg/m2 daily by intravenous infusion for 3 days plus the same dose and schedule of cytarabine used with mitoxantrone. Patients who had an incomplete antileukemic response received a second induction course in which mitoxantrone or daunorubicin was administered for 2 days and cytarabine for 5 days using the same daily dosage schedule. Response rates and median survival information for both the U.S. and international multicenter trials given in Table 3:
- In these studies, two consolidation courses were administered to complete responders on each arm. Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but only 5 days of cytarabine and 2 days of mitoxantrone or daunorubicin were given. The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission. The second consolidation course was generally administered 4 weeks later. Full hematologic recovery was necessary for patients to receive consolidation therapy. For the U.S. trial, median granulocyte nadirs for patients receiving mitoxantrone + cytarabine for consolidation courses 1 and 2 were 10/mm3 for both courses, and for those patients receiving daunorubicin + cytarabine nadirs were 170/mm3 and 260/mm3, respectively. Median platelet nadirs for patients who received mitoxantrone + cytarabine for consolidation courses 1 and 2 were 17,000/mm3 and 14,000/mm3, respectively, and were 33,000/mm3 and 22,000/mm3 in courses 1 and 2 for those patients who received daunorubicin + cytarabine. The benefit of consolidation therapy in ANLL patients who achieve a complete remission remains controversial. However, in the only well-controlled prospective, randomized multicenter trials with mitoxantrone in ANLL, consolidation therapy was given to all patients who achieved a complete remission. During consolidation in the U.S. study, two myelosuppression-related deaths occurred on the mitoxantrone arm and one on the daunorubicin arm. However, in the international study there were eight deaths on the mitoxantrone arm during consolidation which were related to the myelosuppression and none on the daunorubicin arm where less myelosuppression occurred.
# How Supplied
- Mitoxantrone Injection, USP (concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multidose use as follows:
- The above products are packaged individually.
- Store between 20º to 25ºC (68° to 77°F) . DO NOT FREEZE.
- This container closure is not made with natural rubber latex.
## Storage
There is limited information regarding Mitoxantrone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with mitoxantrone and prior to each infusion. Review the Mitoxantrone Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that mitoxantrone should be taken only as prescribed.
- Advise patients that mitoxantrone can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. Advise patients that mitoxantrone can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. Advise patients receiving mitoxantrone to treat multiple sclerosis that they should receive cardiac monitoring prior to each mitoxantrone dose and yearly after stopping mitoxantrone.
- Mitoxantrone may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discoloration of the sclera may also occur.
# Precautions with Alcohol
- Alcohol-Mitoxantrone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MITOXANTRONE®
# Look-Alike Drug Names
There is limited information regarding Mitoxantrone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Mitoxantrone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Mitoxantrone is an antineoplastic agent that is FDA approved for the treatment of multiple sclerosis, pain related to advanced hormone-refractory prostate cancer, and acute nonlymphocytic leukemia (ANLL). There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, diarrhea, inflammatory disease of mucous membrane, nausea, vomiting, decreased hemoglobin, decreased lymphocyte count, decreased white blood cell count, leukopenia, liver function tests abnormal, headache, urinary tract infectious disease, and disorder of menstruation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dosage of Mitoxantrone Injection, USP is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of Mitoxantrone Injection, USP and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with Mitoxantrone Injection, USP. Mitoxantrone Injection, USP should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥ 140 mg/m2. Complete blood counts, including platelets, should be monitored prior to each course of Mitoxantrone Injection, USP and in the event that signs or symptoms of infection develop. Mitoxantrone Injection, USP generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3. Liver function tests should also be monitored prior to each course. Mitoxantrone Injection, USP therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Mitoxantrone Injection, USP clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.
- Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Mitoxantrone Injection, USP.
- Based on data from two Phase 3 comparative trials of mitoxantrone injection plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days.
- For induction, the recommended dosage is 12 mg/m2 of Mitoxantrone Injection daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1 to 7.
- Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. Mitoxantrone Injection should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.
- If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.
- Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1 to 5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mitoxantrone in adult patients.
### Non–Guideline-Supported Use
- MitoXANTRONE 80 mg/m(2) on day 3.
- MitoXANTRONE 60 milligrams/square meter (mg/m(2)).[1]
- LOW-DOSE mitoXANTRONE 8 milligrams (mg)/square meter intravenously every four weeks.[2]
- MitoXANTRONE 12 milligrams/square meter (mg/m(2)) up to a maximum of 14 mg/m(2).[3]
- MitoXANTRONE 10 milligrams.[4]
- MitoXANTRONE 10 mg/m(2) on day 1 (30 min infusion).[5]
- MitoXANTRONE 14 milligrams/square meter intravenously every 3 weeks (30 minute IV infusion).[6]
- MitoXANTRONE initial doses of 14 milligrams/square meter intravenously every three weeks, increasing by 2 milligrams/square meter every second course in the absence of significant myelotoxicity.[7]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Mitoxantrone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mitoxantrone in pediatric patients.
### Non–Guideline-Supported Use
- MitoXANTRONE given in a dose of 18 milligrams/square meter as an intravenous infusion every 3 weeks.[8]
# Contraindications
- Mitoxantrone Injection, USP is contraindicated in patients who have demonstrated prior hypersensitivity to it.
# Warnings
- Patients with pre-existing myelosuppression as the result of prior drug therapy should not receive mitoxantrone unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression.
- The safety of Mitoxantrone Injection, USP (concentrate) in patients with hepatic insufficiency is not established.
- Safety for use by routes other than intravenous administration has not been established.
- Mitoxantrone is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection.
- Mitoxantrone must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction.
- Topoisomerase II inhibitors, including mitoxantrone, have been associated with the development of secondary acute myeloid leukemia and myelosuppression.
- Cardiac Effects
- Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of mitoxantrone therapy in such patients should be determined before starting therapy.
- Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with mitoxantrone. Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with pre-existing cardiovascular disease. Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy. Cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%.
- Multiple Sclerosis
- Changes in cardiac function may occur in patients with multiple sclerosis treated with mitoxantrone. In one controlled trial (Study 1, see CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving mitoxantrone, one receiving a 5 mg/m2 dose and the other receiving the 12 mg/m2 dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m2, who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial. There were no reports of congestive heart failure in either controlled trial.
- MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of mitoxantrone therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Mitoxantrone should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m2. MS patients should have yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.
- Leukemia
- Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for ANLL. In first-line comparative trials of mitoxantrone + cytarabine vs. daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease.
- Hormone-Refractory Prostate Cancer
- Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with mitoxantrone. In a randomized comparative trial of mitoxantrone plus low-dose prednisone vs. low-dose prednisone, 7 of 128 patients (5.5 %) treated with mitoxantrone had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total mitoxantrone dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2.
- Among 112 patients evaluable for safety on the mitoxantrone + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total mitoxantrone doses administered to these patients is not available.
- Pregnancy
- Mitoxantrone may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal growth retardation at doses ≥ 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses ≥ 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.
- Secondary Leukemia
- Mitoxantrone therapy increases the risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.
- In a study of patients with prostate cancer, acute myeloid leukemia occurred in 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years follow-up.
- In a prospective, open-label, tolerability and safety monitoring study of mitoxantrone treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with mitoxantrone and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia.
- In 1774 patients with breast cancer who received mitoxantrone concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related acute myeloid leukemia was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated with mitoxantrone, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years.
- Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. Mitoxantrone is an anthracenedione, a related drug. The occurrence of secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.
- Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections.
### Precautions
- Therapy with mitoxantrone should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation.
- Systemic infections should be treated concomitantly with or just prior to commencing therapy with mitoxantrone.
# Adverse Reactions
## Clinical Trials Experience
- Mitoxantrone has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received mitoxantrone in combination with corticosteroids.
- In Study 1, the proportion of patients who discontinued treatment due to an adverse event was 9.7% (n = 6) in the 12 mg/m2 mitoxantrone arm (leukopenia, depression, decreased LV function, bone pain and emesis, renal failure, and one discontinuation to prevent future complications from repeated urinary tract infections) compared to 3.1% (n = 2) in the placebo arm (hepatitis and myocardial infarction). The following clinical adverse experiences were significantly more frequent in the mitoxantrone groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea.
- Table 4a summarizes clinical adverse events of all intensities occurring in ≥5% of patients in either dose group of mitoxantrone and that were numerically greater on drug than on placebo in Study 1. The majority of these events were of mild to moderate intensity, and nausea was the only adverse event that occurred with severe intensity in more than one patient (three patients [5%] in the 12 mg/m2 group). Of note, alopecia consisted of mild hair thinning.
- Two of the 127 patients treated with mitoxantrone in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m2 did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study.
- The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m2 group, and 81% for the 12 mg/m2 group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m2 patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m2 patients (tonsillitis, urinary tract infection [two], endometritis).
- Table 4b summarizes laboratory abnormalities that occurred in ≥ 5% of patients in either mitoxantrone dose group, and that were numerically more frequent than in the placebo group.
- There was no difference among treatment groups in the incidence or severity of hemorrhagic events.
- In Study 2, mitoxantrone was administered once a month. Clinical adverse events most frequently reported in the mitoxantrone group included amenorrhea (53% of female patients), alopecia (33% of patients), nausea (29% of patients), and asthenia (24% of patients). Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 5% of patients in the mitoxantrone group and numerically more frequent than in the control group.
- Leukopenia and neutropenia were reported in the M + MP group (see Table 5b). Neutropenia occurred within 3 weeks after mitoxantrone administration and was always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the M + MP group and in 3 of 21 patients in the MP group; none of these required hospitalization. There was no difference among treatment groups in the incidence or severity of hemorrhagic events. There were no withdrawals from Study 2 for safety reasons.
- Mitoxantrone has been studied in approximately 600 patients with acute nonlymphocytic leukemia (ANLL). Table 6 represents the adverse reaction experience in the large U.S. comparative study of mitoxantrone + cytarabine vs. daunorubicin + cytarabine. Experience in the large international study was similar. A much wider experience in a variety of other tumor types revealed no additional important reactions other than cardiomyopathy. It should be appreciated that the listed adverse reaction categories include overlapping clinical symptoms related to the same condition, e.g., dyspnea, cough and pneumonia. In addition, the listed adverse reactions cannot all necessarily be attributed to chemotherapy as it is often impossible to distinguish effects of the drug and effects of the underlying disease. It is clear, however, that the combination of mitoxantrone + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression.
- Table 6 summarizes adverse reactions occurring in patients treated with mitoxantrone + cytarabine in comparison with those who received daunorubicin + cytarabine for therapy of ANLL in a large multicenter randomized prospective U.S. trial.
- Adverse reactions are presented as major categories and selected examples of clinically significant subcategories.
- Detailed safety information is available for a total of 353 patients with hormone-refractory prostate cancer treated with mitoxantrone, including 274 patients who received mitoxantrone in combination with corticosteroids.
- Table 7 summarizes adverse reactions of all grades occurring in ≥ 5% of patients in Trial CCI-NOV22.
Hypotension, urticaria, dyspnea, and rashes have been reported occasionally. Anaphylaxis/anaphylactoid reactions have been reported rarely.
Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discoloration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of the infusion.
Topoisomerase II inhibitors, including mitoxantrone, in combination with other antineoplastic agents or alone, have been associated with the development of acute leukemia.
Myelosuppression is rapid in onset and is consistent with the requirement to produce significant marrow hypoplasia in order to achieve a response in acute leukemia. The incidences of infection and bleeding seen in the U.S. trial are consistent with those reported for other standard induction regimens.
In a randomized study where dose escalation was required for neutrophil counts greater than 1000/mm3, Grade 4 neutropenia (ANC < 500 /mm3) was observed in 54% of patients treated with mitoxantrone + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m2, Grade 4 neutropenia in 23% of patients treated with mitoxantrone + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving mitoxantrone + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm3 were noted in 4% and 3% of patients receiving mitoxantrone + corticosteroids on these trials, and there was one patient death on mitoxantrone + hydrocortisone due to intracranial hemorrhage after a fall.
Nausea and vomiting occurred acutely in most patients and may have contributed to reports of dehydration, but were generally mild to moderate and could be controlled through the use of antiemetics. Stomatitis/mucositis occurred within 1 week of therapy.
Congestive heart failure, tachycardia, EKG changes including arrhythmias, chest pain, and asymptomatic decreases in left ventricular ejection fraction have occurred (see WARNINGS).
Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included mitoxantrone.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Mitoxantrone in the drug label.
# Drug Interactions
- Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.
- Following concurrent administration of mitoxantrone with corticosteroids, no evidence of drug interactions has been observed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mitoxantrone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mitoxantrone during labor and delivery.
### Nursing Mothers
- Mitoxantrone is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breastfeeding should be discontinued before starting treatment.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Multiple Sclerosis
- Clinical studies of mitoxantrone did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- Hormone-Refractory Prostate Cancer
- One hundred forty-six patients aged 65 and over and 52 younger patients (<65 years) have been treated with mitoxantrone in controlled clinical studies. These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out.
- Acute Nonlymphocytic Leukemia
- Although definitive studies with mitoxantrone have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly. Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy.
### Gender
There is no FDA guidance on the use of Mitoxantrone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mitoxantrone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mitoxantrone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mitoxantrone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mitoxantrone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mitoxantrone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Mitoxantrone in the drug label.
# IV Compatibility
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
- The dose of mitoxantrone should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). Mitoxantrone Injection, USP (concentrate) may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE.
- Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that mitoxantrone not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted Mitoxantrone Injection, USP (concentrate) should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE.
- Care in the administration of mitoxantrone will reduce the chance of extravasation. Mitoxantrone should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes. MITOXANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritus, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of mitoxantrone extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.
- Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
# Overdosage
## Acute Overdose
- There is no known specific antidote for mitoxantrone. Accidental overdoses have been reported. Four patients receiving 140 to 180 mg/m2 as a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression.
- Although patients with severe renal failure have not been studied, mitoxantrone is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mitoxantrone in the drug label.
# Pharmacology
## Mechanism of Action
- Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
- Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL-2.
## Structure
- Mitoxantrone Injection, USP (concentrate) is a synthetic antineoplastic anthracenedione for intravenous use. It is supplied as a concentrate that MUST BE DILUTED PRIOR TO INJECTION. The concentrate is a sterile, nonpyrogenic, dark blue aqueous solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with the following inactive ingredients: sodium chloride (0.800% w/v), sodium acetate (0.005% w/v), acetic acid (0.046% w/v), and water for injection. The solution has a pH of 3.0 to 4.5 and contains 0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical name is 1,4-dihydroxy-5,8-bis[2-[(2-hydroxyethyl) amino]ethyl]amino]-9,10- anthracenedione dihydrochloride and the structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Mitoxantrone in the drug label.
## Pharmacokinetics
- Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of mitoxantrone can be characterized by a three-compartment model. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours).
- Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2.
- Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.
- In patients administered 15 to 90 mg/m2 of mitoxantrone intravenously, there is a linear relationship between dose and the area under the concentration-time curve (AUC).
- Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 to 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.
- Metabolism and Elimination
- Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates. The pathways leading to the metabolism of mitoxantrone have not been elucidated.
- Special Populations
- Gender
- The effect of gender on mitoxantrone pharmacokinetics is unknown.
- Geriatric
- In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3 L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 for non-elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively.
- Pediatric
- Mitoxantrone pharmacokinetics in the pediatric population are unknown.
- Race
- The effect of race on mitoxantrone pharmacokinetics is unknown.
- Renal Impairment
- Mitoxantrone pharmacokinetics in patients with renal impairment are unknown.
- Hepatic Impairment
- Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with mitoxantrone. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required.
- Drug Interactions
- In vitro drug interaction studies have demonstrated that mitoxantrone did not inhibit CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4 across a broad concentration range. The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity.
- Pharmacokinetic studies of the interaction of mitoxantrone with concomitantly administered medications in humans have not been performed. The pathways leading to the metabolism of mitoxantrone have not been elucidated. To date, postmarketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.
## Nonclinical Toxicology
- Carcinogenesis
- Intravenous treatment of rats and mice, once every 21 days for 24 months, with mitoxantrone resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m2 basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m2 basis). Intravenous treatment of rats, once every 21 days for 12 months with mitoxantrone resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m2 basis).
- Mutagenesis
- Mitoxantrone was clastogenic in the in vivo rat bone marrow assay. Mitoxantrone was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. Mitoxantrone was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma).
# Clinical Studies
- The safety and efficacy of mitoxantrone in multiple sclerosis were assessed in two randomized, multicenter clinical studies.
- One randomized, controlled study (Study 1) was conducted in patients with secondary progressive or progressive relapsing multiple sclerosis. Patients in this study demonstrated significant neurological disability based on the Kurtzke Expanded Disability Status Scale (EDSS). The EDSS is an ordinal scale with 0.5 point increments ranging from 0.0 to 10.0 (increasing score indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 4.5 to 7.5 points). Patients in this study had experienced a mean deterioration in EDSS of about 1.6 points over the 18 months prior to enrollment.
- Patients were randomized to receive placebo, 5 mg/m2 mitoxantrone, or 12 mg/m2 mitoxantrone administered IV every 3 months for 2 years. High-dose methylprednisolone was administered to treat relapses. The intent-to-treat analysis cohort consisted of 188 patients; 149 completed the 2-year study. Patients were evaluated every 3 months, and clinical outcome was determined after 24 months. In addition, a subset of patients was assessed with magnetic resonance imaging (MRI) at baseline, Month 12, and Month 24. Neurologic assessments and MRI reviews were performed by evaluators blinded to study drug and clinical outcome, although the diagnosis of relapse and the decision to treat relapses with steroids were made by unblinded treating physicians. A multivariate analysis of five clinical variables (EDSS, Ambulation Index [AI], number of relapses requiring treatment with steroids, months to first relapse needing treatment with steroids, and Standard Neurological Status [SNS]) was used to determine primary efficacy. The AI is an ordinal scale ranging from 0 to 9 in one point increments to define progressive ambulatory impairment. The SNS provides an overall measure of neurologic impairment and disability, with scores ranging from 0 (normal neurologic examination) to 99 (worst possible score).
- Results of Study 1 are summarized in Table 1.
- A second randomized, controlled study (Study 2) evaluated mitoxantrone in combination with methylprednisolone (MP) and was conducted in patients with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. All patients had experienced at least two relapses with sequelae or neurological deterioration within the previous 12 months. The average deterioration in EDSS was 2.2 points during the previous 12 months. During the screening period, patients were treated with two monthly doses of 1 g of IV MP and underwent monthly MRI scans. Only patients who developed at least one new Gd-enhancing MRI lesion during the 2-month screening period were eligible for randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV MP alone (n=21) or ~12 mg/m2 of IV mitoxantrone plus 1 g of IV MP (n=21) (M+MP) for 6 months. Patients were evaluated monthly, and study outcome was determined after 6 months. The primary measure of effectiveness in this study was a comparison of the proportion of patients in each treatment group who developed no new Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel. Additional outcomes were measured, including EDSS and number of relapses, but all clinical measures in this trial were assessed by an unblinded treating physician. Five patients, all in the MP alone arm, failed to complete the study due to lack of efficacy.
- The results of this trial are displayed in Table 2.
- A multicenter Phase 2 trial of mitoxantrone and low-dose prednisone (M + P) was conducted in 27 symptomatic patients with hormone-refractory prostate cancer. Using NPCP (National Prostate Cancer Project) criteria for disease response, there was one partial responder and 12 patients with stable disease. However, nine patients or 33% achieved a palliative response defined on the basis of reduction in analgesic use or pain intensity.
- These findings led to the initiation of a randomized multicenter trial (CCI-NOV22) comparing the effectiveness of (M + P) to low-dose prednisone alone (P). Eligible patients were required to have metastatic or locally advanced disease that had progressed on standard hormonal therapy, a castrate serum testosterone level, and at least mild pain at study entry. Mitoxantrone was administered at a dose of 12 mg/m2 by short IV infusion every 3 weeks. Prednisone was administered orally at a dose of 5 mg twice a day. Patients randomized to the prednisone arm were crossed over to the M + P arm if they progressed or if they were not improved after a minimum of 6 weeks of therapy with prednisone alone.
- A total of 161 patients were randomized, 80 to the M + P arm and 81 to the P arm. The median mitoxantrone dose administered was 12 mg/m2 per cycle. The median cumulative mitoxantrone dose administered was 73 mg/m2 (range of 12 to 212 mg/m2).
- A primary palliative response (defined as a 2-point decrease in pain intensity in a 6-point pain scale, associated with stable analgesic use, and lasting a minimum of 6 weeks) was achieved in 29% of patients randomized to M + P compared to 12% of patients randomized to P alone (p = 0.011). Two responders left the study after meeting primary response criterion for two consecutive cycles. For the purposes of this analysis, these two patients were assigned a response duration of zero days. A secondary palliative response was defined as a 50% or greater decrease in analgesic use, associated with stable pain intensity, and lasting a minimum of 6 weeks. An overall palliative response (defined as primary plus secondary responses) was achieved in 38% of patients randomized to M + P compared to 21% of patients randomized to P (p = 0.025).
- The median duration of primary palliative response for patients randomized to M + P was 7.6 months compared to 2.1 months for patients randomized to P alone (p = 0.0009). The median duration of overall palliative response for patients randomized to M + P was 5.6 months compared to 1.9 months for patients randomized to P alone (p = 0.0004).
- Time to progression was defined as a 1-point increase in pain intensity, or a > 25% increase in analgesic use, or evidence of disease progression on radiographic studies, or requirement for radiotherapy. The median time to progression for all patients randomized to M + P was 4.4 months compared to 2.3 months for all patients randomized to P alone (p = 0.0001). Median time to death was 11.3 months for all patients on the M + P arm compared to 10.8 months for all patients on P alone (p = 0.2324).
- Forty-eight patients on the P arm crossed over to receive M + P. Of these, thirty patients had progressed on P, while 18 had stable disease on P. The median cycle of crossover was 5 cycles (range of 2 to 16 cycles). Time trends for pain intensity prior to crossover were significantly worse for patients who crossed over than for those who remained on P alone (p = 0.012). Nine patients (19%) demonstrated a palliative response on M + P after crossover. The median time to death for patients who crossed over to M + P was 12.7 months.
- The clinical significance of a fall in prostate-specific antigen (PSA) concentrations after chemotherapy is unclear. On the CCI-NOV22 trial, a PSA fall of 50% or greater for two consecutive follow-up assessments after baseline was reported in 33% of all patients randomized to the M + P arm and 9% of all patients randomized to the P arm. These findings should be interpreted with caution since PSA responses were not defined prospectively. A number of patients were inevaluable for response, and there was an imbalance between treatment arms in the numbers of evaluable patients. In addition, PSA reduction did not correlate precisely with palliative response, the primary efficacy endpoint of this study. For example, among the 26 evaluable patients randomized to the M + P arm who had a ≥50% reduction in PSA, only 13 had a primary palliative response. Also, among 42 evaluable patients on this arm who did not have this reduction in PSA, 8 nonetheless had a primary palliative response.
- Investigators at Cancer and Leukemia Group B (CALGB) conducted a Phase 3 comparative trial of mitoxantrone plus hydrocortisone (M + H) versus hydrocortisone alone (H) in patients with hormone-refractory prostate cancer (CALGB 9182). Eligible patients were required to have metastatic disease that had progressed despite at least one hormonal therapy. Progression at study entry was defined on the basis of progressive symptoms, increases in measurable or osseous disease, or rising PSA levels. Mitoxantrone was administered intravenously at a dose of 14 mg/m2 every 21 days and hydrocortisone was administered orally at a daily dose of 40 mg. A total of 242 subjects were randomized, 119 to the M + H arm and 123 to the H arm. There were no differences in survival between the two arms, with a median of 11.1 months in the M + H arm and 12 months in the H arm (p = 0.3298).
- Using NPCP criteria for response, partial responses were achieved in 10 patients (8.4%) randomized to the M+ H arm compared with 2 patients (1.6%) randomized to the H arm (p = 0.018). The median time to progression, defined by NPCP criteria, for patients randomized to the M + H arm was 7.3 months compared to 4.1 months for patients randomized to H alone (p = 0.0654).
- Approximately 60% of patients on each arm required analgesics at baseline. Analgesic use was measured in this study using a 5-point scale. The best percent change from baseline in mean analgesic use was -17% for 61 patients with available data on the M + H arm, compared with +17% for 61 patients on H alone (p = 0.014). A time trend analysis for analgesic use in individual patients also showed a trend favoring the M + H arm over H alone but was not statistically significant.
- Pain intensity was measured using the Symptom Distress Scale (SDS) Pain Item 2 (a 5-point scale). The best percent change from baseline in mean pain intensity was -14% for 37 patients with available data on the M + H arm, compared with +8% for 38 patients on H alone (p = 0.057). A time trend analysis for pain intensity in individual patients showed no difference between treatment arms.
- In two large randomized multicenter trials, remission induction therapy for acute nonlymphocytic leukemia (ANLL) with mitoxantrone 12 mg/m2 daily for 3 days as a 10-minute intravenous infusion and cytarabine 100 mg/m2 for 7 days given as a continuous 24-hour infusion was compared with daunorubicin 45 mg/m2 daily by intravenous infusion for 3 days plus the same dose and schedule of cytarabine used with mitoxantrone. Patients who had an incomplete antileukemic response received a second induction course in which mitoxantrone or daunorubicin was administered for 2 days and cytarabine for 5 days using the same daily dosage schedule. Response rates and median survival information for both the U.S. and international multicenter trials given in Table 3:
- In these studies, two consolidation courses were administered to complete responders on each arm. Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but only 5 days of cytarabine and 2 days of mitoxantrone or daunorubicin were given. The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission. The second consolidation course was generally administered 4 weeks later. Full hematologic recovery was necessary for patients to receive consolidation therapy. For the U.S. trial, median granulocyte nadirs for patients receiving mitoxantrone + cytarabine for consolidation courses 1 and 2 were 10/mm3 for both courses, and for those patients receiving daunorubicin + cytarabine nadirs were 170/mm3 and 260/mm3, respectively. Median platelet nadirs for patients who received mitoxantrone + cytarabine for consolidation courses 1 and 2 were 17,000/mm3 and 14,000/mm3, respectively, and were 33,000/mm3 and 22,000/mm3 in courses 1 and 2 for those patients who received daunorubicin + cytarabine. The benefit of consolidation therapy in ANLL patients who achieve a complete remission remains controversial. However, in the only well-controlled prospective, randomized multicenter trials with mitoxantrone in ANLL, consolidation therapy was given to all patients who achieved a complete remission. During consolidation in the U.S. study, two myelosuppression-related deaths occurred on the mitoxantrone arm and one on the daunorubicin arm. However, in the international study there were eight deaths on the mitoxantrone arm during consolidation which were related to the myelosuppression and none on the daunorubicin arm where less myelosuppression occurred.
# How Supplied
- Mitoxantrone Injection, USP (concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multidose use as follows:
- The above products are packaged individually.
- Store between 20º to 25ºC (68° to 77°F) [see USP Controlled Room Temperature]. DO NOT FREEZE.
- This container closure is not made with natural rubber latex.
## Storage
There is limited information regarding Mitoxantrone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with mitoxantrone and prior to each infusion. Review the Mitoxantrone Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that mitoxantrone should be taken only as prescribed.
- Advise patients that mitoxantrone can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. Advise patients that mitoxantrone can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. Advise patients receiving mitoxantrone to treat multiple sclerosis that they should receive cardiac monitoring prior to each mitoxantrone dose and yearly after stopping mitoxantrone.
- Mitoxantrone may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discoloration of the sclera may also occur.
# Precautions with Alcohol
- Alcohol-Mitoxantrone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MITOXANTRONE®[9]
# Look-Alike Drug Names
There is limited information regarding Mitoxantrone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mitoxantrone | |
6f9ae7ddd2ccd581062ece1d5ddd9262e4bffb27 | wikidoc | Mixed-handed | Mixed-handed
Cross-dominance, also known as mixed-handedness, mixed dominance and cross laterality, is a motor skills manifestation in which a person not necessarily being truly ambidextrous favors one hand for some crucial and precise fine motor skill operations and the other for others. It can be readily observed, for example, in some police force members who hold a pistol with one hand and write with the other.
It can also refer to mixed laterality, which refers to a person favoring eyes, ears, feet, or hands on opposite sides of the body. Cross-dominance can often be a problem when shooting or in activities that require aim.
# Ambidexterity
One of the most famous varieties of Cross-dominance is Ambidexterity, being equally adept with each hand (or, to a limited degree, feet). The word "ambidextrous" is derived from the Latin roots ambi, meaning "both," and dexter, meaning "right (as opposed to left) or favorable." Thus, "ambidextrous" is literally "right on both sides".
Although ambidexterity is rare at birth, it can be learned. The key in learning is to start paying attention to minor tasks and performing them with one's opposite hand daily. While difficult at first, minor tasks like brushing teeth, opening doors, and eating will become steadily easier if a person keeps at it. Learning to write or throw with both hands is far harder, but with patience and practice, it is feasible for anybody to become proficient with both hands.
Most ambidextrous people still gravitate towards performing certain types of tasks with a specific hand. The degree of versatility with each hand is generally the qualitative factor in determining a person's ambidexterity.
Each side of the brain controls the opposite side of our bodies.
Some people have been known to hesitate upon the decision the brain makes while attempting to use either right or left side, most likely the motor controlled side that would benefit most.
In modern times, it is more common to find people considered ambidextrous who were originally left handed, and learned to be ambidextrous either deliberately or during childhood in institutions such as schools where right-handed habits are often emphasized. Also, since many everyday devices are designed to be only ergonomic for right handed people, many left handed people have no choice but to use the device with the right hand (a good example is a can opener). As a result, left handed people are much more likely to develop motor skills in their non-dominant hand than right handed people (who are not subjected to left-favouring devices). Ambidexterity is often encouraged in activities requiring a great deal of skill in both hands, such as juggling, swimming, percussion or keyboard music, surgery, and combat.
## Ambidexterity And Sport
Ambidexterity, or "switch hitting", is highly prized in the sport of baseball as a batter usually has a higher statistical chance of successfully hitting the baseball when it is thrown by an opposite handed pitcher. Therefore, an ambidextrous hitter can bat from whichever side is most advantageous to him or her in that situation. Pete Rose, who had more hits than anyone else in the history of Major League Baseball was a "switch hitter". There has been at least one ambidextrous pitcher in the history of Major League Baseball, Tony Mullane who won 284 games in the 19th century.
It is also very advantageous in football/soccer as a player can shoot from almost any position no matter on which side the ball is. It is therefore impossible for a defender to try to block the side from which the attacker can shoot better. It is also advantageous for the goalkeeper to be equally able to dive towards his left and his right.
In pool and snooker, a player can reach further across the table if he is able to play with either hand, since the cue must either be placed on the left or the right side of the body. This is best demonstrated by two-time snooker world champion Ronnie O'Sullivan.
Other sports in which a degree of cross-dominance can be useful include basketball, where the player may choose to make a pass or shot with his weaker hand; hockey and ice hockey, where a player may shoot from the left or right-side of his body; and combat sports where the fighter may choose to face his opponent with either his left shoulder forward in a right-handed stance or his right shoulder forward in a left-handed stance.
In skateboarding, it's highly advantageous if a skater can skate successfully with not only their dominant foot but also the less dominant. Hence the term "switch skating".
It is much the same situation in surfing. Surfers who ride equally well in either stance are said to be surfing "switch-foot."
Some players find cross-dominance advantageous in golf, especially if a left-handed player utilizes right-handed clubs. Having more precise coordination with the left hand is believed to allow better-controlled, and stronger drives.
In tennis, a player may be able to reach balls on the backhand side more easily if he or she is able to use the weaker hand. Perfect examples of players who are ambidextrous include Maria Sharapova and Luke Jensen .
## Etymology
In English, the term ambidexter was originally used in a legal sense of jurors who accepted bribes from both parties for their verdict. Jurors found guilty of such bribery had to forfeit decies tantum, ten times as much as they received. Template:Ref label | Mixed-handed
Cross-dominance, also known as mixed-handedness, mixed dominance and cross laterality, is a motor skills manifestation in which a person not necessarily being truly ambidextrous favors one hand for some crucial and precise fine motor skill operations and the other for others. It can be readily observed, for example, in some police force members who hold a pistol with one hand and write with the other.
It can also refer to mixed laterality, which refers to a person favoring eyes, ears, feet, or hands on opposite sides of the body. Cross-dominance can often be a problem when shooting or in activities that require aim.
# Ambidexterity
One of the most famous varieties of Cross-dominance is Ambidexterity, being equally adept with each hand (or, to a limited degree, feet). The word "ambidextrous" is derived from the Latin roots ambi, meaning "both," and dexter, meaning "right (as opposed to left) or favorable." Thus, "ambidextrous" is literally "right on both sides".
Although ambidexterity is rare at birth, it can be learned. The key in learning is to start paying attention to minor tasks and performing them with one's opposite hand daily. While difficult at first, minor tasks like brushing teeth, opening doors, and eating will become steadily easier if a person keeps at it. Learning to write or throw with both hands is far harder, but with patience and practice, it is feasible for anybody to become proficient with both hands.
Most ambidextrous people still gravitate towards performing certain types of tasks with a specific hand. The degree of versatility with each hand is generally the qualitative factor in determining a person's ambidexterity.
Each side of the brain controls the opposite side of our bodies.
Some people have been known to hesitate upon the decision the brain makes while attempting to use either right or left side, most likely the motor controlled side that would benefit most.
In modern times, it is more common to find people considered ambidextrous who were originally left handed, and learned to be ambidextrous either deliberately or during childhood in institutions such as schools where right-handed habits are often emphasized. Also, since many everyday devices are designed to be only ergonomic for right handed people, many left handed people have no choice but to use the device with the right hand (a good example is a can opener). As a result, left handed people are much more likely to develop motor skills in their non-dominant hand than right handed people (who are not subjected to left-favouring devices). Ambidexterity is often encouraged in activities requiring a great deal of skill in both hands, such as juggling, swimming, percussion or keyboard music, surgery, and combat.
## Ambidexterity And Sport
Ambidexterity, or "switch hitting", is highly prized in the sport of baseball as a batter usually has a higher statistical chance of successfully hitting the baseball when it is thrown by an opposite handed pitcher. Therefore, an ambidextrous hitter can bat from whichever side is most advantageous to him or her in that situation. Pete Rose, who had more hits than anyone else in the history of Major League Baseball was a "switch hitter"[1]. There has been at least one ambidextrous pitcher in the history of Major League Baseball, Tony Mullane who won 284 games in the 19th century[2][3].
It is also very advantageous in football/soccer as a player can shoot from almost any position no matter on which side the ball is. It is therefore impossible for a defender to try to block the side from which the attacker can shoot better. It is also advantageous for the goalkeeper to be equally able to dive towards his left and his right.
In pool and snooker, a player can reach further across the table if he is able to play with either hand, since the cue must either be placed on the left or the right side of the body. This is best demonstrated by two-time snooker world champion Ronnie O'Sullivan[4].
Other sports in which a degree of cross-dominance can be useful include basketball, where the player may choose to make a pass or shot with his weaker hand; hockey and ice hockey, where a player may shoot from the left or right-side of his body; and combat sports where the fighter may choose to face his opponent with either his left shoulder forward in a right-handed stance or his right shoulder forward in a left-handed stance.
In skateboarding, it's highly advantageous if a skater can skate successfully with not only their dominant foot but also the less dominant. Hence the term "switch skating".
It is much the same situation in surfing. Surfers who ride equally well in either stance are said to be surfing "switch-foot."
Some players find cross-dominance advantageous in golf, especially if a left-handed player utilizes right-handed clubs. Having more precise coordination with the left hand is believed to allow better-controlled, and stronger drives.
In tennis, a player may be able to reach balls on the backhand side more easily if he or she is able to use the weaker hand. Perfect examples of players who are ambidextrous include Maria Sharapova[5] and Luke Jensen [6].
## Etymology
In English, the term ambidexter was originally used in a legal sense of jurors who accepted bribes from both parties for their verdict. Jurors found guilty of such bribery had to forfeit decies tantum, ten times as much as they received. Template:Ref label | https://www.wikidoc.org/index.php/Mixed-handed | |
f4752854d8f01560dea4181b1586006a4e134cc7 | wikidoc | Mobocertinib | Mobocertinib
# 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
Mobocertinib is a kinase inhibitor that is FDA approved for the treatment of locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, fatigue, musculoskeletal pain, paronychia, diarrhea, dry skin, stomatitis, rash, and a decrease in appetite.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- 160 mg with or without food, once daily at the same time each day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mobocertinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mobocertinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Mobocertinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mobocertinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mobocertinib in pediatric patients.
# Contraindications
There are no contraindications associated with Mobocertinib
# Warnings
QTc Prolongation and Torsades de Pointes
- Torsades de Pointes and life-threatening heart rate-corrected QT can be caused when taking Mobocertinib.
- A QTc interval greater than 500 msec was found in 1.2% of patients in a study of a 250 patient subset who had scheduled and unscheduled ECGs. The patients in the subset were part of a pooled Mobocertinib safety population.
- A change-from-baseline QTc greater than 60 msec was found in 11% of patients in a study of a 250 patient subset who had scheduled and unscheduled ECGs. The patients in the subset were part of a pooled Mobocertinib safety population.
- 0.4% of patients experienced Grade 4 Torsades de Pointes in a study of a 250 patient subset who had scheduled and unscheduled ECGs. The patients in the subset were part of a pooled Mobocertinib safety population.
- Potassium, calcium, sodium, and magnesium abnormalities should be corrected prior to taking Mobocertinib.
- Both electrolytes at baseline and QTc at baseline should be assessed prior to taking Mobocertinib.
- Monitor electrolytes and QTc during treatment periodically.
- Increase monitoring of patients that have risk factors for QTc prolongation.
- Concomitant use of drugs known to prolong the QTc interval should be avoided.
- Concomitant use of Mobocertinib and moderate or strong CYP3A inhibitors should be avoided.
- Advise patients that QTc prolongation severity can cause Mobocertinib treatment to either be withheld, reduced, or permanently discontinued.
Interstitial Lung Disease (ILD)/Pneumonitis
- ILD/pneumonitis can be caused when taking Mobocertinib.
- 4.3% of patients of the pooled Mobocertinib safety population experienced ILD/pneumonitis. Of the 4.3% patients, 0.8% experienced Grade 3 events while 1.2% experienced events that were fatal.
- Monitor patients for any new pulmonary symptoms or worsening pulmonary symptoms that could potentially be indicative of ILD/pneumonitis.
- Advise patients that suspected ILD/pneumonitis in patients should withhold Mobocertinib treatment.
- Advise patients that confirmed ILD/pneumonitis in patients should permanently discontinue Mobocertinib treatment.
Cardiac Toxicity
- Cardiac toxicity that can lead to fatal heart failure can be caused when taking Mobocertinib.
- 2.7% of patients of the pooled Mobocertinib safety population experienced heart failure. Of the 2.7% patients, 1.2% of patients experienced Grade 3 reactions, 0.4% of patients experienced Grade 4 reactions, and 0.4% of patients experienced a fatal case of heart failure.
- Patients receiving Mobocertinib also experienced left bundle branch block (0.4%), ventricular extrasystoles (0.4%), ventricular tachycardia (0.4%), supraventricular extrasystoles (0.4%), Atrial fibrillation (1.6%), first degree atrioventricular block (0.4%), and second degree atrioventricular block (0.4%).
- Monitor patients cardiac function when taking Mobocertinib.
- Monitor patients left ventricular ejection fraction at baseline when taking Mobocertinib.
- Advise patients that cardiac function severity can cause Mobocertinib treatment to either be withheld, reduced, or permanently discontinued.
Diarrhea
- Diarrhea can be caused when taking Mobocertinib.
- 93% of patients of the pooled Mobocertinib safety population experienced diarrhea. Of the 93% patients, 20% of patients experienced Grade 3 symptoms while 0.4% of patients experienced Grade 4 symptoms.
- 5 days is the median time to first onset of diarrhea in patients.
- 3 days is the median time to resolution of diarrhea in the 48% patients who had their diarrhea resolved.
- Advise patients with or without renal impairment that electrolyte imbalance or dehydration could be caused when experiencing diarrhea.
- Advise patients who start experiencing first signs of diarrhea to start using an antidiarrheal agent.
- Advise patients that electrolyte imbalances can cause Mobocertinib treatment to either be withheld, reduced, or permanently discontinued.
Embryo-Fetal Toxicity
- Based on animal data, Mobocertinib potentially can cause harm to females fetus during pregnancy.
- Studies done on rats showed embryolethality at maternal exposures 1.7 times the human exposure based on AUC at one 160 mg dose daily during the period of organogenesis.
- Advise pregnant females about fetal risks when treated with Mobocertinib.
- Advise females of reproductive potential to use effective non hormonal contraception during treatment with Mobocertinib and for at least 1 months after the last dose.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with Mobocertinib and for at least 1 week after the last dose.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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.
Pooled Safety Population Study
- The adverse reactions of Mobocertinib were looked at in 256 patients receiving one daily dosage of 160 mg Mobocertinib. Of the 256 patients, 114 of the patients had EGFR exon 20 insertion mutation-positive locally advanced, metastatic NSCLC from Study AP32788-15-101, and patients with other solid tumors. Nausea, paronychia, musculoskeletal pain, rash, decreased appetite, dry skin, diarrhea, stomatitis, and vomiting were the most common adverse reactions reported (>20%). Increased amylase, decreased potassium, decreased magnesium, increased lipase, decreased lymphocytes, increased creatinine, and decreased hemoglobin were the most common Grade 3 or 4 laboratory abnormalities reported (≥2%).
Study AP32788-15-101
- A subset of patients that have metastatic NSCLC who received prior platinum-based chemotherapy or EGFR exon 20 insertion mutation-positive locally advanced were used in a study to test the safety of Mobocertinib. The total amount of patients were 114 that received 160 mg once daily dosage of Mobocertinib in this study.
- Patients that were excluded from the study included patients with significant, uncontrolled, active cardiovascular disease, prolonged QTc interval, radiation pneumonitis that required steroid treatment, a history of interstitial lung disease, or drug-related pneumonitis.
- 46% of patients experienced severe reactions when treated with Mobocertinib. Pyrexia, nausea, dyspnea, cardiac failure, acute kidney injury, diarrhea, and pleural effusion were the severe adverse reactions reported in the patient subset.
- 1.8% of patients reported fatal adverse reactions when taking Mobocertinib. Pneumonitis and cardiac failure were some of the fatal adverse reactions experienced by patients.
- 17% of patients had to permanently discontinue treatment with Mobocertinib with diarrhea and nausea being some of the adverse reactions reported leading to permanent discontinuation.
- 51% of patients had interruptions in Mobocertinib dosage with diarrhea, nausea and vomiting being some of the adverse reactions reported leading to dosage interruptions.
- 25% of patients had reductions in Mobocertinib dosage with diarrhea being one of the many adverse reactions reported leading to dosage reductions.
Table 3 shows the Adverse Reactions in patients part of Study AP32788-15-101 who are treated with Mobocertinib.
- Peripheral neuropathy, cardiac failure, acute kidney injury, palmar-plantar erythrodysaesthesia, edema, and pneumonitis are clinically relevant adverse reactions reported by patients treated with Mobocertinib.
Table 4 shows the Laboratory Abnormalities in patients part of Study AP32788-15-101 who are treated with Mobocertinib.
## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.
# Drug Interactions
Effect of Other Drugs on Mobocertinib
Effect of Mobocertinib on Other Drugs
Drugs that Prolong the QTc Interval
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Studies done on animals show that fetal harm may occur to pregnant women treated with Mobocertinib. Pregnant rat studies show administration of Mobocertinib leads to maternal toxicity at plasma exposures approximately 1.7 times (10 mg/kg) the human exposure based on AUC, and embryolethality during the period of organogenesis. Decreased fetal weight was recorded in pregnant rats, but there were no clear signs at high doses (10 mg/kg) of Mobocertinib that show fetal malformations occurred. Female patients should be advised if pregnant about the potential risks that may occur to the fetus when treated with Mobocertinib.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mobocertinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mobocertinib during labor and delivery.
### Nursing Mothers
Data on Mobocertinib for its effects on milk production or the effects on the breastfed child have not been found. Advise female patients to not nurse during Mobocertinib treatment, and or 1 week after their last dose of Mobocertinib.
### Pediatric Use
Safety and effectiveness in pediatric populations have not been established.
### Geriatic Use
Of the total number of subjects (114) in the clinical studies treated with Mobocertinib, around 37% of the patients were 65 years or older in age, and 7% were 75 years or older in age. No differences among young patients compared to patients 65 years or older in age were found when looking at safety and efficacy of Mobocertinib. Higher percentages of Grade 3 and 4 adverse reactions occurred in patients 65 years and older when compared to patients younger than 65 years of age (69% vs 47%) based on exploratory analysis. Higher percentages of serious adverse reactions occurred in patients 65 years and older when compared to patients younger than 65 years of age (64% vs 35%) based on exploratory analysis.
### Gender
There is no FDA guidance on the use of Mobocertinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mobocertinib with respect to specific racial populations.
### Renal Impairment
Mild to moderate renal impairment in patients do not require a dosage adjustment of Mobocertinib. Dosage recommendations of Mobocertinib in patients with severe renal impairment have not been established.
### Hepatic Impairment
Mild to moderate hepatic impairment in patients do not require a dosage adjustment of Mobocertinib. Dosage recommendations of Mobocertinib in patients with severe hepatic impairment have not been established.
### Females of Reproductive Potential and Males
Advise females of reproductive potential to use effective non hormonal contraception during treatment with Mobocertinib and for at least 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Mobocertinib and for at least 1 week after the last dose. Fertility may be impaired in both females and males when treated with Mobocertinib.
### Immunocompromised Patients
There is no FDA guidance on the use of Mobocertinib with respect to immunocompromised populations.
# Administration and Monitoring
### Administration
- Recommended dosage of Mobocertinib as prescribed by the doctor can be taken with or without food.
- Swallow Mobocertinib tablets whole.
- Mobocertinib should be taken at the same time each day.
- Instruct patients to not chew, open, or dissolve contents of the tablets.
- If a dosage of Mobocertinib is missed by more than 6 hours, then skip dosage and take next dosage at scheduled time the next day.
- Do not take extra dosage of Mobocertinib if dosage taken is vomited, just take next dosage at scheduled time the next day.
### Monitoring
Dosage Modifications for Moderate CYP3A Inhibitors
- Advise patients to avoid concomitant use of Mobocertinib with a moderate CYP3A inhibitor.
- Reduce Mobocertinib dosage by 50% if concomitant use of a moderate CYP3A inhibitor is unavoidable. Mobocertinib dosage can return to normal amount after the inhibitor is discontinued for 3 to 5 elimination half-lives.
- Monitor patients for QTc interval when concomitant use of a moderate CYP3A inhibitor is unavoidable during Mobocertinib treatment.
Dosage Modifications for Adverse Reactions
Table 1 and 2 show the Reduction in Dosage to Mobocertinib for Patients with Adverse Reactions.
# IV Compatibility
There is limited information regarding the compatibility of Mobocertinib and IV administrations.
# Overdosage
There is limited information regarding Mobocertinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Mobocertinib is a kinase inhibitor.
- It inhibits EGFR exon 20 insertion mutations at lower concentrations than wild type (WT) EGFR by binding to it.
- In vitro, HER2, BLK and HER4 activity were inhibited by Mobocertinib at clinically relevant concentrations.
- Animal tumor implantation models show anti-tumor activity against xenografts with the EGFR exon 20 insertions NPH or ASV done by Mobocertinib.
- Cultured cell models show proliferation of cells driven by different EGFR exon 20 insertion mutation variants were inhibited by Mobocertinib.
## Structure
- Mobocertinib is a kinase inhibitor for oral administration. It has an empirical formula of C46H45N7O8 and a molecular weight of 703.8 g/mol.
- The chemical name is propan-2-yl 2-amino}-2-methoxyanilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate succinate.
## Pharmacodynamics
- Exposure-response relationships and pharmacodynamic response for Mobocertinib are unknown.
Cardiac Electrophysiology
- For one daily dose of 160mg of Mobocertinib, 23.0 msec is the largest mean increase in QTc. 12.4 msec is largest mean increase in the PR interval.
## Pharmacokinetics
- Over the range of 5 to 180 mg once daily of Mobocertinib, the combined AUC0-24h and Cmax is dose proportional.
- Over the range of 5 to 180 mg once daily of Mobocertinib, AP32960 and AP32914 (active metabolites) are dose proportional.
Absorption
- For Mobocertinib, 4 hours is the median time to peak concentration.
- 37% is the mean absolute bioavailability for Mobocertinib.
Effect of Food
- In a high-fat meal, combined molar AUC and Cmax had no clinically meaningful differences AP32960, Mobocertinib, and AP32914 when compared to an overnight fast.
- In a low-fat meal, combined molar AUC and Cmax had no clinically meaningful differences AP32960, Mobocertinib, and AP32914 when compared to an overnight fast.
Distribution
- In vitro, 99.3% is the mean bound fraction for Mobocertinib.
- In vitro, 99.5% is the mean bound fraction for AP32960.
- In vitro, 98.6% is the mean bound fraction for AP32914.
- 0.76 is the blood-to-plasma ratio for Mobocertinib.
- 1.2 is the blood-to-plasma ratio for AP32960.
- 0.71 is the blood-to-plasma ratio for AP32914.
- 3,509 L is the mean apparent volume of distribution for Mobocertinib at steady-state.
Elimination
- 18 hours is the mean plasma elimination half-life at steady state for Mobocertinib.
- 138 L/hr is the mean apparent oral clearance at steady state for Mobocertinib.
- 24 hours is the mean plasma elimination half-life at steady state for AP32960.
- 149 L/hr is the mean apparent oral clearance at steady state for AP32960.
- 18 hours is the mean plasma elimination half-life at steady state for AP32914.
- 159 L/hr is the mean apparent oral clearance at steady state for AP32914.
Metabolism
- CYP3A is primarily metabolized by Mobocertinib.
- AP32960 accounts for 36% of the combined molar AUC of Mobocertinib.
- AP32914 accounts for 4% of the combined molar AUC of Mobocertinib.
Excretion
- In feces, after oral administration of 160 mg oral dose of radiolabeled Mobocertinib, 76% of Mobocertinib was found in which 6% was found unchanged.
- In urine, after oral administration of 160 mg oral dose of radiolabeled Mobocertinib, 4% of Mobocertinib was found in which 1% was found unchanged.
- In AP32960 (active metabolite), the recovered percentage of feces found is 12%.
- In AP32960 (active metabolite), the recovered percentage of urine found is 1%.
Specific Populations
- In Mobocertinib, sex, body weight, race, age, mild to-moderate hepatic impairment, or mild-to-moderate renal impairment had no significant differences in the pharmacokinetics.
- In Mobocertinib, severe renal impairment and severe hepatic impairment differences on pharmacokinetics is unknown.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches:
Effect of CYP3A Inhibitors on Mobocertinib:
- Combined molar AUC of Mobocertinib and its active metabolites increases at a steady state from 374 to 419% when there is a coadministration of strong CYP3A inhibitors such as Itraconazole or Ketoconazole with Mobocertinib.
- Combined molar AUC of Mobocertinib and its active metabolites increases at a steady state by 100-200% when there is a coadministration of a moderate CYP3A inhibitor with Mobocertinib.
Effect of CYP3A Inducers on Mobocertinib:
- Combined molar AUC of Mobocertinib and its active metabolites decrease at a steady state by 92% when there is a coadministration of a strong CYP3A inducer such as Rifampin with Mobocertinib.
- Combined molar AUC of Mobocertinib and its active metabolites decrease at a steady state by 58% when there is a coadministration of a moderate CYP3A inducer such as Efavirenz with Mobocertinib.
Effect of Mobocertinib on CYP3A Substrates:
- AUC of Midazolam decreased by 32% when there is coadministration of a CYP3A substrate such as oral Midazolam with Mobocertinib.
- AUC of Midazolam decreased by 16% when there is coadministration of a CYP3A substrate such as intravenous Midazolam with Mobocertinib.
Effect of Mobocertinib on P-gp Substrates:
- No significant differences clinically in pharmacokinetics when there is coadministration of P-gp substrates such as dabigatran etexilate or digoxin with Mobocertinib.
Effect of Mobocertinib on BCRP Substrates:
- Changes in the pharmacokinetics is unknown when there is coadministration of a BCRP substrate such as sulfasalazine with Mobocertinib.
In Vitro Studies:
CYP Enzymes:
- 2B6, 2C19, 2C9, CYP1A2, 2D6, or 2C8 are not inhibited by Mobocertinib, AP32914, and AP32960.
Transporter Systems:
- BCRP and P-gp are inhibited by Mobocertinib.
- OATP1B1, OCT1, BSEP, OCT2, OATP1B3, MATE2-K, OAT3, OAT1, and MATE1 are not inhibited by Mobocertinib.
- Mobocertinib is a substrate of P-gp.
- Mobocertinib is not a substrate of BCRP, OATP1B1, and OATP1B3.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No studies have been conducted on carcinogenicity in Mobocertinib.
- In vitro bacterial reverse mutation, Mobocertinib was not mutagenic in human peripheral blood lymphocytes.
- In vitro chromosome aberration assay, Mobocertinib did not induce chromosomal aberrations in human peripheral blood lymphocytes.
- Rat studies show Mobocertinib was not clastogenic in an in vivo bone marrow micronucleus test.
- Rat and dog studies show decreases in organ weights affecting multiple reproductive organs at exposures ≥0.3 times the AUC observed at the recommended clinical dose of 160 mg once daily in 4- and 13-week repeat-dose toxicology.
- Rat and dog studies show atrophy of the mammary gland, uterus and prostate gland at exposures ≥0.2 times the AUC at the dosage of 160 mg once daily..
- Rat and dog studies show decreased epithelial thickness/inflammation of the cervix/vagina at exposures ≥0.2 times the AUC at the dosage of 160 mg once daily..
- Male and female reproduction potential may be impaired when treated with Mobocertinib.
Animal Toxicology and/or Pharmacology
- 4- and 13-week repeat-dose toxicology studies done on rats show decreased corneal epithelial thickness at doses ≥0.8 times the human exposure at the dosage of 160 mg once daily.
- Discharge occurred in the sclera injection and partial or complete closure of the eye in 4-week repeat-dose study done on dogs at doses ≥0.3 times the human exposure at the dosage of 160 mg once daily.
- Corneal epithelial atrophy occurred in 4-week repeat-dose study done on dogs at doses ≥0.3 times the human exposure at the dosage of 160 mg once daily.
- Corneal opacity and conjunctival hyperemia occurred in 4-week repeat-dose study done on dogs at doses ≥0.2 times the human exposure at the dosage of 160 mg once daily.
- Decreased corneal epithelial thickness occurred in 4-week repeat-dose study done on dogs at doses ≥0.2 times the human exposure at the dosage of 160 mg once daily.
# Clinical Studies
- A pooled subset of patients with EGFR exon 20 insertion mutation-positive metastatic or locally advanced NSCLC whose disease had progressed on or after platinum-based chemotherapy enrolled in an international, open-label, multicohort clinical trial was used to test the efficacy of Mobocertinib. 114 total patients in the pool received a once daily dosage of 160mg of Mobocertinib. The patient population was largely Asian (60%), and included 66% women, and a median age of 60 years.
Table 5 displays the Efficacy results of Mobocertinib from the Study.
# How Supplied
- 40 mg capsules dose pack (90 or 120 tablets).
- Tablets are white with each tablet being a size 2.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
QTc Interval Prolongation and Torsades de Pointes
- Patients should be informed about the QTc prolongation risks.
- Lightheadedness, dizziness, and syncope are symptoms associated with significant QTc prolongation.
- Patients should be advised to report any signs of significant QTc prolongation to their healthcare provider.
Interstitial Lung Disease (ILD)/Pneumonitis
- Patients should be informed about the severe or fatal ILD/pneumonitis risks.
- Patients should be advised to report any signs of severe or fatal ILD/pneumonitis such as shortness of breath, cough, or chest pain to their healthcare provider.
Cardiac Toxicity
- Patients should be informed about the heart failure risks.
- Patients should be advised to report any signs of heart failure such as syncope, shortness of breath, palpitations, and chest pain to their healthcare provider.
Diarrhea
- Patients should be informed about the risk of getting diarrhea when treated with Mobocertinib.
- Patients should be advised to increase oral fluids, start antidiarrheal treatment, and increase electrolyte intake if they get diarrhea.
- Patients should be advised to report diarrhea if it continues to persist to their healthcare provider.
Embryo-Fetal Toxicity
- Advise female patients about potential risks to fetus when treated with Mobocertinib.
- Advise female patients to report any known or suspected pregnancy to their healthcare provider.
- Advise females of reproductive potential to use effective non hormonal contraception during treatment with Mobocertinib and for at least 1 month after the last dose.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with Mobocertinib and for at least 1 week after the last dose.
Lactation
- Advise female patients to not lactate during and 1 week after the last dose of Mobocertinib.
Infertility
- Fertility may be impaired in both males and females when taking Mobocertinib.
Drug Interactions
- Advise patients when taking Mobocertinib to avoid drinking grapefruit juice and eating grapefruit.
- Advise patients to report any concomitant medications such as over-the-counter drugs, herbal products, vitamins, and prescription medicines to their healthcare provider.
Missed Dose
- If a dosage of Mobocertinib is missed by more than 6 hours, then skip dosage and take next dosage at scheduled time the next day.
- Do not take extra dosage of Mobocertinib if dosage taken is vomited, just take next dosage at scheduled time the next day.
# Precautions with Alcohol
Alcohol-Mobocertinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Exkivity
# Look-Alike Drug Names
There is limited information regarding Mobocertinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Mobocertinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra
# 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
Mobocertinib is a kinase inhibitor that is FDA approved for the treatment of locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, fatigue, musculoskeletal pain, paronychia, diarrhea, dry skin, stomatitis, rash, and a decrease in appetite.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- 160 mg with or without food, once daily at the same time each day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mobocertinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mobocertinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Mobocertinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mobocertinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mobocertinib in pediatric patients.
# Contraindications
There are no contraindications associated with Mobocertinib
# Warnings
QTc Prolongation and Torsades de Pointes
- Torsades de Pointes and life-threatening heart rate-corrected QT can be caused when taking Mobocertinib.
- A QTc interval greater than 500 msec was found in 1.2% of patients in a study of a 250 patient subset who had scheduled and unscheduled ECGs. The patients in the subset were part of a pooled Mobocertinib safety population.
- A change-from-baseline QTc greater than 60 msec was found in 11% of patients in a study of a 250 patient subset who had scheduled and unscheduled ECGs. The patients in the subset were part of a pooled Mobocertinib safety population.
- 0.4% of patients experienced Grade 4 Torsades de Pointes in a study of a 250 patient subset who had scheduled and unscheduled ECGs. The patients in the subset were part of a pooled Mobocertinib safety population.
- Potassium, calcium, sodium, and magnesium abnormalities should be corrected prior to taking Mobocertinib.
- Both electrolytes at baseline and QTc at baseline should be assessed prior to taking Mobocertinib.
- Monitor electrolytes and QTc during treatment periodically.
- Increase monitoring of patients that have risk factors for QTc prolongation.
- Concomitant use of drugs known to prolong the QTc interval should be avoided.
- Concomitant use of Mobocertinib and moderate or strong CYP3A inhibitors should be avoided.
- Advise patients that QTc prolongation severity can cause Mobocertinib treatment to either be withheld, reduced, or permanently discontinued.
Interstitial Lung Disease (ILD)/Pneumonitis
- ILD/pneumonitis can be caused when taking Mobocertinib.
- 4.3% of patients of the pooled Mobocertinib safety population experienced ILD/pneumonitis. Of the 4.3% patients, 0.8% experienced Grade 3 events while 1.2% experienced events that were fatal.
- Monitor patients for any new pulmonary symptoms or worsening pulmonary symptoms that could potentially be indicative of ILD/pneumonitis.
- Advise patients that suspected ILD/pneumonitis in patients should withhold Mobocertinib treatment.
- Advise patients that confirmed ILD/pneumonitis in patients should permanently discontinue Mobocertinib treatment.
Cardiac Toxicity
- Cardiac toxicity that can lead to fatal heart failure can be caused when taking Mobocertinib.
- 2.7% of patients of the pooled Mobocertinib safety population experienced heart failure. Of the 2.7% patients, 1.2% of patients experienced Grade 3 reactions, 0.4% of patients experienced Grade 4 reactions, and 0.4% of patients experienced a fatal case of heart failure.
- Patients receiving Mobocertinib also experienced left bundle branch block (0.4%), ventricular extrasystoles (0.4%), ventricular tachycardia (0.4%), supraventricular extrasystoles (0.4%), Atrial fibrillation (1.6%), first degree atrioventricular block (0.4%), and second degree atrioventricular block (0.4%).
- Monitor patients cardiac function when taking Mobocertinib.
- Monitor patients left ventricular ejection fraction at baseline when taking Mobocertinib.
- Advise patients that cardiac function severity can cause Mobocertinib treatment to either be withheld, reduced, or permanently discontinued.
Diarrhea
- Diarrhea can be caused when taking Mobocertinib.
- 93% of patients of the pooled Mobocertinib safety population experienced diarrhea. Of the 93% patients, 20% of patients experienced Grade 3 symptoms while 0.4% of patients experienced Grade 4 symptoms.
- 5 days is the median time to first onset of diarrhea in patients.
- 3 days is the median time to resolution of diarrhea in the 48% patients who had their diarrhea resolved.
- Advise patients with or without renal impairment that electrolyte imbalance or dehydration could be caused when experiencing diarrhea.
- Advise patients who start experiencing first signs of diarrhea to start using an antidiarrheal agent.
- Advise patients that electrolyte imbalances can cause Mobocertinib treatment to either be withheld, reduced, or permanently discontinued.
Embryo-Fetal Toxicity
- Based on animal data, Mobocertinib potentially can cause harm to females fetus during pregnancy.
- Studies done on rats showed embryolethality at maternal exposures 1.7 times the human exposure based on AUC at one 160 mg dose daily during the period of organogenesis.
- Advise pregnant females about fetal risks when treated with Mobocertinib.
- Advise females of reproductive potential to use effective non hormonal contraception during treatment with Mobocertinib and for at least 1 months after the last dose.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with Mobocertinib and for at least 1 week after the last dose.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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.
Pooled Safety Population Study
- The adverse reactions of Mobocertinib were looked at in 256 patients receiving one daily dosage of 160 mg Mobocertinib. Of the 256 patients, 114 of the patients had EGFR exon 20 insertion mutation-positive locally advanced, metastatic NSCLC from Study AP32788-15-101, and patients with other solid tumors. Nausea, paronychia, musculoskeletal pain, rash, decreased appetite, dry skin, diarrhea, stomatitis, and vomiting were the most common adverse reactions reported (>20%). Increased amylase, decreased potassium, decreased magnesium, increased lipase, decreased lymphocytes, increased creatinine, and decreased hemoglobin were the most common Grade 3 or 4 laboratory abnormalities reported (≥2%).
Study AP32788-15-101
- A subset of patients that have metastatic NSCLC who received prior platinum-based chemotherapy or EGFR exon 20 insertion mutation-positive locally advanced were used in a study to test the safety of Mobocertinib. The total amount of patients were 114 that received 160 mg once daily dosage of Mobocertinib in this study.
- Patients that were excluded from the study included patients with significant, uncontrolled, active cardiovascular disease, prolonged QTc interval, radiation pneumonitis that required steroid treatment, a history of interstitial lung disease, or drug-related pneumonitis.
- 46% of patients experienced severe reactions when treated with Mobocertinib. Pyrexia, nausea, dyspnea, cardiac failure, acute kidney injury, diarrhea, and pleural effusion were the severe adverse reactions reported in the patient subset.
- 1.8% of patients reported fatal adverse reactions when taking Mobocertinib. Pneumonitis and cardiac failure were some of the fatal adverse reactions experienced by patients.
- 17% of patients had to permanently discontinue treatment with Mobocertinib with diarrhea and nausea being some of the adverse reactions reported leading to permanent discontinuation.
- 51% of patients had interruptions in Mobocertinib dosage with diarrhea, nausea and vomiting being some of the adverse reactions reported leading to dosage interruptions.
- 25% of patients had reductions in Mobocertinib dosage with diarrhea being one of the many adverse reactions reported leading to dosage reductions.
Table 3 shows the Adverse Reactions in patients part of Study AP32788-15-101 who are treated with Mobocertinib.
- Peripheral neuropathy, cardiac failure, acute kidney injury, palmar-plantar erythrodysaesthesia, edema, and pneumonitis are clinically relevant adverse reactions reported by patients treated with Mobocertinib.
Table 4 shows the Laboratory Abnormalities in patients part of Study AP32788-15-101 who are treated with Mobocertinib.
## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.
# Drug Interactions
Effect of Other Drugs on Mobocertinib
Effect of Mobocertinib on Other Drugs
Drugs that Prolong the QTc Interval
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Studies done on animals show that fetal harm may occur to pregnant women treated with Mobocertinib. Pregnant rat studies show administration of Mobocertinib leads to maternal toxicity at plasma exposures approximately 1.7 times (10 mg/kg) the human exposure based on AUC, and embryolethality during the period of organogenesis. Decreased fetal weight was recorded in pregnant rats, but there were no clear signs at high doses (10 mg/kg) of Mobocertinib that show fetal malformations occurred. Female patients should be advised if pregnant about the potential risks that may occur to the fetus when treated with Mobocertinib.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mobocertinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mobocertinib during labor and delivery.
### Nursing Mothers
Data on Mobocertinib for its effects on milk production or the effects on the breastfed child have not been found. Advise female patients to not nurse during Mobocertinib treatment, and or 1 week after their last dose of Mobocertinib.
### Pediatric Use
Safety and effectiveness in pediatric populations have not been established.
### Geriatic Use
Of the total number of subjects (114) in the clinical studies treated with Mobocertinib, around 37% of the patients were 65 years or older in age, and 7% were 75 years or older in age. No differences among young patients compared to patients 65 years or older in age were found when looking at safety and efficacy of Mobocertinib. Higher percentages of Grade 3 and 4 adverse reactions occurred in patients 65 years and older when compared to patients younger than 65 years of age (69% vs 47%) based on exploratory analysis. Higher percentages of serious adverse reactions occurred in patients 65 years and older when compared to patients younger than 65 years of age (64% vs 35%) based on exploratory analysis.
### Gender
There is no FDA guidance on the use of Mobocertinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mobocertinib with respect to specific racial populations.
### Renal Impairment
Mild to moderate renal impairment in patients do not require a dosage adjustment of Mobocertinib. Dosage recommendations of Mobocertinib in patients with severe renal impairment have not been established.
### Hepatic Impairment
Mild to moderate hepatic impairment in patients do not require a dosage adjustment of Mobocertinib. Dosage recommendations of Mobocertinib in patients with severe hepatic impairment have not been established.
### Females of Reproductive Potential and Males
Advise females of reproductive potential to use effective non hormonal contraception during treatment with Mobocertinib and for at least 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Mobocertinib and for at least 1 week after the last dose. Fertility may be impaired in both females and males when treated with Mobocertinib.
### Immunocompromised Patients
There is no FDA guidance on the use of Mobocertinib with respect to immunocompromised populations.
# Administration and Monitoring
### Administration
- Recommended dosage of Mobocertinib as prescribed by the doctor can be taken with or without food.
- Swallow Mobocertinib tablets whole.
- Mobocertinib should be taken at the same time each day.
- Instruct patients to not chew, open, or dissolve contents of the tablets.
- If a dosage of Mobocertinib is missed by more than 6 hours, then skip dosage and take next dosage at scheduled time the next day.
- Do not take extra dosage of Mobocertinib if dosage taken is vomited, just take next dosage at scheduled time the next day.
### Monitoring
Dosage Modifications for Moderate CYP3A Inhibitors
- Advise patients to avoid concomitant use of Mobocertinib with a moderate CYP3A inhibitor.
- Reduce Mobocertinib dosage by 50% if concomitant use of a moderate CYP3A inhibitor is unavoidable. Mobocertinib dosage can return to normal amount after the inhibitor is discontinued for 3 to 5 elimination half-lives.
- Monitor patients for QTc interval when concomitant use of a moderate CYP3A inhibitor is unavoidable during Mobocertinib treatment.
Dosage Modifications for Adverse Reactions
Table 1 and 2 show the Reduction in Dosage to Mobocertinib for Patients with Adverse Reactions.
# IV Compatibility
There is limited information regarding the compatibility of Mobocertinib and IV administrations.
# Overdosage
There is limited information regarding Mobocertinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Mobocertinib is a kinase inhibitor.
- It inhibits EGFR exon 20 insertion mutations at lower concentrations than wild type (WT) EGFR by binding to it.
- In vitro, HER2, BLK and HER4 activity were inhibited by Mobocertinib at clinically relevant concentrations.
- Animal tumor implantation models show anti-tumor activity against xenografts with the EGFR exon 20 insertions NPH or ASV done by Mobocertinib.
- Cultured cell models show proliferation of cells driven by different EGFR exon 20 insertion mutation variants were inhibited by Mobocertinib.
## Structure
- Mobocertinib is a kinase inhibitor for oral administration. It has an empirical formula of C46H45N7O8 and a molecular weight of 703.8 g/mol.
- The chemical name is propan-2-yl 2-[5-(acryloylamino)-4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxyanilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate succinate.
## Pharmacodynamics
- Exposure-response relationships and pharmacodynamic response for Mobocertinib are unknown.
Cardiac Electrophysiology
- For one daily dose of 160mg of Mobocertinib, 23.0 msec is the largest mean increase in QTc. 12.4 msec is largest mean increase in the PR interval.
## Pharmacokinetics
- Over the range of 5 to 180 mg once daily of Mobocertinib, the combined AUC0-24h and Cmax is dose proportional.
- Over the range of 5 to 180 mg once daily of Mobocertinib, AP32960 and AP32914 (active metabolites) are dose proportional.
Absorption
- For Mobocertinib, 4 hours is the median time to peak concentration.
- 37% is the mean absolute bioavailability for Mobocertinib.
Effect of Food
- In a high-fat meal, combined molar AUC and Cmax had no clinically meaningful differences AP32960, Mobocertinib, and AP32914 when compared to an overnight fast.
- In a low-fat meal, combined molar AUC and Cmax had no clinically meaningful differences AP32960, Mobocertinib, and AP32914 when compared to an overnight fast.
Distribution
- In vitro, 99.3% is the mean bound fraction for Mobocertinib.
- In vitro, 99.5% is the mean bound fraction for AP32960.
- In vitro, 98.6% is the mean bound fraction for AP32914.
- 0.76 is the blood-to-plasma ratio for Mobocertinib.
- 1.2 is the blood-to-plasma ratio for AP32960.
- 0.71 is the blood-to-plasma ratio for AP32914.
- 3,509 L is the mean apparent volume of distribution for Mobocertinib at steady-state.
Elimination
- 18 hours is the mean plasma elimination half-life at steady state for Mobocertinib.
- 138 L/hr is the mean apparent oral clearance at steady state for Mobocertinib.
- 24 hours is the mean plasma elimination half-life at steady state for AP32960.
- 149 L/hr is the mean apparent oral clearance at steady state for AP32960.
- 18 hours is the mean plasma elimination half-life at steady state for AP32914.
- 159 L/hr is the mean apparent oral clearance at steady state for AP32914.
Metabolism
- CYP3A is primarily metabolized by Mobocertinib.
- AP32960 accounts for 36% of the combined molar AUC of Mobocertinib.
- AP32914 accounts for 4% of the combined molar AUC of Mobocertinib.
Excretion
- In feces, after oral administration of 160 mg oral dose of radiolabeled Mobocertinib, 76% of Mobocertinib was found in which 6% was found unchanged.
- In urine, after oral administration of 160 mg oral dose of radiolabeled Mobocertinib, 4% of Mobocertinib was found in which 1% was found unchanged.
- In AP32960 (active metabolite), the recovered percentage of feces found is 12%.
- In AP32960 (active metabolite), the recovered percentage of urine found is 1%.
Specific Populations
- In Mobocertinib, sex, body weight, race, age, mild to-moderate hepatic impairment, or mild-to-moderate renal impairment had no significant differences in the pharmacokinetics.
- In Mobocertinib, severe renal impairment and severe hepatic impairment differences on pharmacokinetics is unknown.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches:
Effect of CYP3A Inhibitors on Mobocertinib:
- Combined molar AUC of Mobocertinib and its active metabolites increases at a steady state from 374 to 419% when there is a coadministration of strong CYP3A inhibitors such as Itraconazole or Ketoconazole with Mobocertinib.
- Combined molar AUC of Mobocertinib and its active metabolites increases at a steady state by 100-200% when there is a coadministration of a moderate CYP3A inhibitor with Mobocertinib.
Effect of CYP3A Inducers on Mobocertinib:
- Combined molar AUC of Mobocertinib and its active metabolites decrease at a steady state by 92% when there is a coadministration of a strong CYP3A inducer such as Rifampin with Mobocertinib.
- Combined molar AUC of Mobocertinib and its active metabolites decrease at a steady state by 58% when there is a coadministration of a moderate CYP3A inducer such as Efavirenz with Mobocertinib.
Effect of Mobocertinib on CYP3A Substrates:
- AUC of Midazolam decreased by 32% when there is coadministration of a CYP3A substrate such as oral Midazolam with Mobocertinib.
- AUC of Midazolam decreased by 16% when there is coadministration of a CYP3A substrate such as intravenous Midazolam with Mobocertinib.
Effect of Mobocertinib on P-gp Substrates:
- No significant differences clinically in pharmacokinetics when there is coadministration of P-gp substrates such as dabigatran etexilate or digoxin with Mobocertinib.
Effect of Mobocertinib on BCRP Substrates:
- Changes in the pharmacokinetics is unknown when there is coadministration of a BCRP substrate such as sulfasalazine with Mobocertinib.
In Vitro Studies:
CYP Enzymes:
- 2B6, 2C19, 2C9, CYP1A2, 2D6, or 2C8 are not inhibited by Mobocertinib, AP32914, and AP32960.
Transporter Systems:
- BCRP and P-gp are inhibited by Mobocertinib.
- OATP1B1, OCT1, BSEP, OCT2, OATP1B3, MATE2-K, OAT3, OAT1, and MATE1 are not inhibited by Mobocertinib.
- Mobocertinib is a substrate of P-gp.
- Mobocertinib is not a substrate of BCRP, OATP1B1, and OATP1B3.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No studies have been conducted on carcinogenicity in Mobocertinib.
- In vitro bacterial reverse mutation, Mobocertinib was not mutagenic in human peripheral blood lymphocytes.
- In vitro chromosome aberration assay, Mobocertinib did not induce chromosomal aberrations in human peripheral blood lymphocytes.
- Rat studies show Mobocertinib was not clastogenic in an in vivo bone marrow micronucleus test.
- Rat and dog studies show decreases in organ weights affecting multiple reproductive organs at exposures ≥0.3 times the AUC observed at the recommended clinical dose of 160 mg once daily in 4- and 13-week repeat-dose toxicology.
- Rat and dog studies show atrophy of the mammary gland, uterus and prostate gland at exposures ≥0.2 times the AUC at the dosage of 160 mg once daily..
- Rat and dog studies show decreased epithelial thickness/inflammation of the cervix/vagina at exposures ≥0.2 times the AUC at the dosage of 160 mg once daily..
- Male and female reproduction potential may be impaired when treated with Mobocertinib.
Animal Toxicology and/or Pharmacology
- 4- and 13-week repeat-dose toxicology studies done on rats show decreased corneal epithelial thickness at doses ≥0.8 times the human exposure at the dosage of 160 mg once daily.
- Discharge occurred in the sclera injection and partial or complete closure of the eye in 4-week repeat-dose study done on dogs at doses ≥0.3 times the human exposure at the dosage of 160 mg once daily.
- Corneal epithelial atrophy occurred in 4-week repeat-dose study done on dogs at doses ≥0.3 times the human exposure at the dosage of 160 mg once daily.
- Corneal opacity and conjunctival hyperemia occurred in 4-week repeat-dose study done on dogs at doses ≥0.2 times the human exposure at the dosage of 160 mg once daily.
- Decreased corneal epithelial thickness occurred in 4-week repeat-dose study done on dogs at doses ≥0.2 times the human exposure at the dosage of 160 mg once daily.
# Clinical Studies
- A pooled subset of patients with EGFR exon 20 insertion mutation-positive metastatic or locally advanced NSCLC whose disease had progressed on or after platinum-based chemotherapy enrolled in an international, open-label, multicohort clinical trial was used to test the efficacy of Mobocertinib. 114 total patients in the pool received a once daily dosage of 160mg of Mobocertinib. The patient population was largely Asian (60%), and included 66% women, and a median age of 60 years.
Table 5 displays the Efficacy results of Mobocertinib from the Study.
# How Supplied
- 40 mg capsules dose pack (90 or 120 tablets).
- Tablets are white with each tablet being a size 2.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
QTc Interval Prolongation and Torsades de Pointes
- Patients should be informed about the QTc prolongation risks.
- Lightheadedness, dizziness, and syncope are symptoms associated with significant QTc prolongation.
- Patients should be advised to report any signs of significant QTc prolongation to their healthcare provider.
Interstitial Lung Disease (ILD)/Pneumonitis
- Patients should be informed about the severe or fatal ILD/pneumonitis risks.
- Patients should be advised to report any signs of severe or fatal ILD/pneumonitis such as shortness of breath, cough, or chest pain to their healthcare provider.
Cardiac Toxicity
- Patients should be informed about the heart failure risks.
- Patients should be advised to report any signs of heart failure such as syncope, shortness of breath, palpitations, and chest pain to their healthcare provider.
Diarrhea
- Patients should be informed about the risk of getting diarrhea when treated with Mobocertinib.
- Patients should be advised to increase oral fluids, start antidiarrheal treatment, and increase electrolyte intake if they get diarrhea.
- Patients should be advised to report diarrhea if it continues to persist to their healthcare provider.
Embryo-Fetal Toxicity
- Advise female patients about potential risks to fetus when treated with Mobocertinib.
- Advise female patients to report any known or suspected pregnancy to their healthcare provider.
- Advise females of reproductive potential to use effective non hormonal contraception during treatment with Mobocertinib and for at least 1 month after the last dose.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with Mobocertinib and for at least 1 week after the last dose.
Lactation
- Advise female patients to not lactate during and 1 week after the last dose of Mobocertinib.
Infertility
- Fertility may be impaired in both males and females when taking Mobocertinib.
Drug Interactions
- Advise patients when taking Mobocertinib to avoid drinking grapefruit juice and eating grapefruit.
- Advise patients to report any concomitant medications such as over-the-counter drugs, herbal products, vitamins, and prescription medicines to their healthcare provider.
Missed Dose
- If a dosage of Mobocertinib is missed by more than 6 hours, then skip dosage and take next dosage at scheduled time the next day.
- Do not take extra dosage of Mobocertinib if dosage taken is vomited, just take next dosage at scheduled time the next day.
# Precautions with Alcohol
Alcohol-Mobocertinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Exkivity
# Look-Alike Drug Names
There is limited information regarding Mobocertinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mobocertinib | |
3f171c3980d02801eb1ce4e71697f10b9363a3fe | wikidoc | Molar volume | Molar volume
In chemistry, the molar volume Vm of a substance is the ratio of the volume V of a sample of that substance to the number of moles n in the sample: Vm = V/n. Apart from computing molar volume by dividing the volume of the substance by the number of moles of substance, it can also be computed as the substance's molar mass divided by its density. Indeed, if the molar mass of substance X is M(X) and
the density of a sample of X is ρ , then the molar volume of X is given by Vm = M(X)/ρ .
The SI unit of molar volume is cubic metres per mole (m3/mol). It is the reciprocal of amount of substance concentration (moles per volume).
For an ideal gas, the standard molar volume is the volume that is occupied by one mole of substance (in gaseous form) at standard temperature and pressure (STP) of 273.15 K (0C) and 101325 Pa (1 atmosphere or 760 torr). It is 0.022413 m³mol-1 or 22.413 L/mol and is directly related to the universal gas constant R in the ideal gas law.
The molar volume for an ideal gas at 298.15 K and 1 bar is 0.024788 m³mol-1 or 24.788 L/mol.
Cubic centimetres (cm³), a measure of volume one million times smaller than a cubic metre, are sometimes also used, to give units of cm³mol-1.
The molar volume is usually given for a solid substance at 298.15 K (temperature of standard state). Apart from temperature and density, it depends on phase and allotrope of the substance.
# Footnote
- ↑ The ratio of the volume and the mass of a sample is the specific volume of the substance—the inverse of density. | Molar volume
In chemistry, the molar volume Vm of a substance is the ratio of the volume V of a sample of that substance to the number of moles n in the sample: Vm = V/n. [1] Apart from computing molar volume by dividing the volume of the substance by the number of moles of substance, it can also be computed as the substance's molar mass divided by its density. Indeed, if the molar mass of substance X is M(X) [kg/mol] and
the density of a sample of X is ρ [kg/m3], then the molar volume of X is given by Vm = M(X)/ρ [m3/mol].
The SI unit of molar volume is cubic metres per mole (m3/mol). It is the reciprocal of amount of substance concentration (moles per volume).
For an ideal gas, the standard molar volume is the volume that is occupied by one mole of substance (in gaseous form) at standard temperature and pressure (STP) of 273.15 K (0C) and 101325 Pa (1 atmosphere or 760 torr). It is 0.022413 m³mol-1 or 22.413 L/mol and is directly related to the universal gas constant R in the ideal gas law.
The molar volume for an ideal gas at 298.15 K and 1 bar is 0.024788 m³mol-1 or 24.788 L/mol.
Cubic centimetres (cm³), a measure of volume one million times smaller than a cubic metre, are sometimes also used, to give units of cm³mol-1.
The molar volume is usually given for a solid substance at 298.15 K (temperature of standard state). Apart from temperature and density, it depends on phase and allotrope of the substance.
# Footnote
- ↑ The ratio of the volume and the mass of a sample is the specific volume of the substance—the inverse of density. | https://www.wikidoc.org/index.php/Molar_volume | |
5a8d89c91f16a76acad0c50e3e621f910abca475 | wikidoc | Moniliformin | Moniliformin
Moniliformin is a quite unusual mycotoxin, a feed contaminant that is quite lethal to fowl.
Moniliformin is formed in many cereals by a number of Fusarium species that include, besides Fusarium moniliforme, Fusarium avenaceum. Fusarium subglutinans, Fusarium proliferatum and others.
# Physicochemical information
Solubility information: Moniliformin is soluble in water and polar solvents, such as methanol.
λmax: 226, 259 in methanol
# Sources and references
- ↑ Moniliformin product page from Fermentek
- ↑ Moniliformin information leaflet by Romerlab | Moniliformin
Template:Cleanup
Moniliformin is a quite unusual mycotoxin, a feed contaminant that is quite lethal to fowl.
Moniliformin is formed in many cereals by a number of Fusarium species that include, besides Fusarium moniliforme, Fusarium avenaceum. Fusarium subglutinans, Fusarium proliferatum and others.[1] [2]
# Physicochemical information
Solubility information: Moniliformin is soluble in water and polar solvents, such as methanol.
λmax: 226, 259 in methanol
# Sources and references
- ↑ Moniliformin product page from Fermentek
- ↑ Moniliformin information leaflet by Romerlab
Template:Organic-compound-stub | https://www.wikidoc.org/index.php/Moniliformin | |
76f2ce2a2a5de667209468e6c69d2add4b5a9ac3 | wikidoc | Monoterpenes | Monoterpenes
Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings. Biochemical modifications such as oxidation or rearrangement produce the related monoterpenoids.
# Acyclic
Biosynthetically, isopentenyl pyrophosphate and dimethylallyl pyrophosphate are combined to form geranyl pyrophosphate.
Elimination of the pyrophosphate group leads to the formation of acyclic monoterpenes such as ocimene and the myrcenes. Hydrolysis of the phosphate groups leads to the prototypical acyclic monoterpenoid geraniol. Additional rearrangements and oxidations provide compounds such as citral, citronellal, citronellol, linalool, and many others. Many monoterpenes found in marine organisms are halogenated, such as halomon.
# Monocyclic
In addition to linear attachments, the isoprene units can make connections to form rings. The most common ring size in monoterpenes is a six-membered ring. A classic example is the cyclization of geranyl pyrophosphate to form limonene.
File:LimoneneBiosynthesis.png
The terpinenes, phellandrenes, and terpinolene are formed similarly. Hydroxylation of any of these compounds followed by dehydration can lead to the aromatic p-cymene. Important terpenoids derived from monocyclic terpenes are menthol, thymol, carvacrol and many others.
# Bicyclic
Geranyl pyrophosphate can also undergo two sequential cyclization reactions to form bicyclic monoterpenes, such as pinene which is the primary constituent of pine resin.
Other bicyclic monoterpenes include carene, sabinene, camphene, and thujene. Camphor, borneol and eucalyptol are examples of bicyclic monoterpenoids containing ketone, alcohol, and ether functional groups, respectively. | Monoterpenes
Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings. Biochemical modifications such as oxidation or rearrangement produce the related monoterpenoids.
## Acyclic
Biosynthetically, isopentenyl pyrophosphate and dimethylallyl pyrophosphate are combined to form geranyl pyrophosphate.
Elimination of the pyrophosphate group leads to the formation of acyclic monoterpenes such as ocimene and the myrcenes. Hydrolysis of the phosphate groups leads to the prototypical acyclic monoterpenoid geraniol. Additional rearrangements and oxidations provide compounds such as citral, citronellal, citronellol, linalool, and many others. Many monoterpenes found in marine organisms are halogenated, such as halomon.
## Monocyclic
In addition to linear attachments, the isoprene units can make connections to form rings. The most common ring size in monoterpenes is a six-membered ring. A classic example is the cyclization of geranyl pyrophosphate to form limonene.
File:LimoneneBiosynthesis.png
The terpinenes, phellandrenes, and terpinolene are formed similarly. Hydroxylation of any of these compounds followed by dehydration can lead to the aromatic p-cymene. Important terpenoids derived from monocyclic terpenes are menthol, thymol, carvacrol and many others.
## Bicyclic
Geranyl pyrophosphate can also undergo two sequential cyclization reactions to form bicyclic monoterpenes, such as pinene which is the primary constituent of pine resin.
Other bicyclic monoterpenes include carene, sabinene, camphene, and thujene. Camphor, borneol and eucalyptol are examples of bicyclic monoterpenoids containing ketone, alcohol, and ether functional groups, respectively.
# External links
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Monoterpenes | |
28f74d3010ef9a0ed6732872381812331c49d60b | wikidoc | Moorbad Gmös | Moorbad Gmös
The Mud Spa Gmös (Moorbad Gmös) in the vicinity of the town of Laakirchen (situated on the edge of the Salzkammergut) is one of the few moor land areas in the Alpine foothills of Upper Austria. The moor dates back to the Mindel glaciation and was created by a "dead ice-hole". In 1987 the local authorities of Upper Austria declared the Area of 3.4 ha of the Gmöser Moor a natural preserve. A path around the area has since then given the visitor the opportunity of observing rare flora and fauna species. In 2002 the spa was chosen as background scenery for the TV-production "Schloßhotel Orth".
# About the area
The mud spa was formed on a Moraine of the Mindel glaciation and forms one of the few moors in the Alpine foothills on the east side of the Traun River. Up to the time that humans began to interfere with nature, a moor landscape with its variety of flora and fauna was able to develop. Due to cultivation of the moor landscape by man (drainage, peat-working, litter-harvesting etc.) the 3,4 ha Gmöser Moor can today be designated as a moor land forest or as a lower moor land which the original forms of flora and fauna have survived.
This was the reason that the Gmöser Moor was declared to be a natural preserve.
## Fauna
Due to the number of animals - of which some are severely endangered and all under protection - the Gmöser Moor represents a unique refuse and environment in form of a biotope for the region.
For example, you cand find Amphibians such as Yellow-bellied toads (Bombina variageta) - decidedly water inhabitants - and Reptiles such as the Grass Snake (Natrix natrix) which live in damp forests, swamp and moor lands.
A great number of Bird species find the best conditions for breeding and have been observed for a number of years.
The Fieldfare (Turdus pilaris ) is to be found her with the only breeding colony of the whole area.
The Marsh warbler (Acrocephalus palustris ) is not solely bound to reed landscapeds, but is mainly to be found in bushy areas. It is a summer guest for us and spends the winter in Africa.
The Whinchat (Saxicola rubetra ) can be found in the surrounding meadows, as it is a typical meadow bird, which breeds on the ground. In the surroundings of the Gmöser Moor this bird could only be observed one or two times when breeding. The Whinchat is also a summer guest in Austria and spends the winter in Africa
The Eurasian Nuthatch (Sitta europaea ) remains with us all year round. It breeds in caves and draws the observer's attention to itself by being able to crawl headfirst down trees.
The Golden Oriole (Oriolus oriolus ) only visits us as a summer guest at the end of April on its return journey from Africa. It only breeds irregularly in Gmös, whereby its nest is strictly obscured high up in the trees. The male bird can be easily recognized by its bright yellow and black feathers.
The Common Kestrel (Falco tinnunculus ) can be observed over all open areas with flattering wings spread over a certain area and then pouncing down with closed wings ont its prey of mice or other small mammals.
Other observed Bird species:
### hatching bird species
Mallard (Anas platyrhynchos), Grey Partridge (Perdix perdix), Pheasant (Phasianus colchicus), Quail (Coturnix coturnix), Moorhen (Gallinula chloropus), Wood Pigeon (Columba palumbus), Great Spotted Woodpecker (Dendrocopos major), Skylark (Alauda arvensis), Wren (Troglodytes troglodytes), Robin (Erithacus rubecula), Black Redstart (Phoenicurus ochruros), Blackbird (Turdus merula), Song Thrush (Turdus philomelos), Garden Warbler (Sylvia borin), Blackcap (Sylvia atricapilla), Willow Warbler (Phylloscopus trochilus), Chiffchaff (Phylloscopus collybita), Goldcrest (Regulus regulus), Firecrest (Regulus ignicapillus), Spotted Flycatcher (Muscicapa striata), Marsh Tit (Poecile palustris), Blue Tit (Parus caeruleus), Great Tit (Parus major), Coal Tit (Periparus ater), Short-toed Treecreeper (Certhia brachydactyla), Starling (Sturnus vulgaris), Eurasian Jay (Garrulus glandarius), European Magpie (Pica pica), Carrion Crow (Corvus corone), Tree Sparrow (Passer montanus), House Sparrow (Passer domesticus), Chaffinch (Fringilla coelebs), Greenfinch (Carduelis chloris), Goldfinch (Carduelis carduelis), Yellowhammer (Emberiza citrinella) und Reed Bunting (Emberiza schoeniclus).
### migrants, former breeding birds and guests
Grey Heron (Ardea cinerea), White Stork (Ciconia ciconia), Garganey (Anas querquedula), Tufted Duck (Aythya fuligula), Red Kite (Milvus milvus), Hen Harrier (Circus cyaneus), Eurasian Sparrowhawk (Accipiter nisus), Goshawk (Accipiter gentilis), Honey Buzzard (Pernis apivorus), Buzzard (Buteo buteo), Hobby (Falco subbuteo), Lapwing (Vanellus vanellus), Curlew (Numenius arquata), Green Sandpiper (Tringa ochropus), Eurasian Woodcock (Scolopax rusticola), Common Snipe (Gallinago gallinago), Collared Dove (Streptopelia decaocto), Cuckoo (Cuculus canorus), Long-eared Owl (Asio otus), Tawny Owl (Strix aluco), Common Swift (Apus apus), Hoopoe (Upupa epops), Grey-headed Woodpecker (Picus canus), Green Woodpecker (Picus viridis), Barn Swallow (Hirundo rustica), House Martin (Delichon urbica), Tree Pipit (Anthus trivialis), Dunnock (Prunella modularis), Redstart (Phoenicurus phoenicurus), Wheatear (Oenanthe oenanthe), Redwing (Turdus iliacus), Mistle Thrush (Turdus viscivorus), Sedge Warbler (Acrocephalus schoenobaenus), Aquatic Warbler (Acrocephalus paludicola), Reed Warbler (Acrocephalus scirpaceus), Icterine Warbler (Hippolais icterina), Lesser Whitethroat (Sylvia curruca), Whitethroat (Sylvia communis), Wood Warbler (Phylloscopus sibilatrix), Pied Flycatcher (Ficedula hypoleuca), Collared Flycatcher (Ficedula albicollis), Crested Tit (Lophophanes cristatus), Long-tailed Tit (Aegithalos caudatus), Red-backed Shrike (Lanius collurio), Jackdaw (Corvus monedula), Common Raven (Corvus corax), Brambling (Fringilla montifringilla), Hawfinch (Coccothraustes coccothraustes), Serin (Serinus serinus), Siskin (Carduelis spinus), Bullfinch (Pyrrhula pyrrhula), Linnet (Carduelis cannabina), Common Rosefinch (Carpodacus erythrinus) and Common Crossbill (Loxia curvirostra).
The manifold biotope structures and the special climate features which are prevalent in a moor landscape result in an extremely diverse insect world, which serves as a food source for the birds of the area.
In the area where peat is dug, one can observe the most different sorts of Dragonflies and a great number of Mosquitos (Culicidadae).
## Flora
The vegetation of the moor landscape is dominated mainly by moor land forests dominated by moor birch trees. Here one can observe the remnants of a great number of plants which are typical for moor land areas. Among these are the Downy birch (Betula pubescens), European heather (Calluna vulgaris), Milk Parsley (Peucedanum palustre), Blanket Mire (Eriophorum vaginatum) und Common sedge (Carex nigra).
Peat diggings can be found both in the centre and on the edges of the moor. The older sites are covered with marsh moss, whereas others can be identified by their duckweed, marsh cinquefoil and sparganium growdth.
Peat Moss (Sphagnum sp.) is an excellent water store. They die off at the point where they stand in water and continue growing above this point. The underlying dead particles are continually compressed downwards by the new growth from above. Thus, over a period of several ten thousands of centuries, provided that the climate and environmental conditions are in order, smaller or larger layers of peat are create. The moor layer in Gmös is, however, not exceptionally thick, as the peat mosses could not compete with the pressure applied and could therefore not turn into an ombrothopfic moor.
On the pond within the moor landscape a wide-spread reed-cultivation has developed.
# The Mud Spa
## History of the Mud Spa in Gmös
Around 1900 Johann Vizithum - a farmer in the neighbouring village of Rahstorf - used to dig peat in order to obtain fuel to run his threshing machine. He had suffered over years from severe Arthritis and realised, that whenever he trod barefoot in the mud, he experienced a definite improvement of his ailments. This was the reason that the Mud bath Gmös was founded in 1907. Since that time peat has been manually dug and prepared on a daily basis. Following the applications the peat is returned to the moor.
### 100-year anniversary
100 years ago – in time of the Austro-Hungarian Monarchy, when the Emperor of Austria had spent his summer holidays at the spas of Karlovy Vary, Františkovy Lázně and Mariánské Lázně in the Czech Republic – even a small Upper-Austrian village got its first mud spa. 1907 the first owner named the spa after his wife Cäcilia and people from all over the country came not only because of the established guest house but also because of the new bath house.
Comparing the pictures of that time and of today you would hardly recognize it. Cäcilienbad has been renamed into Moorbad Gmös, the infrastructure has been adapted to the contemporary requirements and even the methods of treatment have been improved and expanded in order to guarantee the patient’s recovery.
The 100-year anniversary will take place on July 7th 2007. Accompanied by art and music performances one will be able to visit the bath and guest rooms of the spa, watch the way of the mud – from nature into the mud packs – and walk through the preserve mud area. Free massages and a rich culinary choice round off the celebrations.
On August 11th an event of the Gmundner Festival is guest in Gmös for the first time. Peter Raab reads Thomas Bernhard's „Wut und Komik" in a Matinee .
## The Cure in the Bath House
The traditional cure in Gmös is a combination of mud baths, mud packs and massages. This results in a synergetic effect, which in turn positively enforces the healing and soothing processes. The mud bath and the mud packs especially cleanse the muscles and the body.
### Massages
Individually specified massages are essential for improving the muscular function and serve to improve all the muscular movements apparatus. Foot- and ear-reflex zone massage and special forms of traditional massage are used as supportive measures. Thus any tension and over acidification of the muscles, which often lead to pain and loss of mobility, can be treated.
### The Mud-bath
The mud-bath is prepared directly from peat taken from the moor together with moor water which is rich in content. In order to increase the typical thermal factor the water is mixed with peat.
### Mud-Packs
The parts if the body to be treated are covered with permeable fleece packs containing peat. According to requirement either the whole or parts of the body are then wrapped and subjected to a 50 Min cleansing procedure.
### Indications
The cure helps with rheumatism, lumbago, sciatica, gout, all wear symptoms of the joints and the spine, chronic arthritis, the symptoms following broken bones and all over-tension of the muscles.
## The Guest House
The guest house is in the direct vicinity of the Bath-House, in order to offer those guests who do not live near the possibility of being treated. Both the Guest House and the Spa are family businesses, which with their maximum capacity of 16 guests, offer everybody individual treatment.
# Chapel Gmös
Following suggestions of our guests, the building of the Chapel Gmös began in 1982. After a construction period of 3 months the consecration ceremony could be carried out in the form of mass conducted by the abbot - Mr. Siebenhütter - of the monastery in Lambach. The musical accompaniment was by the "Laakirchner Stubenmusi" and the MGV Steyrermühl. A number of honorary guests were present and in their speeches thanked the Forstinger family for their leading role in the construction of the chapel. The efforts of the "Committee for the construction of a chapel in Gmös" which was set up by guests of long-standing were crowned by renowned success. The idea of building a chapel was based on the need of the guests to find peace, contemplation, refection, meditation all within the bounds of a moor land area. The 75th jubilee of the spa itself was enriched by the construction of this beautiful building. Since then the spa in Gmös has contributed with its treatment with peat and massages not only to the beaty and stillness of the surrounding nature and rustic life but also to the positive effect of spiritual influences on both body and spirit. | Moorbad Gmös
The Mud Spa Gmös (Moorbad Gmös) in the vicinity of the town of Laakirchen (situated on the edge of the Salzkammergut) is one of the few moor land areas in the Alpine foothills of Upper Austria. The moor dates back to the Mindel glaciation and was created by a "dead ice-hole". In 1987 the local authorities of Upper Austria declared the Area of 3.4 ha of the Gmöser Moor a natural preserve. A path around the area has since then given the visitor the opportunity of observing rare flora and fauna species. In 2002 the spa was chosen as background scenery for the TV-production "Schloßhotel Orth".
# About the area
The mud spa was formed on a Moraine of the Mindel glaciation and forms one of the few moors in the Alpine foothills on the east side of the Traun River. Up to the time that humans began to interfere with nature, a moor landscape with its variety of flora and fauna was able to develop. Due to cultivation of the moor landscape by man (drainage, peat-working, litter-harvesting etc.) the 3,4 ha Gmöser Moor can today be designated as a moor land forest or as a lower moor land which the original forms of flora and fauna have survived.
This was the reason that the Gmöser Moor was declared to be a natural preserve.
## Fauna
Due to the number of animals - of which some are severely endangered and all under protection - the Gmöser Moor represents a unique refuse and environment in form of a biotope for the region.
For example, you cand find Amphibians such as Yellow-bellied toads (Bombina variageta) - decidedly water inhabitants - and Reptiles such as the Grass Snake (Natrix natrix) which live in damp forests, swamp and moor lands.
A great number of Bird species find the best conditions for breeding and have been observed for a number of years.
The Fieldfare (Turdus pilaris [1]) is to be found her with the only breeding colony of the whole area.
The Marsh warbler (Acrocephalus palustris [2]) is not solely bound to reed landscapeds, but is mainly to be found in bushy areas. It is a summer guest for us and spends the winter in Africa.
The Whinchat (Saxicola rubetra [3]) can be found in the surrounding meadows, as it is a typical meadow bird, which breeds on the ground. In the surroundings of the Gmöser Moor this bird could only be observed one or two times when breeding. The Whinchat is also a summer guest in Austria and spends the winter in Africa
The Eurasian Nuthatch (Sitta europaea [4]) remains with us all year round. It breeds in caves and draws the observer's attention to itself by being able to crawl headfirst down trees.
The Golden Oriole (Oriolus oriolus [5]) only visits us as a summer guest at the end of April on its return journey from Africa. It only breeds irregularly in Gmös, whereby its nest is strictly obscured high up in the trees. The male bird can be easily recognized by its bright yellow and black feathers.
The Common Kestrel (Falco tinnunculus [6]) can be observed over all open areas with flattering wings spread over a certain area and then pouncing down with closed wings ont its prey of mice or other small mammals.
Other observed Bird species[7]:
### hatching bird species
Mallard (Anas platyrhynchos), Grey Partridge (Perdix perdix), Pheasant (Phasianus colchicus), Quail (Coturnix coturnix), Moorhen (Gallinula chloropus), Wood Pigeon (Columba palumbus), Great Spotted Woodpecker (Dendrocopos major), Skylark (Alauda arvensis), Wren (Troglodytes troglodytes), Robin (Erithacus rubecula), Black Redstart (Phoenicurus ochruros), Blackbird (Turdus merula), Song Thrush (Turdus philomelos), Garden Warbler (Sylvia borin), Blackcap (Sylvia atricapilla), Willow Warbler (Phylloscopus trochilus), Chiffchaff (Phylloscopus collybita), Goldcrest (Regulus regulus), Firecrest (Regulus ignicapillus), Spotted Flycatcher (Muscicapa striata), Marsh Tit (Poecile palustris), Blue Tit (Parus caeruleus), Great Tit (Parus major), Coal Tit (Periparus ater), Short-toed Treecreeper (Certhia brachydactyla), Starling (Sturnus vulgaris), Eurasian Jay (Garrulus glandarius), European Magpie (Pica pica), Carrion Crow (Corvus corone), Tree Sparrow (Passer montanus), House Sparrow (Passer domesticus), Chaffinch (Fringilla coelebs), Greenfinch (Carduelis chloris), Goldfinch (Carduelis carduelis), Yellowhammer (Emberiza citrinella) und Reed Bunting (Emberiza schoeniclus).
### migrants, former breeding birds and guests
Grey Heron (Ardea cinerea), White Stork (Ciconia ciconia), Garganey (Anas querquedula), Tufted Duck (Aythya fuligula), Red Kite (Milvus milvus), Hen Harrier (Circus cyaneus), Eurasian Sparrowhawk (Accipiter nisus), Goshawk (Accipiter gentilis), Honey Buzzard (Pernis apivorus), Buzzard (Buteo buteo), Hobby (Falco subbuteo), Lapwing (Vanellus vanellus), Curlew (Numenius arquata), Green Sandpiper (Tringa ochropus), Eurasian Woodcock (Scolopax rusticola), Common Snipe (Gallinago gallinago), Collared Dove (Streptopelia decaocto), Cuckoo (Cuculus canorus), Long-eared Owl (Asio otus), Tawny Owl (Strix aluco), Common Swift (Apus apus), Hoopoe (Upupa epops), Grey-headed Woodpecker (Picus canus), Green Woodpecker (Picus viridis), Barn Swallow (Hirundo rustica), House Martin (Delichon urbica), Tree Pipit (Anthus trivialis), Dunnock (Prunella modularis), Redstart (Phoenicurus phoenicurus), Wheatear (Oenanthe oenanthe), Redwing (Turdus iliacus), Mistle Thrush (Turdus viscivorus), Sedge Warbler (Acrocephalus schoenobaenus), Aquatic Warbler (Acrocephalus paludicola), Reed Warbler (Acrocephalus scirpaceus), Icterine Warbler (Hippolais icterina), Lesser Whitethroat (Sylvia curruca), Whitethroat (Sylvia communis), Wood Warbler (Phylloscopus sibilatrix), Pied Flycatcher (Ficedula hypoleuca), Collared Flycatcher (Ficedula albicollis), Crested Tit (Lophophanes cristatus), Long-tailed Tit (Aegithalos caudatus), Red-backed Shrike (Lanius collurio), Jackdaw (Corvus monedula), Common Raven (Corvus corax), Brambling (Fringilla montifringilla), Hawfinch (Coccothraustes coccothraustes), Serin (Serinus serinus), Siskin (Carduelis spinus), Bullfinch (Pyrrhula pyrrhula), Linnet (Carduelis cannabina), Common Rosefinch (Carpodacus erythrinus) and Common Crossbill (Loxia curvirostra).
The manifold biotope structures and the special climate features which are prevalent in a moor landscape result in an extremely diverse insect world, which serves as a food source for the birds of the area.
In the area where peat is dug, one can observe the most different sorts of Dragonflies and a great number of Mosquitos (Culicidadae).
## Flora
The vegetation of the moor landscape is dominated mainly by moor land forests dominated by moor birch trees. Here one can observe the remnants of a great number of plants which are typical for moor land areas. Among these are the Downy birch (Betula pubescens), European heather (Calluna vulgaris), Milk Parsley (Peucedanum palustre), Blanket Mire (Eriophorum vaginatum) und Common sedge (Carex nigra).
Peat diggings can be found both in the centre and on the edges of the moor. The older sites are covered with marsh moss, whereas others can be identified by their duckweed, marsh cinquefoil and sparganium growdth.
Peat Moss (Sphagnum sp.) is an excellent water store. They die off at the point where they stand in water and continue growing above this point. The underlying dead particles are continually compressed downwards by the new growth from above. Thus, over a period of several ten thousands of centuries, provided that the climate and environmental conditions are in order, smaller or larger layers of peat are create. The moor layer in Gmös is, however, not exceptionally thick, as the peat mosses could not compete with the pressure applied and could therefore not turn into an ombrothopfic moor.
On the pond within the moor landscape a wide-spread reed-cultivation has developed.
# The Mud Spa
## History of the Mud Spa in Gmös
Around 1900 Johann Vizithum - a farmer in the neighbouring village of Rahstorf - used to dig peat in order to obtain fuel to run his threshing machine. He had suffered over years from severe Arthritis and realised, that whenever he trod barefoot in the mud, he experienced a definite improvement of his ailments. This was the reason that the Mud bath Gmös was founded in 1907. Since that time peat has been manually dug and prepared on a daily basis. Following the applications the peat is returned to the moor.
### 100-year anniversary
100 years ago – in time of the Austro-Hungarian Monarchy, when the Emperor of Austria had spent his summer holidays at the spas of Karlovy Vary, Františkovy Lázně and Mariánské Lázně in the Czech Republic – even a small Upper-Austrian village got its first mud spa. 1907 the first owner named the spa after his wife Cäcilia and people from all over the country came not only because of the established guest house but also because of the new bath house.
Comparing the pictures of that time and of today you would hardly recognize it. Cäcilienbad has been renamed into Moorbad Gmös, the infrastructure has been adapted to the contemporary requirements and even the methods of treatment have been improved and expanded in order to guarantee the patient’s recovery.
The 100-year anniversary will take place on July 7th 2007. Accompanied by art and music performances one will be able to visit the bath and guest rooms of the spa, watch the way of the mud – from nature into the mud packs – and walk through the preserve mud area. Free massages and a rich culinary choice round off the celebrations.
On August 11th an event of the Gmundner Festival is guest in Gmös for the first time. Peter Raab reads Thomas Bernhard's „Wut und Komik" in a Matinee [2].
## The Cure in the Bath House
The traditional cure in Gmös is a combination of mud baths, mud packs and massages. This results in a synergetic effect, which in turn positively enforces the healing and soothing processes. The mud bath and the mud packs especially cleanse the muscles and the body.
### Massages
Individually specified massages are essential for improving the muscular function and serve to improve all the muscular movements apparatus. Foot- and ear-reflex zone massage and special forms of traditional massage are used as supportive measures. Thus any tension and over acidification of the muscles, which often lead to pain and loss of mobility, can be treated.
### The Mud-bath
The mud-bath is prepared directly from peat taken from the moor together with moor water which is rich in content. In order to increase the typical thermal factor the water is mixed with peat.
### Mud-Packs
The parts if the body to be treated are covered with permeable fleece packs containing peat. According to requirement either the whole or parts of the body are then wrapped and subjected to a 50 Min cleansing procedure.
### Indications
The cure helps with rheumatism, lumbago, sciatica, gout, all wear symptoms of the joints and the spine, chronic arthritis, the symptoms following broken bones and all over-tension of the muscles.
## The Guest House
The guest house is in the direct vicinity of the Bath-House, in order to offer those guests who do not live near the possibility of being treated. Both the Guest House and the Spa are family businesses, which with their maximum capacity of 16 guests, offer everybody individual treatment.
# Chapel Gmös
Following suggestions of our guests, the building of the Chapel Gmös began in 1982. After a construction period of 3 months the consecration ceremony could be carried out in the form of mass conducted by the abbot - Mr. Siebenhütter - of the monastery in Lambach. The musical accompaniment was by the "Laakirchner Stubenmusi" and the MGV Steyrermühl. A number of honorary guests were present and in their speeches thanked the Forstinger family for their leading role in the construction of the chapel. The efforts of the "Committee for the construction of a chapel in Gmös" which was set up by guests of long-standing were crowned by renowned success. The idea of building a chapel was based on the need of the guests to find peace, contemplation, refection, meditation all within the bounds of a moor land area. The 75th jubilee of the spa itself was enriched by the construction of this beautiful building. Since then the spa in Gmös has contributed with its treatment with peat and massages not only to the beaty and stillness of the surrounding nature and rustic life but also to the positive effect of spiritual influences on both body and spirit.
# External links
- Wikimedia Commons has media related to Moorbad Gmös.
www.gmoes.at - official website of Moorbad Gmös
DORIS interMAP-Entry detailed view of the area in the map of the local authorities
The municipality's Information about the preserve
Template:Coor title dms
de:Moorbad Gmös
Template:WikiDoc Sources
- www.gmoes.at - official website of Moorbad Gmös
- DORIS interMAP-Entry detailed view of the area in the map of the local authorities
- The municipality's Information about the preserve | https://www.wikidoc.org/index.php/Moorbad_Gm%C3%B6s | |
e2391965d6535c23d28c2bc6ab50f8bfb60451d3 | wikidoc | Moral hazard | Moral hazard
# Overview
Adverse selection, anti-selection, or negative selection is a term used in economics, insurance, statistics, and risk management. On the most abstract level, it refers to a market process in which bad results occur due to information asymmetries between buyers and sellers: the "bad" products or customers are more likely to be selected. A bank that sets one price for all its checking account customers runs the risk of being adversely selected against by its high-balance, low-activity (and hence most profitable) customers. Two ways to model adverse selection are with signaling games and screening games.
# Example: Insurance
The term adverse selection was originally used in insurance. It describes a situation where, as a result of private information, the insured are more likely to suffer a loss than the uninsured.
For example, suppose that there are two groups among the population, smokers and non-smokers. An insurer selling life policies can't tell which is which, so they each pay the same premiums. Non-smokers, on average, are more likely to live longer, while smokers, on average, are more likely to die younger. So the life policy is a better buy for the smokers' beneficiaries. The insurance company anticipates or learns that the mortality rate of the combined policy holders exceeds that of the general population, and sets the premiums accordingly. The result is that non-smokers tend to go uninsured. However, if the non-smokers could buy a policy on terms that are actuarially fair given their characteristics, they would do so. So market failure is involved.
Furthermore, as a result of the higher premiums, not only do some non-smokers who do not want to pay the higher premiums cancel their policies and go uninsured, some smokers who cannot afford the higher premiums cancel their policies and go uninsured. Since there are fixed costs in running an insurance company, the insurance company must spread the fixed costs across fewer policies. This results in a reduction of profits or actual losses which forces the insurance company to again raise premiums.
With further rises in premiums, more non-smokers and smokers who cannot afford the higher premiums decide to cancel their coverage and go uninsured. This means the insurance company has even fewer policies to spread fixed costs across and results in further premium increases. This vicious cycle continues until the premiums become so high that no non-smoker or smoker can afford the policies or there are too few policies to spread fixed costs across. At this point, the insurance company goes out of business and no one has insurance.
In the early days of life insurance, adverse selection forced many life insurance companies out of business until the life insurance actuaries learned to compensate for adverse selection and underwriting procedures were improved to minimize adverse selection.
Whether examples of this sort apply in reality is an open question. Smokers may tend to reckless behavior in general, so be relatively disinclined to insure. Or they may be in denial and not want to recognize their enhanced mortality. When the insured are less at risk than the uninsured, this is known as advantageous selection.
# Asymmetric information
Insurance is not as profitable when buyers have better information about their risk than sellers. Premiums set according to average risk will not be sufficient to cover claims because buyers will be selected for higher risk (buyers carrying less risk are less likely to purchase insurance.)
In the usual case, a key condition for there to be adverse selection is an asymmetry of information - people buying insurance know whether they are smokers or not, whereas the insurance company doesn't. If the insurance company knew who smokes and who doesn't, it could set rates differently for each group and there would be no adverse selection. However, other conditions may produce adverse selection even when there is no asymmetry of information. For example, some U.S. states require health insurance providers to insure all who apply at the same cost. In this case, there may not be an actual asymmetry of information: the insurance company may know who is or isn't a smoker, but because the insurer is not allowed to act on that information, there is a "virtual" asymmetry of information.
# The Stock Market
Here, the risk of adverse selection is generally when you do business with people of whom you have no knowledge. This is one of two main sorts of market failure often associated with stocks. (The other is moral hazard.) Adverse selection can be a problem when there is asymmetric information between the seller and the buyer; in particular, a trade will often produce an asymmetric premium for buyer or seller, if one trader has better/more complete information (e.g., about what other traders are doing, the complete trading book for a stock, etc.) than the average. When a buyer has better information than does the seller (or conversely), a trade may occur at a lower (higher) strike price than otherwise. Ideally, trade prices should be set in an environment in which all the traders have complete knowledge of ambient market conditions (or, at least, equal knowledge thereof) .
When there is adverse selection, people who know there is an above-average probability of a certain favorable price move - more than the average investor of the group - will trade, whereas those who know there is a below-average probability of a favorable price move may decide it is too expensive to be worth trading, and hold off trading. In this way, the 'better informed' investors will obtain a trading advantage (i.e., a trading premium) over the others.
One common source of adverse selection in the stock market is insider trading, in which an insider (such as a corporations officers or directors) or a related party trades based on material non-public information obtained during the performance of the insider's duties at the corporation, or otherwise misappropriated. Many jurisdictions attempt to address this problem by making the practice illegal. | Moral hazard
# Overview
Adverse selection, anti-selection, or negative selection is a term used in economics, insurance, statistics, and risk management. On the most abstract level, it refers to a market process in which bad results occur due to information asymmetries between buyers and sellers: the "bad" products or customers are more likely to be selected. A bank that sets one price for all its checking account customers runs the risk of being adversely selected against by its high-balance, low-activity (and hence most profitable) customers. Two ways to model adverse selection are with signaling games and screening games.
# Example: Insurance
The term adverse selection was originally used in insurance. It describes a situation where, as a result of private information, the insured are more likely to suffer a loss than the uninsured.[1]
For example, suppose that there are two groups among the population, smokers and non-smokers. An insurer selling life policies can't tell which is which, so they each pay the same premiums. Non-smokers, on average, are more likely to live longer, while smokers, on average, are more likely to die younger. So the life policy is a better buy for the smokers' beneficiaries. The insurance company anticipates or learns that the mortality rate of the combined policy holders exceeds that of the general population, and sets the premiums accordingly. The result is that non-smokers tend to go uninsured. However, if the non-smokers could buy a policy on terms that are actuarially fair given their characteristics, they would do so. So market failure is involved.
Furthermore, as a result of the higher premiums, not only do some non-smokers who do not want to pay the higher premiums cancel their policies and go uninsured, some smokers who cannot afford the higher premiums cancel their policies and go uninsured. Since there are fixed costs in running an insurance company, the insurance company must spread the fixed costs across fewer policies. This results in a reduction of profits or actual losses which forces the insurance company to again raise premiums.
With further rises in premiums, more non-smokers and smokers who cannot afford the higher premiums decide to cancel their coverage and go uninsured. This means the insurance company has even fewer policies to spread fixed costs across and results in further premium increases. This vicious cycle continues until the premiums become so high that no non-smoker or smoker can afford the policies or there are too few policies to spread fixed costs across. At this point, the insurance company goes out of business and no one has insurance.
In the early days of life insurance, adverse selection forced many life insurance companies out of business until the life insurance actuaries learned to compensate for adverse selection and underwriting procedures were improved to minimize adverse selection.
Whether examples of this sort apply in reality is an open question. Smokers may tend to reckless behavior in general, so be relatively disinclined to insure. Or they may be in denial and not want to recognize their enhanced mortality. When the insured are less at risk than the uninsured, this is known as advantageous selection.
# Asymmetric information
Insurance is not as profitable when buyers have better information about their risk than sellers. Premiums set according to average risk will not be sufficient to cover claims because buyers will be selected for higher risk (buyers carrying less risk are less likely to purchase insurance.) [2]
In the usual case, a key condition for there to be adverse selection is an asymmetry of information - people buying insurance know whether they are smokers or not, whereas the insurance company doesn't. If the insurance company knew who smokes and who doesn't, it could set rates differently for each group and there would be no adverse selection. However, other conditions may produce adverse selection even when there is no asymmetry of information. For example, some U.S. states require health insurance providers to insure all who apply at the same cost. In this case, there may not be an actual asymmetry of information: the insurance company may know who is or isn't a smoker, but because the insurer is not allowed to act on that information, there is a "virtual" asymmetry of information.
# The Stock Market
Here, the risk of adverse selection is generally when you do business with people of whom you have no knowledge. This is one of two main sorts of market failure often associated with stocks. (The other is moral hazard.) Adverse selection can be a problem when there is asymmetric information between the seller and the buyer; in particular, a trade will often produce an asymmetric premium for buyer or seller, if one trader has better/more complete information (e.g., about what other traders are doing, the complete trading book for a stock, etc.) than the average. When a buyer has better information than does the seller (or conversely), a trade may occur at a lower (higher) strike price than otherwise. Ideally, trade prices should be set in an environment in which all the traders have complete knowledge of ambient market conditions (or, at least, equal knowledge thereof) .
When there is adverse selection, people who know there is an above-average probability of a certain favorable price move - more than the average investor of the group - will trade, whereas those who know there is a below-average probability of a favorable price move may decide it is too expensive to be worth trading, and hold off trading. In this way, the 'better informed' investors will obtain a trading advantage (i.e., a trading premium) over the others.
One common source of adverse selection in the stock market is insider trading, in which an insider (such as a corporations officers or directors) or a related party trades based on material non-public information obtained during the performance of the insider's duties at the corporation, or otherwise misappropriated. Many jurisdictions attempt to address this problem by making the practice illegal. | https://www.wikidoc.org/index.php/Moral_hazard | |
d449cb2c1949d73ab33d3996824a37041250fccc | wikidoc | Morton's toe | Morton's toe
Morton's toe is the common term for the second toe (second from innermost) being longer than the great toe (Hallux).
The name derives from American orthopaedic surgeon Dudley Joy Morton (1884-1960), who originally described it as part of Morton's triad (a.k.a Morton's syndrome or Morton's foot syndrome): a congenital short first metatarsal bone, a hypermobile first metatarsal segment, and calluses under the second and third metatarsals.
Although commonly described as a disorder, it is sufficiently common to be considered a normal variant of foot shape (its prevalence varies with different populations, but around 10% of feet worldwide have this form). In shoe-wearing cultures it can be problematic: for instance, in causing nail problems from wearing shoes with a profile that doesn't accommodate the longer second toe.
It has a long association with disputed anthropological and ethnic interpretations. Morton called it Metatarsus atavicus, considering it an atavism recalling prehuman grasping toes. In statuary and shoe fitting it has been called the Greek foot (as opposed to the Egyptian foot, where the great toe is longer). It was an idealised form in Greek sculpture, and this persisted as an aesthetic standard through Roman and Renaissance periods and later (the Statue of Liberty has toes of this proportion). The French call it pied ancestral or pied de Néanderthal.
Confusion has arisen from the term also sometimes being used for a different condition, Morton's neuroma, a term coined by Thomas George Morton (1835-1903) for a syndrome involving pain caused by neuroma between the third and fourth toes. | Morton's toe
Morton's toe is the common term for the second toe (second from innermost) being longer than the great toe (Hallux).
The name derives from American orthopaedic surgeon Dudley Joy Morton (1884-1960), who originally described it as part of Morton's triad (a.k.a Morton's syndrome or Morton's foot syndrome): a congenital short first metatarsal bone, a hypermobile first metatarsal segment, and calluses under the second and third metatarsals.
Although commonly described as a disorder, it is sufficiently common to be considered a normal variant of foot shape (its prevalence varies with different populations, but around 10% of feet worldwide have this form). In shoe-wearing cultures it can be problematic: for instance, in causing nail problems from wearing shoes with a profile that doesn't accommodate the longer second toe.
It has a long association with disputed anthropological and ethnic interpretations. Morton called it Metatarsus atavicus, considering it an atavism recalling prehuman grasping toes. In statuary and shoe fitting it has been called the Greek foot (as opposed to the Egyptian foot, where the great toe is longer). It was an idealised form in Greek sculpture, and this persisted as an aesthetic standard through Roman and Renaissance periods and later (the Statue of Liberty has toes of this proportion). The French call it pied ancestral or pied de Néanderthal[1].
Confusion has arisen from the term also sometimes being used for a different condition, Morton's neuroma, a term coined by Thomas George Morton (1835-1903) for a syndrome involving pain caused by neuroma between the third and fourth toes. | https://www.wikidoc.org/index.php/Morton%27s_toe | |
b798836749f806edf148171bc009c537db324e54 | wikidoc | Motor neuron | Motor neuron
In vertebrates, the term motor neuron (or motoneuron) classically applies to neurons located in the central nervous system (CNS) which project their axons outside the CNS and directly or indirectly control muscles. Motor neuron is often synonymous with efferent neuron.
# Anatomy and physiology
According to their targets, motoneurons are classified into three broad categories:
"Somatic motoneurons", which directly innervate skeletal muscles, involved in locomotion (such as muscles of the limbs, abdominal and intercostal muscles).
“Special visceral motoneurons” — also called “branchial motoneurons”— which directly innervate branchial muscles (that motorize the gills in fish and the face and neck in land vertebrates).
“General visceral motoneurons” — "visceral motoneurons" for short— which indirectly innervate smooth muscles of the viscera (like the heart, or the muscles of the arteries): they synapse onto neurons located in ganglia of the autonomic nervous system (sympathetic and parasympathetic), located in the peripheral nervous system (PNS), which themselves directly innervate visceral muscles (and also some gland cells).
In other words:
- the motor command of skeletal and branchial muscles is monosynaptic (involving only one motoneuron —respectively “somatic “ and “branchial”— which synapses onto the muscle).
- the command of visceral muscles is disynaptic (involving two neurons: the “general visceral motoneuron” located in the CNS, which synapses onto a ganglionic neuron, located in the PNS, which synapses onto the muscle).
It could be argued that, in the command of visceral muscles, the ganglionic neuron —parasympathetic or sympathetic— is the real “motoneuron”, being the one that directly innervates the muscle (while the “general visceral motoneuron” is, strictly speaking, a “preganglionic” neuron). But, for historical reasons, the term motoneuron is reserved for the CNS neuron.
All motoneurons are cholinergic (that is, release the neurotransmitter acetylcholine). Parasympathetic ganglionic neurons are also cholinergic, while most sympathetic ganglionic neurons are noradrenergic (that is, release the neurotransmitter noradrenaline). (see Table)
# Function
The interface between a motoneuron and muscle fiber is a specialized synapse called the neuromuscular junction. Upon adequate stimulation, the motoneuron releases a flood of neurotransmitters that bind to postsynaptic receptors and triggers a response in the muscle fiber.
- In invertebrates, depending on the neurotransmitter released and the type of receptor it binds, the response in the muscle fiber could either be excitatory or inhibitory.
- For vertebrates, however, the response of a muscle fiber to a neurotransmitter can only be excitatory, in other words, contractile. Muscle relaxation and inhibition of muscle contraction in verterbrates is obtained only by inhibition of the motoneuron itself. Although muscle innervation may eventually play a role in the maturation of motor activity. This is why muscle relaxants work by acting on the motoneurons that innervate muscles (by decreasing their electrophysiological activity) or on cholinergic neuromuscular junctions, rather than on the muscles themselves.
# Somatic motoneurons
Somatic motoneurons are further subdivided into two types: alpha efferent neurons and gamma efferent neurons. (Both types are called efferent to indicate the flow of information from the central nervous system (CNS) to the periphery.)
- Alpha motoneurons innervate extrafusal muscle fibers (typically referred to simply as muscle fibers) located throughout the muscle.
- Gamma motoneurons innervate intrafusal muscle fibers found within the muscle spindle.
In addition to voluntary skeletal muscle contraction, alpha motoneurons also contribute to muscle tone, the continuous force generated by noncontracting muscle to oppose stretching. When a muscle is stretched, sensory neurons within the muscle spindle detect the degree of stretch and send a signal to the CNS. The CNS activates alpha motoneurons in the spinal cord which cause extrafusal muscle fibers to contract and thereby resist further stretching. This process is also called the stretch reflex.
Gamma motoneurons regulate the sensitivity of the spindle to muscle stretching. With activation of gamma neurons, intrafusal muscle fibers contract so that only a small stretch is required to activate spindle sensory neurons and the stretch reflex.
# Motor units
A single motoneuron may synapse with one or more muscle fibers. The motoneuron and all of the muscle fibers to which it connects is a motor unit. | Motor neuron
Template:Infobox neuron
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In vertebrates, the term motor neuron (or motoneuron) classically applies to neurons located in the central nervous system (CNS) which project their axons outside the CNS and directly or indirectly control muscles. Motor neuron is often synonymous with efferent neuron.
# Anatomy and physiology
According to their targets, motoneurons are classified into three broad categories:
"Somatic motoneurons", which directly innervate skeletal muscles, involved in locomotion (such as muscles of the limbs, abdominal and intercostal muscles).
“Special visceral motoneurons” — also called “branchial motoneurons”— which directly innervate branchial muscles (that motorize the gills in fish and the face and neck in land vertebrates).
“General visceral motoneurons” — "visceral motoneurons" for short— which indirectly innervate smooth muscles of the viscera (like the heart, or the muscles of the arteries): they synapse onto neurons located in ganglia of the autonomic nervous system (sympathetic and parasympathetic), located in the peripheral nervous system (PNS), which themselves directly innervate visceral muscles (and also some gland cells).
In other words:
- the motor command of skeletal and branchial muscles is monosynaptic (involving only one motoneuron —respectively “somatic “ and “branchial”— which synapses onto the muscle).
- the command of visceral muscles is disynaptic (involving two neurons: the “general visceral motoneuron” located in the CNS, which synapses onto a ganglionic neuron, located in the PNS, which synapses onto the muscle).
It could be argued that, in the command of visceral muscles, the ganglionic neuron —parasympathetic or sympathetic— is the real “motoneuron”, being the one that directly innervates the muscle (while the “general visceral motoneuron” is, strictly speaking, a “preganglionic” neuron). But, for historical reasons, the term motoneuron is reserved for the CNS neuron.
All motoneurons are cholinergic (that is, release the neurotransmitter acetylcholine). Parasympathetic ganglionic neurons are also cholinergic, while most sympathetic ganglionic neurons are noradrenergic (that is, release the neurotransmitter noradrenaline). (see Table)
# Function
The interface between a motoneuron and muscle fiber is a specialized synapse called the neuromuscular junction. Upon adequate stimulation, the motoneuron releases a flood of neurotransmitters that bind to postsynaptic receptors and triggers a response in the muscle fiber.
- In invertebrates, depending on the neurotransmitter released and the type of receptor it binds, the response in the muscle fiber could either be excitatory or inhibitory.
- For vertebrates, however, the response of a muscle fiber to a neurotransmitter can only be excitatory, in other words, contractile. Muscle relaxation and inhibition of muscle contraction in verterbrates is obtained only by inhibition of the motoneuron itself. Although muscle innervation may eventually play a role in the maturation of motor activity. This is why muscle relaxants work by acting on the motoneurons that innervate muscles (by decreasing their electrophysiological activity) or on cholinergic neuromuscular junctions, rather than on the muscles themselves.
# Somatic motoneurons
Somatic motoneurons are further subdivided into two types: alpha efferent neurons and gamma efferent neurons. (Both types are called efferent to indicate the flow of information from the central nervous system (CNS) to the periphery.)
- Alpha motoneurons innervate extrafusal muscle fibers (typically referred to simply as muscle fibers) located throughout the muscle.
- Gamma motoneurons innervate intrafusal muscle fibers found within the muscle spindle.
In addition to voluntary skeletal muscle contraction, alpha motoneurons also contribute to muscle tone, the continuous force generated by noncontracting muscle to oppose stretching. When a muscle is stretched, sensory neurons within the muscle spindle detect the degree of stretch and send a signal to the CNS. The CNS activates alpha motoneurons in the spinal cord which cause extrafusal muscle fibers to contract and thereby resist further stretching. This process is also called the stretch reflex.
Gamma motoneurons regulate the sensitivity of the spindle to muscle stretching. With activation of gamma neurons, intrafusal muscle fibers contract so that only a small stretch is required to activate spindle sensory neurons and the stretch reflex.
# Motor units
A single motoneuron may synapse with one or more muscle fibers. The motoneuron and all of the muscle fibers to which it connects is a motor unit. | https://www.wikidoc.org/index.php/Motoneuron | |
08189d8a922fd66813257782dc90196604bf86c4 | wikidoc | Mouth mirror | Mouth mirror
# Overview
A mouth mirror or dentist's mirror is an instrument in dentistry commonly used in the dental armamentarium. The head of the mirror is usually round, and the most common sizes used are the No 4 and No 5. A No. 2 is sometimes used when a smaller mirror is needed, such as when working on posterior teeth with a dental dam in place. The mouth mirror has a wide range of uses. Three of its most important functions are allowing indirect vision by the dental health care provider, reflecting light onto desired surfaces, and retraction of soft tissues.
Indirect vision is needed in certain locations of the mouth where visibility is difficult or impossible. The posterior (or lingual) surfaces of the anterior maxillary teeth is a notable area where mouth mirrors are often employed. Other areas of the mouth can be viewed more readily with the mouth mirror, even though it would be possible to see them if the dentist or dental hygienist adjusted their body into a poor position. Without the mouth mirror, poor body positioning would occur daily and lead to chronic musculo-skeletal problems, especially of the back and neck.
There are other areas of the mouth where lighting is difficult, even with the over head lights used regularly in dental offices. In these instances, the mouth mirror is used to reflect light onto those surfaces. This is especially useful if the mirror is simultaneously being used for indirect vision of an obscure area.
Additionally, the mouth mirror is used to retract tissues, such as the tongue or cheeks, to gain better visualization of the teeth.
Dentist's mirrors are also commonly used by engineers to allow vision in tight spaces and around corners in equipment. They are a common tool in optics and laser labs as well. | Mouth mirror
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A mouth mirror or dentist's mirror is an instrument in dentistry commonly used in the dental armamentarium. The head of the mirror is usually round, and the most common sizes used are the No 4 and No 5. A No. 2 is sometimes used when a smaller mirror is needed, such as when working on posterior teeth with a dental dam in place. The mouth mirror has a wide range of uses. Three of its most important functions are allowing indirect vision by the dental health care provider, reflecting light onto desired surfaces, and retraction of soft tissues.
Indirect vision is needed in certain locations of the mouth where visibility is difficult or impossible. The posterior (or lingual) surfaces of the anterior maxillary teeth is a notable area where mouth mirrors are often employed. Other areas of the mouth can be viewed more readily with the mouth mirror, even though it would be possible to see them if the dentist or dental hygienist adjusted their body into a poor position. Without the mouth mirror, poor body positioning would occur daily and lead to chronic musculo-skeletal problems, especially of the back and neck.
There are other areas of the mouth where lighting is difficult, even with the over head lights used regularly in dental offices. In these instances, the mouth mirror is used to reflect light onto those surfaces. This is especially useful if the mirror is simultaneously being used for indirect vision of an obscure area.
Additionally, the mouth mirror is used to retract tissues, such as the tongue or cheeks, to gain better visualization of the teeth.
Dentist's mirrors are also commonly used by engineers to allow vision in tight spaces and around corners in equipment. They are a common tool in optics and laser labs as well. | https://www.wikidoc.org/index.php/Mouth_mirror | |
cf879b443464cf304ab62d0b7d7e10d1aecac2ec | wikidoc | Moving pages | Moving pages
# Overview
There are several reasons why you might wish to rename a page (one that you have found or created):
- The title has been misspelled.
- The title does not follow the wiki's naming conventions
- The scope of the article has been reduced, extended or otherwise changed.
The terms "rename" and "move" mean the same in this context. They just refer to different models for picturing the operation:
- rename: keep the page but give it another name; the page history is now attached to the new name; a new page with the old name is created which redirects to the new name and whose page history records the renaming.
- move: move the contents and the page history to a new page; change the old page into a redirect; change the page history into one that only records the renaming.
Since the system marks the page with the old name as new page, it applies the first of the two models. This model avoids "changing the history", a kind of "historical revisionism". The move is shown in the history of the page (i.e. under the new name), although, oddly, the supplied reason of the move is only shown in the history under the old page name.
Even though the pages in all namespaces have a "move" link, a page can not be moved if it is in the image or category namespace. To change the name of an image, one needs to upload it again, and copy the image description. To change the name of a category, one needs to change all category tags, and copy the editable part.
# How to
Note that you have to be logged in to rename a page this way; regarding the set preferences:
- there is no button for this in the nostalgia skin;
- the button is in the quickbar, so this must be on.
With the correct page displayed, click on the "Move" tab near the top of the page. You'll be asked for a new name for the page, and given the option to also move the page's talk page. NOTE: Unless you know what you're doing, it's safest to say yes. The reason for the move can be given, like an edit summary.
Click the "move page" button and the page will be renamed to the new title. The old title will become a redirect page, so any links to the old title will still go to the new page. However, note that double redirects (pages that redirect to the original page), will not automatically follow to the new page, so you will have to refer them manually (as explained below)
# Page histories
The "move page" function keeps the entire edit history of the page, before and after the move, in one place, as if the page were always named that way. So, you should never just move a page by cutting all the text out of one page, and pasting it into a new one; old revisions, notes, and attributions are much harder to keep track of if you do that. (But you may have to if, for instance, you're splitting a page into multiple topics. If you do, please include a note in the new pages's edit summary and talk page stating where you took the text from.)
The move itself is shown in the edit history of the page with the old title.
## Moving redirect pages
A page that is a redirect can be moved like any other page. This is however not advised while it has the same detrimental effect on page history as copy-pasting content to a new page, and making the old page a redirect: when moving a redirect page to a new page name, the redirect on the old page (now directing to the new redirect page) will have to be changed in order to avoid double redirects. So the content of the old page will no longer redirect to the page containing the history of that old page. The only effect is that the whereabouts of the page history of the old page (now seemingly a "recently created page") are a bit trickier to find, while on the other hand the new page has a history attached to it not clarifying why it would need to be a redirect page.
If a redirect page does not redirect to the page it would need to be redirecting to, the only viable strategy that respects page histories is to adapt the redirect on that page, without moving the page.
# Moving over a redirect
If the new title already exists but is just a redirect to the old title, with just one line in the page history, the creation of the redirect, then you can rename the page. The most common case in which this applies is that of re-renaming a page back to its original name. As mentioned, this works only if the redirect that was automatically created in the first renaming, has not been edited.
The result is that the history of the page is preserved (note that you may have to refresh the history page on your browser), but without any sign of the two moves. The edit history of the page with the intermediate title shows the latest move only. The information about the first move (including user name, date and time) is lost: it is no longer in any page history or on any watchlist or Related Changes page, and not even in User contributions; only if the first move has been recent enough, then it is still available in the Recent Changes; how long depends on the edit activity on the site; e.g. one may be able to retrieve the edit lines of the last 2000 edits, which may cover months or just a few hours. To avoid loss of information, copy the edit line concerned to one of the talk pages. This has to be done before the second move, using the page history of the page with the original name; if the second move is soon enough after the first move, it can also be done afterwards, using Recent Changes.
The information about the second move is more complete in the Recent Changes than in the edit history of the page with the intermediate title: it mentions "B moved to A over redirect".
More moves back and forth are possible, and always the page history of the current title does not show any moves, and that of the other title only contains the edit line of the latest move. There is no record at all of a "move war" (except again, on Recent Changes) unless documented on the talk pages.
Earlier there was a bug, which has been fixed but not retroactively, as follows:
# Other notes
If the new title already exists and isn't just a redirect to the old title, with no history, the wiki will tell you that you can't rename the page. You'll either have to manually merge the two pages together, or -- only if there's no real content in the page -- list it on Moderation/Speedy Deletions in order to make room for moving the page.
Another thing to remember is that redirects to redirects aren't automatically followed (this prevents infinite loops and spaghetti linking). Always check the What links here for your page, and if there are multiple levels of redirects, go fix the links to point to the new location directly. But this can be troublesome because your new moving might be reverted soon. Take some time to make sure there is no objection to your moving; always check the talk page first.
Avoid moving a page while the edit box of the corresponding Talk page is open: when you hit "Save page" you overwrite the redirect to the new talk page (you do not get the usual warning that the page has been edited while your edit box was open) and get a duplication of the contents of the talk page, with your latest addition added to the old instead of the new one.
It is useful to copy the message "Page ... moved to ..." to the new talk page, especially if there has been discussion about the name of the page.
# Undoing a move
Normally, to undo a move from page A to page B, simply:
- move page B back to page A
- list page B (now a history-free redirect) on Moderation/Speedy Deletions
The software requires that, however, the redirect be pointing to the page you're moving it from. Therefore, if a Vandal moved Page A to Page B to Page C, you would have to:
- move page C to page B
- move page B to page A
This doesn't work: move page C to page A.
If page A has subsequently been edited, or the move software is behaving weirdly, only an admin can sort things out:
- delete page A (make sure it has no useful history - you may wish to add an explicit author credit on a talk page to compensate)
- move page B to page A.
- delete page B (should be a history-free redirect to page A)
"Move wars" are highly unproductive, and leave vast numbers of pointless redirects littering the place, which some poor soul will have to fix.
# Swapping two pages
To swap pages A and B, including history:
- Move page A to page C (previously non-existing)
- list A on Moderation/Deletions
- Move page B to page A (allowed because A is deleted)
- delete B as above
- Move page C to page B (allowed because B is deleted)
- delete C as above | Moving pages
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
There are several reasons why you might wish to rename a page (one that you have found or created):
- The title has been misspelled.
- The title does not follow the wiki's naming conventions
- The scope of the article has been reduced, extended or otherwise changed.
The terms "rename" and "move" mean the same in this context. They just refer to different models for picturing the operation:
- rename: keep the page but give it another name; the page history is now attached to the new name; a new page with the old name is created which redirects to the new name and whose page history records the renaming.
- move: move the contents and the page history to a new page; change the old page into a redirect; change the page history into one that only records the renaming.
Since the system marks the page with the old name as new page, it applies the first of the two models. This model avoids "changing the history", a kind of "historical revisionism". The move is shown in the history of the page (i.e. under the new name), although, oddly, the supplied reason of the move is only shown in the history under the old page name.
Even though the pages in all namespaces have a "move" link, a page can not be moved if it is in the image or category namespace. To change the name of an image, one needs to upload it again, and copy the image description. To change the name of a category, one needs to change all category tags, and copy the editable part.
# How to
Note that you have to be logged in to rename a page this way; regarding the set preferences:
- there is no button for this in the nostalgia skin;
- the button is in the quickbar, so this must be on.
With the correct page displayed, click on the "Move" tab near the top of the page. You'll be asked for a new name for the page, and given the option to also move the page's talk page. NOTE: Unless you know what you're doing, it's safest to say yes. The reason for the move can be given, like an edit summary.
Click the "move page" button and the page will be renamed to the new title. The old title will become a redirect page, so any links to the old title will still go to the new page. However, note that double redirects (pages that redirect to the original page), will not automatically follow to the new page, so you will have to refer them manually (as explained below)
# Page histories
The "move page" function keeps the entire edit history of the page, before and after the move, in one place, as if the page were always named that way. So, you should never just move a page by cutting all the text out of one page, and pasting it into a new one; old revisions, notes, and attributions are much harder to keep track of if you do that. (But you may have to if, for instance, you're splitting a page into multiple topics. If you do, please include a note in the new pages's edit summary and talk page stating where you took the text from.)
The move itself is shown in the edit history of the page with the old title.
## Moving redirect pages
A page that is a redirect can be moved like any other page. This is however not advised while it has the same detrimental effect on page history as copy-pasting content to a new page, and making the old page a redirect: when moving a redirect page to a new page name, the redirect on the old page (now directing to the new redirect page) will have to be changed in order to avoid double redirects. So the content of the old page will no longer redirect to the page containing the history of that old page. The only effect is that the whereabouts of the page history of the old page (now seemingly a "recently created page") are a bit trickier to find, while on the other hand the new page has a history attached to it not clarifying why it would need to be a redirect page.
If a redirect page does not redirect to the page it would need to be redirecting to, the only viable strategy that respects page histories is to adapt the redirect on that page, without moving the page.
# Moving over a redirect
If the new title already exists but is just a redirect to the old title, with just one line in the page history, the creation of the redirect, then you can rename the page. The most common case in which this applies is that of re-renaming a page back to its original name. As mentioned, this works only if the redirect that was automatically created in the first renaming, has not been edited.
The result is that the history of the page is preserved (note that you may have to refresh the history page on your browser), but without any sign of the two moves. The edit history of the page with the intermediate title shows the latest move only. The information about the first move (including user name, date and time) is lost: it is no longer in any page history or on any watchlist or Related Changes page, and not even in User contributions; only if the first move has been recent enough, then it is still available in the Recent Changes; how long depends on the edit activity on the site; e.g. one may be able to retrieve the edit lines of the last 2000 edits, which may cover months or just a few hours. To avoid loss of information, copy the edit line concerned to one of the talk pages. This has to be done before the second move, using the page history of the page with the original name; if the second move is soon enough after the first move, it can also be done afterwards, using Recent Changes.
The information about the second move is more complete in the Recent Changes than in the edit history of the page with the intermediate title: it mentions "B moved to A over redirect".
More moves back and forth are possible, and always the page history of the current title does not show any moves, and that of the other title only contains the edit line of the latest move. There is no record at all of a "move war" (except again, on Recent Changes) unless documented on the talk pages.
Earlier there was a bug, which has been fixed but not retroactively, as follows:
# Other notes
If the new title already exists and isn't just a redirect to the old title, with no history, the wiki will tell you that you can't rename the page. You'll either have to manually merge the two pages together, or -- only if there's no real content in the page -- list it on Moderation/Speedy Deletions in order to make room for moving the page.
Another thing to remember is that redirects to redirects aren't automatically followed (this prevents infinite loops and spaghetti linking). Always check the What links here for your page, and if there are multiple levels of redirects, go fix the links to point to the new location directly. But this can be troublesome because your new moving might be reverted soon. Take some time to make sure there is no objection to your moving; always check the talk page first.
Avoid moving a page while the edit box of the corresponding Talk page is open: when you hit "Save page" you overwrite the redirect to the new talk page (you do not get the usual warning that the page has been edited while your edit box was open) and get a duplication of the contents of the talk page, with your latest addition added to the old instead of the new one.
It is useful to copy the message "Page ... moved to ..." to the new talk page, especially if there has been discussion about the name of the page.
# Undoing a move
Normally, to undo a move from page A to page B, simply:
- move page B back to page A
- list page B (now a history-free redirect) on Moderation/Speedy Deletions
The software requires that, however, the redirect be pointing to the page you're moving it from. Therefore, if a Vandal moved Page A to Page B to Page C, you would have to:
- move page C to page B
- move page B to page A
This doesn't work: move page C to page A.
If page A has subsequently been edited, or the move software is behaving weirdly, only an admin can sort things out:
- delete page A (make sure it has no useful history - you may wish to add an explicit author credit on a talk page to compensate)
- move page B to page A.
- delete page B (should be a history-free redirect to page A)
"Move wars" are highly unproductive, and leave vast numbers of pointless redirects littering the place, which some poor soul will have to fix.
# Swapping two pages
To swap pages A and B, including history:
- Move page A to page C (previously non-existing)
- list A on Moderation/Deletions
- Move page B to page A (allowed because A is deleted)
- delete B as above
- Move page C to page B (allowed because B is deleted)
- delete C as above
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Moving_a_page | |
dbd3ce414a48ded42ff35b3828b56309660d5500 | wikidoc | MuSK protein | MuSK protein
MuSK (for Muscle-Specific Kinase) is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin.
# MuSK signaling
Upon activation by its ligand agrin, MuSK signals via the proteins called casein kinase 2 (CK2), Dok-7 and rapsyn, to induce "clustering" of acetylcholine receptors (AChR). Both CK2 and Dok-7 are required for MuSK-induced formation of the neuromuscular junction, since mice lacking Dok-7 failed to form AChR clusters or neuromuscular synapses, and since downregulation of CK2 also impedes recruitment of AChR to the primary MuSK scaffold. In addition to the proteins mentioned, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.
# Role in disease
Antibodies directed against this protein (Anti-MuSK autoantibodies) are found in those patients with myasthenia gravis not demonstrating antibodies to the acetylcholine receptor (sero-negative). The disease still appears to result in an autoimmune loss of acetylcholine receptor activity, but the phenotype of these patients appears to be different from those of many other myasthenic patients: more likely women, less eye involvement, more likely to have weakness of neck and oropharynx, and more likely to be African-American in ethnicity. | MuSK protein
MuSK (for Muscle-Specific Kinase) is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin.
# MuSK signaling
Upon activation by its ligand agrin, MuSK signals via the proteins called casein kinase 2 (CK2),[1] Dok-7[2] and rapsyn, to induce "clustering" of acetylcholine receptors (AChR). Both CK2 and Dok-7 are required for MuSK-induced formation of the neuromuscular junction, since mice lacking Dok-7 failed to form AChR clusters or neuromuscular synapses, and since downregulation of CK2 also impedes recruitment of AChR to the primary MuSK scaffold. In addition to the proteins mentioned, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.
# Role in disease
Antibodies directed against this protein (Anti-MuSK autoantibodies) are found in those patients with myasthenia gravis not demonstrating antibodies to the acetylcholine receptor (sero-negative).[3] The disease still appears to result in an autoimmune loss of acetylcholine receptor activity,[4] but the phenotype of these patients appears to be different from those of many other myasthenic patients: more likely women, less eye involvement, more likely to have weakness of neck and oropharynx, and more likely to be African-American in ethnicity. | https://www.wikidoc.org/index.php/MuSK | |
73ca74b7d1b2fb2248b028505be736bb90b348c8 | wikidoc | Muconic acid | Muconic acid
# Overview
Muconic acid is a dicarboxylic acid. There are three isomeric forms designated trans,trans-muconic acid, cis,trans-muconic acid, and cis,cis-muconic acid which differ by the geometry around the double bonds.
trans,trans-Muconic acid is a metabolite of benzene in humans. The determination of its concentration in urine is therefore used as a biomarker of occupational or environmental exposure to benzene. Synthetically, trans,trans-muconic acid can be prepared from adipic acid.
cis,cis-Muconic acid is produced by some bacteria by the enzymatic degradation of various aromatic chemical compounds. | Muconic acid
Template:Chembox new
# Overview
Muconic acid is a dicarboxylic acid. There are three isomeric forms designated trans,trans-muconic acid, cis,trans-muconic acid, and cis,cis-muconic acid which differ by the geometry around the double bonds.
trans,trans-Muconic acid is a metabolite of benzene in humans. The determination of its concentration in urine is therefore used as a biomarker of occupational or environmental exposure to benzene.[1][2] Synthetically, trans,trans-muconic acid can be prepared from adipic acid.[3]
cis,cis-Muconic acid is produced by some bacteria by the enzymatic degradation of various aromatic chemical compounds. | https://www.wikidoc.org/index.php/Muconic_acid | |
d0a10c96dfbe4ed78318614d8496682a4010c6d6 | wikidoc | Sly syndrome | Sly syndrome
# Overview
Mucopolysaccharidosis Type VII or Sly syndrome (named after its discoverer William Sly in 1969) is also sometimes called MPS. The defective gene lies on chromosome 7. MPS is transmitted as an autosomal recessive trait.
It is an extremely rare inherited metabolic disorder characterized by a deficiency of the enzyme β-glucuronidase, a lysosomal enzyme. Sly syndrome belongs to a group of disorders known as the mucopolysaccharidoses, which are lysosomal storage diseases. In Sly syndrome, the deficiency in β-glucuronidase leads to the accumulation of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body.
# Symptoms
The symptoms of Sly syndrome are similar to those of Hurler syndrome (MPS I). The symptoms include:
- in the head, neck, and face: coarse (Hurler-like) facies and macrocephaly, frontal prominence, premature closure of sagittal lambdoid sutures, and J-shaped sella turcica
- in the eyes: corneal opacity and iris colobmata
- in the nose: anteverted nostrils and a depressed nostril bridge
- in the mouth and oral areas: prominent alveolar processes and cleft palate
- in the thorax: usually pectus carinatum or exacavatum and oar-shaped ribs; also a protruding abdomen and inguinal or umbilical hernia
- in the extremities: talipes, an underdeveloped ilium, aseptic necrosis of femoral head, and shortness of tubular bones occurs
- in the spine: kyphosis or scoliosis and hook-like deformities in thoracic and lumbar vertebrate
- in the bones: dysotosis multiplex
In addition recurrent pulmonary infections occur. Hepatomegaly occurs in the gastrointestinal system. Splenomegaly occurs in the hematopoietic system. Inborn mucopolysaccharide metabolic disorders due to β-glucuronidase deficiency with granular inclusions in granulocytes occurs in the biochemical and metabolic systems. Growth and motor skills are affected, and mental retardation also occurs.
# Symptoms
MPS type VII occurs in only 1:250,000 people.
# Other names
Mucopolysaccahridosis Type VII is also known as β-glucurondinase deficiency, β-glucurondinase deficiency mucopolysaccahridosis,
GUSB deficiency, mucopolysaccahride storage disease VII, MCA, and MR. | Sly syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Mucopolysaccharidosis Type VII or Sly syndrome (named after its discoverer William Sly in 1969) is also sometimes called MPS. The defective gene lies on chromosome 7. MPS is transmitted as an autosomal recessive trait.
It is an extremely rare inherited metabolic disorder characterized by a deficiency of the enzyme β-glucuronidase, a lysosomal enzyme. Sly syndrome belongs to a group of disorders known as the mucopolysaccharidoses, which are lysosomal storage diseases. In Sly syndrome, the deficiency in β-glucuronidase leads to the accumulation of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body.
# Symptoms
The symptoms of Sly syndrome are similar to those of Hurler syndrome (MPS I). The symptoms include:
- in the head, neck, and face: coarse (Hurler-like) facies and macrocephaly, frontal prominence, premature closure of sagittal lambdoid sutures, and J-shaped sella turcica
- in the eyes: corneal opacity and iris colobmata
- in the nose: anteverted nostrils and a depressed nostril bridge
- in the mouth and oral areas: prominent alveolar processes and cleft palate
- in the thorax: usually pectus carinatum or exacavatum and oar-shaped ribs; also a protruding abdomen and inguinal or umbilical hernia
- in the extremities: talipes, an underdeveloped ilium, aseptic necrosis of femoral head, and shortness of tubular bones occurs
- in the spine: kyphosis or scoliosis and hook-like deformities in thoracic and lumbar vertebrate
- in the bones: dysotosis multiplex
In addition recurrent pulmonary infections occur. Hepatomegaly occurs in the gastrointestinal system. Splenomegaly occurs in the hematopoietic system. Inborn mucopolysaccharide metabolic disorders due to β-glucuronidase deficiency with granular inclusions in granulocytes occurs in the biochemical and metabolic systems. Growth and motor skills are affected, and mental retardation also occurs.
# Symptoms
MPS type VII occurs in only 1:250,000 people.
# Other names
Mucopolysaccahridosis Type VII is also known as β-glucurondinase deficiency, β-glucurondinase deficiency mucopolysaccahridosis,
GUSB deficiency, mucopolysaccahride storage disease VII, MCA, and MR.
# External links
- The Matthew Evangelista Foundation Inc. is a charity that is trying to raise money to find treatment for Sly syndrome.
- http://www.mpssociety.org/
Template:Metabolic pathology
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Mucopolysaccharidosis_Type_VII | |
2d287088a5e175fe0dca48e0ebdb3bf68a48bb01 | wikidoc | Mucous gland | Mucous gland
Mucous glands, found in several different parts of the body, typically stain lighter than serous glands during standard histological preparation. Most are multicellular, but goblet cell are single-celled glands.
# Mucous salivary glands
The mucous salivary glands are similar in structure to the labial and buccal glands.
They are found especially at the back part behind the vallate papillae, but are also present at the apex and marginal parts.
In this connection the anterior lingual glands (Blandin or Nuhn) require special notice.
They are situated on the under surface of the apex of the tongue, one on either side of the frenulum, where they are covered by a fasciculus of muscular fibers derived from the Styloglossus and Longitudinalis inferior.
They are from 12 to 25 mm. long, and about 8 mm. broad, and each opens by three or four ducts on the under surface of the apex. | Mucous gland
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
Mucous glands, found in several different parts of the body, typically stain lighter than serous glands during standard histological preparation. Most are multicellular, but goblet cell are single-celled glands.
# Mucous salivary glands
The mucous salivary glands are similar in structure to the labial and buccal glands.
They are found especially at the back part behind the vallate papillae, but are also present at the apex and marginal parts.
In this connection the anterior lingual glands (Blandin or Nuhn) require special notice.
They are situated on the under surface of the apex of the tongue, one on either side of the frenulum, where they are covered by a fasciculus of muscular fibers derived from the Styloglossus and Longitudinalis inferior.
They are from 12 to 25 mm. long, and about 8 mm. broad, and each opens by three or four ducts on the under surface of the apex. | https://www.wikidoc.org/index.php/Mucous_gland | |
c6ec293cff6551238fa9eb7c539346009aa1f430 | wikidoc | Muscle spasm | Muscle spasm
# Overview
A spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes. Spasmodic muscle contraction may also be due to a large number of medical conditions, however, including the dystonias.
By extension, a spasm is temporary burst of energy, activity, or emotion.
A subtype of spasms is colic, an episodic pain due to spasms of smooth muscle in a particular organ (e.g. the bile duct). A characteristic of colic is the sensation of having to move about, and the pain may induce nausea or vomiting if severe. Series of spasms or permanent spasms are called a spasmism.
In very severe cases, the spasm can induce muscular contractions that are more forceful than the sufferer could generate under normal circumstances. This can lead to torn tendons and ligaments.
Some argue that hysterical strength is a type of spasm induced by the brain under extreme circumstances.
# Causes
- Drugs side effect: Hydrochlorothiazide | Muscle spasm
Template:SignSymptom infobox
# Overview
A spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes. Spasmodic muscle contraction may also be due to a large number of medical conditions, however, including the dystonias.
By extension, a spasm is temporary burst of energy, activity, or emotion.
A subtype of spasms is colic, an episodic pain due to spasms of smooth muscle in a particular organ (e.g. the bile duct). A characteristic of colic is the sensation of having to move about, and the pain may induce nausea or vomiting if severe. Series of spasms or permanent spasms are called a spasmism.
In very severe cases, the spasm can induce muscular contractions that are more forceful than the sufferer could generate under normal circumstances. This can lead to torn tendons and ligaments.
Some argue that hysterical strength is a type of spasm induced by the brain under extreme circumstances.
# Causes
- Drugs side effect: Hydrochlorothiazide | https://www.wikidoc.org/index.php/Muscle_spasm | |
32bd5e06dad60c327ce925186f8cad035f49b378 | wikidoc | Mutarotation | Mutarotation
# Overview
Mutarotation is the term given to the change in the specific rotation of plane polarized light, when it is passed through an aldohexose (a monosaccharides with six carbon atoms and H-C=O group). Mutarotation refers to the conversion of a pure anomer of a hemiacetal carbohydrate to an equilibrium mixture of two anomers.
As the name suggests, it is the change in rotation ("Muta" means "Change").
Plane polarized light is obtained by passing ordinary light through a nicol prism.
During mutarotation, either α or β forms keep changing into the chain structure periodically to and fro.
Mutarotation also refers to the interconversion between the α and β anomers. However it must be converted to the open chain structure first before it can change conformation to the α or β position.
For example, in glucose, carbon 1 (the aldehyde carbon) is the anomeric carbon. In fructose, carbon 2 (the keto carbon) is anomeric. Unlike the epimers, which are stable under ordinary conditions, anomers interconvert spontaneosly.
de:Mutarotation
it:Mutarotazione
nl:Mutarotatie | Mutarotation
# Overview
Mutarotation is the term given to the change in the specific rotation of plane polarized light, when it is passed through an aldohexose (a monosaccharides with six carbon atoms and H-C=O group). Mutarotation refers to the conversion of a pure anomer of a hemiacetal carbohydrate to an equilibrium mixture of two anomers.
As the name suggests, it is the change in rotation ("Muta" means "Change").
Plane polarized light is obtained by passing ordinary light through a nicol prism.
During mutarotation, either α or β forms keep changing into the chain structure periodically to and fro.
Mutarotation also refers to the interconversion between the α and β anomers. However it must be converted to the open chain structure first before it can change conformation to the α or β position.
For example, in glucose, carbon 1 (the aldehyde carbon) is the anomeric carbon. In fructose, carbon 2 (the keto carbon) is anomeric. Unlike the epimers, which are stable under ordinary conditions, anomers interconvert spontaneosly.
Template:Carbohydrates
de:Mutarotation
it:Mutarotazione
nl:Mutarotatie
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Mutarotation | |
fa7cbfa3a258ef12bdb357d665cd7e435814a2cc | wikidoc | NLP Modeling | NLP Modeling
NLP modeling is a method or strategy of learning that occurs as a function of observing, retaining and replicating patterns of language and behavior observed in others. It is most often associated with the work of Richard Bandler and linguist John Grinder who implemented some of the seminal studies in the area and initiated Neuro-linguistic programming.
# Modeling project
This theory holds that masters of a skill often fail to take into account the implicit processes involved in carrying out complex skills when they are teaching novices. To combat these tendencies, NLP modeling projects are designed to unconsciously assimilate the tacit processes. In order for modeling to be successful, the learner works on minimizing preconceptions with access to the master (although modeling from books, historical records of people's words, or video is not unknown), and engages in unconscious micro-muscle modeling so as to accurately reproduce the desired skill.
A "modeling project" involves spending time studying and observing in depth, discussing, and imitating and practicing many different aspects of the subject's thoughts, feelings, beliefs and behaviors (ie, acting ""as if" the modeler is the expert) until the modeler can replicate these with some consistency and precision. Once this has been achieved, the modeler then refines the target skills by removing certain features to eventually discover the essential features distinguishing average performance and top performance, thus building a learnable/transferable model, and tests it by seeing if it can be taught. The aim of NLP modeling is to discover the elements of what the expert is doing that the expert is not aware of.
The NLP theory behind modeling does not state that anyone can be Einstein. Rather it says that know-how can be separated from the person, documented and transferred experientially, and that the ability to perform the skills can be transferred subject to the modelers own limits, which can change, and improves with practice.
# Detail and examples
Typically a "modeling project" might cover the following sources of behavior:
- Beliefs
- Values
- Internal strategies
- Outcomes
- Sensory perceptions and submodalities
- Physiology (body movement and body language)
- Language patterns
- Fall-back strategies ("what if it isn't working")
- Conscious and unconscious communications
- World view
- Locus of consciousness (ie where ones attention is)
Each of these is individually a deep and rich field; there is no point where one knows everything, but as a process of replication, the goal is met when the modeler has enough parts of the puzzle to piece together and document how the subject seems to be doing his competent skills.
Many trainers stress that fully identifying with the model ("embodied" modeling) is an essential part of the modeling process. However, when NLP practitioners do any modeling at all in practice, it is often Analytic Modeling.
Ideally, the result is that the modeler feels that the information of "how the skill is done" is sufficient, and the rest is practice or external limitation rather than understanding of the process.
Other uses include:
- Modeling how a therapeutic client maintains and engages in their "problem behavior", with the intent of learning enough to change it for the better
- Modeling famous or dead people to gain a sense of how they did what they did, and their views and beliefs which allowed them to do so. (Robert Dilts is a proponent of this process, having described models of notable people such as Jesus of Nazareth, Sherlock Holmes, Albert Einstein and Nikola Tesla)
# Other information
- Robert Dilts and John Grinder argue for a distinction between Analytic Modeling and "NLP modeling" that requires unconscious uptake via imitation. (announced October 17 2005-) | NLP Modeling
Template:Neuro-linguistic programming
NLP modeling is a method or strategy of learning that occurs as a function of observing, retaining and replicating patterns of language and behavior observed in others. It is most often associated with the work of Richard Bandler and linguist John Grinder who implemented some of the seminal studies in the area and initiated Neuro-linguistic programming.[1]
# Modeling project
This theory holds that masters of a skill often fail to take into account the implicit processes involved in carrying out complex skills when they are teaching novices. To combat these tendencies, NLP modeling projects are designed to unconsciously assimilate the tacit processes. In order for modeling to be successful, the learner works on minimizing preconceptions with access to the master (although modeling from books, historical records of people's words, or video is not unknown), and engages in unconscious micro-muscle modeling so as to accurately reproduce the desired skill.
A "modeling project" involves spending time studying and observing in depth, discussing, and imitating and practicing many different aspects of the subject's thoughts, feelings, beliefs and behaviors (ie, acting ""as if" the modeler is the expert) until the modeler can replicate these with some consistency and precision. Once this has been achieved, the modeler then refines the target skills by removing certain features to eventually discover the essential features distinguishing average performance and top performance, thus building a learnable/transferable model, and tests it by seeing if it can be taught. The aim of NLP modeling is to discover the elements of what the expert is doing that the expert is not aware of. [2]
The NLP theory behind modeling does not state that anyone can be Einstein. Rather it says that know-how can be separated from the person, documented and transferred experientially, and that the ability to perform the skills can be transferred subject to the modelers own limits, which can change, and improves with practice.
# Detail and examples
Typically a "modeling project" might cover the following sources of behavior:
- Beliefs
- Values
- Internal strategies
- Outcomes
- Sensory perceptions and submodalities
- Physiology (body movement and body language)
- Language patterns
- Fall-back strategies ("what if it isn't working")
- Conscious and unconscious communications
- World view
- Locus of consciousness (ie where ones attention is)
Each of these is individually a deep and rich field; there is no point where one knows everything, but as a process of replication, the goal is met when the modeler has enough parts of the puzzle to piece together and document how the subject seems to be doing his competent skills.
Many trainers stress that fully identifying with the model ("embodied" modeling) is an essential part of the modeling process. However, when NLP practitioners do any modeling at all in practice, it is often Analytic Modeling.
Ideally, the result is that the modeler feels that the information of "how the skill is done" is sufficient, and the rest is practice or external limitation rather than understanding of the process.
Other uses include:
- Modeling how a therapeutic client maintains and engages in their "problem behavior", with the intent of learning enough to change it for the better
- Modeling famous or dead people to gain a sense of how they did what they did, and their views and beliefs which allowed them to do so. (Robert Dilts is a proponent of this process, having described models of notable people such as Jesus of Nazareth, Sherlock Holmes, Albert Einstein and Nikola Tesla)
# Other information
- Robert Dilts and John Grinder argue for a distinction between Analytic Modeling and "NLP modeling" that requires unconscious uptake via imitation. (announced October 17 2005-[2]) | https://www.wikidoc.org/index.php/NLP_Modeling | |
f3d15e907a2c10583cd0a660b1b46e494485f273 | wikidoc | Neuregulin 1 | Neuregulin 1
Neuregulin 1 or NRG1 is a cell adhesion molecule that in humans is encoded by the NRG1 gene. NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart.
# Structure
Neuregulin 1 (NRG1) was originally identified as a 44-kD glycoprotein that interacts with the NEU/ERBB2 receptor tyrosine kinase to increase its phosphorylation on tyrosine residues. It is known that an extraordinary variety of different isoforms are produced from the NRG1 gene by alternative splicing. These isoforms include heregulins (HRGs), glial growth factors (GGFs) and sensory and motor neuron-derived factor (SMDF). They are tissue-specific and differ significantly in their structure. The HRG isoforms all contain immunoglobulin (Ig) and epidermal growth factor-like (EGF-like) domains. GGF and GGF2 isoforms contain a kringle-like sequence plus Ig and EGF-like domains; and the SMDF isoform shares only the EGF-like domain with other isoforms. The receptors for all NRG1 isoforms are the ERBB family of tyrosine kinase transmembrane receptors. Through their displayed interaction with ERBB receptors, NRG1 isoforms induce the growth and differentiation of epithelial, neuronal, glial, and other types of cells.
# Function
## Synaptic plasticity
Neuregulin 1 is thought to play a role in synaptic plasticity. It has been shown that a loss of Neuregulin 1 within cortical projection neurons results in increased inhibitory connections and reduced synaptic plasticity. Similarly, overexpression of Neuregulin 1 results in disrupted excitatory-inhibitory connections, reduced synaptic plasticity, and abnormal dendritic spine growth. Mutations in human L1 cell adhesion molecules are reported to cause a number of neuronal disorders. In addition, recent research in Drosophila model has also shown Nrg's involvement in regulating dendritic pruning in ddaC neurons in a Rab5/ESCRT-mediated endocytic pathway. Thus, careful regulation of the amount of Neuregulin 1 must be maintained in order to preserve an intricate balance between excitatory and inhibitory connections within the central nervous system (CNS). Any disruption in this inhibitory system may contribute to impaired synaptic plasticity, a symptom endemic in schizophrenic patients.
# Isoforms
At least six major types (different N termini) of neuregulin 1 are known. Six types exist in humans and rodents (type I, II and III NRG1 are expressed in excitatory and inhibitory neurons, as well as astrocytes), and some types (I and IV) can be regulated by neuronal activity.
# Clinical significance
Neuregulin 1-ErbB4 interactions are thought to play a role in the pathological mechanism of schizophrenia. A high-risk deCODE (Icelandic) haplotype was discovered in 2002 on the 5'-end of the gene. The SNP8NRG243177 allele from this haplotype was associated in 2006 with a heightened expression of the Type IV NRG1 in the brains of people suffering from schizophrenia. Further, the NRG1-ErbB4 signalling complex has been highlighted as a potential target for new antipsychotic treatment.
Additionally, Neuregulin 1 has been shown to modulate anxiety-like behaviors. Endogenous Neuregulin 1 may bind to its receptor, ErbB4, expressed on GABAergic neurons within the basolateral amygdala. Administration of exogenous Neuregulin 1 to the basolateral amygdala of anxious mice produced an anxiolytic effect, which has been attributed to the enhancement of GABAergic neurotransmission. Thus, treatments aimed at reducing anxiety, which may contribute to emotional instability in many schizophrenic patients, by targeting the effects of mutations in NRG1 and ERBB4, may yield positive results for those afflicted by both anxiety disorders as well as schizophrenia.
Neuregulin has been shown to be involved in the myelination of central nervous system (CNS) axons. There exist at least two modes of myelination within the CNS—one that is independent of neuronal activity and another that is promoted by the activation of NMDA receptors by glutamate on oligodendrocytes. Neuregulin is involved in the "switching" of oligodendrocytes from the mode of myelination that is independent of neuronal activity to the mode that is dependent upon glutamate binding to NMDA receptors. It is thought that Neuregulin 1 found on axons of CNS neurons interacts with its receptor, ErbB4, to promote the myelination of that axon, and any disruption in this signaling contributes to decreased myelination. Since Neuregulin 1 promotes myelination and is decreased in schizophrenic patients, along with the finding that schizophrenic patients experience white matter deficits, mutations within Neuregulin 1 may underlie cognitive deficits associated with lower white matter integrity, especially within frontotemporal connections.
The protein also has the putative ability to protect the brain from damage induced by stroke. Those with a genetic variant of neuregulin 1 tended to be more creative.
There is evidence that NRG1 is a tumor suppressor gene.
There is also strong evidence that NRG1 plays a critical role in Schwann cell maturation, survival, and motility, important in research related to neurofibromatosis type two (NF2).
## Heart
Neuregulin-1 (NRG-1), a cardioactive growth factor released from endothelial cells, is necessary for cardiac development, structural maintenance, and functional integrity of the heart. NRG-1 and its receptor family ErbB can play a beneficial role in the treatment of chronic heart failure (CHF) by promoting survival of cardiac myocytes, improving sarcomeric structure, balancing Ca2+ homeostasis, and enhancing pumping function. Downstream effectors of NRG-1/ErbB, include cardiac-specific myosin light chain kinase (cMLCK), Protein Phosphatase type 1 (PP1), sarcoplasmic reticulum Ca2+-ATPase 2 (SERCA2), and focal adhesion kinase (FAK). The beneficial effects of neuregulin-1 make recombinant human neuregulin-1 (rhNRG-1) a potential drug for treatment of CHF.
## Maintenance of heart structure
NRG-1 treatment of adult rat ventricular myocytes stimulate the formation of a multiprotein complex between ErbB2, FAK, and p130(CAS), which modulates the restoration of cell–cell contacts between isolated myocytes, allowing for synchronous beating. Furthermore, FAK is also involved in the maintenance of sarcomeric organization, cell survival, and myocyte–myocyte interactions. The sarcomeric effects of NRG-1 protects myocytes against structural disarray induced by stressors, including cytotoxic agents.
## Cardiomyocyte survival under stress
Under conditions of stress, including viral infection, cytotoxic agents, and oxidative stress, activation of NRG-1/ErbB signaling can protect myocardial cells against apoptosis. In contrast to embryonic and neonatal cardiomyocytes, adult myocardial cells are terminally differentiated and have lost the ability to proliferate. Therefore, growth of adult cardiac cells is commonly characterized by hypertrophy and an increased content of contractile proteins. However, studies have shown NRG-1 promotes myocardial regeneration through hyperplasia, and prevents hypertrophy surrounding infarcted areas.
## Restoration of cardiomyocytes
The cMLCK protein is an important regulator of sarcomere assembly through activation of the myosin regulatory light chain, as well as playing a role in heart contractility. In contrast to smooth and skeletal muscle MLCKs, cMLCK expression is restricted to cardiac myocytes. Overexpression of cMLCK increases cell contractility. Treatment of cardiac myocytes with rhNRG-1 significantly upregulated cMLCK expression or activity??? in CHF rat models, together with an improvement in both cardiomyocyte structure and pumping function. Therefore, cMLCK is a downstream protein regulated by NRG-1/ErbB signaling and plays a role in rhNRG-1-mediated improvements in CHF.
## Improvements in cardiac efficiency
Altered calcium homeostasis has been suggested to play a role in the development of heart failure. Modulated by phospholamban (PLB), SERCA2 regulates uptake of Ca2+ into the sarcoplasmic reticulum (SR) from the cytoplasm and contributes to the relaxation of cardiomyocytes. This process is also important for determining the SR Ca2+ load after relaxation and, thus, impacts on contractility.
PP1 dephosphorylates PLB, inhibiting SERCA2 activity. In the failing heart, PP1 expression is upregulated, resulting in increased PLB dephosphorylation and decreased SERCA2 activity. Preliminary studies have revealed that rhNRG-normalizes SERCA function and enhances myocardial contractility through the inhibition of increasedPP1 expression, which leads to increased PLB phosphorylation and activation of SERCA2.
# Interactions
Neuregulin 1 has been shown to interact with ERBB3 and LIMK1.
A schizophrenia associated- missense mutation in Neuregulin 1 has been shown to be associated with changes in cytokine expression using lymphoblastoid cells of heterozygous carriers vs homozygous wild type individuals
Specifically, the missense mutation involves a single nucleotide change of a valine to a leucine within the transmembrane domain of Type 3 Neuregulin 1. It is thought that this single nucleotide change affects the ability of γ-secretase to cleave the intracellular domain (ICD) of the Type 3 isoform of Neureglin 1. That is, the valine to leucine mutation within the transmembrane domain of Type 3 Neuregulin 1 decreases the amount of ICD that γ-secretase is able to cleave. The ICD of Type 3 Neuregulin 1 has been shown to suppress transcription of inflammatory cytokines, including IL-1β, IL-6, IL-10, IL-8, IL12-p70, and TNF-α. Using recombinant ErbB4 to stimulate the cleavage of the intracellular domain of Type 3 Neuregulin 1, a receptor for Type 3 Neuregulin 1, Marballi et al. showed that increased levels of the ICD lead to a decrease in IL-6 levels. Given the involvement of Neuregulin 1 in schizophrenia and the finding that the valine to leucine missense mutation in mice produces working memory deficits, NRG1 seems a likely genetic candidate that confers susceptibility to the development of schizophrenia. | Neuregulin 1
Neuregulin 1 or NRG1 is a cell adhesion molecule that in humans is encoded by the NRG1 gene.[1][2] NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart.[3][4]
# Structure
Neuregulin 1 (NRG1) was originally identified as a 44-kD glycoprotein that interacts with the NEU/ERBB2 receptor tyrosine kinase to increase its phosphorylation on tyrosine residues. It is known that an extraordinary variety of different isoforms are produced from the NRG1 gene by alternative splicing. These isoforms include heregulins (HRGs), glial growth factors (GGFs) and sensory and motor neuron-derived factor (SMDF). They are tissue-specific and differ significantly in their structure. The HRG isoforms all contain immunoglobulin (Ig) and epidermal growth factor-like (EGF-like) domains. GGF and GGF2 isoforms contain a kringle-like sequence plus Ig and EGF-like domains; and the SMDF isoform shares only the EGF-like domain with other isoforms. The receptors for all NRG1 isoforms are the ERBB family of tyrosine kinase transmembrane receptors. Through their displayed interaction with ERBB receptors, NRG1 isoforms induce the growth and differentiation of epithelial, neuronal, glial, and other types of cells.[5]
# Function
## Synaptic plasticity
Neuregulin 1 is thought to play a role in synaptic plasticity. It has been shown that a loss of Neuregulin 1 within cortical projection neurons results in increased inhibitory connections and reduced synaptic plasticity.[6] Similarly, overexpression of Neuregulin 1 results in disrupted excitatory-inhibitory connections, reduced synaptic plasticity, and abnormal dendritic spine growth. Mutations in human L1 cell adhesion molecules are reported to cause a number of neuronal disorders. In addition, recent research in Drosophila model has also shown Nrg's involvement in regulating dendritic pruning in ddaC neurons in a Rab5/ESCRT-mediated endocytic pathway.[7] Thus, careful regulation of the amount of Neuregulin 1 must be maintained in order to preserve an intricate balance between excitatory and inhibitory connections within the central nervous system (CNS). Any disruption in this inhibitory system may contribute to impaired synaptic plasticity, a symptom endemic in schizophrenic patients.
# Isoforms
At least six major types (different N termini) of neuregulin 1 are known.[8] Six types exist in humans and rodents (type I, II and III NRG1 are expressed in excitatory and inhibitory neurons, as well as astrocytes), and some types (I and IV) can be regulated by neuronal activity.[9]
# Clinical significance
Neuregulin 1-ErbB4 interactions are thought to play a role in the pathological mechanism of schizophrenia.[10][11] A high-risk deCODE (Icelandic) haplotype was discovered in 2002 on the 5'-end of the gene.[12] The SNP8NRG243177 allele from this haplotype was associated in 2006 with a heightened expression of the Type IV NRG1 in the brains of people suffering from schizophrenia.[13][14] Further, the NRG1-ErbB4 signalling complex has been highlighted as a potential target for new antipsychotic treatment.[15][16]
Additionally, Neuregulin 1 has been shown to modulate anxiety-like behaviors. Endogenous Neuregulin 1 may bind to its receptor, ErbB4, expressed on GABAergic neurons within the basolateral amygdala. Administration of exogenous Neuregulin 1 to the basolateral amygdala of anxious mice produced an anxiolytic effect, which has been attributed to the enhancement of GABAergic neurotransmission.[17] Thus, treatments aimed at reducing anxiety, which may contribute to emotional instability in many schizophrenic patients, by targeting the effects of mutations in NRG1 and ERBB4, may yield positive results for those afflicted by both anxiety disorders as well as schizophrenia.
Neuregulin has been shown to be involved in the myelination of central nervous system (CNS) axons.[18] There exist at least two modes of myelination within the CNS—one that is independent of neuronal activity and another that is promoted by the activation of NMDA receptors by glutamate on oligodendrocytes. Neuregulin is involved in the "switching" of oligodendrocytes from the mode of myelination that is independent of neuronal activity to the mode that is dependent upon glutamate binding to NMDA receptors. It is thought that Neuregulin 1 found on axons of CNS neurons interacts with its receptor, ErbB4, to promote the myelination of that axon, and any disruption in this signaling contributes to decreased myelination.[19] Since Neuregulin 1 promotes myelination and is decreased in schizophrenic patients, along with the finding that schizophrenic patients experience white matter deficits, mutations within Neuregulin 1 may underlie cognitive deficits associated with lower white matter integrity, especially within frontotemporal connections.
The protein also has the putative ability to protect the brain from damage induced by stroke.[20] Those with a genetic variant of neuregulin 1 tended to be more creative.[21]
There is evidence that NRG1 is a tumor suppressor gene.[22]
There is also strong evidence that NRG1 plays a critical role in Schwann cell maturation, survival, and motility,[23] important in research related to neurofibromatosis type two (NF2).[citation needed]
## Heart
Neuregulin-1 (NRG-1), a cardioactive growth factor released from endothelial cells, is necessary for cardiac development, structural maintenance, and functional integrity of the heart. NRG-1 and its receptor family ErbB can play a beneficial role in the treatment of chronic heart failure (CHF) by promoting survival of cardiac myocytes, improving sarcomeric structure, balancing Ca2+ homeostasis, and enhancing pumping function. Downstream effectors of NRG-1/ErbB, include cardiac-specific myosin light chain kinase (cMLCK), Protein Phosphatase type 1 (PP1), sarcoplasmic reticulum Ca2+-ATPase 2 (SERCA2), and focal adhesion kinase (FAK). The beneficial effects of neuregulin-1 make recombinant human neuregulin-1 (rhNRG-1) a potential drug for treatment of CHF.[24]
## Maintenance of heart structure
NRG-1 treatment of adult rat ventricular myocytes stimulate the formation of a multiprotein complex between ErbB2, FAK, and p130(CAS), which modulates the restoration of cell–cell contacts between isolated myocytes, allowing for synchronous beating.[25] Furthermore, FAK is also involved in the maintenance of sarcomeric organization, cell survival, and myocyte–myocyte interactions.[26] The sarcomeric effects of NRG-1 protects myocytes against structural disarray induced by stressors, including cytotoxic agents.[27]
## Cardiomyocyte survival under stress
Under conditions of stress, including viral infection, cytotoxic agents, and oxidative stress, activation of NRG-1/ErbB signaling can protect myocardial cells against apoptosis.[25] In contrast to embryonic and neonatal cardiomyocytes, adult myocardial cells are terminally differentiated and have lost the ability to proliferate. Therefore, growth of adult cardiac cells is commonly characterized by hypertrophy and an increased content of contractile proteins.[28] However, studies have shown NRG-1 promotes myocardial regeneration through hyperplasia, and prevents hypertrophy surrounding infarcted areas.[29]
## Restoration of cardiomyocytes
The cMLCK protein is an important regulator of sarcomere assembly through activation of the myosin regulatory light chain, as well as playing a role in heart contractility.[30][31] In contrast to smooth and skeletal muscle MLCKs, cMLCK expression is restricted to cardiac myocytes.[31] Overexpression of cMLCK increases cell contractility.[30] Treatment of cardiac myocytes with rhNRG-1 significantly upregulated cMLCK expression or activity??? in CHF rat models, together with an improvement in both cardiomyocyte structure and pumping function.[24] Therefore, cMLCK is a downstream protein regulated by NRG-1/ErbB signaling and plays a role in rhNRG-1-mediated improvements in CHF.
## Improvements in cardiac efficiency
Altered calcium homeostasis has been suggested to play a role in the development of heart failure. Modulated by phospholamban (PLB), SERCA2 regulates uptake of Ca2+ into the sarcoplasmic reticulum (SR) from the cytoplasm and contributes to the relaxation of cardiomyocytes.[32] This process is also important for determining the SR Ca2+ load after relaxation and, thus, impacts on contractility.[32][33]
PP1 dephosphorylates PLB, inhibiting SERCA2 activity.[34] In the failing heart, PP1 expression is upregulated, resulting in increased PLB dephosphorylation and decreased SERCA2 activity.[35] Preliminary studies have revealed that rhNRG-normalizes SERCA function and enhances myocardial contractility through the inhibition of increasedPP1 expression, which leads to increased PLB phosphorylation and activation of SERCA2.
# Interactions
Neuregulin 1 has been shown to interact with ERBB3[36][37][38] and LIMK1.[39]
A schizophrenia associated- missense mutation in Neuregulin 1 has been shown to be associated with changes in cytokine expression using lymphoblastoid cells of heterozygous carriers vs homozygous wild type individuals [40]
Specifically, the missense mutation involves a single nucleotide change of a valine to a leucine within the transmembrane domain of Type 3 Neuregulin 1. It is thought that this single nucleotide change affects the ability of γ-secretase to cleave the intracellular domain (ICD) of the Type 3 isoform of Neureglin 1.[41] That is, the valine to leucine mutation within the transmembrane domain of Type 3 Neuregulin 1 decreases the amount of ICD that γ-secretase is able to cleave. The ICD of Type 3 Neuregulin 1 has been shown to suppress transcription of inflammatory cytokines, including IL-1β, IL-6, IL-10, IL-8, IL12-p70, and TNF-α. Using recombinant ErbB4 to stimulate the cleavage of the intracellular domain of Type 3 Neuregulin 1, a receptor for Type 3 Neuregulin 1, Marballi et al. showed that increased levels of the ICD lead to a decrease in IL-6 levels. Given the involvement of Neuregulin 1 in schizophrenia and the finding that the valine to leucine missense mutation in mice produces working memory deficits,[42] NRG1 seems a likely genetic candidate that confers susceptibility to the development of schizophrenia. | https://www.wikidoc.org/index.php/NRG1 | |
d43825f55405cdcab8e74dee18c3bba29c3737bc | wikidoc | Sleep eating | Sleep eating
Synonyms and keywords: sleep-related eating (disorder); nocturnal sleep-related eating disorder; NS-RED; sleep-eating syndrome
# Overview
Sleep eating is a sleep-related disorder, although some specialists consider it to be a combination of a sleep and an eating disorder. It is a relatively rare and little known condition that is gaining recognition in sleep medicine.
Sleep eating is characterized by sleepwalking and excessive nocturnal overeating (compulsive hyperphagia). Sleep eaters are comparable to sleepwalkers in many ways: they are at risk for self-injury during an episode, they may (or may not) experience excessive daytime sleepiness, and they are usually emotionally distressed, tired, angry, or anxious. Sleep eaters are also at risk for the same health complications as compulsive overeaters, with the added dangers of sleepwalking. Common concerns include excessive weight gain, daytime sleepiness, choking while eating, sleep disruption, and injury from cooking or preparing food such as from knives, utensils, or hot cooking surfaces. There is also the potential for starting a fire.
As with sleepwalkers, sleep eaters are unaware and unconscious of their behavior. If there is any memory of the episode, it is usually sketchy. A sleep eater will roam the house, particularly the kitchen, and may eat large quantities of food (as well as non-food items). In the morning, sleep eaters have no recollection of the episode. However, in many cases there are clues to their behavior. One woman woke up with a stomachache and chocolate smeared on her face and hands. Candy wrappers littered the kitchen floor. The next morning her husband informed her that she had been eating during the night. She was shocked and distressed because she had no recollection of the event.
As in the case described above, food consumed by sleep eaters tends to be either high sugar or high fat. Odd combinations of foods, such as potato chips dipped in peanut butter or butter smeared on hotdogs, as well as non-food items, have been reported. Oddly, one person was discovered cutting a bar of soap into slices and then eating it as if it were a slice of cheese!
Sleep eating is classified as a parasomnia. It is a rare version of sleepwalking, which is an arousal disorder.
# Causes
There is really no one cause of Sleep Eating Disorder, however people with some particular
histories appear to be at a higher risk of acquiring the disorder.
There are some of the correlations that have been found among people suffering from SED.
- Sleep Walking: People who sleep walked as children are at higher risk of acquiring SED than those who did not. This is true whether they continued to sleep walk passed childhood or not.
- Sufferers Of Other Sleep Disorders: There is a high correlation among people who suffer from other sleep disorders and SED. These disorder include;
- Narcolepsy
Restless Leg Syndrome & Periodic Limb Movement Narcolepsy
Obstructive Sleep Apnea
- Narcolepsy
- Restless Leg Syndrome & Periodic Limb Movement Narcolepsy
- Obstructive Sleep Apnea
- People On Some Particular Medication: Medications especially those used to treat depression and insomnia appear to increase the SED risk factor. Clinical studies show a strong link between SED and insomnia drug zolpidem (Ambien).
- Other Eating Disorders & Dieting
- Addictive Substance withdrawal: For example alcohol, nicotine and some painkillers.
- Stress: SED can be triggered by a bout of excessive stress normally persists long after the stress is gone.
- Going to bed hungry: This may be a tricky cause to understand. In some people sleeping on an empty stomach can trigger SED. Others may actually suffer from SED but have it masked by the fact that they sleep on full stomach. For the first case, SED becomes a behavioral problem, and it may be corrected by simply eliminating the cause i.e. sleeping while hungry. This may have to be done for a prolonged period of time before it can go away, but such people will remain vulnerable to future bouts of SED if they start sleeping on empty stomach. For the later group, the empty stomach isn't the problem, it just reveals the disorder.
It should be noted that it is not uncommon for someone to suffer from SED without having a history of any of the above high risk factors.
# Diffrential Diagnosis
- Night eating syndrome: It is different from sleep eating in that the individual is awake during episodes of nocturnal bingeing.
# Epidemiology and Demographics
The actual number of sleep-eating sufferers is unknown; however, it is estimated that 1 to 3 percent of the population is affected by sleep eating. A higher percentage of persons with eating disorders, as many as 10 to 15 percent, are affected. For this reason, sleep eating is more common in younger women. Symptoms typically begin in the late 20s. Episodes may reoccur, in combination with a stressful situation, or an episode may occur only once or twice. Additionally, many parasomnias seem to run in families, which may indicate that sleep eating is genetically linked.
# Natural History, Complications and Prognosis
Like any other disorder, SED does have a handful of consequences that might come up among the patients. If you are suffering from the disorder you may expect any of the following;
## Weight Gain
SED is in part an eating disorder, so if ones body is prone to weight gain the disorder may bring it out, worsen it or make it hard to combat if one is trying to fight it. The weight gain is in large part attributed to eating foods with high calorie content. Add to that eating the food in the middle of ones sleep without any other activity to burn the calories and weight gain problem is multiplied many times over.
## Insomnia
Night episodes tend to occur in middle of heavy sleep cycles(REM). Interfering with REM cycles deprives the body of a significant amount of recuperation time so much so that a 10 minute may bring about tiredness during the day that would otherwise be related to little or no sleep.
## Food Poisoning
One of the symptoms of sleep eating disorder is that patients may consume items not meant to be eaten during the night episodes. This can easily lead to food poisoning, and because it may go on for many consecutive nights even minor intakes of harmful items may build up to a toxic level in the body.
## Reduced Control Of Diabetes and Increased cholesterol
This should come as no suprise that eating high sugar and high calorie foods makes controlling ones body sugar levels and cholesterol difficult.
## Depression
The nature of SED and some of the consequences(especially the first two) is that it can induce a depression in patients.
## Poor Nutrition
Many patients tend to compensate for the disorder by reducing their food consumption during the day, since only a certain type of foods are consumed during the night episodes, the patients soon find themselves lacking vital nutritional elements in the body.
# Diagnosis
In 1968, Roger Broughton published a paper in Science (159: 1070-1078) that outlined the major features of arousal disorders. They are:
- Abnormal behavior that occurs during an arousal from slow wave sleep;
- The absence of awareness during the episode;
- Automatic and repetitive motor activity;
- Slow reaction time and reduced sensitivity to environment;
- Difficulty in waking despite vigorous attempts;
- No memory of the episode in the morning (retrograde amnesia); and
- No or little dream recall associated with the event.
## History and Symptoms
It is well accepted that the symptoms for sleep eating disorder tend to vary among the patients. However, the episodes tend to have a number of common characteristics.
These characteristics include
- Episodes only occur during the night and not during naps.
- The foods consumed tend to be of high calorie content but may also contain other house hold items that are not meant to be consumed like soap. Also some foods are consumed in a manner not preferred by the patients for example taking licking lots of sugar, drinking syrup(e.g. pan cake syrup) and various other twists.
- The episodes occur frequently, like every night, and in more cases happening more than once a night.
- The episodes last very short times 5 – 10 minutes. However some patients may have longer episodes where they even cook, but these are not common. During this time the food is eaten very fast.
- Alcoholic beverages are not normally consumed during the episodes.
- Without any evidence the patients do not recall the episodes and many times will not recall even with evidence, however it is not uncommon for the evidence to trigger some memories of the episode.
- Studies have also shown that it is difficult to awaken the sufferer during an episode.
- Patients tend to follow specific routines during the episodes. The routines can change for example, a patient may consume 5 foods in the same order for 20 consecutive episodes, then switch the foods around for next 15 episodes and so on. However, since a patient may not always have access to the same foods all the time, they tend to improvise to cater for what is missing.
# Treatment
The first step in treating any sleep disorder is to ascertain any underlying causes. As with most parasomnias, sleep eating is usually the result of an underlying problem, which may include another sleep disorder, prescription drug abuse, nicotine withdrawal, chronic autoimmune hepatitis, encephalitis (or hypothalmic injury), or acute stress.
It is important to keep in mind that throughout life, people experience varying patterns of sleep and nutrition during positive and negative situations. Problems with eating are defined as overeating or not eating enough. Problems with sleeping can be simplified with two symptoms, too much or not enough sleep. Medical attention is required for abnormal behaviors in either or both areas.
For some people who have been diagnosed with sleep eating, interventions without the use of medications have proven helpful. Courses on stress management, group or one-on-one counseling with a therapist, or self-confidence training may alleviate the stress and anxiety that leads to nighttime bingeing. Although considered an alternative treatment, hypnosis may be an option for some sleep eaters. A change in diet that includes avoiding certain foods and eating at specified times of the day, as well as reducing the intake of caffeine or alcohol, may be therapeutic. Professional advice may also suggest avoiding certain medications.
If the underlying problem is diagnosed as sleepwalking, medications in the benzodiazepinefamily have had some success. In sleepwalkers, this class of drugs reduces motor activity during sleep. Another class of drug found to be effective for sleep eaters has been the dopaminergic agents such as Sinemet (carbidopa or levodopa) and Mirapex (pramipexole dihydrochloride). | Sleep eating
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S
Synonyms and keywords: sleep-related eating (disorder); nocturnal sleep-related eating disorder; NS-RED; sleep-eating syndrome
# Overview
Sleep eating is a sleep-related disorder, although some specialists consider it to be a combination of a sleep and an eating disorder. It is a relatively rare and little known condition that is gaining recognition in sleep medicine.
Sleep eating is characterized by sleepwalking and excessive nocturnal overeating (compulsive hyperphagia). Sleep eaters are comparable to sleepwalkers in many ways: they are at risk for self-injury during an episode, they may (or may not) experience excessive daytime sleepiness, and they are usually emotionally distressed, tired, angry, or anxious. Sleep eaters are also at risk for the same health complications as compulsive overeaters, with the added dangers of sleepwalking. Common concerns include excessive weight gain, daytime sleepiness, choking while eating, sleep disruption, and injury from cooking or preparing food such as from knives, utensils, or hot cooking surfaces. There is also the potential for starting a fire.
As with sleepwalkers, sleep eaters are unaware and unconscious of their behavior. If there is any memory of the episode, it is usually sketchy. A sleep eater will roam the house, particularly the kitchen, and may eat large quantities of food (as well as non-food items). In the morning, sleep eaters have no recollection of the episode. However, in many cases there are clues to their behavior. One woman woke up with a stomachache and chocolate smeared on her face and hands. Candy wrappers littered the kitchen floor. The next morning her husband informed her that she had been eating during the night. She was shocked and distressed because she had no recollection of the event.
As in the case described above, food consumed by sleep eaters tends to be either high sugar or high fat. Odd combinations of foods, such as potato chips dipped in peanut butter or butter smeared on hotdogs, as well as non-food items, have been reported. Oddly, one person was discovered cutting a bar of soap into slices and then eating it as if it were a slice of cheese!
Sleep eating is classified as a parasomnia. It is a rare version of sleepwalking, which is an arousal disorder.
# Causes
There is really no one cause of Sleep Eating Disorder, however people with some particular
histories appear to be at a higher risk of acquiring the disorder.
There are some of the correlations that have been found among people suffering from SED.
- Sleep Walking: People who sleep walked as children are at higher risk of acquiring SED than those who did not. This is true whether they continued to sleep walk passed childhood or not.
- Sufferers Of Other Sleep Disorders: There is a high correlation among people who suffer from other sleep disorders and SED. These disorder include;
- Narcolepsy
Restless Leg Syndrome & Periodic Limb Movement Narcolepsy
Obstructive Sleep Apnea
- Narcolepsy
- Restless Leg Syndrome & Periodic Limb Movement Narcolepsy
- Obstructive Sleep Apnea
- People On Some Particular Medication: Medications especially those used to treat depression and insomnia appear to increase the SED risk factor. Clinical studies show a strong link between SED and insomnia drug zolpidem (Ambien).
- Other Eating Disorders & Dieting
- Addictive Substance withdrawal: For example alcohol, nicotine and some painkillers.
- Stress: SED can be triggered by a bout of excessive stress normally persists long after the stress is gone.
- Going to bed hungry: This may be a tricky cause to understand. In some people sleeping on an empty stomach can trigger SED. Others may actually suffer from SED but have it masked by the fact that they sleep on full stomach. For the first case, SED becomes a behavioral problem, and it may be corrected by simply eliminating the cause i.e. sleeping while hungry. This may have to be done for a prolonged period of time before it can go away, but such people will remain vulnerable to future bouts of SED if they start sleeping on empty stomach. For the later group, the empty stomach isn't the problem, it just reveals the disorder.
It should be noted that it is not uncommon for someone to suffer from SED without having a history of any of the above high risk factors.
# Diffrential Diagnosis
- Night eating syndrome: It is different from sleep eating in that the individual is awake during episodes of nocturnal bingeing.
# Epidemiology and Demographics
The actual number of sleep-eating sufferers is unknown; however, it is estimated that 1 to 3 percent of the population is affected by sleep eating. A higher percentage of persons with eating disorders, as many as 10 to 15 percent, are affected. For this reason, sleep eating is more common in younger women. Symptoms typically begin in the late 20s. Episodes may reoccur, in combination with a stressful situation, or an episode may occur only once or twice. Additionally, many parasomnias seem to run in families, which may indicate that sleep eating is genetically linked.
# Natural History, Complications and Prognosis
Like any other disorder, SED does have a handful of consequences that might come up among the patients. If you are suffering from the disorder you may expect any of the following;
## Weight Gain
SED is in part an eating disorder, so if ones body is prone to weight gain the disorder may bring it out, worsen it or make it hard to combat if one is trying to fight it. The weight gain is in large part attributed to eating foods with high calorie content. Add to that eating the food in the middle of ones sleep without any other activity to burn the calories and weight gain problem is multiplied many times over.
## Insomnia
Night episodes tend to occur in middle of heavy sleep cycles(REM). Interfering with REM cycles deprives the body of a significant amount of recuperation time so much so that a 10 minute may bring about tiredness during the day that would otherwise be related to little or no sleep.
## Food Poisoning
One of the symptoms of sleep eating disorder is that patients may consume items not meant to be eaten during the night episodes. This can easily lead to food poisoning, and because it may go on for many consecutive nights even minor intakes of harmful items may build up to a toxic level in the body.
## Reduced Control Of Diabetes and Increased cholesterol
This should come as no suprise that eating high sugar and high calorie foods makes controlling ones body sugar levels and cholesterol difficult.
## Depression
The nature of SED and some of the consequences(especially the first two) is that it can induce a depression in patients.
## Poor Nutrition
Many patients tend to compensate for the disorder by reducing their food consumption during the day, since only a certain type of foods are consumed during the night episodes, the patients soon find themselves lacking vital nutritional elements in the body.
# Diagnosis
In 1968, Roger Broughton published a paper in Science (159: 1070-1078) that outlined the major features of arousal disorders. They are:
- Abnormal behavior that occurs during an arousal from slow wave sleep;
- The absence of awareness during the episode;
- Automatic and repetitive motor activity;
- Slow reaction time and reduced sensitivity to environment;
- Difficulty in waking despite vigorous attempts;
- No memory of the episode in the morning (retrograde amnesia); and
- No or little dream recall associated with the event.
## History and Symptoms
It is well accepted that the symptoms for sleep eating disorder tend to vary among the patients. However, the episodes tend to have a number of common characteristics.
These characteristics include
- Episodes only occur during the night and not during naps.
- The foods consumed tend to be of high calorie content but may also contain other house hold items that are not meant to be consumed like soap. Also some foods are consumed in a manner not preferred by the patients for example taking licking lots of sugar, drinking syrup(e.g. pan cake syrup) and various other twists.
- The episodes occur frequently, like every night, and in more cases happening more than once a night.
- The episodes last very short times 5 – 10 minutes. However some patients may have longer episodes where they even cook, but these are not common. During this time the food is eaten very fast.
- Alcoholic beverages are not normally consumed during the episodes.
- Without any evidence the patients do not recall the episodes and many times will not recall even with evidence, however it is not uncommon for the evidence to trigger some memories of the episode.
- Studies have also shown that it is difficult to awaken the sufferer during an episode.
- Patients tend to follow specific routines during the episodes. The routines can change for example, a patient may consume 5 foods in the same order for 20 consecutive episodes, then switch the foods around for next 15 episodes and so on. However, since a patient may not always have access to the same foods all the time, they tend to improvise to cater for what is missing.
# Treatment
The first step in treating any sleep disorder is to ascertain any underlying causes. As with most parasomnias, sleep eating is usually the result of an underlying problem, which may include another sleep disorder, prescription drug abuse, nicotine withdrawal, chronic autoimmune hepatitis, encephalitis (or hypothalmic injury), or acute stress.
It is important to keep in mind that throughout life, people experience varying patterns of sleep and nutrition during positive and negative situations. Problems with eating are defined as overeating or not eating enough. Problems with sleeping can be simplified with two symptoms, too much or not enough sleep. Medical attention is required for abnormal behaviors in either or both areas.
For some people who have been diagnosed with sleep eating, interventions without the use of medications have proven helpful. Courses on stress management, group or one-on-one counseling with a therapist, or self-confidence training may alleviate the stress and anxiety that leads to nighttime bingeing. Although considered an alternative treatment, hypnosis may be an option for some sleep eaters. A change in diet that includes avoiding certain foods and eating at specified times of the day, as well as reducing the intake of caffeine or alcohol, may be therapeutic. Professional advice may also suggest avoiding certain medications.
If the underlying problem is diagnosed as sleepwalking, medications in the benzodiazepinefamily have had some success. In sleepwalkers, this class of drugs reduces motor activity during sleep. Another class of drug found to be effective for sleep eaters has been the dopaminergic agents such as Sinemet (carbidopa or levodopa) and Mirapex (pramipexole dihydrochloride). | https://www.wikidoc.org/index.php/NS-RED | |
61a4903592b53e428ab8b94a4c129fff6bc966ce | wikidoc | Onychophagia | Onychophagia
Nail biting is the habit of biting one's fingernails or toenails during periods of nervousness, stress, hunger, or boredom . It can also be a sign of mental or emotional disorder. It can be obsessive compulsive or can even be a completely unconscious act where the affected person is not or barely aware of the behavior whilst performing it. It has been documented that some people bite their nails in their sleep, sometimes exclusively. This has been linked to stress while dreaming or stress from the dream, or simply stress in general. It is considered to be the most widespread form of mild self mutilation. According to Freudian theory, nail biting is a symptom of oral fixation. The clinical name for nail biting is chronic onychophagia.
It occurs in:
- 28% to 33% of children ages 7-10 years old,
- 44% of adolescents,
- 19% to 29% of young adults and
- 5% of older adults
# Negative effects
Nail biting may result in the transportation of bacteria that are buried under the surface of the nail that are hard to clean and easy to get in the mouth. Likewise, broken skin on the cuticle may be susceptible to microbial and viral infections. These pathogens can be spread between digits via saliva.
Extreme nailbiting can be considered to be a form of masochistic self-mutilation. Bitten fingertips can become very sensitive to pain, usually at the place the skin meets the edge of the nail.
# Nail Biting and IQ
Studies by Russian researchers on children living in the Ural mountains region have found that nail biting may be contributing to the loss of IQ due to lead poisoning. This is specially true among children who are still mentally developing. Nail biters who work with iron (plumbers, painters or printers) may also be susceptible to poisoning in a similar way.
# Treatment
Causes of fingernail Biting
## Behavioral therapy
Some patients have found behavioral therapy to be beneficial on its own or as a complement to medication. The first part of nail biting therapy consists of Habit Reversal Training (HRT), a four part process that seeks to "unlearn" the habit of nail biting and possibly replace it with a more constructive habit. In addition to HRT, stimulus control therapy is used to both identify and then eliminate the stimulus that frequently triggers biting urges.
One might also use a mouthpiece to prevent the bite. This can be found at nailbitestopper.com
The symptoms have been found to respond best to a combination of medication and therapy.
## Medication
Nail biting has been shown to respond well to certain types of medication. The medications used to treat the problem include the newest, most potent anti-depressants. These medications are also used to treat Trichotillomania and OCD and include clomipramine, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, nefazodone and venlafaxine. Also, small amounts of the anti-psychotics used to treat schizophrenia such as risperidone, olazapine, quetiapine, ziprasidone, and aripiprazole can be used to augment anti-depressants. It is important to note that the use of anti-psychotics to treat nail biting does not necessarily indicate that the patient is suffering from psychosis. | Onychophagia
Nail biting is the habit of biting one's fingernails or toenails during periods of nervousness, stress, hunger, or boredom [1]. It can also be a sign of mental or emotional disorder. It can be obsessive compulsive or can even be a completely unconscious act where the affected person is not or barely aware of the behavior whilst performing it. It has been documented that some people bite their nails in their sleep, sometimes exclusively. This has been linked to stress while dreaming or stress from the dream, or simply stress in general. It is considered to be the most widespread form of mild self mutilation. According to Freudian theory, nail biting is a symptom of oral fixation. The clinical name for nail biting is chronic onychophagia.
It occurs in:[2]
- 28% to 33% of children ages 7-10 years old,
- 44% of adolescents,
- 19% to 29% of young adults and
- 5% of older adults
# Negative effects
Nail biting may result in the transportation of bacteria that are buried under the surface of the nail that are hard to clean and easy to get in the mouth. [3]Likewise, broken skin on the cuticle may be susceptible to microbial and viral infections. These pathogens can be spread between digits via saliva.
Extreme nailbiting can be considered to be a form of masochistic self-mutilation. Bitten fingertips can become very sensitive to pain, usually at the place the skin meets the edge of the nail.
# Nail Biting and IQ
Studies by Russian researchers on children living in the Ural mountains region have found that nail biting may be contributing to the loss of IQ due to lead poisoning. This is specially true among children who are still mentally developing. Nail biters who work with iron (plumbers, painters or printers) may also be susceptible to poisoning in a similar way.
# Treatment
[4]
Causes of fingernail Biting
## Behavioral therapy
Some patients have found behavioral therapy to be beneficial on its own or as a complement to medication. The first part of nail biting therapy consists of Habit Reversal Training (HRT), a four part process that seeks to "unlearn" the habit of nail biting and possibly replace it with a more constructive habit. In addition to HRT, stimulus control therapy is used to both identify and then eliminate the stimulus that frequently triggers biting urges.[5]
One might also use a mouthpiece to prevent the bite. This can be found at nailbitestopper.com
The symptoms have been found to respond best to a combination of medication and therapy.
## Medication
Nail biting has been shown to respond well to certain types of medication. The medications used to treat the problem include the newest, most potent anti-depressants. These medications are also used to treat Trichotillomania and OCD and include clomipramine, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, nefazodone and venlafaxine. Also, small amounts of the anti-psychotics used to treat schizophrenia such as risperidone, olazapine, quetiapine, ziprasidone, and aripiprazole can be used to augment anti-depressants. It is important to note that the use of anti-psychotics to treat nail biting does not necessarily indicate that the patient is suffering from psychosis. [6] | https://www.wikidoc.org/index.php/Nail-biting | |
a607587788080627c8b8b2e38a7694093e9e2fd7 | wikidoc | Nanoarchaeum | Nanoarchaeum
Nanoarchaeum equitans is a species of tiny microbe, discovered in 2002 in a hydrothermal vent off the coast of Iceland by Karl Stetter. Since it grows in temperatures approaching boiling, it is considered to be a thermophile. Nanoarchaeum appears to be an obligatory symbiont on the archaeon Ignicoccus; it must be in contact with the host organism to survive. Its cells are only 400 nm in diameter, making it the next smallest known living organism, excepting possibly nanobacteria and nanobes, whose status as living organisms are controversial. Its genome is only 490,885 nucleotides long; the smallest non-viral genome ever sequenced next to C. ruddii's in 2006.
Genetically, Nanoarchaeum is peculiar in that its 16S rRNA sequence is undetectable by the most common methods. Initial examination of single-stranded ribosomal RNA indicated that the organism most likely belonged to the Archaea domain. However, its difference from the existing phyla, Euryarchaeota and Crenarchaeota, was as great as the difference between the phyla. Therefore, it was given its own phylum, called Nanoarchaeota. However, another group (see References) compared all of the open reading frames to the other Archaea. They argue that the initial sample, ribosomal RNA only, was biased and Nanoarchaeum actually belongs to the Euryarchaeota phylum.
The sequencing of the Nanoarchaeum genome has revealed a wealth of information about the organism's biology. The genes for several vital metabolic pathways appear to be missing. Nanoarchaeum cannot synthesize most nucleotides, amino acids, lipids, and cofactors. The cell most likely obtains these biomolecules from Ignicoccus. However, unlike many parasitic microbes, Nanoarchaeum has many DNA repair enzymes, as well as everything necessary to carry out DNA replication, transcription, and translation. This may explain why the genome lacks the large stretches of non-coding DNA characteristic of other parasites. The organism's ability to produce its own ATP is also in question. Nanoarchaeum lacks the ability to metabolize hydrogen and sulfur for energy, as many thermophiles do. It does have five subunits of an ATP synthase as well as pathways for oxidative deamination. Whether it obtains energy from biological molecules imported from Ignicoccus, or whether it receives ATP directly is currently unknown. The genome and proteome composition of N. equitans are marked with the signatures of dual adaptation – one to high temperature and the other to obligatory parasitism (or symbiosis). | Nanoarchaeum
Nanoarchaeum equitans is a species of tiny microbe, discovered in 2002 in a hydrothermal vent off the coast of Iceland by Karl Stetter. Since it grows in temperatures approaching boiling, it is considered to be a thermophile. Nanoarchaeum appears to be an obligatory symbiont on the archaeon Ignicoccus; it must be in contact with the host organism to survive. Its cells are only 400 nm in diameter, making it the next smallest known living organism, excepting possibly nanobacteria and nanobes, whose status as living organisms are controversial. Its genome is only 490,885 nucleotides long; the smallest non-viral genome ever sequenced next to C. ruddii's in 2006.
Genetically, Nanoarchaeum is peculiar in that its 16S rRNA sequence is undetectable by the most common methods. Initial examination of single-stranded ribosomal RNA indicated that the organism most likely belonged to the Archaea domain. However, its difference from the existing phyla, Euryarchaeota and Crenarchaeota, was as great as the difference between the phyla. Therefore, it was given its own phylum, called Nanoarchaeota. However, another group (see References) compared all of the open reading frames to the other Archaea. They argue that the initial sample, ribosomal RNA only, was biased and Nanoarchaeum actually belongs to the Euryarchaeota phylum.
The sequencing of the Nanoarchaeum genome has revealed a wealth of information about the organism's biology. The genes for several vital metabolic pathways appear to be missing. Nanoarchaeum cannot synthesize most nucleotides, amino acids, lipids, and cofactors. The cell most likely obtains these biomolecules from Ignicoccus. However, unlike many parasitic microbes, Nanoarchaeum has many DNA repair enzymes, as well as everything necessary to carry out DNA replication, transcription, and translation. This may explain why the genome lacks the large stretches of non-coding DNA characteristic of other parasites. The organism's ability to produce its own ATP is also in question. Nanoarchaeum lacks the ability to metabolize hydrogen and sulfur for energy, as many thermophiles do. It does have five subunits of an ATP synthase as well as pathways for oxidative deamination. Whether it obtains energy from biological molecules imported from Ignicoccus, or whether it receives ATP directly is currently unknown. The genome and proteome composition of N. equitans are marked with the signatures of dual adaptation – one to high temperature and the other to obligatory parasitism (or symbiosis). | https://www.wikidoc.org/index.php/Nanoarchaeum | |
952a6eb98543008637d99612ba9fbf464a6e5efb | wikidoc | Nanomedicine | Nanomedicine
Nanomedicine is the medical application of nanotechnology. It covers areas such as nanoparticle drug delivery and possible future applications of molecular nanotechnology (MNT) and nanovaccinology. Current problems for nanomedicine involve understanding the issues related to toxicity and environmental impact of nanoscale materials.
Nanomedicine research is directly funded, with the US National Institutes of Health in 2005 funding a five-year plan to set up four nanomedicine centers. In April 2006, the journal Nature Materials estimated that 130 nanotech-based drugs and delivery systems were being developed worldwide.
# Introduction
In the near future, advancement in nanomedicine will deliver a valuable set of research tools and clinically helpful devices. The National Nanotechnology Initiative expects new commercial applications in the pharmaceutical industry that will include advanced drug delivery systems, new therapies, and in vivo imaging. Farther down the line, neuro-electronic interfaces and cell repair machines could revolutionize medicine and the medical field, but now nanomedicine is becoming one of the biggest industries in the world. In 2004, nanomedicine sales reached 6.8 billion dollars, and with over 200 companies and 38 products worldwide, a minimum of 3.8 billion dollars in nanotechnology R&D is being invested every year. As the nanomedicine industry continues to grow, there is no doubt that it will have a significant impact on the economy. The most important innovations are taking place in drug delivery which involves developing nanoscale particles or molecules to improve bioavailability. Bioavailability refers to the presence of drug molecules where they are needed in the body and where they will do the most good. Drug delivery focuses on maximizing bioavailability both at specific places in the body and over a period of time. Over 65 billion dollars is wasted every year because of poor bioavailability. In vivo imaging is another area where tools and devices are being developed. Using nanoparticle contrast agents, images such as ultrasound and MRI have a favorable distribution and improved contrast. The new therapies and surgeries that are being developed might be effective in treating illnesses and diseases such as cancer. Finally, a shift from the possible to the potential will be made when nanorobots such as neuro-electronic interfaces and cell repair machines are discussed.
# Drug Delivery
Drug delivery systems, lipid- or polymer-based nanoparticles, can be designed to improve the pharmacological and therapeutic properties of drugs. The strength of drug delivery systems is their ability to alter the pharmacokinetics and biodistribution of the drug. Nanoparticles have unusual properties that can be used to improve drug delivery. Where larger particles would have been cleared from the body, cells take up these nanoparticles because of their size. Complex drug delivery mechanisms are being developed, including the ability to get drugs through cell membranes and into cell cytoplasm. Efficiency is important because many diseases depend upon processes within the cell and can only be impeded by drugs that make their way into the cell. Triggered response is one way for drug molecules to be used more efficiently. Drugs are placed in the body and only activate on encountering a particular signal. For example, a drug with poor solubility will be replaced by a drug delivery system where both hydrophilic and hydrophobic environments exist, improving the solubility. Also, a drug may cause tissue damage, but with drug delivery, regulated drug release can eliminate the problem. If a drug is cleared too quickly from the body, this could force a patient to use high doses, but with drug delivery systems clearance can be reduced by altering the pharmacokinetics of the drug. Poor biodistribution is a problem that can affect normal tissues through widespread distribution, but the particulates from drug delivery systems lower the volume of distribution and reduce the effect on non-target tissue. Potential nanodrugs will work by very specific and well-understood mechanisms, one of the major impacts of nanotechnology and nanoscience will be in leading development of completely new drugs with more useful behavior and less side effects.
# Cancer
Nanoparticles of cadmium selenide (quantum dots) glow when exposed to ultraviolet light. When injected, they seep into cancer tumors. The surgeon can see the glowing tumor, and use it as a guide for more accurate tumor removal.
Sensor test chips containing thousands of nanowires, able to detect proteins and other biomarkers left behind by cancer cells, could enable the detection and diagnosis of cancer in the early stages from a few drops of a patient's blood.
Researchers at Rice University under Prof. Jennifer West, have demonstrated the use of 120 nm diameter nanoshells coated with gold to kill cancer tumors in mice. The nanoshells can be targeted to bond to cancerous cells by conjugating antibodies or peptides to the nanoshell surface. By irradiating the area of the tumor with an infrared laser, which passes through flesh without heating it, the gold is heated sufficiently to cause death to the cancer cells.
One scientist, University of Michigan’s James Baker, believes he has discovered a highly efficient and successful way of delivering cancer-treatment drugs that is less harmful to the surrounding body. Baker has developed a nanotechnology that can locate and then eliminate cancerous cells. He looks at a molecule called a dendrimer. This molecule has over a hundred hooks on it that allow it to attach to cells in the body for a variety of purposes. Baker then attaches folic-acid to a few of the hooks (folic-acid, being a vitamin, is received by cells in the body). Cancer cells have more vitamin receptors than normal cells, so Baker's vitamin-laden dendrimer will be absorbed by the cancer cell. To the rest of the hooks on the dendrimer, Baker places anti-cancer drugs that will be absorbed with the dendrimer into the cancer cell, thereby delivering the cancer drug to the cancer cell and nowhere else (Bullis 2006).
# Surgery
At Rice University, a flesh welder is used to fuse two pieces of chicken meat into a single piece. The two pieces of chicken are placed together touching. A greenish liquid containing gold-coated nanoshells is dribbled along the seam. An infrared laser is traced along the seam, causing the two sides to weld together. This could solve the difficulties and blood leaks caused when the surgeon tries to restitch the arteries he/she has cut during a kidney or heart transplant. The flesh welder could meld the artery into a perfect seal.
# In vivo/ Therapy
Nanodevices could be observed at work inside the body using MRI, especially if their components were manufactured using mostly 13C atoms rather than the natural 12C isotope of carbon, since 13C has a nonzero nuclear magnetic moment. Medical nanodevices would first be injected into a human body, and would then go to work in a specific organ or tissue mass. The doctor will monitor the progress, and make certain that the nanodevices have gotten to the correct target treatment region. The doctor wants to be able to scan a section of the body, and actually see the nanodevices congregated neatly around their target (a tumor mass, etc.) so that he or she can be sure that the procedure was successful. Tracking movement can help determine how well drugs are being distributed or how substances are metabolized. It is difficult to track a small group of cells throughout the body so scientists used to dye the cells. These dyes needed to be excited by light of a certain wavelength in order for them to light up. While different color dyes absorb different frequencies of light, there was a need for as many light sources as cells. A way around this problem is with luminescent tags. These tags are quantum dots attached to proteins that penetrate cell walls. The dots can be random in size, can be made of bio-inert material, and they demonstrate the nanoscale property that color is size-dependent. As a result, sizes are selected so that the frequency of light used to make a group of quantum dots fluoresce is an even multiple of the frequency required to make another group incandesce. Then both groups can be lit with a single light source.
In photodynamic therapy, a particle is placed within the body and is illuminated with light from the outside. The light gets absorbed by the particle and if the particle is metal, energy from the light will heat the particle and surrounding tissue. Light may also be used to produce high energy oxygen molecules which will chemically react with and destroy most organic molecules that are next to them (like tumors). This therapy is appealing for many reasons. It does not leave a “toxic trail” of reactive molecules throughout the body (chemotherapy) because it is directed where only the light is shined and the particles exist. Photodynamic therapy has potential for a noninvasive procedure for dealing with diseases, growths, and tumors.
# Nanorobots
The somewhat speculative claims about the possibility of using nanorobots in medicine, advocates say, would totally change the world of medicine once it is realized. Nanomedicine would make use of these nanorobots, introduced into the body, to repair or detect damages and infections. According to Robert Freitas of the Institute for Molecular Manufacturing, a typical blood borne medical nanorobot would be between 0.5-3 micrometres in size, because that is the maximum size possible due to capillary passage requirement. Carbon would be the primary element used to build these nanorobots due to the inherent strength and other characteristics of some forms of carbon (diamond/fullerene composites), and nanorobots would be fabricated in desktop nanofactories specialized for this purpose. Cancer could be treated very effectively, according to nanomedicine advocates. Nanorobots could counter the problem of identifying and isolating cancer cells as they could be introduced into the bloodstream. These nanorobots would search out cancer affected cells using certain molecular markers. Medical nanorobots would then destroy these cells, and only these cells. Nanomedicines could be a very helpful and hopeful therapy for patients, since current treatments like radiation therapy and chemotherapy often end up destroying more healthy cells than cancerous ones. From this point of view, it provides a non-depressed therapy for cancer patients. Nanorobots could also be useful in precision tissue- and cell-targeted drug delivery , in performing nanosurgery , and in treatments for hypoxemia and respiratory illness , dentistry , bacteremic infections, physical trauma , gene therapy via chromosome replacement therapy , and even biological aging
. Indefinite lifespan is often predicted to be made available by nanomedicine.
# Neuro-electronic Interfaces
Neuro-electronic interfaces are a visionary goal dealing with the construction of nanodevices that will permit computers to be joined and linked to the nervous system. This idea requires the building of a molecular structure that will permit control and detection of nerve impulses by an external computer. The computers will be able to interpret, register, and respond to signals the body gives off when it feels sensations. The demand for such structures is huge because many diseases involve the decay of the nervous system (ALS and multiple sclerosis). Also, many injuries and accidents may impair the nervous system resulting in dysfunctional systems and paraplegia. If computers could control the nervous system through neuro-electronic interface, problems that impair the system could be controlled so that effects of diseases and injuries could be overcome. Two considerations must be made when selecting the power source for such applications. They are refuelable and nonrefuelable strategies. A refuelable strategy implies energy is refilled continuously or periodically with external sonic, chemical, tethered, or electrical sources. A nonrefuelable strategy implies that all power is drawn from internal energy storage which would stop when all energy is drained.
One limitation to this innovation is the fact that electrical interference is a possibility. Electric fields, electromagnetic pulses (EMP), and stray fields from other in vivo electrical devices can all cause interference. Also, thick insulators are required to prevent electron leakage, and if high conductivity of the in vivo medium occurs there is a risk of sudden power loss and “shorting out.” Finally, thick wires are also needed to conduct substantial power levels without overheating. Little practical progress has been made even though research is happening. The wiring of the structure is extremely difficult because they must be positioned precisely in the nervous system so that it is able to monitor and respond to nervous signals. The structures that will provide the interface must also be compatible with the body’s immune system so that they will remain unaffected in the body for a long time. In addition, the structures must also sense ionic currents and be able to cause currents to flow backward. While the potential for these structures is amazing, there is no timetable for when they will be available.
# Cell repair machines
Using drugs and surgery, doctors can only encourage tissues to repair themselves. With molecular machines, there will be more direct repairs. Cell repair will utilize the same tasks that living systems already prove possible. Access to cells is possible because biologists can stick needles into cells without killing them. Thus, molecular machines are capable of entering the cell. Also, all specific biochemical interactions show that molecular systems can recognize other molecules by touch, build or rebuild every molecule in a cell, and can disassemble damaged molecules. Finally, cells that replicate prove that molecular systems can assemble every system found in a cell. Therefore, since nature has demonstrated the basic operations needed to perform molecular-level cell repair, in the future, nanomachine based systems will be built that are able to enter cells, sense differences from healthy ones and make modifications to the structure.
The possibilities of these cell repair machines are impressive. Comparable to the size of viruses or bacteria, their compact parts will allow them to be more complex. The early machines will be specialized. As they open and close cell membranes or travel through tissue and enter cells and viruses, machines will only be able to correct a single molecular disorder like DNA damage or enzyme deficiency. Later, cell repair machines will be programmed with more abilities with the help of advanced AI systems.
Nanocomputers will be needed to guide these machines. These computers will direct machines to examine, take apart, and rebuild damaged molecular structures. Repair machines will be able to repair whole cells by working structure by structure. Then by working cell by cell and tissue by tissue, whole organs can be repaired. Finally, by working organ by organ, health is restored to the body. Cells damaged to the point of inactivity can be repaired because of the ability of molecular machines to build cells from scratch. Therefore, cell repair machines will free medicine from reliance on self repair.
A new wave of technology and medicine is being created and its impact on the world is going to be monumental. From the possible applications such as drug delivery and in vivo imaging to the potential machines of the future, advancements in nanomedicine are being made every day. It will not be long for the 10 billion dollar industry to explode into a 100 billion or 1 trillion dollar industry, and drug delivery, in vivo imaging and therapy is just the beginning. | Nanomedicine
Template:Nanotech
Nanomedicine is the medical application of nanotechnology. It covers areas such as nanoparticle drug delivery and possible future applications of molecular nanotechnology (MNT) and nanovaccinology. Current problems for nanomedicine involve understanding the issues related to toxicity and environmental impact of nanoscale materials.
Nanomedicine research is directly funded, with the US National Institutes of Health in 2005 funding a five-year plan to set up four nanomedicine centers. In April 2006, the journal Nature Materials estimated that 130 nanotech-based drugs and delivery systems were being developed worldwide. [1]
# Introduction
In the near future, advancement in nanomedicine will deliver a valuable set of research tools and clinically helpful devices. The National Nanotechnology Initiative expects new commercial applications in the pharmaceutical industry that will include advanced drug delivery systems, new therapies, and in vivo imaging. Farther down the line, neuro-electronic interfaces and cell repair machines could revolutionize medicine and the medical field, but now nanomedicine is becoming one of the biggest industries in the world. In 2004, nanomedicine sales reached 6.8 billion dollars, and with over 200 companies and 38 products worldwide, a minimum of 3.8 billion dollars in nanotechnology R&D is being invested every year. As the nanomedicine industry continues to grow, there is no doubt that it will have a significant impact on the economy. The most important innovations are taking place in drug delivery which involves developing nanoscale particles or molecules to improve bioavailability. Bioavailability refers to the presence of drug molecules where they are needed in the body and where they will do the most good. Drug delivery focuses on maximizing bioavailability both at specific places in the body and over a period of time. Over 65 billion dollars is wasted every year because of poor bioavailability. In vivo imaging is another area where tools and devices are being developed. Using nanoparticle contrast agents, images such as ultrasound and MRI have a favorable distribution and improved contrast. The new therapies and surgeries that are being developed might be effective in treating illnesses and diseases such as cancer. Finally, a shift from the possible to the potential will be made when nanorobots such as neuro-electronic interfaces and cell repair machines are discussed.
# Drug Delivery
Drug delivery systems, lipid- or polymer-based nanoparticles, can be designed to improve the pharmacological and therapeutic properties of drugs. The strength of drug delivery systems is their ability to alter the pharmacokinetics and biodistribution of the drug. Nanoparticles have unusual properties that can be used to improve drug delivery. Where larger particles would have been cleared from the body, cells take up these nanoparticles because of their size. Complex drug delivery mechanisms are being developed, including the ability to get drugs through cell membranes and into cell cytoplasm. Efficiency is important because many diseases depend upon processes within the cell and can only be impeded by drugs that make their way into the cell. Triggered response is one way for drug molecules to be used more efficiently. Drugs are placed in the body and only activate on encountering a particular signal. For example, a drug with poor solubility will be replaced by a drug delivery system where both hydrophilic and hydrophobic environments exist, improving the solubility. Also, a drug may cause tissue damage, but with drug delivery, regulated drug release can eliminate the problem. If a drug is cleared too quickly from the body, this could force a patient to use high doses, but with drug delivery systems clearance can be reduced by altering the pharmacokinetics of the drug. Poor biodistribution is a problem that can affect normal tissues through widespread distribution, but the particulates from drug delivery systems lower the volume of distribution and reduce the effect on non-target tissue. Potential nanodrugs will work by very specific and well-understood mechanisms, one of the major impacts of nanotechnology and nanoscience will be in leading development of completely new drugs with more useful behavior and less side effects.
# Cancer
Nanoparticles of cadmium selenide (quantum dots) glow when exposed to ultraviolet light. When injected, they seep into cancer tumors. The surgeon can see the glowing tumor, and use it as a guide for more accurate tumor removal.
Sensor test chips containing thousands of nanowires, able to detect proteins and other biomarkers left behind by cancer cells, could enable the detection and diagnosis of cancer in the early stages from a few drops of a patient's blood.[1]
Researchers at Rice University under Prof. Jennifer West, have demonstrated the use of 120 nm diameter nanoshells coated with gold to kill cancer tumors in mice. The nanoshells can be targeted to bond to cancerous cells by conjugating antibodies or peptides to the nanoshell surface. By irradiating the area of the tumor with an infrared laser, which passes through flesh without heating it, the gold is heated sufficiently to cause death to the cancer cells.[2]
One scientist, University of Michigan’s James Baker, believes he has discovered a highly efficient and successful way of delivering cancer-treatment drugs that is less harmful to the surrounding body. Baker has developed a nanotechnology that can locate and then eliminate cancerous cells. He looks at a molecule called a dendrimer. This molecule has over a hundred hooks on it that allow it to attach to cells in the body for a variety of purposes. Baker then attaches folic-acid to a few of the hooks (folic-acid, being a vitamin, is received by cells in the body). Cancer cells have more vitamin receptors than normal cells, so Baker's vitamin-laden dendrimer will be absorbed by the cancer cell. To the rest of the hooks on the dendrimer, Baker places anti-cancer drugs that will be absorbed with the dendrimer into the cancer cell, thereby delivering the cancer drug to the cancer cell and nowhere else (Bullis 2006).
# Surgery
At Rice University, a flesh welder is used to fuse two pieces of chicken meat into a single piece. The two pieces of chicken are placed together touching. A greenish liquid containing gold-coated nanoshells is dribbled along the seam. An infrared laser is traced along the seam, causing the two sides to weld together. This could solve the difficulties and blood leaks caused when the surgeon tries to restitch the arteries he/she has cut during a kidney or heart transplant. The flesh welder could meld the artery into a perfect seal.
# In vivo/ Therapy
Nanodevices could be observed at work inside the body using MRI, especially if their components were manufactured using mostly 13C atoms rather than the natural 12C isotope of carbon, since 13C has a nonzero nuclear magnetic moment. Medical nanodevices would first be injected into a human body, and would then go to work in a specific organ or tissue mass. The doctor will monitor the progress, and make certain that the nanodevices have gotten to the correct target treatment region. The doctor wants to be able to scan a section of the body, and actually see the nanodevices congregated neatly around their target (a tumor mass, etc.) so that he or she can be sure that the procedure was successful. Tracking movement can help determine how well drugs are being distributed or how substances are metabolized. It is difficult to track a small group of cells throughout the body so scientists used to dye the cells. These dyes needed to be excited by light of a certain wavelength in order for them to light up. While different color dyes absorb different frequencies of light, there was a need for as many light sources as cells. A way around this problem is with luminescent tags. These tags are quantum dots attached to proteins that penetrate cell walls. The dots can be random in size, can be made of bio-inert material, and they demonstrate the nanoscale property that color is size-dependent. As a result, sizes are selected so that the frequency of light used to make a group of quantum dots fluoresce is an even multiple of the frequency required to make another group incandesce. Then both groups can be lit with a single light source.
In photodynamic therapy, a particle is placed within the body and is illuminated with light from the outside. The light gets absorbed by the particle and if the particle is metal, energy from the light will heat the particle and surrounding tissue. Light may also be used to produce high energy oxygen molecules which will chemically react with and destroy most organic molecules that are next to them (like tumors). This therapy is appealing for many reasons. It does not leave a “toxic trail” of reactive molecules throughout the body (chemotherapy) because it is directed where only the light is shined and the particles exist. Photodynamic therapy has potential for a noninvasive procedure for dealing with diseases, growths, and tumors.
# Nanorobots
The somewhat speculative claims about the possibility of using nanorobots [2] [3] in medicine, advocates say, would totally change the world of medicine once it is realized. Nanomedicine [4] [5] would make use of these nanorobots, introduced into the body, to repair or detect damages and infections. According to Robert Freitas of the Institute for Molecular Manufacturing, a typical blood borne medical nanorobot would be between 0.5-3 micrometres in size, because that is the maximum size possible due to capillary passage requirement. Carbon would be the primary element used to build these nanorobots due to the inherent strength and other characteristics of some forms of carbon (diamond/fullerene composites), and nanorobots would be fabricated in desktop nanofactories [6] specialized for this purpose. Cancer could be treated very effectively, according to nanomedicine advocates. Nanorobots could counter the problem of identifying and isolating cancer cells as they could be introduced into the bloodstream. These nanorobots would search out cancer affected cells using certain molecular markers. Medical nanorobots would then destroy these cells, and only these cells. Nanomedicines could be a very helpful and hopeful therapy for patients, since current treatments like radiation therapy and chemotherapy often end up destroying more healthy cells than cancerous ones. From this point of view, it provides a non-depressed therapy for cancer patients. Nanorobots could also be useful in precision tissue- and cell-targeted drug delivery [7] [8], in performing nanosurgery [9], and in treatments for hypoxemia and respiratory illness[10] [11], dentistry [12] [13], bacteremic infections[14], physical trauma [15], gene therapy via chromosome replacement therapy [16] [17], and even biological aging
[18]. Indefinite lifespan is often predicted to be made available by nanomedicine. [19]
# Neuro-electronic Interfaces
Neuro-electronic interfaces are a visionary goal dealing with the construction of nanodevices that will permit computers to be joined and linked to the nervous system. This idea requires the building of a molecular structure that will permit control and detection of nerve impulses by an external computer. The computers will be able to interpret, register, and respond to signals the body gives off when it feels sensations. The demand for such structures is huge because many diseases involve the decay of the nervous system (ALS and multiple sclerosis). Also, many injuries and accidents may impair the nervous system resulting in dysfunctional systems and paraplegia. If computers could control the nervous system through neuro-electronic interface, problems that impair the system could be controlled so that effects of diseases and injuries could be overcome. Two considerations must be made when selecting the power source for such applications. They are refuelable and nonrefuelable strategies. A refuelable strategy implies energy is refilled continuously or periodically with external sonic, chemical, tethered, or electrical sources. A nonrefuelable strategy implies that all power is drawn from internal energy storage which would stop when all energy is drained.
One limitation to this innovation is the fact that electrical interference is a possibility. Electric fields, electromagnetic pulses (EMP), and stray fields from other in vivo electrical devices can all cause interference. Also, thick insulators are required to prevent electron leakage, and if high conductivity of the in vivo medium occurs there is a risk of sudden power loss and “shorting out.” Finally, thick wires are also needed to conduct substantial power levels without overheating. Little practical progress has been made even though research is happening. The wiring of the structure is extremely difficult because they must be positioned precisely in the nervous system so that it is able to monitor and respond to nervous signals. The structures that will provide the interface must also be compatible with the body’s immune system so that they will remain unaffected in the body for a long time. In addition, the structures must also sense ionic currents and be able to cause currents to flow backward. While the potential for these structures is amazing, there is no timetable for when they will be available.
# Cell repair machines
Using drugs and surgery, doctors can only encourage tissues to repair themselves. With molecular machines, there will be more direct repairs. Cell repair will utilize the same tasks that living systems already prove possible. Access to cells is possible because biologists can stick needles into cells without killing them. Thus, molecular machines are capable of entering the cell. Also, all specific biochemical interactions show that molecular systems can recognize other molecules by touch, build or rebuild every molecule in a cell, and can disassemble damaged molecules. Finally, cells that replicate prove that molecular systems can assemble every system found in a cell. Therefore, since nature has demonstrated the basic operations needed to perform molecular-level cell repair, in the future, nanomachine based systems will be built that are able to enter cells, sense differences from healthy ones and make modifications to the structure.
The possibilities of these cell repair machines are impressive. Comparable to the size of viruses or bacteria, their compact parts will allow them to be more complex. The early machines will be specialized. As they open and close cell membranes or travel through tissue and enter cells and viruses, machines will only be able to correct a single molecular disorder like DNA damage or enzyme deficiency. Later, cell repair machines will be programmed with more abilities with the help of advanced AI systems.
Nanocomputers will be needed to guide these machines. These computers will direct machines to examine, take apart, and rebuild damaged molecular structures. Repair machines will be able to repair whole cells by working structure by structure. Then by working cell by cell and tissue by tissue, whole organs can be repaired. Finally, by working organ by organ, health is restored to the body. Cells damaged to the point of inactivity can be repaired because of the ability of molecular machines to build cells from scratch. Therefore, cell repair machines will free medicine from reliance on self repair.
A new wave of technology and medicine is being created and its impact on the world is going to be monumental. From the possible applications such as drug delivery and in vivo imaging to the potential machines of the future, advancements in nanomedicine are being made every day. It will not be long for the 10 billion dollar industry to explode into a 100 billion or 1 trillion dollar industry, and drug delivery, in vivo imaging and therapy is just the beginning. | https://www.wikidoc.org/index.php/Nanomedicine | |
3e20f84aedc18abbe8904f985ab94dca4c83e70a | wikidoc | Nanopin film | Nanopin film
# Overview
Nanopin film is an experimental material in nanotechnology developed in 2005 with unusual superhydrophobic properties . A droplet of water makes contact with the surface of this film and forms an almost perfect sphere with a contact angle of 178°. The film is able to do this because it is covered with nanoscale topped off pins or cones perpendicular to the surface. The surface is regarded as a composite material with mostly air and a small fraction made up by the tops of the cones. When the contact angle of the cone material is sufficiently large Cassie's law predicts large contact angle values for the composite.
This particular nanopin film is produced with borosilicate glass as the primary substrate. A solution of CoCl26H2O or cobalt chloride hexahydrate is heated at 60 °C for 24 hours in a chemical bath deposition to form a brucite type cobalt(II) hydroxide layer with composition
The top coating is provided by lauric acid in a separate step. A 3 square micrometer surface now contains on average 166 such cones with cone height of around 100 nm and the cone diameter at the tip of 6.5 nm. The Cassie's law prediction for this material with the lauric acid surface area of 0.000612 and flat film contact angle of 75° is 177.8°. | Nanopin film
# Overview
Nanopin film is an experimental material in nanotechnology developed in 2005 with unusual superhydrophobic properties [1]. A droplet of water makes contact with the surface of this film and forms an almost perfect sphere with a contact angle of 178°. The film is able to do this because it is covered with nanoscale topped off pins or cones perpendicular to the surface. The surface is regarded as a composite material with mostly air and a small fraction made up by the tops of the cones. When the contact angle of the cone material is sufficiently large Cassie's law predicts large contact angle values for the composite.
This particular nanopin film is produced with borosilicate glass as the primary substrate. A solution of CoCl2•6H2O or cobalt chloride hexahydrate is heated at 60 °C for 24 hours in a chemical bath deposition to form a brucite type cobalt(II) hydroxide layer with composition
The top coating is provided by lauric acid in a separate step. A 3 square micrometer surface now contains on average 166 such cones with cone height of around 100 nm and the cone diameter at the tip of 6.5 nm. The Cassie's law prediction for this material with the lauric acid surface area of 0.000612 and flat film contact angle of 75° is 177.8°.
# External links
- Picture of droplet on surface nanopin film | https://www.wikidoc.org/index.php/Nanopin_film | |
8d57ad39996074c4447b7f2b364711503def622d | wikidoc | Nasal cavity | Nasal cavity
# Overview
The nasal cavity (or nasal fossa) is a large air-filled space above and behind the nose in the middle of the face.
# Function
The nasal cavity conditions the air to be received by the areas of the respiratory tract and nose. Owing to the large surface area provided by the conchae, the air passing through the nasal cavity is warmed or cooled to within 1 degree of body temperature. In addition, the air is humidified, and dust and other particulate matter is removed by vibrissae, short, thick hairs, present in the vestibule. The cilia of the respiratory epithelium move the particulate matter towards the pharynx where it is swallowed.
# Borders
The lateral wall of the nasal cavity is mainly made up by the maxilla, however there is a deficiency that is compensated by: the perpendicular plate of the palatine bone, the medial pterygoid plate, the labyrinth of the ethmoid and the inferior concha.
The nasal cavity is enclosed by the nasal bone above.
The floor of the nasal cavity, which forms the roof of the mouth, is made up by the bones of the hard palate: the horizontal plate of the palatine bone posteriorly and the palatine process of the maxilla anteriorly. To the front of the nasal cavity is the nose, while the back is continuous with the pharynx. The paranasal sinuses are connected to the nasal cavity through small orifices called ostia.
The nasal cavity is divided in two by a vertical fin called the nasal septum. On the sides of the nasal cavity are three horizontal outgrowths called turbinates or conchae (singular "concha"). These turbinates disrupt the airflow, directing air toward the olfactory epithelium on the surface of the turbinates and the septum. The vomeronasal organ is located at the back of the septum and has a role in pheromone detection.
Cilia and mucus along the inside wall of the nasal cavity trap and remove dust and pathogens from the air as it flows through the nasal cavity. The cilia move the mucus down the nasal cavity to the pharynx, where it can be swallowed.
The nasal cavity is divided into two segments: the respiratory segment and the olfactory segment. The respiratory segment is lined with ciliated pseudostratified columnar epithelium (also called respiratory epithelium). The conchae are located in this region. The respiratory segment has a very vascularized lamina propria allowing the venous plexuses of the conchal mucosa to engorge with blood, restricting airflow and causing air to be directed to the other side of the nose. This cycle occurs approximately every 20-30 minutes. Nose bleeds in the inferior concha are common in this region. The olfactory segment is lined with a specialized type of pseudostratified columnar epithelium, known as olfactory epithelium, which contains receptors for the sense of the smell. This segment is located along the dorsal roof of the nasal cavity. Histological sections appear yellowish-brown due to the presence of lipofuscin pigments. Olfactory mucosal cell types include: bipolar neurons, supporting (sustentacular) cells, basal cells, and Bowman's glands. The axons of the bipolar neurons form the olfactory nerve (cranial nerve I) which enters the brain through the cribiform plate. Bowman's glands are serous glands in the lamina propria, whose secretions trap and dissolve oderiferous substances.
# Blood and nerve supply
There is a rich blood supply to the nasal cavity. In some animals, such as dogs, the capillary beds flowing through the nasal cavity help cool the blood flow to the brain.
Blood supply comes from branches of both the internal and external carotid artery, including branches of the facial artery and maxillary artery. The named arteries of the nose are:
- Sphenopalatine artery, a branch of the maxillary artery.
- Anterior ethmoidal artery, a branch of the ophthalmic artery
- Branches of facial artery supplying the vestibule of the nasal cavity.
# Innervation
Innervation of the nasal cavity responsible for the sense of smell is via the olfactory nerve, which sends microscopic fibers from the olfactory bulb through the cribiform plate to reach the top of the nasal cavity.
General sensory innervation is by branches of the trigeminal nerve (V1 & V2):
- Nasociliary nerve (V1)
- Nasopalatine nerve (V2)
- Posterior nasal branches of Maxillary nerve (V2)
The entire nasal cavity is innervated by autonomic fibers. Sympathetic innervation to the blood vessels of the mucosa causes them to constrict, while parasympathetic innervation of the mucosa controls secrection by mucous glands.
# Diseases
Diseases of the nasal cavity include viral infections and nasal cavity cancer.
Empty nose syndrome.
# Additional images
- Nose and nasal cavities
- Normal Nose CT Front cross section
- Coronal section of nasal cavities.
- Anatomy of the nasal cavity
- The skull from the front.
- Left orbicularis oculi, seen from behind.
- Lateral wall of nasal cavity.
- Nerves of the wall of the nasal cavity | Nasal cavity
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The nasal cavity (or nasal fossa) is a large air-filled space above and behind the nose in the middle of the face.
# Function
The nasal cavity conditions the air to be received by the areas of the respiratory tract and nose. Owing to the large surface area provided by the conchae, the air passing through the nasal cavity is warmed or cooled to within 1 degree of body temperature. In addition, the air is humidified, and dust and other particulate matter is removed by vibrissae, short, thick hairs, present in the vestibule. The cilia of the respiratory epithelium move the particulate matter towards the pharynx where it is swallowed.
# Borders
The lateral wall of the nasal cavity is mainly made up by the maxilla, however there is a deficiency that is compensated by: the perpendicular plate of the palatine bone, the medial pterygoid plate, the labyrinth of the ethmoid and the inferior concha.
The nasal cavity is enclosed by the nasal bone above.
The floor of the nasal cavity, which forms the roof of the mouth, is made up by the bones of the hard palate: the horizontal plate of the palatine bone posteriorly and the palatine process of the maxilla anteriorly. To the front of the nasal cavity is the nose, while the back is continuous with the pharynx. The paranasal sinuses are connected to the nasal cavity through small orifices called ostia.
The nasal cavity is divided in two by a vertical fin called the nasal septum. On the sides of the nasal cavity are three horizontal outgrowths called turbinates or conchae (singular "concha"). These turbinates disrupt the airflow, directing air toward the olfactory epithelium on the surface of the turbinates and the septum. The vomeronasal organ is located at the back of the septum and has a role in pheromone detection.
Cilia and mucus along the inside wall of the nasal cavity trap and remove dust and pathogens from the air as it flows through the nasal cavity. The cilia move the mucus down the nasal cavity to the pharynx, where it can be swallowed.
The nasal cavity is divided into two segments: the respiratory segment and the olfactory segment. The respiratory segment is lined with ciliated pseudostratified columnar epithelium (also called respiratory epithelium). The conchae are located in this region. The respiratory segment has a very vascularized lamina propria allowing the venous plexuses of the conchal mucosa to engorge with blood, restricting airflow and causing air to be directed to the other side of the nose. This cycle occurs approximately every 20-30 minutes. Nose bleeds in the inferior concha are common in this region. The olfactory segment is lined with a specialized type of pseudostratified columnar epithelium, known as olfactory epithelium, which contains receptors for the sense of the smell. This segment is located along the dorsal roof of the nasal cavity. Histological sections appear yellowish-brown due to the presence of lipofuscin pigments. Olfactory mucosal cell types include: bipolar neurons, supporting (sustentacular) cells, basal cells, and Bowman's glands. The axons of the bipolar neurons form the olfactory nerve (cranial nerve I) which enters the brain through the cribiform plate. Bowman's glands are serous glands in the lamina propria, whose secretions trap and dissolve oderiferous substances.
# Blood and nerve supply
There is a rich blood supply to the nasal cavity. In some animals, such as dogs, the capillary beds flowing through the nasal cavity help cool the blood flow to the brain.
Blood supply comes from branches of both the internal and external carotid artery, including branches of the facial artery and maxillary artery. The named arteries of the nose are:
- Sphenopalatine artery, a branch of the maxillary artery.
- Anterior ethmoidal artery, a branch of the ophthalmic artery
- Branches of facial artery supplying the vestibule of the nasal cavity.
# Innervation
Innervation of the nasal cavity responsible for the sense of smell is via the olfactory nerve, which sends microscopic fibers from the olfactory bulb through the cribiform plate to reach the top of the nasal cavity.
General sensory innervation is by branches of the trigeminal nerve (V1 & V2):
- Nasociliary nerve (V1)
- Nasopalatine nerve (V2)
- Posterior nasal branches of Maxillary nerve (V2)
The entire nasal cavity is innervated by autonomic fibers. Sympathetic innervation to the blood vessels of the mucosa causes them to constrict, while parasympathetic innervation of the mucosa controls secrection by mucous glands.
# Diseases
Diseases of the nasal cavity include viral infections and nasal cavity cancer.
Empty nose syndrome.
# Additional images
- Nose and nasal cavities
- Normal Nose CT Front cross section
- Coronal section of nasal cavities.
- Anatomy of the nasal cavity
- The skull from the front.
- Left orbicularis oculi, seen from behind.
- Lateral wall of nasal cavity.
- Nerves of the wall of the nasal cavity | https://www.wikidoc.org/index.php/Nasal_antrum | |
65449af0cdfff7c103e16f6353769fbd6466b9b8 | wikidoc | Nasal concha | Nasal concha
In anatomy, a nasal concha (or turbinate) is a long, narrow and curled bone shelf (shaped like an elongated sea-shell) which protrudes into the breathing passage of the nose. Turbinate bone refers to any of the scrolled spongy bones of the nasal passages in humans and other vertebrates.
In humans, the turbinates divide the nasal airway into three groove-like air passages –and are responsible for forcing inhaled air to flow in a steady, regular pattern around the largest possible surface of cilia and climate controlling tissue.
# Structure and functions of turbinates
Turbinates are composed of pseudostratified columnar, ciliated respiratory epithelium with a thick, vascular and erectile glandular tissue layer.
The turbinates are located laterally in the nasal cavities, curling medially and downwards into the nasal airway. Each pair is composed of one turbinate in either side of the nasal cavity, divided by the septum.
The inferior turbinates are the largest turbinates, and can be as long as the index finger, and are responsible for the majority of airflow direction, humidification, heating, and filtering of air inhaled through the nose.
The middle turbinates are smaller, usually as long as the little finger. They project downwards over the openings of the maxillary and ethmoid sinuses, and act as buffers to protect the sinuses from coming in direct contact with pressurized nasal airflow. Most inhaled airflow travels between the inferior turbinate and the middle turbinate.
The superior turbinates are smaller structures, connected to the middle turbinates by nerve-endings, and serve to protect the olfactory bulb.
## Role of turbinates in the respiratory system
The turbinates compose most of the mucosal tissue of the nose and are required for functional respiration. The turbinates are enriched with airflow pressure and temperature sensing nerve receptors (linked to the “trigeminal” nerve route, the fifth cranial nerve), allowing for tremendous erectile capabilities of nasal congestion and decongestion (very much like the penis), in response to the climatic conditions and changing needs of the body.
The turbinates are also responsible for filtration, heating and humidification of air inhaled through the nose. Of these three, filtration is the most important reason to breathe through the nose. As air passes over the turbinate tissues it is heated to body temperature, humidified (up to 98% water saturation) and filtered.
## Role of turbinates as an immunological defense
The respiratory epithelium which covers the erectile tissue (or Lamina propria) of the turbinates plays a major role in the body’s first line of immunological defense. The respiratory epithelium is partially composed of mucus producing goblet cells. This secreted mucus covers the nasal cavities, and serves as a filter, by trapping air-borne particles larger than 2 to 3 micrometers. The respiratory epithelium also serves as a means of access for the lymphatic system which protects the body from being infected by viruses or bacteria.
## Role of turbinates in olfaction
The turbinates provide, first and foremost, the humidity needed to preserve the delicate olfactory (smell) epithelium needed to keep the olfactory receptors healthy and alert. If the epithelial layer gets dry or irritated, it may cease to function. This is usually a temporary condition, but over time, may lead to chronic anosmia. The turbinates also increase the surface area of the inside of the nose, and by directing and deflecting airflow across the maximum mucosal surface of the inner nose, they are able to propel the inspired air. This, coupled with the humidity and filtration provided by the turbinates, helps to carry more scent molecules towards the higher, and very narrow regions of the nasal airways, where olfaction nerve receptors are located.
The superior turbinates literally hood-over, and protect the nerve axons piercing through the cribriform plate (a porous bone plate that separates the nose from the brain) into the nose. Some areas of the middle turbinates are also innervated by the olfactory bulb. All three turbinates are innervated by pain and temperature receptors, via the trigeminal nerve (or, the fifth cranial nerve). Research has shown that there is a strong connection between these nerve endings and activation of the olfactory receptors, but science has yet to fully explain this interaction.
# Turbinate dysfunction
Large, swollen turbinates may lead to blockage of nasal breathing. Allergies, exposure to environmental irritants, or a persistent inflammation within the sinuses, can lead to turbinate swelling. Deformity of the nasal septum can also result in enlarged turbinates.
Treatment of the underlying allergy or irritant may reduce turbinate swelling. In cases that do not resolve, or for treatment of deviated septum, turbinate reduction surgery may be required. Bipolar radiofrequency ablation, a technique used for coblation tonsillectomy, is also used for the treatment of swollen turbinates. Generally, because the turbinates are essential for respiration, only small amounts of turbinate tissue should be removed. Extensive reduction of the inferior or middle turbinates can cause empty nose syndrome. | Nasal concha
Template:Infobox Anatomy
In anatomy, a nasal concha (or turbinate) is a long, narrow and curled bone shelf (shaped like an elongated sea-shell) which protrudes into the breathing passage of the nose. Turbinate bone refers to any of the scrolled spongy bones of the nasal passages in humans and other vertebrates.
[1]
In humans, the turbinates divide the nasal airway into three groove-like air passages –and are responsible for forcing inhaled air to flow in a steady, regular pattern around the largest possible surface of cilia and climate controlling tissue.
# Structure and functions of turbinates
Turbinates are composed of pseudostratified columnar, ciliated respiratory epithelium with a thick, vascular and erectile glandular tissue layer.
[2] The turbinates are located laterally in the nasal cavities, curling medially and downwards into the nasal airway. Each pair is composed of one turbinate in either side of the nasal cavity, divided by the septum.[2]
The inferior turbinates are the largest turbinates, and can be as long as the index finger, and are responsible for the majority of airflow direction, humidification, heating, and filtering of air inhaled through the nose.[1]
The middle turbinates are smaller, usually as long as the little finger. They project downwards over the openings of the maxillary and ethmoid sinuses, and act as buffers to protect the sinuses from coming in direct contact with pressurized nasal airflow. Most inhaled airflow travels between the inferior turbinate and the middle turbinate.[1]
The superior turbinates are smaller structures, connected to the middle turbinates by nerve-endings, and serve to protect the olfactory bulb.[1]
## Role of turbinates in the respiratory system
The turbinates compose most of the mucosal tissue of the nose and are required for functional respiration. The turbinates are enriched with airflow pressure and temperature sensing nerve receptors (linked to the “trigeminal” nerve route, the fifth cranial nerve), allowing for tremendous erectile capabilities of nasal congestion and decongestion (very much like the penis), in response to the climatic conditions and changing needs of the body.[2]
The turbinates are also responsible for filtration, heating and humidification of air inhaled through the nose. Of these three, filtration is the most important reason to breathe through the nose.[citation needed] As air passes over the turbinate tissues it is heated to body temperature, humidified (up to 98% water saturation) and filtered.[2]
## Role of turbinates as an immunological defense
The respiratory epithelium which covers the erectile tissue (or Lamina propria) of the turbinates plays a major role in the body’s first line of immunological defense. The respiratory epithelium is partially composed of mucus producing goblet cells. This secreted mucus covers the nasal cavities, and serves as a filter, by trapping air-borne particles larger than 2 to 3 micrometers. The respiratory epithelium also serves as a means of access for the lymphatic system which protects the body from being infected by viruses or bacteria.[1]
## Role of turbinates in olfaction
The turbinates provide, first and foremost, the humidity needed to preserve the delicate olfactory (smell) epithelium needed to keep the olfactory receptors healthy and alert. If the epithelial layer gets dry or irritated, it may cease to function. This is usually a temporary condition, but over time, may lead to chronic anosmia[2]. The turbinates also increase the surface area of the inside of the nose, and by directing and deflecting airflow across the maximum mucosal surface of the inner nose, they are able to propel the inspired air. This, coupled with the humidity and filtration provided by the turbinates, helps to carry more scent molecules towards the higher, and very narrow regions of the nasal airways, where olfaction nerve receptors are located[1].
The superior turbinates literally hood-over, and protect the nerve axons piercing through the cribriform plate (a porous bone plate that separates the nose from the brain) into the nose. Some areas of the middle turbinates are also innervated by the olfactory bulb. All three turbinates are innervated by pain and temperature receptors, via the trigeminal nerve (or, the fifth cranial nerve)[2]. Research has shown that there is a strong connection between these nerve endings and activation of the olfactory receptors, but science has yet to fully explain this interaction.
# Turbinate dysfunction
Large, swollen turbinates may lead to blockage of nasal breathing. Allergies, exposure to environmental irritants, or a persistent inflammation within the sinuses, can lead to turbinate swelling. Deformity of the nasal septum can also result in enlarged turbinates.
[3]
Treatment of the underlying allergy or irritant may reduce turbinate swelling. In cases that do not resolve, or for treatment of deviated septum, turbinate reduction surgery may be required. Bipolar radiofrequency ablation, a technique used for coblation tonsillectomy, is also used for the treatment of swollen turbinates. Generally, because the turbinates are essential for respiration, only small amounts of turbinate tissue should be removed. Extensive reduction of the inferior or middle turbinates can cause empty nose syndrome.[3] | https://www.wikidoc.org/index.php/Nasal_concha | |
3d44b14b8897c0e00a7c8b831213688278582731 | wikidoc | User:Navneet | User:Navneet
# Navneet Kaur, M.B.,B.S.
Contact:
Email: mann.navneet94@gmail.com
# Medical Education
August 2012 – Jan 2020
- Bachelor of Medicine and Bachelor of Surgery (M.B.B.S.) from Sri Guru Ram Das Institute of Medical Sciences and Research (SGRDIMSR), Baba Farid University of Health Sciences (BFUHS), Amritsar, Punjab, India.
# Professional Affiliations
- ECFMG Certified – March 2020.
- Registered General practitioner, India.
- Member of Medical Student Association of India.
# US Clinical Experience
June 2021- present
- RESEARCH SCHOLAR, at WikiDoc Scholar Program, under Dr. Michael Gibson, Professor of Medicine at Harvard Medical School and Researcher at Baim Institute for Clinical Research
June 2021- July 2021
- CLINICAL TELE-ROTATION, with Dr. Charles L. Lawler, MD, Board Certified Internist, Former Program Director, Associate Professor University of Illinois, Elmhurst Health Care, Elmhurst, IL
July 2020 -August 2020
- EXTERNSHIP, at SUNY Downstate under Dr. Rattanjit Kohli, MD (Internal Medicine) Brooklyn, New York.
April 2019
- OBSERVERSHIP, under Dr. Gurkaramjit S Khaira, MD, Hospitalist (Clinical Medicine) at Geisinger Health System, GCMC hospital, Scranton, PA
# Publications
## Peer Reviewed Journal Articles/Abstract
- BITEMPORAL HEMIANOPIA- AN INDICATION OF ETHAMBUTOL TOXICITY. Dinesh Kumar, Navneet Kaur, Snimer Kaur Sidhu, Zoya Gurpreet Paul, Rahul VC Tiwari. JCR. 2020; 7(11): 2730-2732. doi:10.31838/jcr.07.19.398
- Case report on Morvan syndrome. Arveen Kaur, Navneet Kaur. Published in International Journal of Basic and Applied Medical Sciences, CIBTech - Syndrome.pdf
## Oral presentation
- Anti microbial Resistance and COVID-19, an awareness campaign, Navneet Kaur, Ravneet Kaur, Yashjot Kaur. Presented at: MSAI with support from WORLD HEALTH ORGANISATION (WHO-INDIA Office);
- HerChoice- Pro women, Pro Choice, an awareness session followed by group discussion about Safe Abortion, abortion care , abortion as a human right, and the stigma attached.Navneet Kaur, Yashjot Kaur, Ravneet Kaur, Jasleen Kaur. Oral Presentation presented at: Medical Student Association of India; Amritsar, IND;
- Case presentation of Morvan syndrome, a rare neurological disorder, from North India, in a young male. Navneet Kaur Oral Presentation presented at: MSAI Online MedFest 2020; IND
# Communication Languages
- English
- Hindi
- Punjabi
- Urdu | User:Navneet
# Navneet Kaur, M.B.,B.S.
Contact:
Email: mann.navneet94@gmail.com
# Medical Education
August 2012 – Jan 2020
- Bachelor of Medicine and Bachelor of Surgery (M.B.B.S.) from Sri Guru Ram Das Institute of Medical Sciences and Research (SGRDIMSR), Baba Farid University of Health Sciences (BFUHS), Amritsar, Punjab, India.
# Professional Affiliations
- ECFMG Certified – March 2020.
- Registered General practitioner, India.
- Member of Medical Student Association of India.
# US Clinical Experience
June 2021- present
- RESEARCH SCHOLAR, at WikiDoc Scholar Program, under Dr. Michael Gibson, Professor of Medicine at Harvard Medical School and Researcher at Baim Institute for Clinical Research
June 2021- July 2021
- CLINICAL TELE-ROTATION, with Dr. Charles L. Lawler, MD, Board Certified Internist, Former Program Director, Associate Professor University of Illinois, Elmhurst Health Care, Elmhurst, IL
July 2020 -August 2020
- EXTERNSHIP, at SUNY Downstate under Dr. Rattanjit Kohli, MD (Internal Medicine) Brooklyn, New York.
April 2019
- OBSERVERSHIP, under Dr. Gurkaramjit S Khaira, MD, Hospitalist (Clinical Medicine) at Geisinger Health System, GCMC hospital, Scranton, PA
# Publications
## Peer Reviewed Journal Articles/Abstract
- BITEMPORAL HEMIANOPIA- AN INDICATION OF ETHAMBUTOL TOXICITY. Dinesh Kumar, Navneet Kaur, Snimer Kaur Sidhu, Zoya Gurpreet Paul, Rahul VC Tiwari. JCR. 2020; 7(11): 2730-2732. doi:10.31838/jcr.07.19.398 [ http://www.jcreview.com/?mno=110209 ]
- Case report on Morvan syndrome. Arveen Kaur, Navneet Kaur. Published in International Journal of Basic and Applied Medical Sciences, CIBTech https://www.cibtech.org/J-MEDICAL-SCIENCES/PUBLICATIONS/2020/VOL_10_NO_2/JMS-02-ARVEEN-Morvan- Syndrome.pdf
## Oral presentation
- Anti microbial Resistance and COVID-19, an awareness campaign, Navneet Kaur, Ravneet Kaur, Yashjot Kaur. Presented at: MSAI with support from WORLD HEALTH ORGANISATION (WHO-INDIA Office); [April, 2021]
- HerChoice- Pro women, Pro Choice, an awareness session followed by group discussion about Safe Abortion, abortion care , abortion as a human right, and the stigma attached.Navneet Kaur, Yashjot Kaur, Ravneet Kaur, Jasleen Kaur. Oral Presentation presented at: Medical Student Association of India; Amritsar, IND; [August, 2020]
- Case presentation of Morvan syndrome, a rare neurological disorder, from North India, in a young male. Navneet Kaur Oral Presentation presented at: MSAI Online MedFest 2020; IND [July,2020]
# Communication Languages
- English
- Hindi
- Punjabi
- Urdu | https://www.wikidoc.org/index.php/Navneet_Kaur | |
21d1398066cebe5ad52e3af43156f17a63e97873 | wikidoc | Nd:YAG laser | Nd:YAG laser
# Overview
Nd:YAG (neodymium-doped yttrium aluminium garnet; Nd:Y3Al5O12) is a crystal that is used as a lasing medium for solid-state lasers. The dopant, triply ionized neodymium, typically replaces yttrium in the crystal structure of the yttrium aluminium garnet, since they are of similar size. Generally the crystalline host is doped with around 1% neodymium by weight.
Laser operation of Nd:YAG was first demonstrated by Geusic et al. at Bell Laboratories in 1964.
# Technology
Nd:YAG lasers are optically pumped using a flashlamp or laser diodes. They are one of the most common types of laser, and are used for many different applications.
Nd:YAG lasers typically emit light with a wavelength of 1064 nm, in the infrared. However, there are also transitions near 940, 1120, 1320, and 1440 nm. Nd:YAG lasers operate in both pulsed and continuous mode. Pulsed Nd:YAG lasers are typically operated in the so called Q-switching mode: An optical switch is inserted in the laser cavity waiting for a maximum population inversion in the neodymium ions before it opens. Then the light wave can run through the cavity, depopulating the excited laser medium at maximum population inversion. In this Q-switched mode output powers of 20 megawatts and pulse durations of less than 10 nanoseconds are achieved.
Nd:YAG absorbs mostly in the bands between 730-760 nm and 790-820 nm. Krypton flashlamps, with high output at those bands, are therefore more efficient for pumping Nd:YAG lasers than the xenon lamps, which produce more white light and hence more energy therefore goes wasted.
The amount of the neodymium dopant in the material varies according to its use. For continual wave output, the doping is significantly lower than for pulsed lasers. The lightly doped CW rods can be optically distinguished by being less colored, almost white, while higher-doped rods are pink-purplish.
Other common host materials for neodymium are: YLF (yttrium lithium fluoride, 1047 and 1053 nm), YVO4 (yttrium orthovanadate, 1064 nm), and glass. A particular host material is chosen in order to obtain a desired combination of optical, mechanical, and thermal properties. Nd:YAG lasers and variants are pumped either by flash lamps, continuous gas discharge lamps, or near-infrared laser diodes (DPSS lasers). Prestabilized laser (PSL) types of Nd:YAG lasers have proved to be particularly useful in providing the main beams for gravitational wave interferometers such as LIGO, VIRGO, GEO600 and TAMA.
# Applications
## Ophthalmology
Frequency-doubled Nd:YAG lasers (wavelength 532 nm) are used in the medical field to correct posterior capsular opacification (after-cataract). These lasers are used for peripheral iridotomy in patients with acute angle closure glaucoma, where it has superseded surgical iridectomy. They are also used in place of argon lasers for pan-retinal photocoagulation in patients with diabetic retinopathy.
## Cosmetic medicine
These lasers are also used extensively in the field of cosmetic medicine for laser hair removal and the treatment of minor vascular defects such as spider veins on the face and legs.
## Manufacturing
It is used in manufacturing as a means of engraving, etching, or marking a variety of metals and plastics. Nd:YAG lasers are extensively used in manufacturing for cutting and welding steel and super alloys. For automotive applications (cutting and welding steel) the power levels are typically 1-5 kW. Super alloy drilling (for gas turbine parts) typically uses pulsed Nd:YAG lasers (millisecond pulses, not Q-switched). Nd:YAG lasers are also employed to make subsurface markings in transparent materials such as glass or acrylic glass.
## Fluid dynamics
Nd:YAG lasers can also be used for flow visualization techniques in fluid dynamics (for example particle image velocimetry or induced fluorescence).
## Dentistry
Nd:YAG lasers are used for soft tissue surgeries in the oral cavity, such as gingivectomy, periodontal sulcular debridement, frenectomy, biopsy, and coagulation of graft donor sites.
# Additional frequencies
For many applications, the infrared light is frequency-doubled or -tripled using nonlinear optical materials such as lithium triborate to obtain visible (532 nm, green) or ultraviolet light. A green laser pointer is a frequency doubled Nd:YVO4 DPSS laser. Nd:YAG can be also made to lase at its non-principal wavelength. The line at 946 nm is typically employed in "blue laser pointer" DPSS lasers, where it is doubled to 473 nm.
# References and notes
- Siegman, Anthony E. (1986). Lasers. University Science Books. ISBN 0-935702-11-3..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}
- Yariv, Amnon (1989). Quantum Electronics (3rd Edition ed.). Wiley. ISBN 0-471-60997-8.CS1 maint: Extra text (link)
- Koechner, Walter (1988). Solid-State Laser Engineering (2nd Edition ed.). Springer-Verlag. ISBN 3-540-18747-2.CS1 maint: Extra text (link)
- ↑ Koechner §2.3, pp48–53.
- ↑ Geusic, J.E., Marcos, H.M, and Van Uitert, L.G.: "Laser oscillations in Nd-doped yttrium aluminum, yttrium gallium and gadolinium garnets". Applied Physics Letters 4 10, 182-184 (1964).
- ↑ Jump up to: 3.0 3.1 Yariv, §10.3, p. 208-211.
- ↑ Koechner §6.1.1, pp. 251–264.
- ↑ Palafox, Gilbert N. (2003). "Rapid in-vitro physiologic flow experimentation using rapid prototyping and particle image velocimetry" (pdf). 2003 Summer Bioengineering Conference: 419. Retrieved 2007-10-10. Unknown parameter |coauthors= ignored (help)
ca:Làser Nd:YAG
de:Nd:YAG-Laser
nl:Nd-YAG-laser
sv:Nd:YAG-laser
it:Laser Nd:YAG | Nd:YAG laser
# Overview
Nd:YAG (neodymium-doped yttrium aluminium garnet; Nd:Y3Al5O12) is a crystal that is used as a lasing medium for solid-state lasers. The dopant, triply ionized neodymium, typically replaces yttrium in the crystal structure of the yttrium aluminium garnet, since they are of similar size. Generally the crystalline host is doped with around 1% neodymium by weight.[1]
Laser operation of Nd:YAG was first demonstrated by Geusic et al. at Bell Laboratories in 1964[2].
# Technology
Nd:YAG lasers are optically pumped using a flashlamp or laser diodes. They are one of the most common types of laser, and are used for many different applications.
Nd:YAG lasers typically emit light with a wavelength of 1064 nm, in the infrared.[3] However, there are also transitions near 940, 1120, 1320, and 1440 nm. Nd:YAG lasers operate in both pulsed and continuous mode. Pulsed Nd:YAG lasers are typically operated in the so called Q-switching mode: An optical switch is inserted in the laser cavity waiting for a maximum population inversion in the neodymium ions before it opens. Then the light wave can run through the cavity, depopulating the excited laser medium at maximum population inversion. In this Q-switched mode output powers of 20 megawatts and pulse durations of less than 10 nanoseconds are achieved.[citation needed]
Nd:YAG absorbs mostly in the bands between 730-760 nm and 790-820 nm.[3] Krypton flashlamps, with high output at those bands, are therefore more efficient for pumping Nd:YAG lasers than the xenon lamps, which produce more white light and hence more energy therefore goes wasted.[4]
The amount of the neodymium dopant in the material varies according to its use. For continual wave output, the doping is significantly lower than for pulsed lasers. The lightly doped CW rods can be optically distinguished by being less colored, almost white, while higher-doped rods are pink-purplish.
Other common host materials for neodymium are: YLF (yttrium lithium fluoride, 1047 and 1053 nm), YVO4 (yttrium orthovanadate, 1064 nm), and glass. A particular host material is chosen in order to obtain a desired combination of optical, mechanical, and thermal properties. Nd:YAG lasers and variants are pumped either by flash lamps, continuous gas discharge lamps, or near-infrared laser diodes (DPSS lasers). Prestabilized laser (PSL) types of Nd:YAG lasers have proved to be particularly useful in providing the main beams for gravitational wave interferometers such as LIGO, VIRGO, GEO600 and TAMA.
# Applications
## Ophthalmology
Frequency-doubled Nd:YAG lasers (wavelength 532 nm) are used in the medical field to correct posterior capsular opacification (after-cataract). These lasers are used for peripheral iridotomy in patients with acute angle closure glaucoma, where it has superseded surgical iridectomy. They are also used in place of argon lasers for pan-retinal photocoagulation in patients with diabetic retinopathy.
## Cosmetic medicine
These lasers are also used extensively in the field of cosmetic medicine for laser hair removal and the treatment of minor vascular defects such as spider veins on the face and legs.
## Manufacturing
It is used in manufacturing as a means of engraving, etching, or marking a variety of metals and plastics. Nd:YAG lasers are extensively used in manufacturing for cutting and welding steel and super alloys. For automotive applications (cutting and welding steel) the power levels are typically 1-5 kW. Super alloy drilling (for gas turbine parts) typically uses pulsed Nd:YAG lasers (millisecond pulses, not Q-switched). Nd:YAG lasers are also employed to make subsurface markings in transparent materials such as glass or acrylic glass.
## Fluid dynamics
Nd:YAG lasers can also be used for flow visualization techniques in fluid dynamics (for example particle image velocimetry or induced fluorescence).[5]
## Dentistry
Nd:YAG lasers are used for soft tissue surgeries in the oral cavity, such as gingivectomy, periodontal sulcular debridement, frenectomy, biopsy, and coagulation of graft donor sites.
# Additional frequencies
For many applications, the infrared light is frequency-doubled or -tripled using nonlinear optical materials such as lithium triborate to obtain visible (532 nm, green) or ultraviolet light. A green laser pointer is a frequency doubled Nd:YVO4 DPSS laser. Nd:YAG can be also made to lase at its non-principal wavelength. The line at 946 nm is typically employed in "blue laser pointer" DPSS lasers, where it is doubled to 473 nm.
# References and notes
- Siegman, Anthony E. (1986). Lasers. University Science Books. ISBN 0-935702-11-3..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}
- Yariv, Amnon (1989). Quantum Electronics (3rd Edition ed.). Wiley. ISBN 0-471-60997-8.CS1 maint: Extra text (link)
- Koechner, Walter (1988). Solid-State Laser Engineering (2nd Edition ed.). Springer-Verlag. ISBN 3-540-18747-2.CS1 maint: Extra text (link)
- ↑ Koechner §2.3, pp48–53.
- ↑ Geusic, J.E., Marcos, H.M, and Van Uitert, L.G.: "Laser oscillations in Nd-doped yttrium aluminum, yttrium gallium and gadolinium garnets". Applied Physics Letters 4 10, 182-184 (1964).
- ↑ Jump up to: 3.0 3.1 Yariv, §10.3, p. 208-211.
- ↑ Koechner §6.1.1, pp. 251–264.
- ↑ Palafox, Gilbert N. (2003). "Rapid in-vitro physiologic flow experimentation using rapid prototyping and particle image velocimetry" (pdf). 2003 Summer Bioengineering Conference: 419. Retrieved 2007-10-10. Unknown parameter |coauthors= ignored (help)
ca:Làser Nd:YAG
de:Nd:YAG-Laser
nl:Nd-YAG-laser
sv:Nd:YAG-laser
it:Laser Nd:YAG
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nd:YAG | |
b96ee9a79db09b4a81ab3557f9fb747213a882d1 | wikidoc | Necatoriasis | Necatoriasis
# Overview
Necatoriasis is the condition of infection by Necator hookworms, such as Necator americanus. This hookworm infection is a type of helminthiasis (infection) which is a type of neglected tropical disease.
# Signs and symptoms
When adult worms attach to the villi of the small intestine, they suck on the host's blood, which may cause abdominal pain, diarrhea, cramps, and weight loss that can lead to anorexia. Heavy infections can lead to the development of iron deficiency and hypochromic microcytic anemia. This form of anemia in children can give rise to physical and mental retardation. Infection caused by cutaneous larvae migrans, a skin disease in humans, is characterized by skin ruptures and severe itching.
# Cause
Necatoriasis is caused by N. americanus. N. americanus can be divided into two areas – larvae and adult stage. The third stage larvae are guided to human skin by following thermal gradients. Typically, the larvae enter through the hands and feet following contact with contaminated soil. A papular, pruritic, itchy rash will develop around the site of entry into the human host. This is also known as “ground itch”. Generally, migration through the lungs is asymptomatic but a mild cough and pharyngeal irritation may occur during larval migration in the airways. Once larvae break through the alveoli and are swallowed, they enter the gastrointestinal tract and attach to the intestinal mucosa where they mature into adult worms. The hookworms attach to the mucosal lining using their cutting plates which allows them to penetrate blood vessels and feed on the host’s blood supply. Each worm consumes 30μl of blood per day. The major issue results from this intestinal blood loss which can lead to iron-deficiency anemia in moderate to heavy infections. Other common symptoms include epigastric pain and tenderness, nausea, exertional dyspnea, pain in lower extremities and in joints, sternal pain, headache, fatigue, and impotence. Death is rare in humans.
# Diagnosis
The standard method for diagnosing necatoriasis is through identification of N. americanus eggs in a fecal sample using a microscope. Eggs can be difficult to visualize in a lightly infected sample so a concentration method is generally used such as floatation or sedimentation. However, the eggs of A. duodenale and N. americanus cannot be distinguished; thus, the larvae must be examined to identify these hookworms. Larvae cannot be found in stool specimens unless the specimen was left at ambient temperature for a day or more.
The most common technique used to diagnose a hookworm infection is to take a stool sample, fix it in 10% formalin, concentrate it using the formalin-ethyl acetate sedimentation technique, and then create a wet mount of the sediment for viewing under a microscope.
# Prevention
Education, improved sanitation, and controlled disposal of human feces are critical for prevention. Nonetheless, wearing shoes in endemic areas helps reduce the prevalence of infection.
# Treatment
An infection of N. americanus parasites can be treated by using benzimidazoles, albendazole, and mebendazole. A blood transfusion may be necessary in severe cases of anemia. Light infections are usually left untreated in areas where reinfection is common. Iron supplements and a diet high in protein will speed the recovery process. In a case study involving 56-60 men with Trichuris trichiura and/or N. americanus infections, both albendazole and mebendazole were 90% effective in curing T. trichiura. However, albendazole had a 95% cure rate for N. americanus, while mebendazole only had a 21% cure rate. This suggests albendazole is most effective for treating both T. trichiura and N. americanus.
Cryotherapy by application of liquid nitrogen to the skin has been used to kill cutaneous larvae migrans, but the procedure has a low cure rate and a high incidence of pain and severe skin damage, so it now is passed over in favor of suitable pharmaceuticals. Topical application of some pharmaceuticals has merit, but requires repeated, persistent applications and is less effective than some systemic treatments.
## Antimicrobial Regimen
- Necator americanus
- Preferred regimen: Albendazole 400 mg PO single dose
- Alternative regimen (1): Mebendazole 100 mg PO bid or 500 mg daily for 3 days
- Alternative regimen (2): Pyrantel pamoate 11 mg/kg PO qd (maximum 1 g/day) for 3 days
# Epidemiology
Necator americanus was first discovered in Brazil and then was found in Texas. Later, it was found to be indigenous in Africa, China, southwest Pacific islands, India, and Southeast Asia. This parasite is a tropical parasite and is the most common species in humans. Roughly 95% of hookworms found in the southern region of the United States are N. americanus. This parasite is found in humans, but can also be found in pigs and dogs.
Transmission of N. americanus infection requires the deposition of egg-containing feces on shady, well-drained soil and is favored by warm, humid (tropical) conditions. Therefore, infections worldwide are usually reported in places where direct contact with contaminated soil occurs. | Necatoriasis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Necatoriasis is the condition of infection by Necator hookworms, such as Necator americanus.[1] This hookworm infection is a type of helminthiasis (infection) which is a type of neglected tropical disease.
# Signs and symptoms
When adult worms attach to the villi of the small intestine, they suck on the host's blood, which may cause abdominal pain, diarrhea, cramps, and weight loss that can lead to anorexia. Heavy infections can lead to the development of iron deficiency and hypochromic microcytic anemia. This form of anemia in children can give rise to physical and mental retardation. Infection caused by cutaneous larvae migrans, a skin disease in humans, is characterized by skin ruptures and severe itching.[2]
# Cause
Necatoriasis is caused by N. americanus. N. americanus can be divided into two areas – larvae and adult stage. The third stage larvae are guided to human skin by following thermal gradients.[3] Typically, the larvae enter through the hands and feet following contact with contaminated soil. A papular, pruritic, itchy rash will develop around the site of entry into the human host.[4] This is also known as “ground itch”. Generally, migration through the lungs is asymptomatic but a mild cough and pharyngeal irritation may occur during larval migration in the airways. Once larvae break through the alveoli and are swallowed, they enter the gastrointestinal tract and attach to the intestinal mucosa where they mature into adult worms. The hookworms attach to the mucosal lining using their cutting plates which allows them to penetrate blood vessels and feed on the host’s blood supply. Each worm consumes 30μl of blood per day. The major issue results from this intestinal blood loss which can lead to iron-deficiency anemia in moderate to heavy infections. Other common symptoms include epigastric pain and tenderness, nausea, exertional dyspnea, pain in lower extremities and in joints, sternal pain, headache, fatigue, and impotence.[5] Death is rare in humans.
# Diagnosis
The standard method for diagnosing necatoriasis is through identification of N. americanus eggs in a fecal sample using a microscope. Eggs can be difficult to visualize in a lightly infected sample so a concentration method is generally used such as floatation or sedimentation.[6] However, the eggs of A. duodenale and N. americanus cannot be distinguished; thus, the larvae must be examined to identify these hookworms. Larvae cannot be found in stool specimens unless the specimen was left at ambient temperature for a day or more.
The most common technique used to diagnose a hookworm infection is to take a stool sample, fix it in 10% formalin, concentrate it using the formalin-ethyl acetate sedimentation technique, and then create a wet mount of the sediment for viewing under a microscope.
# Prevention
Education, improved sanitation, and controlled disposal of human feces are critical for prevention. Nonetheless, wearing shoes in endemic areas helps reduce the prevalence of infection.
# Treatment
An infection of N. americanus parasites can be treated by using benzimidazoles, albendazole, and mebendazole. A blood transfusion may be necessary in severe cases of anemia. Light infections are usually left untreated in areas where reinfection is common. Iron supplements and a diet high in protein will speed the recovery process.[7] In a case study involving 56-60 men with Trichuris trichiura and/or N. americanus infections, both albendazole and mebendazole were 90% effective in curing T. trichiura. However, albendazole had a 95% cure rate for N. americanus, while mebendazole only had a 21% cure rate. This suggests albendazole is most effective for treating both T. trichiura and N. americanus.[8]
Cryotherapy by application of liquid nitrogen to the skin has been used to kill cutaneous larvae migrans, but the procedure has a low cure rate and a high incidence of pain and severe skin damage, so it now is passed over in favor of suitable pharmaceuticals. Topical application of some pharmaceuticals has merit, but requires repeated, persistent applications and is less effective than some systemic treatments.[9]
## Antimicrobial Regimen
- Necator americanus
- Preferred regimen: Albendazole 400 mg PO single dose[10]
- Alternative regimen (1): Mebendazole 100 mg PO bid or 500 mg daily for 3 days
- Alternative regimen (2): Pyrantel pamoate 11 mg/kg PO qd (maximum 1 g/day) for 3 days[11]
# Epidemiology
Necator americanus was first discovered in Brazil and then was found in Texas. Later, it was found to be indigenous in Africa, China, southwest Pacific islands, India, and Southeast Asia. This parasite is a tropical parasite and is the most common species in humans. Roughly 95% of hookworms found in the southern region of the United States are N. americanus. This parasite is found in humans, but can also be found in pigs and dogs.
Transmission of N. americanus infection requires the deposition of egg-containing feces on shady, well-drained soil and is favored by warm, humid (tropical) conditions. Therefore, infections worldwide are usually reported in places where direct contact with contaminated soil occurs. | https://www.wikidoc.org/index.php/Necatoriasis | |
deee148838c0727524df5c39d3e8722ab9f8195c | wikidoc | Neosalvarsan | Neosalvarsan
Neosalvarsan is a synthetic antibiotic that is an organoarsenic compound. It became available in 1912 and superseded the more toxic and less water-soluble salvarsan as an effective treatment for syphilis. Because both of these arsenicals carried considerable risk of side-effects, they were replaced for this indication by penicillin in the 1940s.
Both salvarsan and neosalvarsan were developed in the laboratory of Paul Ehrlich in Frankfurt, Germany. Their discoveries were the result of the first organized team effort to optimize the biological activity of a lead compound through systematic chemical modifications. This scheme is the basis for most modern pharmaceutical research. Both salvarsan and neosalvarsan are prodrugs, that is to say that they are metabolised to the active drug in the body.
# Structure
The structure of Salvarsan and, presumably this derivative, was once believed to feature an As=As bond as shown in the figure.. In 2005, Salvarsan was shown to be a mixture of the cyclic trimer and a pentamer. The revised structure features As-As single bonds, not double bonds. | Neosalvarsan
Template:Chembox new
Neosalvarsan is a synthetic antibiotic that is an organoarsenic compound. It became available in 1912 and superseded the more toxic and less water-soluble salvarsan as an effective treatment for syphilis. Because both of these arsenicals carried considerable risk of side-effects, they were replaced for this indication by penicillin in the 1940s.
Both salvarsan and neosalvarsan were developed in the laboratory of Paul Ehrlich in Frankfurt, Germany. Their discoveries were the result of the first organized team effort to optimize the biological activity of a lead compound through systematic chemical modifications. This scheme is the basis for most modern pharmaceutical research. Both salvarsan and neosalvarsan are prodrugs, that is to say that they are metabolised to the active drug in the body.
# Structure
The structure of Salvarsan and, presumably this derivative, was once believed to feature an As=As bond as shown in the figure.. In 2005, Salvarsan was shown to be a mixture of the cyclic trimer and a pentamer.[1][2] The revised structure features As-As single bonds, not double bonds. | https://www.wikidoc.org/index.php/Neosalvarsan | |
67e115c5501b61e292935519eb2b8e2fe3319ada | wikidoc | Neotyphodium | Neotyphodium
Neotyphodium is a form genus containing species of endophytic fungi. These endophytes are asexual, seed-borne symbionts of cool-season grasses, and grow intercellularly throughout the aerial tissues of their hosts, including shoot apical meristems, leaf sheaths and blades, inflorescences, seeds and embryos.
# Taxonomic considerations
Neotyphodium species are closely related to teleomorphic species of the genus Epichloë, from which many have evolved by processes involving interspecific hybridization.. Molecular phylogenetic evidence demonstrates that asexual Neotyphodium species are derived either from individual Epichloë species, or more commonly, from hybrids with at least two ancestral Epichloë species. Hence, the form genus Neotyphodium is very closely associated with the teleomorphic genus Epichloë. In keeping with the code of botanical nomenclature, the form genus refers to the asexual spore or vegetative state, and the teleomorphic genus refers to the sexual state.
# Life cycle
The taxonomic dichotomy is especially interesting in this group of symbionts, because vegetative propagation of fungal mycelium occurs by vertical transmission, i.e., fungal growth into newly developing host tillers (=individual grass plants). Importantly, all Neotyphodium and some Epichloëspecies infect new grass plants solely by growing into the seeds of their grass hosts, and infecting the growing seedling. Manifestation of the sexual state - which only occurs in Epichloë fungi — causes choke disease, a condition in which grass inflorescences are engulfed by rapid fungal outgrowth forming a stroma. The fungal stroma suppresses host seed production and culminates in the ejection of meiospores (ascospores) that mediate horizontal (contagious) transmission of the fungus to new plants..
# Effects on the grass plant and on herbivores
It has been proposed that vertically transmitted symbionts should evolve to be mutualists since their reproductive fitness is intimately tied to that of their hosts. In fact, some positive effects of Neotyphodium species on their host plants include increased growth, drought tolerance, and herbivore and pathogen resistance. Resistance against herbivores has been attributed to endophyte-produced alkaloids. Although grass-endophyte symbioses have been widely recognized to be mutualistic in many wild and cultivated grasses, the interactions can be highly variable and sometimes antagonistic, especially under nutrient-poor conditions in the soil.
# Neotyphodium alkaloids
Ergoline alkaloids (which are ergot alkaloids, named after the ergot fungus, Claviceps purpurea, a close relative of the Neotyphodium/Epichloë endophytes) are characterized by a ring system derived from 4-prenyl tryptophan. Among the most abundant ergot alkaloids in endophyte-symbiotic grasses is ergovaline, comprising an ergoline moiety attached to a bicyclic tripeptide containing the amino acids, L-proline, L-alanine, and L-valine. Another group of endophyte alkaloids are the indole-diterpenoids, such as lolitrem B. Both the ergoline and indole-diterpenoid alkaloids have biological activity against mammalian herbivores, and also activity against some insects. Peramine is a pyrrolopyrazine alkaloid thought to be biosynthesized from the guanidinium-group-containing amino acid, L-arginine, and pyrrolidine-5-carboxylate, a precursor of L-proline, and is an insect-feeding deterrent. The loline alkaloids are 1-aminopyrrolizidines with an oxygen atom linking bridgehead carbons 2 and 7, and are biosynthesized from the amino acids, L-proline and L-homoserine. The lolines have insecticidal and insect-deterrent activities comparable to nicotine. Many, but not all, Neotyphodium species produce up to three classes of these alkaloids.
# Species
- Neotyphodium aotearoae
- Neotyphodium australiense
- Neotyphodium chilense
- Neotyphodium chisosum
- Neotyphodium coenophialum
- Neotyphodium gansuense
- Neotyphodium huerfanum
- Neotyphodium lolii
- Neotyphodium melicicola
- Neotyphodium occultans
- Neotyphodium siegelii
- Neotyphodium starrii
- Neotyphodium tembladerae
- Neotyphodium typhinum
- Neotyphodium uncinatum | Neotyphodium
Neotyphodium is a form genus containing species of endophytic fungi. These endophytes are asexual, seed-borne symbionts of cool-season grasses, and grow intercellularly throughout the aerial tissues of their hosts, including shoot apical meristems, leaf sheaths and blades, inflorescences, seeds and embryos.[1]
# Taxonomic considerations
Neotyphodium species are closely related to teleomorphic species of the genus Epichloë, from which many have evolved by processes involving interspecific hybridization.[2]. Molecular phylogenetic evidence demonstrates that asexual Neotyphodium species are derived either from individual Epichloë species, or more commonly, from hybrids with at least two ancestral Epichloë species.[2][3] Hence, the form genus Neotyphodium is very closely associated with the teleomorphic genus Epichloë.[4] In keeping with the code of botanical nomenclature, the form genus refers to the asexual spore or vegetative state, and the teleomorphic genus refers to the sexual state.
# Life cycle
The taxonomic dichotomy is especially interesting in this group of symbionts, because vegetative propagation of fungal mycelium occurs by vertical transmission, i.e., fungal growth into newly developing host tillers (=individual grass plants). Importantly, all Neotyphodium and some Epichloëspecies infect new grass plants solely by growing into the seeds of their grass hosts, and infecting the growing seedling. [5] Manifestation of the sexual state - which only occurs in Epichloë fungi — causes choke disease, a condition in which grass inflorescences are engulfed by rapid fungal outgrowth forming a stroma. The fungal stroma suppresses host seed production and culminates in the ejection of meiospores (ascospores) that mediate horizontal (contagious) transmission of the fungus to new plants..
# Effects on the grass plant and on herbivores
It has been proposed that vertically transmitted symbionts should evolve to be mutualists since their reproductive fitness is intimately tied to that of their hosts.[6] In fact, some positive effects of Neotyphodium species on their host plants include increased growth, drought tolerance, and herbivore and pathogen resistance.[5][7] Resistance against herbivores has been attributed to endophyte-produced alkaloids.[8] Although grass-endophyte symbioses have been widely recognized to be mutualistic in many wild and cultivated grasses, the interactions can be highly variable and sometimes antagonistic, especially under nutrient-poor conditions in the soil.[9]
# Neotyphodium alkaloids
Ergoline alkaloids (which are ergot alkaloids, named after the ergot fungus, Claviceps purpurea, a close relative of the Neotyphodium/Epichloë endophytes) are characterized by a ring system derived from 4-prenyl tryptophan.[10] Among the most abundant ergot alkaloids in endophyte-symbiotic grasses is ergovaline, comprising an ergoline moiety attached to a bicyclic tripeptide containing the amino acids, L-proline, L-alanine, and L-valine. Another group of endophyte alkaloids are the indole-diterpenoids, such as lolitrem B.[11] Both the ergoline and indole-diterpenoid alkaloids have biological activity against mammalian herbivores, and also activity against some insects. Peramine is a pyrrolopyrazine alkaloid thought to be biosynthesized from the guanidinium-group-containing amino acid, L-arginine, and pyrrolidine-5-carboxylate, a precursor of L-proline,[12] and is an insect-feeding deterrent. The loline alkaloids are 1-aminopyrrolizidines with an oxygen atom linking bridgehead carbons 2 and 7, and are biosynthesized from the amino acids, L-proline and L-homoserine.[13] The lolines have insecticidal and insect-deterrent activities comparable to nicotine. Many, but not all, Neotyphodium species produce up to three classes of these alkaloids.
# Species
- Neotyphodium aotearoae
- Neotyphodium australiense
- Neotyphodium chilense
- Neotyphodium chisosum
- Neotyphodium coenophialum
- Neotyphodium gansuense
- Neotyphodium huerfanum
- Neotyphodium lolii
- Neotyphodium melicicola
- Neotyphodium occultans
- Neotyphodium siegelii
- Neotyphodium starrii
- Neotyphodium tembladerae
- Neotyphodium typhinum
- Neotyphodium uncinatum | https://www.wikidoc.org/index.php/Neotyphodium |
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