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f2fa83a4bf6c3bdb5dab6abb95d06162a80ed5ab	wikidoc	Methyllithium	Methyllithium Methyllithium is an organolithium reagent with the empirical formula CH3Li. This s-block organometallic compound adopts an oligomeric structure both in solution and in the solid state. This highly reactive compound, invariably used as a solution in alkanes or ethers, is a reagent in organic synthesis as well as organometallic chemistry. Operations involving methyllithium require anhydrous conditions, because the compound is highly reactive toward water. Oxygen and carbon dioxide are also incompatible with MeLi. Methyllithium is usually not prepared, but purchased as a solution in various ethers. # Synthesis In the direct synthesis, methyl bromide is treated with a suspension of lithium in diethyl ether. The lithium bromide forms a complex with the methyllithium. Most commercially available methyllithium consists of this complex. "Halide-free" methyllithium is prepared from methyl chloride. Lithium chloride precipitates from the diethyl ether since it does not form a strong complex with methyllithium. The filtrate consists of fairly pure methyllithium. # Reactivity Methyllithium is both strongly basic and highly nucleophilic due to the partial negative charge on carbon and is therefore particularly reactive towards electron and proton donors. THF, usually a chemically inert solvent, is attacked by MeLi. Water and alcohols react violently. Most reactions involving methyllithium are conducted below room temperature. Although MeLi can be used for deprotonations, n-butyllithium is more commonly employed since it is less expensive, more reactive and less dangerous. Methyllithium is mainly used as the synthetic equivalent of the methyl anion synthon. For example, ketones react to give tertiary alcohols in a two-step process: Nonmetal halides are converted to methyl compounds with methyllithium: Such reactions more commonly employ the Grignard reagents methyl magnesium halides, which are less dangerous than MeLi, equally effective, and more conveniently prepared in situ. Transition metal methyl compounds are typically prepared from methyllithium: # Structure Two structures have been verified by single crystal X-ray crystallography as well as by 6Li, 7Li, and 13C NMR spectroscopy. The tetrameric cluster consists of a distorted cubane, with carbon and lithium atoms at alternate corners. The Li---Li distances are 2.68 Å, almost identical with the Li-Li bond in gaseous dilithium. The C-Li distances are 2.31 Å. Carbon is bonded to three hydrogen atoms and three Li atoms. The nonvolatility of (MeLi)4 and its insolubility in alkanes results from the fact that the clusters interact via further inter-cluster agostic interactions. In contrast the bulkier cluster (tertiary-butylLi)4, where intercluster interactions are precluded by steric effects, is volatile as well as soluble in alkanes. File:Tetramer1.jpg File:Methyllithium-tetramer-1-3D-balls.png File:Methyllithium-tetramer-2-3D-balls.png Colour code: Li- blue C- black H- white The hexameric form features hexagonal prisms with Li and C atoms again at alternate corners. File:Hexamer1.jpg File:Methyllithium-hexamer-2-3D-balls.png File:Methyllithium-hexamer-3-3D-balls.png Colour code: Li- blue C- black H- white The degree of aggregation, "n" for (MeLi)n, depends upon the solvent and the presence of additives (such as lithium bromide). Hydrocarbon solvents such as benzene favour formation of the hexamer, whereas ethereal solvents favour the tetramer. # Bonding These clusters are considered "electron-deficient," that is, they do not follow the octet rule because the molecules lack sufficient electrons to form four 2-centered, 2-electron bonds around each carbon atom, in contrast to most organic compounds. The hexamer is a 30 electron compound (30 valence electrons.) If one allocates 18 electrons for the strong C-H bonds, 12 electrons remain for Li-C and Li-Li bonding. There are six electrons for six metal-metal bonds and one electron per methyl-η3 lithium interaction. The strength of the C-Li bond has been estimated at around 57 kcal/mol from IR spectroscopic measurements.	Methyllithium Template:Chembox new Methyllithium is an organolithium reagent with the empirical formula CH3Li. This s-block organometallic compound adopts an oligomeric structure both in solution and in the solid state. This highly reactive compound, invariably used as a solution in alkanes or ethers, is a reagent in organic synthesis as well as organometallic chemistry. Operations involving methyllithium require anhydrous conditions, because the compound is highly reactive toward water. Oxygen and carbon dioxide are also incompatible with MeLi. Methyllithium is usually not prepared, but purchased as a solution in various ethers. # Synthesis In the direct synthesis, methyl bromide is treated with a suspension of lithium in diethyl ether. The lithium bromide forms a complex with the methyllithium. Most commercially available methyllithium consists of this complex. "Halide-free" methyllithium is prepared from methyl chloride.[1] Lithium chloride precipitates from the diethyl ether since it does not form a strong complex with methyllithium. The filtrate consists of fairly pure methyllithium. # Reactivity Methyllithium is both strongly basic and highly nucleophilic due to the partial negative charge on carbon and is therefore particularly reactive towards electron and proton donors. THF, usually a chemically inert solvent, is attacked by MeLi. Water and alcohols react violently. Most reactions involving methyllithium are conducted below room temperature. Although MeLi can be used for deprotonations, n-butyllithium is more commonly employed since it is less expensive, more reactive and less dangerous. Methyllithium is mainly used as the synthetic equivalent of the methyl anion synthon. For example, ketones react to give tertiary alcohols in a two-step process: Nonmetal halides are converted to methyl compounds with methyllithium: Such reactions more commonly employ the Grignard reagents methyl magnesium halides, which are less dangerous than MeLi, equally effective, and more conveniently prepared in situ. Transition metal methyl compounds are typically prepared from methyllithium:[2] # Structure Two structures have been verified by single crystal X-ray crystallography as well as by 6Li, 7Li, and 13C NMR spectroscopy. The tetrameric cluster consists of a distorted cubane, with carbon and lithium atoms at alternate corners. The Li---Li distances are 2.68 Å, almost identical with the Li-Li bond in gaseous dilithium. The C-Li distances are 2.31 Å. Carbon is bonded to three hydrogen atoms and three Li atoms. The nonvolatility of (MeLi)4 and its insolubility in alkanes results from the fact that the clusters interact via further inter-cluster agostic interactions. In contrast the bulkier cluster (tertiary-butylLi)4, where intercluster interactions are precluded by steric effects, is volatile as well as soluble in alkanes.[3] File:Tetramer1.jpg File:Methyllithium-tetramer-1-3D-balls.png File:Methyllithium-tetramer-2-3D-balls.png Colour code: Li- blue C- black H- white The hexameric form features hexagonal prisms with Li and C atoms again at alternate corners. File:Hexamer1.jpg File:Methyllithium-hexamer-2-3D-balls.png File:Methyllithium-hexamer-3-3D-balls.png Colour code: Li- blue C- black H- white The degree of aggregation, "n" for (MeLi)n, depends upon the solvent and the presence of additives (such as lithium bromide). Hydrocarbon solvents such as benzene[4] favour formation of the hexamer, whereas ethereal solvents favour the tetramer. # Bonding These clusters are considered "electron-deficient," that is, they do not follow the octet rule because the molecules lack sufficient electrons to form four 2-centered, 2-electron bonds around each carbon atom, in contrast to most organic compounds. The hexamer is a 30 electron compound (30 valence electrons.) If one allocates 18 electrons for the strong C-H bonds, 12 electrons remain for Li-C and Li-Li bonding. There are six electrons for six metal-metal bonds and one electron per methyl-η3 lithium interaction. The strength of the C-Li bond has been estimated at around 57 kcal/mol from IR spectroscopic measurements.[4]	https://www.wikidoc.org/index.php/Methyl_lithium
a16ecf9de0a599b090719242c074495bec139ced	wikidoc	Methyl orange	Methyl orange Methyl orange is a pH indicator frequently used in titrations. It is often chosen to be used in titrations because of its clear colour change. Because it changes colour at the pH of a mid-strength acid, it is usually used in titrations for acids. Unlike a universal indicator, methyl orange does not have a full spectrum of colour change, but has a sharper end point. # Indicator colours In a solution becoming less acidic, methyl orange moves from red to orange and finally to yellow with the reverse occurring for a solution increasing in acidity. It should be noted that the entire colour change occurs in acidic conditions. In an acid it is reddish and in alkali it is yellow. # Other Indicators - Modified (or screened) methyl orange, an indicator consisting of a solution of methyl orange and xylene cyanol, changes from gray to green as the solution becomes more basic. - A number of other common indicators are tabulated in the article on pH indicators.	Methyl orange Template:Chembox new Methyl orange is a pH indicator frequently used in titrations. It is often chosen to be used in titrations because of its clear colour change. Because it changes colour at the pH of a mid-strength acid, it is usually used in titrations for acids. Unlike a universal indicator, methyl orange does not have a full spectrum of colour change, but has a sharper end point. # Indicator colours Template:PH indicator template Template:PH indicator template In a solution becoming less acidic, methyl orange moves from red to orange and finally to yellow with the reverse occurring for a solution increasing in acidity. It should be noted that the entire colour change occurs in acidic conditions. In an acid it is reddish and in alkali it is yellow. # Other Indicators - Modified (or screened) methyl orange, an indicator consisting of a solution of methyl orange and xylene cyanol, changes from gray to green as the solution becomes more basic. - A number of other common indicators are tabulated in the article on pH indicators. # External links - Informative page on different titration indicators, including Methyl Orange de:Methylorange it:Metilarancio Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Methyl_orange
a96a66fb3ddccea7ba419750328bdd4ce0e4554a	wikidoc	Microorganism	Microorganism # Overview A microorganism (also spelled as microrganism) or microbe is an organism that is microscopic (too small to be seen by the human eye). The study of microorganisms is called microbiology. Microorganisms include bacteria, fungi, archaea or protists, but not viruses and prions, which are generally classified as non-living. Most microorganisms are single-celled, or unicellular, but some are microscopic, and some unicellular protists are visible to the average human. Microorganisms live almost everywhere on Earth where there is liquid water, including hot springs, on the ocean floor, and deep inside rocks within Earth's crust. Microorganisms are critical to nutrient recycling in ecosystems as they act as decomposers. As some microorganisms can also fix nitrogen, they are an important part of the nitrogen cycle. However, pathogenic microbes can invade other organisms and cause diseases that kill millions of people every year. # History ## Evolution Single-celled microorganisms were the first forms of life to develop on earth, approximately 3–4 billion years ago. Further evolution was slow, and for about 3 billion years in the Precambrian eon, all organisms were microscopic. So, for most of the history of life on Earth the only form of life were microorganisms. Bacteria, algae and fungi have been identified in amber that is 220 million years old, which shows that the morphology of microorganisms have changed little since the triassic period. Most microorganisms can reproduce rapidly and microbes such as bacteria can also freely exchange genes by conjugation, transformation and transduction between widely-divergent species. This horizontal gene transfer, coupled with a high mutation rate and many other means of genetic variation, allows microorganisms to swiftly evolve (via natural selection) to survive in new environments and respond to environmental stresses. This rapid evolution has led to the recent development of 'super-bugs' — pathogenic bacteria that are resistant to modern antibiotics. ## Discovery The existence of microorganisms was hypothesized during the late Middle Ages but they were not observed or proven until the invention of the microscope in the 17th century. In The Canon of Medicine (1020), Abū Alī ibn Sīnā (Avicenna) stated that bodily secretion is contaminated by foul foreign earthly bodies before being infected, but he did not view them as primary causes of disease. When the Black Death bubonic plague reached al-Andalus in the 14th century, Ibn Khatima and Ibn al-Khatib hypothesized that infectious diseases are caused by microorganisms which enter the human body. Such ideas became more popular in Europe during the Renaissance, particularly through the writing of the Italian monk Girolamo Fracastoro. Prior to Anton van Leeuwenhoek's discovery of microorganisms in 1675, it had been a mystery as to why grapes could be turned into wine, milk into cheese, or why food would spoil. Leeuwenhoek did not make the connection between these processes and microorganisms, but using the microscope, he did establish that there were forms of life that were not visible to the naked eye. Leeuwenhoek's discovery, along with subsequent observations by Lazzaro Spallanzani and Louis Pasteur, ended the long-held belief that life spontaneously appeared from non-living substances during the process of spoilage. Lazzarro Spallanzani found that microorganisms could only settle in a broth if the broth was exposed to the air. He also found that boiling the broth would sterilise it and kill the microorganisms. Louis Pasteur expanded upon Spallanzani's findings by exposing boiled broths to the air, in vessels that contained a filter to prevent all particles from passing through to the growth medium, and also in vessels with no filter at all, with air being admitted via a curved tube that would not allow dust particles to come in contact with the broth. By boiling the broth beforehand, Pasteur ensured that no microorganisms survived within the broths at the beginning of his experiment. Nothing grew in the broths in the course of Pasteur's experiment. This meant that the living organisms that grew in such broths came from outside, as spores on dust, rather than spontaneously generated within the broth. Thus, Pasteur dealt the death blow to the theory of spontaneous generation and supported germ theory. In 1876, Robert Koch established that microbes can cause disease. He did this by finding that the blood of cattle who were infected with anthrax always had large numbers of Bacillus anthracis. Koch also found that he could transmit anthrax from one animal to another by taking a small sample of blood from the infected animal and injecting it into a healthy one, causing the healthy animal to become sick. He also found that he could grow the bacteria in a nutrient broth, inject it into a healthy animal, and cause illness. Based upon these experiments, he devised criteria for establishing a causal link between a microbe and a disease in what are now known as Koch's postulates. Though these postulates cannot be applied in all cases, they do retain historical importance in the development of scientific thought and can still be used today. # Classification Microorganisms can be found almost anywhere in the taxonomic organization of life on the planet. Bacteria and archaea are almost always microscopic, while a number of eukaryotes are also microscopic, including most protists and a number of fungi. Viruses are generally regarded as not living and therefore are not microbes, although the field of microbiology also encompasses the study of viruses. ## Prokaryotes Prokaryotes are organisms that lack a cell nucleus and the other organelles found in eukaryotes. Prokaryotes are almost always unicellular, although some such as myxobacteria can aggregate into complex structures as part of their life cycle. These organisms are divided into two groups, the archaea and the bacteria. ### Bacteria Bacteria are the most diverse and abundant group of organisms on Earth. Bacteria inhabit practically all environments where some liquid water is available and the temperature is below +140 °C. They are found in sea water, soil, animals' gastrointestinal tracts, hot springs and even deep beneath the Earth's crust in rocks. Practically all surfaces which have not been specially sterilized are covered in bacteria. The number of bacteria in the world is estimated to be around five million trillion trillion, or 5 × 1030. Bacteria are practically all invisible to the naked eye, with few extremely rare exceptions, such as Thiomargarita namibiensis. They are unicellular organisms and lack organelles. Their genome is usually a single loop of DNA, although they can also harbor small pieces of DNA called plasmids. Bacteria are surrounded by a cell wall, which provides strength and rigidity to their cells. They reproduce by binary fission or sometimes by budding. Some species form extremely resilient spores, but for bacteria this is a mechanism for survival, not reproduction. Under optimal conditions bacteria can grow extremely rapidly and can double as quickly as every 10 minutes. ### Archaea Archaea are also single-celled organisms that lack nuclei. In the past, the differences between bacteria and archaea were not recognised and archaea were classified with bacteria as part of the kingdom Monera. Archaea differ from bacteria in their genetics and biochemistry. For example, while bacterial cell membranes are made from phosphoglycerides with ester bonds, archaean membranes are made of ether lipids. Archaea were originally described in extreme environments, such as hot springs, but have since been found in all types of habitats. Only now are scientists beginning to appreciate how common archaea are in the environment, with crenarchaeota being the most common form of life in the ocean, dominating ecosystems below 150 m in depth. These organisms are also common in soil and play a vital role in ammonia oxidation. ## Eukaryotes All living things which are individually visible to the naked eye are eukaryotes (with few exceptions, such as Thiomargarita namibiensis), including humans. However, a large number of eukaryotes are also microorganisms. Unlike bacteria and archaea, eukaryotes contain organelles such as the cell nucleus, the Golgi apparatus and mitochondria in their cells. The nucleus is an organelle which houses the DNA that makes up a cell's genome. DNA itself is arranged in complex chromosomes. Mitochondria are organelles vital in metabolism as they are the site of the citric acid cycle and oxidative phosphorylation. They evolved from symbiotic bacteria and retain a remnant genome. Like bacteria, plant cells have cell walls, and contain organelles such as chloroplasts in addition to the organelles in other eukaryotes. Chloroplasts produce energy from light by photosynthesis, and were also originally symbiotic bacteria. Unicellular eukaryotes are those eukaryotic organisms that consist of a single cell throughout their life cycle. This qualification is significant since most multicellular eukaryotes consist of a single cell called a zygote at the beginning of their life cycles. Microbial eukaryotes can be either haploid or diploid, and some organisms have multiple cell nuclei (see coenocyte). However, not all microorganisms are unicellular as some microscopic eukaryotes are made from multiple cells. ### Protists Of eukaryotic groups, the protists are most commonly unicellular and microscopic. This is a diverse group of organisms which are not easy to classify. Several algae species are multicellular protists, and slime molds have unique life cycles with unicellular, colonial, and multicellular stages. ### Animals All animals are multicellular, but some are too small to be seen by the naked eye. Microscopic arthropods include dust mites and spider mites. Microscopic crustaceans include copepods and the cladocera. Another common group of microscopic animals are the rotifers, which are filter feeders that are usually found in fresh water. ### Fungi The fungi have several unicellular species, such as baker's yeast (Saccharomyces cerevisiae). ### Plants The green algae are a large group of photosynthetic eukaryotes that include many microscopic organisms. Although some green algae are classified as protists, others such as charophyta are classified with embryophyte plants, which are the most familiar group of land plants. # Habitats and ecology Microorganisms are found in almost every habitat present in nature. Even in hostile environments such as the poles, deserts, geysers, rocks, and the deep sea, some types of microorganisms have adapted to the extreme conditions and sustained colonies; these organisms are known as extremophiles. Extremophiles have been isolated from rocks as much as 7 kilometres below the earth's surface, and it has been suggested that the amount of living organisms below the earth's surface may be comparable with the amount of life on or above the surface. Extremophiles have been known to survive for a prolonged time in a vacuum, and can be highly resistant to radiation, which may even allow them to survive in space. Many types of microorganisms have intimate symbiotic relationships with other larger organisms; some of which are mutually beneficial (mutualism), while others can be damaging to the host organism (parasitism). If microorganisms can cause disease in a host they are known as pathogens. ## Extremophiles Certain microbes have adapted so that they can survive and even thrive in conditions that are normally fatal to most lifeforms. Microorganisms have been found around underwater black smokers and in geothermal hot springs, as well as in extremely salty bodies of water. ## Soil microbes The nitrogen cycle in soils depends on the fixation of atmospheric nitrogen. One way this can occur is in the nodules in the roots of legumes that contain symbiotic bacteria of the genera Rhizobium, Mesorhizobium, Sinorhizobium, Bradyrhizobium, and Azorhizobium. ## Symbiotic microbes Symbiotic microbes # Importance Microorganisms are vital to humans and the environment, as they participate in the Earth's element cycles such as the carbon cycle and nitrogen cycle, as well as fulfilling other vital roles in virtually all ecosystems, such as recycling other organisms' dead remains and waste products through decomposition. Microbes also have an important place in most higher-order multicellular organisms as symbionts. Many blame the failure of Biosphere 2 on an improper balance of microbes. ## Use in food Microorganisms are used in brewing, baking and other food-making processes. The lactobacillus / lactobacilli and yeasts in sourdough bread are especially useful. To make bread, one uses a small amount (20-25%) of "starter" dough which has the yeast culture, and mixes it with flour and water. Some of this resulting dough is then saved to be used as the starter for subsequent batches. The culture can be kept at room temperature and continue yielding bread for years as long as it remains supplied with new flour and water. This technique was often used when "on the trail" in the American Old West. Microorganisms are also used to control the fermentation process in the production of cultured dairy products such as yogurt and cheese. The cultures also provide flavour and aroma, and to inhibit undesirable organisms. ## Use in water treatment Microbes are used in the biological treatment of sewage and industrial waste effluents. ## Use in energy Microbes are used in fermentation to produce ethanol. ## Use in science Microbes are also essential tools in biotechnology, biochemistry, genetics, and molecular biology. Microbes can be harnessed for uses such as creating steroids and treating skin diseases. Scientists are also considering using microbes for living fuel cells, and as a solution for pollution. ## Use in warfare In the Middle Ages, dead corpses were thrown over walls during sieges, this meant that any bacteria carrying the disease that killed the person/creature would multiply in the vicinity of the opposing side. # Importance in human health ## Human digestion Microorganisms can form an endosymbiotic relationship with other, larger, organisms. For example, the bacteria that live within the human digestive system contribute to gut immunity, synthesise vitamins such as folic acid and biotin, and ferment complex undigestible carbohydrates. ## Diseases and immunology Microorganisms are the cause of many infectious diseases. The organisms involved include bacteria, causing diseases such as plague, tuberculosis and anthrax; protozoa, causing diseases such as malaria, sleeping sickness and toxoplasmosis; and also fungi causing diseases such as ringworm, candidiasis or histoplasmosis. However, other diseases such as influenza, yellow fever or AIDS are caused by viruses, which are not living organisms and are not therefore microorganisms. As of 2007, no clear examples of archaean pathogens are known, although a relationship has been proposed between the presence of some methanogens and human periodontal disease. # Hygiene Hygiene is the avoidance of infection or food spoiling by eliminating microorganisms from the surroundings. As microorganisms, particularly bacteria, are found practically everywhere, this means in most cases the reduction of harmful microorganisms to acceptable levels. However, in some cases it is required that an object or substance is completely sterile, i.e. devoid of all living entities and viruses. A good example of this is a hypodermic needle. In food preparation microorganisms are reduced by preservation methods (such as the addition of vinegar), clean utensils used in preparation, short storage periods or by cool temperatures. If complete sterility is needed, the two most common methods are irradiation and the use of an autoclave, which resembles a pressure cooker. There are several methods for investigating the level of hygiene in a sample of food, drinking water, equipment etc. Water samples can be filtrated through an extremely fine filter. This filter is then placed in a nutrient medium. Microorganisms on the filter then grow to form a visible colony. Harmful microorganisms can be detected in food by placing a sample in a nutrient broth designed to enrich the organisms in question. Various methods, such as selective media or PCR, can then be used for detection. The hygiene of hard surfaces, such as cooking pots, can be tested by touching them with a solid piece of nutrient medium and then allowing the microorganisms to grow on it. There are no conditions where all microorganisms would grow, and therefore often several different methods are needed. For example, a food sample might be analyzed on three different nutrient mediums designed to indicate the presence of "total" bacteria (conditions where many, but not all, bacteria grow), molds (conditions where the growth of bacteria is prevented by e.g. antibiotics) and coliform bacteria (these indicate a sewage contamination).	Microorganism Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview A microorganism (also spelled as microrganism) or microbe is an organism that is microscopic (too small to be seen by the human eye). The study of microorganisms is called microbiology. Microorganisms include bacteria, fungi, archaea or protists, but not viruses and prions, which are generally classified as non-living. Most microorganisms are single-celled, or unicellular, but some are microscopic, and some unicellular protists are visible to the average human. Microorganisms live almost everywhere on Earth where there is liquid water, including hot springs, on the ocean floor, and deep inside rocks within Earth's crust. Microorganisms are critical to nutrient recycling in ecosystems as they act as decomposers. As some microorganisms can also fix nitrogen, they are an important part of the nitrogen cycle. However, pathogenic microbes can invade other organisms and cause diseases that kill millions of people every year.[1] # History ## Evolution Single-celled microorganisms were the first forms of life to develop on earth, approximately 3–4 billion years ago.[2][3][4] Further evolution was slow,[5] and for about 3 billion years in the Precambrian eon, all organisms were microscopic.[6] So, for most of the history of life on Earth the only form of life were microorganisms.[7] Bacteria, algae and fungi have been identified in amber that is 220 million years old, which shows that the morphology of microorganisms have changed little since the triassic period.[8] Most microorganisms can reproduce rapidly and microbes such as bacteria can also freely exchange genes by conjugation, transformation and transduction between widely-divergent species.[9] This horizontal gene transfer, coupled with a high mutation rate and many other means of genetic variation, allows microorganisms to swiftly evolve (via natural selection) to survive in new environments and respond to environmental stresses. This rapid evolution has led to the recent development of 'super-bugs' — pathogenic bacteria that are resistant to modern antibiotics.[10] ## Discovery The existence of microorganisms was hypothesized during the late Middle Ages but they were not observed or proven until the invention of the microscope in the 17th century. In The Canon of Medicine (1020), Abū Alī ibn Sīnā (Avicenna) stated that bodily secretion is contaminated by foul foreign earthly bodies before being infected, but he did not view them as primary causes of disease. When the Black Death bubonic plague reached al-Andalus in the 14th century, Ibn Khatima and Ibn al-Khatib hypothesized that infectious diseases are caused by microorganisms which enter the human body.[11] Such ideas became more popular in Europe during the Renaissance, particularly through the writing of the Italian monk Girolamo Fracastoro.[12] Prior to Anton van Leeuwenhoek's discovery of microorganisms in 1675, it had been a mystery as to why grapes could be turned into wine, milk into cheese, or why food would spoil. Leeuwenhoek did not make the connection between these processes and microorganisms, but using the microscope, he did establish that there were forms of life that were not visible to the naked eye.[13][14] Leeuwenhoek's discovery, along with subsequent observations by Lazzaro Spallanzani and Louis Pasteur, ended the long-held belief that life spontaneously appeared from non-living substances during the process of spoilage. Lazzarro Spallanzani found that microorganisms could only settle in a broth if the broth was exposed to the air. He also found that boiling the broth would sterilise it and kill the microorganisms. Louis Pasteur expanded upon Spallanzani's findings by exposing boiled broths to the air, in vessels that contained a filter to prevent all particles from passing through to the growth medium, and also in vessels with no filter at all, with air being admitted via a curved tube that would not allow dust particles to come in contact with the broth. By boiling the broth beforehand, Pasteur ensured that no microorganisms survived within the broths at the beginning of his experiment. Nothing grew in the broths in the course of Pasteur's experiment. This meant that the living organisms that grew in such broths came from outside, as spores on dust, rather than spontaneously generated within the broth. Thus, Pasteur dealt the death blow to the theory of spontaneous generation and supported germ theory. In 1876, Robert Koch established that microbes can cause disease. He did this by finding that the blood of cattle who were infected with anthrax always had large numbers of Bacillus anthracis. Koch also found that he could transmit anthrax from one animal to another by taking a small sample of blood from the infected animal and injecting it into a healthy one, causing the healthy animal to become sick. He also found that he could grow the bacteria in a nutrient broth, inject it into a healthy animal, and cause illness. Based upon these experiments, he devised criteria for establishing a causal link between a microbe and a disease in what are now known as Koch's postulates.[15] Though these postulates cannot be applied in all cases, they do retain historical importance in the development of scientific thought and can still be used today.[16] # Classification Microorganisms can be found almost anywhere in the taxonomic organization of life on the planet. Bacteria and archaea are almost always microscopic, while a number of eukaryotes are also microscopic, including most protists and a number of fungi. Viruses are generally regarded as not living and therefore are not microbes, although the field of microbiology also encompasses the study of viruses. ## Prokaryotes Prokaryotes are organisms that lack a cell nucleus and the other organelles found in eukaryotes. Prokaryotes are almost always unicellular, although some such as myxobacteria can aggregate into complex structures as part of their life cycle. These organisms are divided into two groups, the archaea and the bacteria. ### Bacteria Bacteria are the most diverse and abundant group of organisms on Earth. Bacteria inhabit practically all environments where some liquid water is available and the temperature is below +140 °C. They are found in sea water, soil, animals' gastrointestinal tracts, hot springs and even deep beneath the Earth's crust in rocks.[18] Practically all surfaces which have not been specially sterilized are covered in bacteria. The number of bacteria in the world is estimated to be around five million trillion trillion, or 5 × 1030.[19] Bacteria are practically all invisible to the naked eye, with few extremely rare exceptions, such as Thiomargarita namibiensis.[20] They are unicellular organisms and lack organelles. Their genome is usually a single loop of DNA, although they can also harbor small pieces of DNA called plasmids. Bacteria are surrounded by a cell wall, which provides strength and rigidity to their cells. They reproduce by binary fission or sometimes by budding. Some species form extremely resilient spores, but for bacteria this is a mechanism for survival, not reproduction. Under optimal conditions bacteria can grow extremely rapidly and can double as quickly as every 10 minutes.[21] ### Archaea Archaea are also single-celled organisms that lack nuclei. In the past, the differences between bacteria and archaea were not recognised and archaea were classified with bacteria as part of the kingdom Monera. Archaea differ from bacteria in their genetics and biochemistry. For example, while bacterial cell membranes are made from phosphoglycerides with ester bonds, archaean membranes are made of ether lipids. Archaea were originally described in extreme environments, such as hot springs, but have since been found in all types of habitats.[22] Only now are scientists beginning to appreciate how common archaea are in the environment, with crenarchaeota being the most common form of life in the ocean, dominating ecosystems below 150 m in depth.[23][24] These organisms are also common in soil and play a vital role in ammonia oxidation.[25] ## Eukaryotes All living things which are individually visible to the naked eye are eukaryotes (with few exceptions, such as Thiomargarita namibiensis), including humans. However, a large number of eukaryotes are also microorganisms. Unlike bacteria and archaea, eukaryotes contain organelles such as the cell nucleus, the Golgi apparatus and mitochondria in their cells. The nucleus is an organelle which houses the DNA that makes up a cell's genome. DNA itself is arranged in complex chromosomes.[26] Mitochondria are organelles vital in metabolism as they are the site of the citric acid cycle and oxidative phosphorylation. They evolved from symbiotic bacteria and retain a remnant genome.[27] Like bacteria, plant cells have cell walls, and contain organelles such as chloroplasts in addition to the organelles in other eukaryotes. Chloroplasts produce energy from light by photosynthesis, and were also originally symbiotic bacteria.[27] Unicellular eukaryotes are those eukaryotic organisms that consist of a single cell throughout their life cycle. This qualification is significant since most multicellular eukaryotes consist of a single cell called a zygote at the beginning of their life cycles. Microbial eukaryotes can be either haploid or diploid, and some organisms have multiple cell nuclei (see coenocyte). However, not all microorganisms are unicellular as some microscopic eukaryotes are made from multiple cells. ### Protists Of eukaryotic groups, the protists are most commonly unicellular and microscopic. This is a diverse group of organisms which are not easy to classify. Several algae species are multicellular protists, and slime molds have unique life cycles with unicellular, colonial, and multicellular stages. ### Animals All animals are multicellular, but some are too small to be seen by the naked eye. Microscopic arthropods include dust mites and spider mites. Microscopic crustaceans include copepods and the cladocera. Another common group of microscopic animals are the rotifers, which are filter feeders that are usually found in fresh water. ### Fungi The fungi have several unicellular species, such as baker's yeast (Saccharomyces cerevisiae). ### Plants The green algae are a large group of photosynthetic eukaryotes that include many microscopic organisms. Although some green algae are classified as protists, others such as charophyta are classified with embryophyte plants, which are the most familiar group of land plants. # Habitats and ecology Microorganisms are found in almost every habitat present in nature. Even in hostile environments such as the poles, deserts, geysers, rocks, and the deep sea, some types of microorganisms have adapted to the extreme conditions and sustained colonies; these organisms are known as extremophiles. Extremophiles have been isolated from rocks as much as 7 kilometres below the earth's surface,[28] and it has been suggested that the amount of living organisms below the earth's surface may be comparable with the amount of life on or above the surface.[18] Extremophiles have been known to survive for a prolonged time in a vacuum, and can be highly resistant to radiation, which may even allow them to survive in space.[29] Many types of microorganisms have intimate symbiotic relationships with other larger organisms; some of which are mutually beneficial (mutualism), while others can be damaging to the host organism (parasitism). If microorganisms can cause disease in a host they are known as pathogens. ## Extremophiles Certain microbes have adapted so that they can survive and even thrive in conditions that are normally fatal to most lifeforms. Microorganisms have been found around underwater black smokers and in geothermal hot springs, as well as in extremely salty bodies of water. ## Soil microbes The nitrogen cycle in soils depends on the fixation of atmospheric nitrogen. One way this can occur is in the nodules in the roots of legumes that contain symbiotic bacteria of the genera Rhizobium, Mesorhizobium, Sinorhizobium, Bradyrhizobium, and Azorhizobium.[30] ## Symbiotic microbes Symbiotic microbes # Importance Microorganisms are vital to humans and the environment, as they participate in the Earth's element cycles such as the carbon cycle and nitrogen cycle, as well as fulfilling other vital roles in virtually all ecosystems, such as recycling other organisms' dead remains and waste products through decomposition. Microbes also have an important place in most higher-order multicellular organisms as symbionts. Many blame the failure of Biosphere 2 on an improper balance of microbes. ## Use in food Microorganisms are used in brewing, baking and other food-making processes. The lactobacillus / lactobacilli and yeasts in sourdough bread are especially useful. To make bread, one uses a small amount (20-25%) of "starter" dough which has the yeast culture, and mixes it with flour and water. Some of this resulting dough is then saved to be used as the starter for subsequent batches. The culture can be kept at room temperature and continue yielding bread for years as long as it remains supplied with new flour and water. This technique was often used when "on the trail" in the American Old West. Microorganisms are also used to control the fermentation process in the production of cultured dairy products such as yogurt and cheese. The cultures also provide flavour and aroma, and to inhibit undesirable organisms.[31] ## Use in water treatment Microbes are used in the biological treatment of sewage and industrial waste effluents. ## Use in energy Microbes are used in fermentation to produce ethanol. ## Use in science Microbes are also essential tools in biotechnology, biochemistry, genetics, and molecular biology. Microbes can be harnessed for uses such as creating steroids and treating skin diseases. Scientists are also considering using microbes for living fuel cells, and as a solution for pollution. ## Use in warfare In the Middle Ages, dead corpses were thrown over walls during sieges, this meant that any bacteria carrying the disease that killed the person/creature would multiply in the vicinity of the opposing side. # Importance in human health ## Human digestion Microorganisms can form an endosymbiotic relationship with other, larger, organisms. For example, the bacteria that live within the human digestive system contribute to gut immunity, synthesise vitamins such as folic acid and biotin, and ferment complex undigestible carbohydrates.[32] ## Diseases and immunology Microorganisms are the cause of many infectious diseases. The organisms involved include bacteria, causing diseases such as plague, tuberculosis and anthrax; protozoa, causing diseases such as malaria, sleeping sickness and toxoplasmosis; and also fungi causing diseases such as ringworm, candidiasis or histoplasmosis. However, other diseases such as influenza, yellow fever or AIDS are caused by viruses, which are not living organisms and are not therefore microorganisms. As of 2007, no clear examples of archaean pathogens are known,[33] although a relationship has been proposed between the presence of some methanogens and human periodontal disease.[34] # Hygiene Hygiene is the avoidance of infection or food spoiling by eliminating microorganisms from the surroundings. As microorganisms, particularly bacteria, are found practically everywhere, this means in most cases the reduction of harmful microorganisms to acceptable levels. However, in some cases it is required that an object or substance is completely sterile, i.e. devoid of all living entities and viruses. A good example of this is a hypodermic needle. In food preparation microorganisms are reduced by preservation methods (such as the addition of vinegar), clean utensils used in preparation, short storage periods or by cool temperatures. If complete sterility is needed, the two most common methods are irradiation and the use of an autoclave, which resembles a pressure cooker. There are several methods for investigating the level of hygiene in a sample of food, drinking water, equipment etc. Water samples can be filtrated through an extremely fine filter. This filter is then placed in a nutrient medium. Microorganisms on the filter then grow to form a visible colony. Harmful microorganisms can be detected in food by placing a sample in a nutrient broth designed to enrich the organisms in question. Various methods, such as selective media or PCR, can then be used for detection. The hygiene of hard surfaces, such as cooking pots, can be tested by touching them with a solid piece of nutrient medium and then allowing the microorganisms to grow on it. There are no conditions where all microorganisms would grow, and therefore often several different methods are needed. For example, a food sample might be analyzed on three different nutrient mediums designed to indicate the presence of "total" bacteria (conditions where many, but not all, bacteria grow), molds (conditions where the growth of bacteria is prevented by e.g. antibiotics) and coliform bacteria (these indicate a sewage contamination).	https://www.wikidoc.org/index.php/Micro-organism
0af04e664ba50e467e87ff4b2e80a48249ebd2a2	wikidoc	Microcephalin	Microcephalin Microcephalin (MCPH1) is a gene that is expressed during fetal brain development. Certain mutations in MCPH1, when homozygous, cause primary microcephaly—a severely diminished brain. Hence it has been assumed that variants have a role in brain development, but in normal individuals no effect on mental ability or behavior has yet been demonstrated in either this or another similarly studied microcephaly gene, ASPM. However, an association has been established between normal variation in brain structure as measured with MRI (i.e., primarily cortical surface area and total brain volume) and common genetic variants within both the MCPH1 gene and another similarly studied microcephaly gene, CDK5RAP2. # Structure Microcephalin proteins contain the following three domains: - N-terminal BRCT domain - Central microcephalin protein domain (InterPro: IPR022047) - C-terminal BRCT domain # Expression in the brain MCPH1 is expressed in the fetal brain, in the developing forebrain, and on the walls of the lateral ventricles. Cells of this area divide, producing neurons that migrate to eventually form the cerebral cortex. # Evolution A derived form of MCPH1 called haplogroup D appeared about 37,000 years ago (any time between 14,000 and 60,000 years ago) and has spread to become the most common form of microcephalin throughout the world except Sub-Saharan Africa; this rapid spread suggests a selective sweep. However, scientists have not identified the evolutionary pressures that may have caused the spread of these mutations. This variant of the gene is thought to contribute to increased brain volume. Modern distributions of chromosomes bearing the ancestral forms of MCPH1 and ASPM are correlated with the incidence of tonal languages, but the nature of this relationship is far from clear. Haplogroup D may have originated from a lineage separated from modern humans approximately 1.1 million years ago and later introgressed into humans. This finding supports the possibility of admixture between modern humans and extinct Homo spp. While Neanderthals have been suggested as the possible source of this haplotype, the haplotype was not found in the individuals used to prepare the first draft of the Neanderthal genome. # Controversy The research results began to attract considerable controversy in the science world. John Derbyshire wrote that as a result of the findings, "our cherished national dream of a well-mixed and harmonious meritocracy may be unattainable." Richard Lewontin considers the two published papers as "egregious examples of going well beyond the data to try to make a splash." Bruce Lahn maintains that the science of the studies is sound, and freely admits that a direct link between these particular genes and either cognition or intelligence has not been clearly established. Lahn is now engaging himself with other areas of study. Later genetic association studies by Mekel-Bobrov et al. and Evans et al. also reported that the genotype for MCPH1 was under positive selection. An analysis by Timpson et al., found "no meaningful associations with brain size and various cognitive measures". However, a later study by Rimol et al. demonstrated a link between brain size and structure and two microcephaly genes, MCPH1 (only in females) and CDK5RAP2 (only in males). In contrast to previous studies, which only considered small numbers of exonic single nucleotide polymorphisms (SNPs) and did not investigate sex-specific effects, this study used microarray technology to genotype a range of SNPs associated with all four MCPH genes, including upstream and downstream regions, and allowed for separate effects for males and females. # Model organisms Model organisms have been used in the study of MCPH1 function. A conditional knockout mouse line, called Mcph1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and six significant abnormalities were observed. Homozygous mutant animals were infertile, did not have a pinna reflex, had a moderate degree of hearing impairment, abnormal cornea morphology, lens morphology and cataracts, and displayed chromosomal instability in a micronucleus test. # Family members In addition to MCPH1 the other five family members are: MCPH2, CDK5RAP2, MCPH4, ASPM and CENPJ.	Microcephalin Microcephalin (MCPH1) is a gene that is expressed during fetal brain development. Certain mutations in MCPH1, when homozygous, cause primary microcephaly—a severely diminished brain.[1][2][3] Hence it has been assumed that variants have a role in brain development,[4][5] but in normal individuals no effect on mental ability or behavior has yet been demonstrated in either this or another similarly studied microcephaly gene, ASPM.[6][7] However, an association has been established between normal variation in brain structure as measured with MRI (i.e., primarily cortical surface area and total brain volume) and common genetic variants within both the MCPH1 gene and another similarly studied microcephaly gene, CDK5RAP2.[8] # Structure Microcephalin proteins contain the following three domains: - N-terminal BRCT domain - Central microcephalin protein domain (InterPro: IPR022047) - C-terminal BRCT domain # Expression in the brain MCPH1 is expressed in the fetal brain, in the developing forebrain, and on the walls of the lateral ventricles. Cells of this area divide, producing neurons that migrate to eventually form the cerebral cortex. # Evolution A derived form of MCPH1 called haplogroup D appeared about 37,000 years ago (any time between 14,000 and 60,000 years ago) and has spread to become the most common form of microcephalin throughout the world except Sub-Saharan Africa; this rapid spread suggests a selective sweep.[9][10] However, scientists have not identified the evolutionary pressures that may have caused the spread of these mutations.[11] This variant of the gene is thought to contribute to increased brain volume.[12] Modern distributions of chromosomes bearing the ancestral forms of MCPH1 and ASPM are correlated with the incidence of tonal languages, but the nature of this relationship is far from clear.[13] Haplogroup D may have originated from a lineage separated from modern humans approximately 1.1 million years ago and later introgressed into humans. This finding supports the possibility of admixture between modern humans and extinct Homo spp.[10] While Neanderthals have been suggested as the possible source of this haplotype, the haplotype was not found in the individuals used to prepare the first draft of the Neanderthal genome.[14][15] # Controversy The research results began to attract considerable controversy in the science world. John Derbyshire wrote that as a result of the findings, "our cherished national dream of a well-mixed and harmonious meritocracy [...] may be unattainable."[16] Richard Lewontin considers the two published papers as "egregious examples of going well beyond the data to try to make a splash." Bruce Lahn maintains that the science of the studies is sound, and freely admits that a direct link between these particular genes and either cognition or intelligence has not been clearly established. Lahn is now engaging himself with other areas of study.[17][18] Later genetic association studies by Mekel-Bobrov et al. and Evans et al. also reported that the genotype for MCPH1 was under positive selection. An analysis by Timpson et al., found "no meaningful associations with brain size and various cognitive measures".[19] However, a later study by Rimol et al.[8] demonstrated a link between brain size and structure and two microcephaly genes, MCPH1 (only in females) and CDK5RAP2 (only in males). In contrast to previous studies, which only considered small numbers of exonic single nucleotide polymorphisms (SNPs) and did not investigate sex-specific effects, this study used microarray technology to genotype a range of SNPs associated with all four MCPH genes, including upstream and downstream regions, and allowed for separate effects for males and females. # Model organisms Model organisms have been used in the study of MCPH1 function. A conditional knockout mouse line, called Mcph1tm1a(EUCOMM)Wtsi[26][27] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[28][29][30] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[24][31] Twenty four tests were carried out on mutant mice and six significant abnormalities were observed.[24] Homozygous mutant animals were infertile, did not have a pinna reflex, had a moderate degree of hearing impairment, abnormal cornea morphology, lens morphology and cataracts, and displayed chromosomal instability in a micronucleus test.[24] # Family members In addition to MCPH1 the other five family members are: MCPH2, CDK5RAP2, MCPH4, ASPM and CENPJ.	https://www.wikidoc.org/index.php/Microcephalin
273c371b57327f69eb823ff2b7720c313fa78bb8	wikidoc	Microchapters	Microchapters # The Goals of Creating Microchapters The goals of creating microchapters are as follows: - Reduce content on any one page so that the page loads more rapidly - Allow users to navigate to the desired content more rapidly - To lower the barrier to entry for younger contributors by focusing their efforts on a manageable scope of content - To issue microcredits for CME # Structure of Microchapters In order to automate the creation and cataloguing of microchapters, only the first letter of the first word should be capitalized in the titles of microchapters. Example: Pericarditis Causes should be Pericarditis causes # Navigation Box Template You can find the template to create the Navigation box on the right hand side here: How to create an expanded navigation box ## Setting up an Navigation Box on a Page The navigation box is a template that is placed at the top of the page. Search for the words "type page name here" and replace this with the name of the disease or chapter Do not search and replace the term PAGENAME Save the Navigation Box Template as Template:Type page name here # Things to Remove as your are Editing and Creating Microchapters The template WikiDoc Cardiology Network Infobox Replace the search infobox template (SI) with the template for the disease you are working on. The structure of the home page for the disease should parallel that of the navigation box Please improve the English as needed # Structure of Microchapters ## Overview This should provide a brief description of the high points of the condition. Focus more on the diagnosis and treatment of the condition. Language from copyleft government sites is often quite good and can serve as a guide. The content of this section should link to the more detailed microchapters ## Patient Info Search government sites like the NHLBI, NLM for copyleft patient information. This information should be written at an 8th grade level of comprehension. Make sure the link to the wikidoc page is at the top ## Pathophysiology This includes the biologic mechanism underlying the disease state. This includes a description of the embryological or developmental abnormalities, molecular abnormalities, genetic abnormalities and pathology images. ## Demographics and Epidemiology This microchapter includes a discussion of the incidence and prevalence of the disease in both developed and developing worlds. ## Screening This microchapter includes screening procedures for the disease and is rarely included in the navigation box. ## Natural History, Complications, and Prognosis This microchapter describes what happens if the disease is not treated (the natural history), what the complications of the disease are, and the outlook or prognosis of the disease. ## Causes This is list of all the conditions that cause the disease. There are also conditions that may be associated with the disorder but do not cause it. Please insert the following table to help organize the content and complete it to the best of your ability: ## Complete Differential Diagnosis of the Causes of ... (By organ system) This is not the microchapter to describe what the disease causes. That is the chapter on natural history and complications. This is not the chapter where guidance is provided re how to distinguish the disorder form other disorders. That is the next chapter. ## Differentiating ____ from Other Diseases This microchapter describes the findings that distinguish the disease at hand from others with similar symptoms, physical examination findings and laboratory results. Oraganization of the distinguishing features in a table such as in the pericarditis chapter can be helpful. ## History and Symptoms This microchapter describes the typical symptoms that a patient verbalizes. It does not include findings from the physical exam (signs of the disease). It is helpful to organize the symptoms by frequency. ## Physical Examination These are the signs of disease on physical examination of the patient. Symptoms do not belong in this microchapter. It is helpful to organize the findings as follows: Appearance of the Patient Vital Signs Skin Eyes Ear Nose and Throat Heart Lungs Abdomen Extremities Neurologic ## Laboratory Tests The content of this microchapter includes information about electrolyes (K, Na), kidney function ( Cr, Bun), liver function tests ( LFTs, SGOT, SGPT), the complete blood count (CBC), the white blood count (WBC), hct, hb). This does not include the results of imaging studies like the chest x ray, CT, MRI etc. It does not include the images from pathology studies. Those go under pathophysiology. ## Imaging Studies There are a variety of other microchapters devoted to imaging studies and other diagnostic studies. ## Treatment This word does not link to anything. Only Medical Treatment and Surgery link to chapters. ## Medical Treatment The drugs used to treat the condition are described here. This includes the dose and duration of therapy. This includes when to escalate therapy or what to do if there is a treatment failure. ## Surgery This should include the indications (reasons) for the procedure, a description of the pre-operative tests, the surgery itself and the post-operative care. ## Primary Prevention This microchapter describes therapies that are used to prevent a first occurrence of the disease. ## Secondary Prevention This microchapter describes therapies that are used to prevent a second occurrence or a recurrence of the disease. # Tips and Tricks If you put a colon : in front of the contents, that indents the contents slightly to the right	Microchapters Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # The Goals of Creating Microchapters The goals of creating microchapters are as follows: - Reduce content on any one page so that the page loads more rapidly - Allow users to navigate to the desired content more rapidly - To lower the barrier to entry for younger contributors by focusing their efforts on a manageable scope of content - To issue microcredits for CME # Structure of Microchapters In order to automate the creation and cataloguing of microchapters, only the first letter of the first word should be capitalized in the titles of microchapters. Example: Pericarditis Causes should be Pericarditis causes # Navigation Box Template You can find the template to create the Navigation box on the right hand side here: How to create an expanded navigation box ## Setting up an Navigation Box on a Page The navigation box is a template that is placed at the top of the page. Search for the words "type page name here" and replace this with the name of the disease or chapter Do not search and replace the term PAGENAME Save the Navigation Box Template as Template:Type page name here # Things to Remove as your are Editing and Creating Microchapters The template WikiDoc Cardiology Network Infobox Replace the search infobox template (SI) with the template for the disease you are working on. The structure of the home page for the disease should parallel that of the navigation box Please improve the English as needed # Structure of Microchapters ## Overview This should provide a brief description of the high points of the condition. Focus more on the diagnosis and treatment of the condition. Language from copyleft government sites is often quite good and can serve as a guide. The content of this section should link to the more detailed microchapters ## Patient Info Search government sites like the NHLBI, NLM for copyleft patient information. This information should be written at an 8th grade level of comprehension. Make sure the link to the wikidoc page is at the top ## Pathophysiology This includes the biologic mechanism underlying the disease state. This includes a description of the embryological or developmental abnormalities, molecular abnormalities, genetic abnormalities and pathology images. ## Demographics and Epidemiology This microchapter includes a discussion of the incidence and prevalence of the disease in both developed and developing worlds. ## Screening This microchapter includes screening procedures for the disease and is rarely included in the navigation box. ## Natural History, Complications, and Prognosis This microchapter describes what happens if the disease is not treated (the natural history), what the complications of the disease are, and the outlook or prognosis of the disease. ## Causes This is list of all the conditions that cause the disease. There are also conditions that may be associated with the disorder but do not cause it. Please insert the following table to help organize the content and complete it to the best of your ability: ## Complete Differential Diagnosis of the Causes of ... (By organ system) This is not the microchapter to describe what the disease causes. That is the chapter on natural history and complications. This is not the chapter where guidance is provided re how to distinguish the disorder form other disorders. That is the next chapter. ## Differentiating ____ from Other Diseases This microchapter describes the findings that distinguish the disease at hand from others with similar symptoms, physical examination findings and laboratory results. Oraganization of the distinguishing features in a table such as in the pericarditis chapter can be helpful. ## History and Symptoms This microchapter describes the typical symptoms that a patient verbalizes. It does not include findings from the physical exam (signs of the disease). It is helpful to organize the symptoms by frequency. ## Physical Examination These are the signs of disease on physical examination of the patient. Symptoms do not belong in this microchapter. It is helpful to organize the findings as follows: Appearance of the Patient Vital Signs Skin Eyes Ear Nose and Throat Heart Lungs Abdomen Extremities Neurologic ## Laboratory Tests The content of this microchapter includes information about electrolyes (K, Na), kidney function ( Cr, Bun), liver function tests ( LFTs, SGOT, SGPT), the complete blood count (CBC), the white blood count (WBC), hct, hb). This does not include the results of imaging studies like the chest x ray, CT, MRI etc. It does not include the images from pathology studies. Those go under pathophysiology. ## Imaging Studies There are a variety of other microchapters devoted to imaging studies and other diagnostic studies. ## Treatment This word does not link to anything. Only Medical Treatment and Surgery link to chapters. ## Medical Treatment The drugs used to treat the condition are described here. This includes the dose and duration of therapy. This includes when to escalate therapy or what to do if there is a treatment failure. ## Surgery This should include the indications (reasons) for the procedure, a description of the pre-operative tests, the surgery itself and the post-operative care. ## Primary Prevention This microchapter describes therapies that are used to prevent a first occurrence of the disease. ## Secondary Prevention This microchapter describes therapies that are used to prevent a second occurrence or a recurrence of the disease. # Tips and Tricks If you put a colon : in front of the contents, that indents the contents slightly to the right	https://www.wikidoc.org/index.php/Microchapters
adbb4521bc093fac6ab1453b0c48478be04fe510	wikidoc	Microfilament	Microfilament Microfilaments (or actin filaments) are the thinnest filaments of the cytoskeleton found in the cytoplasm of all eukaryotic cells. These linear polymers of actin subunits are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton tensile forces. Microfilaments are highly versatile, functioning in (a) actoclampin-driven expansile molecular motors, where each elongating filament harnesses the hydrolysis energy of its "on-board" ATP to drive actoclampin end-tracking motors to propel cell crawling, ameboid movement, and changes in cell shape, and (b) actomyosin-driven contractile molecular motors, where the thin filaments serve as tensile platforms for myosin's ATP hydrolysis-dependent pulling action in muscle contraction and uropod advancement. # Organization Actin filaments are assembled in two general types of structures: bundles and networks. Actin-binding proteins dictate the formation of either structure since they cross-link actin filaments in the double-stranded helix. # Bundles In non-muscle actin bundles, the filaments are held together such that they are parallel to each other by actin-bundling and/or cationic species. Bundles play a role in many cellular processes such as cell division (cytokinesis) and cell movement. # In vitro self-assembly The thinnest fibers of the cytoskeleton (measuring approximately 7 nm in diameter), microfilaments are formed by the head-to-tail polymerization of actin monomers (also known as globular or G-actin). Actin subunits as part of a fiber at referred to as filamentous actin (or F-actin). Each microfilament is made up of two helical interlaced strands of subunits. Much like microtubules, actin filaments are polarized, with their fast-growing (+)-ends (also known as barbed ends, because of their appearance in electron micrographs after binding of myosin S1 sub-fragments) and a slow-growing (-)-end (or pointed end, again based on the pattern created by S1 binding). Filaments elongate approximately 10 times faster at their plus (+) ends than their minus (-) ends. At steady-state, the polymerization rate at the plus end matches the depolymerization rate at the minus end, and microfilaments are said to be treadmilling. A treadmilling filament need not move; even so, there is a net monomer uptake at the (+)-end and a net monomer loss from the (-)-end, such that the overall length a treadmilling microfilament does not change. Notably, no mechanical force is generated by treadmilling. In vitro actin polymerization, nucleation, starts with the self-association of three G-actin monomers to form a trimer. ATP-actin then binds the plus (+) end, and the ATP is subsequently hydrolyzed with a half time of about 2 seconds and the inorganic phosphate released with a half-time of about 6 minutes, which reduces the binding strength between neighboring units and generally destabilizes the filament. In vivo actin polymerization is catalyzed by a new class of filament end-tracking molecular motors known as actoclampins (see next section). Recent evidence suggests that ATP hydrolysis can be prompt in such cases (i.e., the rate of monomer incorporation is matched by the rate of ATP hydrolysis). ADP-actin dissociates slowly from the minus end, but this process is greatly accelerated by ADP-cofilin, which severs ADP-rich regions nearest the (–)-ends. Upon release, ADP-actin undergoes exchange of its bound ADP for solution-phase ATP, thereby forming the ATP-actin monomeric units needed for further (+)-end filament elongation. This rapid turnover is important for the cell's movement. End-capping proteins such as CapZ prevent the addition or loss of monomers at the filament end where actin turnover is unfavourable like in the muscle apparatus. # Microfilament-based motility by actoclampin molecular motors Intracellular actin cytoskeletal assembly and disassembly are tightly regulated by cell signaling mechanisms. Many signal transduction systems use the actin cytoskeleton as a scaffold holding them at or near the inner face of the peripheral membrane. This subcellular location allows immediate and exquisite responsiveness to transmembrane receptor action and signal-processing enzyme cascades. Because actin monomers must be recycled to sustain high rates of actin-based moltility during chemotaxis, cell signalling is believed to activate cofilin, an actin-filament depolymerizing protein which binds to ADP-rich actin subunits nearest the filament's (-)-end and promotes filament fragmentation, with concomitant depolymerization to liberate actin monomers. The protein profilin enhances the ability of monomers to assemble by stimulating the exchange of actin-bound ADP for solution-phase ATP to yield Actin-ATP and ADP. In most animal cells, monomeric actin is bound to profilin and thymosin-beta4, both of which preferentially bind with one-to-one stoichiometry to ATP-containing monomers. Although thymosin-beta4 is strictly a monomer-sequestering protein, the behavior of profilin is far more complex. Profilin is transferred to the leading edge by virtue of its PIP2 binding site, and profilin also employs its poly-L-proline binding site to dock onto end-tracking proteins. Once bound, Profilin-Actin-ATP is loaded into the monomer-insertion site of actoclampin motors (see below). Another important component in filament formation is the Arp2/3 complex, which binds to the side of an already existing filament (or "mother filament"), where it nucleates the formation of a new actin filament and creates a fan-like branched filament network. In non-muscle cells, actin filaments are formed at/near membrane surfaces. Their formation and turnover are regulated by many proteins, including - Filament end-tracking protein (e.g., formins, VASP, N-WASP) - Filament-nucleator known as the Actin-Related Protein-2/3 (or Arp2/3) complex - Filament cross-linkers (e.g., α-actinin and fascin) - Actin monomer-binding proteins profilin and thymosin-β4 - Filament (+)-end cappers such as Capping Protein and CapG, etc. - Filament-severing proteins like gelsolin - (-)-End depolymerizing proteins such as ADF/cofilin The actin filament network in non-muscle cells is highly dynamic. As first proposed by Dickinson & Purich (Biophysical Journal 92: 622-631), the actin filament network is arranged with the (+)-end of each filament attached to the cell's peripheral membrane by means of clamped-filament elongation motors ("actoclampins") formed from a filament (+)-end and a clamping protein (formins, VASP, Mena, WASP, and N-WASP). The primary substrate for these elongation motors is Profilin-Actin-ATP complex which is directly transferred to elongating filament ends (Dickinson, Southwick & Purich, 2002). The (-)-end of each filament is oriented toward the cell's interior. In the case of lamellipodial growth, the Arp2/3 complex generates a branched network, and in filopods, a parallel array of filaments is formed. Actoclampins are the actin filament (+)-end-tracking molecular motors that generate the propulsive forces needed for actin-based motility of lamellipodia, filopodia, invadipodia, dendritic spines, intracellular vesicles, and motile processes in endocytosis, exocytosis, podosome formation, and phagocytosis. Actoclampin motors also propel such intracellular pathogens as Listeria monocytogenes, Shigella flexneri, Vaccinia and Rickettsia. When assembled under suitable conditions, these end-tracking molecular motors can also propel biomimetic particles. The term actoclampin is derived from acto- to indicate the involvement of an actin filament, as in actomyosin, and clamp to indicate a clasping device used for strengthening flexible/moving objects and for securely fastening two or more components, followed by the suffix -in to indicate its protein origin. An actin filament end-tracking protein may thus be termed a clampin. Dickinson and Purich (2002) recognized that prompt ATP hydrolysis could explain the forces achieved during actin-based motility. They proposed a simple mechanoenzymatic sequence known as the Lock, Load & Fire Model, in which an end-tracking protein remains tightly bound ("locked" or clamped) onto the end of one sub-filament of the double-stranded actin filament. After binding to Glycyl-Prolyl-Prolyl-Prolyl-Prolyl-Prolyl-registers on tracker proteins, Profilin-ATP-actin is delivered ("loaded") to the unclamped end of the other sub-filament, whereupon ATP within the already clamped terminal subunit of the other subfragment is hydrolyzed ("fired"), providing the energy needed to release that arm of the end-tracker, which then can bind another Profilin-ATP-actin to begin a new monomer-addition round. The following steps describe one force-generating cycle of an actoclampin molecular motor: - The polymerization cofactor profilin and the ATP·actin combine to form a profilin-ATP-actin complex that then binds to the end-tracking unit - The cofactor and monomer are transferred to the (+)-end of an actin already clamped filament - The tracking unit and cofactor dissociate from the adjacent protofilament, in a step that can be facilitated by ATP hydrolysis energy to modulate the affinity of the cofactor and/or the tracking unit for the filament; and this mechanoenzymatic cycle is then repeated, starting this time on the other sub-filament growth site. When operating with the benefit of ATP hydrolysis, AC motors generate per-filament forces of 8–9 pN, which is far greater than the per-filament limit of 1–2 pN for motors operating without ATP hydrolysis (Dickinson and Purich, 2002, 2006; Dickinson, Caro and Purich, 2004). The term actoclampin is generic and applies to all actin filament end-tracking molecular motors, irrespective of whether they are driven actively by an ATP-activated mechanism or passively. Some actoclampins (e.g., those involving Ena/VASP proteins, WASP, and N-WASP) apparently require Arp2/3-mediated filament initiation to form the actin polymerization nucleus that is then "loaded" onto the end-tracker before processive motility can commence. To generate a new filament, Arp2/3 requires a "mother" filament, monomeric ATP-actin, and an activating domain from Listeria ActA or the VCA region of N-WASP. Ther Arp2/3 complex binds to the side of the mother filament, forming a Y-shaped branch having a 70 degree angle with respect to the longitudinal axis of the mother filament. Then upon activation by ActA or VCA, the Arp complex is believed to undergo a major conformational change, bringing its two actin-related protein subunits near enough to each other to generate a new filament gat. Whether ATP hydrolysis may be required for nucleation and/or Y-branch release is a matter under active investigation.	Microfilament Microfilaments (or actin filaments) are the thinnest filaments of the cytoskeleton found in the cytoplasm of all eukaryotic cells. These linear polymers of actin subunits are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton tensile forces. Microfilaments are highly versatile, functioning in (a) actoclampin-driven expansile molecular motors, where each elongating filament harnesses the hydrolysis energy of its "on-board" ATP to drive actoclampin end-tracking motors to propel cell crawling, ameboid movement, and changes in cell shape, and (b) actomyosin-driven contractile molecular motors, where the thin filaments serve as tensile platforms for myosin's ATP hydrolysis-dependent pulling action in muscle contraction and uropod advancement. # Organization Actin filaments are assembled in two general types of structures: bundles and networks. Actin-binding proteins dictate the formation of either structure since they cross-link actin filaments in the double-stranded helix. # Bundles In non-muscle actin bundles, the filaments are held together such that they are parallel to each other by actin-bundling and/or cationic species. Bundles play a role in many cellular processes such as cell division (cytokinesis) and cell movement. # In vitro self-assembly The thinnest fibers of the cytoskeleton (measuring approximately 7 nm in diameter), microfilaments are formed by the head-to-tail polymerization of actin monomers (also known as globular or G-actin). Actin subunits as part of a fiber at referred to as filamentous actin (or F-actin). Each microfilament is made up of two helical interlaced strands of subunits. Much like microtubules, actin filaments are polarized, with their fast-growing (+)-ends (also known as barbed ends, because of their appearance in electron micrographs after binding of myosin S1 sub-fragments) and a slow-growing (-)-end (or pointed end, again based on the pattern created by S1 binding). Filaments elongate approximately 10 times faster at their plus (+) ends than their minus (-) ends. At steady-state, the polymerization rate at the plus end matches the depolymerization rate at the minus end, and microfilaments are said to be treadmilling. A treadmilling filament need not move; even so, there is a net monomer uptake at the (+)-end and a net monomer loss from the (-)-end, such that the overall length a treadmilling microfilament does not change. Notably, no mechanical force is generated by treadmilling. In vitro actin polymerization, nucleation, starts with the self-association of three G-actin monomers to form a trimer. ATP-actin then binds the plus (+) end, and the ATP is subsequently hydrolyzed with a half time of about 2 seconds[1] and the inorganic phosphate released with a half-time of about 6 minutes,[1] which reduces the binding strength between neighboring units and generally destabilizes the filament. In vivo actin polymerization is catalyzed by a new class of filament end-tracking molecular motors known as actoclampins (see next section). Recent evidence suggests that ATP hydrolysis can be prompt in such cases (i.e., the rate of monomer incorporation is matched by the rate of ATP hydrolysis). ADP-actin dissociates slowly from the minus end, but this process is greatly accelerated by ADP-cofilin, which severs ADP-rich regions nearest the (–)-ends. Upon release, ADP-actin undergoes exchange of its bound ADP for solution-phase ATP, thereby forming the ATP-actin monomeric units needed for further (+)-end filament elongation. This rapid turnover is important for the cell's movement. End-capping proteins such as CapZ prevent the addition or loss of monomers at the filament end where actin turnover is unfavourable like in the muscle apparatus. # Microfilament-based motility by actoclampin molecular motors Intracellular actin cytoskeletal assembly and disassembly are tightly regulated by cell signaling mechanisms. Many signal transduction systems use the actin cytoskeleton as a scaffold holding them at or near the inner face of the peripheral membrane. This subcellular location allows immediate and exquisite responsiveness to transmembrane receptor action and signal-processing enzyme cascades. Because actin monomers must be recycled to sustain high rates of actin-based moltility during chemotaxis, cell signalling is believed to activate cofilin, an actin-filament depolymerizing protein which binds to ADP-rich actin subunits nearest the filament's (-)-end and promotes filament fragmentation, with concomitant depolymerization to liberate actin monomers. The protein profilin enhances the ability of monomers to assemble by stimulating the exchange of actin-bound ADP for solution-phase ATP to yield Actin-ATP and ADP. In most animal cells, monomeric actin is bound to profilin and thymosin-beta4, both of which preferentially bind with one-to-one stoichiometry to ATP-containing monomers. Although thymosin-beta4 is strictly a monomer-sequestering protein, the behavior of profilin is far more complex. Profilin is transferred to the leading edge by virtue of its PIP2 binding site, and profilin also employs its poly-L-proline binding site to dock onto end-tracking proteins. Once bound, Profilin-Actin-ATP is loaded into the monomer-insertion site of actoclampin motors (see below). Another important component in filament formation is the Arp2/3 complex, which binds to the side of an already existing filament (or "mother filament"), where it nucleates the formation of a new actin filament and creates a fan-like branched filament network. In non-muscle cells, actin filaments are formed at/near membrane surfaces. Their formation and turnover are regulated by many proteins, including - Filament end-tracking protein (e.g., formins, VASP, N-WASP) - Filament-nucleator known as the Actin-Related Protein-2/3 (or Arp2/3) complex - Filament cross-linkers (e.g., α-actinin and fascin) - Actin monomer-binding proteins profilin and thymosin-β4 - Filament (+)-end cappers such as Capping Protein and CapG, etc. - Filament-severing proteins like gelsolin - (-)-End depolymerizing proteins such as ADF/cofilin The actin filament network in non-muscle cells is highly dynamic. As first proposed by Dickinson & Purich (Biophysical Journal 92: 622-631), the actin filament network is arranged with the (+)-end of each filament attached to the cell's peripheral membrane by means of clamped-filament elongation motors ("actoclampins") formed from a filament (+)-end and a clamping protein (formins, VASP, Mena, WASP, and N-WASP). The primary substrate for these elongation motors is Profilin-Actin-ATP complex which is directly transferred to elongating filament ends (Dickinson, Southwick & Purich, 2002). The (-)-end of each filament is oriented toward the cell's interior. In the case of lamellipodial growth, the Arp2/3 complex generates a branched network, and in filopods, a parallel array of filaments is formed. Actoclampins are the actin filament (+)-end-tracking molecular motors that generate the propulsive forces needed for actin-based motility of lamellipodia, filopodia, invadipodia, dendritic spines, intracellular vesicles, and motile processes in endocytosis, exocytosis, podosome formation, and phagocytosis. Actoclampin motors also propel such intracellular pathogens as Listeria monocytogenes, Shigella flexneri, Vaccinia and Rickettsia. When assembled under suitable conditions, these end-tracking molecular motors can also propel biomimetic particles. The term actoclampin is derived from acto- to indicate the involvement of an actin filament, as in actomyosin, and clamp to indicate a clasping device used for strengthening flexible/moving objects and for securely fastening two or more components, followed by the suffix -in to indicate its protein origin. An actin filament end-tracking protein may thus be termed a clampin. Dickinson and Purich (2002) recognized that prompt ATP hydrolysis could explain the forces achieved during actin-based motility. They proposed a simple mechanoenzymatic sequence known as the Lock, Load & Fire Model, in which an end-tracking protein remains tightly bound ("locked" or clamped) onto the end of one sub-filament of the double-stranded actin filament. After binding to Glycyl-Prolyl-Prolyl-Prolyl-Prolyl-Prolyl-registers on tracker proteins, Profilin-ATP-actin is delivered ("loaded") to the unclamped end of the other sub-filament, whereupon ATP within the already clamped terminal subunit of the other subfragment is hydrolyzed ("fired"), providing the energy needed to release that arm of the end-tracker, which then can bind another Profilin-ATP-actin to begin a new monomer-addition round. The following steps describe one force-generating cycle of an actoclampin molecular motor: - The polymerization cofactor profilin and the ATP·actin combine to form a profilin-ATP-actin complex that then binds to the end-tracking unit - The cofactor and monomer are transferred to the (+)-end of an actin already clamped filament - The tracking unit and cofactor dissociate from the adjacent protofilament, in a step that can be facilitated by ATP hydrolysis energy to modulate the affinity of the cofactor and/or the tracking unit for the filament; and this mechanoenzymatic cycle is then repeated, starting this time on the other sub-filament growth site. When operating with the benefit of ATP hydrolysis, AC motors generate per-filament forces of 8–9 pN, which is far greater than the per-filament limit of 1–2 pN for motors operating without ATP hydrolysis (Dickinson and Purich, 2002, 2006; Dickinson, Caro and Purich, 2004). The term actoclampin is generic and applies to all actin filament end-tracking molecular motors, irrespective of whether they are driven actively by an ATP-activated mechanism or passively. Some actoclampins (e.g., those involving Ena/VASP proteins, WASP, and N-WASP) apparently require Arp2/3-mediated filament initiation to form the actin polymerization nucleus that is then "loaded" onto the end-tracker before processive motility can commence. To generate a new filament, Arp2/3 requires a "mother" filament, monomeric ATP-actin, and an activating domain from Listeria ActA or the VCA region of N-WASP. Ther Arp2/3 complex binds to the side of the mother filament, forming a Y-shaped branch having a 70 degree angle with respect to the longitudinal axis of the mother filament. Then upon activation by ActA or VCA, the Arp complex is believed to undergo a major conformational change, bringing its two actin-related protein subunits near enough to each other to generate a new filament gat. Whether ATP hydrolysis may be required for nucleation and/or Y-branch release is a matter under active investigation.	https://www.wikidoc.org/index.php/Microfilament
657bacef2a919075ca3c70badeff7e2bf5cebc99	wikidoc	Micrognathism	Micrognathism Synonyms and keywords: Micrognathia, mandibular hypoplasia # Overview Micrognathism is a condition where the jaw is undersized. # Natural History, Complications, Prognosis It is common in infants, but is usually self-corrected during growth, due to the jaws increasing in size. It may be a cause of abnormal tooth alignment and in severe cases can cause hamper feeding. # Causes - 49,XXXXX syndrome - Atkin-Flaitz-Patil syndrome - Bowen-Conradi syndrome - Camptomelic dysplasia - Cardiofaciocutaneous syndrome - Carey-Fineman-Ziter syndrome - Catel-Manzke syndrome - Cerebrocostomandibular syndrome - Cerebrohepatorenal syndrome - CHARGE syndrome - Chromosome 18 trisomy syndrome - Chromosome 8 recombinant syndrome - Chromosome 8 trisomy syndrome - CODAS (cerebral, ocular, dental, auricular, skeletal) syndrome - Coffin-Lowry syndrome - Cohen syndrome - Cornelia de Lange syndrome - Craniomandibular dermatodysostosis - Cri du chat syndrome 5p− - De la Chapelle dysplasia - Diamond-Blackfan anemia - DiGeorge's syndrome - Dubowitz syndrome - Femoral hypoplasia - unusual facies syndrome - Fetal akinesia-hypokinesia sequence - Fetal aminopterin-like syndrome - Hurst's microtia-absent patellae-micrognathia syndrome - Juvenile chronic arthritis - Kyphomelic dysplasia - Lathosterolosis - Lethal congenital contracture syndrome - Lethal restrictive dermopathy - Loeys-Dietz syndrome - Lujan-Fryns syndrome - Marden-Walker syndrome - Marfan's syndrome - Micrognathia with peromelia - Miller-Dieker syndrome - Nager acrofacial dysostosis - Noonan's syndrome - Opitz-Frias syndrome - Orofaciodigital syndrome type 4 - Otopalatodigital syndrome type 2 - Pallister-Hall syndrome - Pierre Robin syndrome - Postaxial acrofacial dysostosis syndrome - Rothmund-Thomson syndrome - Schwartz-Jampel-Aberfeld syndrome - Scott craniodigital syndrome - Smith-Lemli-Opitz syndrome - Syphilis, congenital - Ter Haar syndrome - Toriello-Carey syndrome - Treacher Collins-Franceschetti syndrome - Trichorhinophalangeal syndrome type 1 - Trichorhinophalangeal syndrome type 3 - Turner's syndrome - Van Bogaert-Hozay syndrome - Wagner vitreoretinal degeneration syndrome - Weissenbacher-Zweymuller syndrome - Wolf-Hirschhorn syndrome - Yunis-Varon syndrome Its causes also include , , Hallerman-Streiff syndrome, Trisomy 13, Trisomy 18, X0 syndrome (Turner syndrome), Progeria, Treacher Collins syndrome, Smith-Lemli-Opitz syndrome, Russell-Silver syndrome, Seckel syndrome, Cri du chat syndrome and Marfan syndrome. # Diagnosis ## Skull X ray It can be detected by dental or skull X-Ray testing.	Micrognathism Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: Micrognathia, mandibular hypoplasia # Overview Micrognathism is a condition where the jaw is undersized. # Natural History, Complications, Prognosis It is common in infants, but is usually self-corrected during growth, due to the jaws increasing in size. It may be a cause of abnormal tooth alignment and in severe cases can cause hamper feeding. # Causes - 49,XXXXX syndrome - Atkin-Flaitz-Patil syndrome - Bowen-Conradi syndrome - Camptomelic dysplasia - Cardiofaciocutaneous syndrome - Carey-Fineman-Ziter syndrome - Catel-Manzke syndrome - Cerebrocostomandibular syndrome - Cerebrohepatorenal syndrome - CHARGE syndrome - Chromosome 18 trisomy syndrome - Chromosome 8 recombinant syndrome - Chromosome 8 trisomy syndrome - CODAS (cerebral, ocular, dental, auricular, skeletal) syndrome - Coffin-Lowry syndrome - Cohen syndrome - Cornelia de Lange syndrome - Craniomandibular dermatodysostosis - Cri du chat syndrome 5p− - De la Chapelle dysplasia - Diamond-Blackfan anemia - DiGeorge's syndrome - Dubowitz syndrome - Femoral hypoplasia - unusual facies syndrome - Fetal akinesia-hypokinesia sequence - Fetal aminopterin-like syndrome - Hurst's microtia-absent patellae-micrognathia syndrome - Juvenile chronic arthritis - Kyphomelic dysplasia - Lathosterolosis - Lethal congenital contracture syndrome - Lethal restrictive dermopathy - Loeys-Dietz syndrome - Lujan-Fryns syndrome - Marden-Walker syndrome - Marfan's syndrome - Micrognathia with peromelia - Miller-Dieker syndrome - Nager acrofacial dysostosis - Noonan's syndrome - Opitz-Frias syndrome - Orofaciodigital syndrome type 4 - Otopalatodigital syndrome type 2 - Pallister-Hall syndrome - Pierre Robin syndrome - Postaxial acrofacial dysostosis syndrome - Rothmund-Thomson syndrome - Schwartz-Jampel-Aberfeld syndrome - Scott craniodigital syndrome - Smith-Lemli-Opitz syndrome - Syphilis, congenital - Ter Haar syndrome - Toriello-Carey syndrome - Treacher Collins-Franceschetti syndrome - Trichorhinophalangeal syndrome type 1 - Trichorhinophalangeal syndrome type 3 - Turner's syndrome - Van Bogaert-Hozay syndrome - Wagner vitreoretinal degeneration syndrome - Weissenbacher-Zweymuller syndrome - Wolf-Hirschhorn syndrome - Yunis-Varon syndrome Its causes also include , , Hallerman-Streiff syndrome, Trisomy 13, Trisomy 18, X0 syndrome (Turner syndrome), Progeria, Treacher Collins syndrome, Smith-Lemli-Opitz syndrome, Russell-Silver syndrome, Seckel syndrome, Cri du chat syndrome and Marfan syndrome. # Diagnosis ## Skull X ray It can be detected by dental or skull X-Ray testing.	https://www.wikidoc.org/index.php/Micrognathia
e7114c92c0765f5d2c4ceb74c17a0af3bb8d9310	wikidoc	Microsporidia	Microsporidia # Overview Microsporidia are parasites of animals, now considered to be extremely reduced fungi. Most infect insects, but they are also responsible for common diseases of crustaceans and fish, and have been found in most other animal groups, including humans and other mammals which can be parasitized by species of Encephalitozoon. Replication takes place within the host's cells, which are infected by means of unicellular spores. These vary from 1-40 μm, making them some of the smallest eukaryotes. They also have the shortest eukaryotic genomes. Microsporidia are unusual in lacking mitochondria and in having mitosomes. They also lack motile structures such as flagella. The spores are protected by a layered wall including proteins and chitin. Their interior is dominated by a unique coiled structure called a polar tube (not to be confused with the polar filaments of Myxozoa). In most cases there are two closely associated nuclei, forming a diplokaryon, but sometimes there is only one. During infection, the polar tube penetrates the host cell (the process has been compared by Patrick J. Keeling to "turning a garden hose inside out"), and the contents of the spore are pumped through it. Keeling likens the system to a combination of "harpoon and hypodermic syringe", adding that it is "one of the most sophisticated infection mechanisms in biology". Once inside the host cell, the sporoplasm grows, dividing or forming a multinucleate plasmodium before producing new spores. The life cycle varies considerably. Some have a simple asexual life cycle, while others have a complex life cycle involving multiple hosts and both asexual and sexual reproduction. Different types of spores may be produced at different stages, probably with different functions including autoinfection (transmission within a single host). The Microsporidia often cause chronic, debilitating diseases rather than lethal infections. Effects on the host include reduced longevity, fertility, weight, and general vigor. Vertical transmission of microsporidia is frequently reported. In the case of insect hosts, vertical transmission often occurs as transovarial transmission, where the microsporidian parasites pass from the ovaries of the female host into eggs and eventually multiply in the infected larvae. Amblyospora salinaria n. sp. which infects the mosquito Culex salinarius Coquillett, and Amblyospora californica which infects the mosquito Culex tarsalis Coquillett, provide typical examples of transovarial transmission of microsporidia (Andreadis and Hall 1979a,b; Jahn et al. 1986; Becnel and Andreadis 1998). Because they are unicellular, Microsporidia were traditionally treated as protozoa, and like other amitochondriate eukaryotes were considered to have diverged very early on. However, other genes place them alongside or within the Fungi, and this is supported by several chemical and morphological features. In particular, they appear to be allied with the Zygomycota or Ascomycota. Microsporidium was once the vernacular name for a member of the class Microsporea (Corliss and Levine 1963). # Classification - Subclass: Dihaplophasea Order: Meiodihaplophasida Superfamily Thelohanioidea Family Thelohaniidae Family Duboscqiidae Family Janacekiidae Family Pereziidae Family Striatosporidae Family Cylindrosporidae Superfamily Burenelloidea Family Burenellidae Superfamily Amblyosporoidae Family Amblyosporidae Order Dissociodihaplophasida Superfamily Nosematoidea Family Nosematidae Family Ichthyosporidiidae Family Caudosporidae Family Pseudopleistophoridae Family Mrazekiidae Superfamily Culicosporoidea Family Culicosporidae Family Culicosporellidae Family Golbergiidae Family Spragueidae Superfamily Ovavesiculoidea Family Ovavesiculidae Family Tetramicridae - Order: Meiodihaplophasida Superfamily Thelohanioidea Family Thelohaniidae Family Duboscqiidae Family Janacekiidae Family Pereziidae Family Striatosporidae Family Cylindrosporidae Superfamily Burenelloidea Family Burenellidae Superfamily Amblyosporoidae Family Amblyosporidae - Superfamily Thelohanioidea Family Thelohaniidae Family Duboscqiidae Family Janacekiidae Family Pereziidae Family Striatosporidae Family Cylindrosporidae - Family Thelohaniidae - Family Duboscqiidae - Family Janacekiidae - Family Pereziidae - Family Striatosporidae - Family Cylindrosporidae - Superfamily Burenelloidea Family Burenellidae - Family Burenellidae - Superfamily Amblyosporoidae Family Amblyosporidae - Family Amblyosporidae - Order Dissociodihaplophasida Superfamily Nosematoidea Family Nosematidae Family Ichthyosporidiidae Family Caudosporidae Family Pseudopleistophoridae Family Mrazekiidae Superfamily Culicosporoidea Family Culicosporidae Family Culicosporellidae Family Golbergiidae Family Spragueidae Superfamily Ovavesiculoidea Family Ovavesiculidae Family Tetramicridae - Superfamily Nosematoidea Family Nosematidae Family Ichthyosporidiidae Family Caudosporidae Family Pseudopleistophoridae Family Mrazekiidae - Family Nosematidae - Family Ichthyosporidiidae - Family Caudosporidae - Family Pseudopleistophoridae - Family Mrazekiidae - Superfamily Culicosporoidea Family Culicosporidae Family Culicosporellidae Family Golbergiidae Family Spragueidae - Family Culicosporidae - Family Culicosporellidae - Family Golbergiidae - Family Spragueidae - Superfamily Ovavesiculoidea Family Ovavesiculidae Family Tetramicridae - Family Ovavesiculidae - Family Tetramicridae - Subclass Haplophasea Order Glugeida Family Glugeidae Family Pleistophoridae Family Encephalitozoonidae Family Abelsporidae Family Tuzetiidae Family Microfilidae Family Unikaryonidae Order Chyridiopsida Family Chytridiopsida Family Buxtehudiidae Family Enterocytozoonidae Family Burkeidae - Order Glugeida Family Glugeidae Family Pleistophoridae Family Encephalitozoonidae Family Abelsporidae Family Tuzetiidae Family Microfilidae Family Unikaryonidae - Family Glugeidae Family Pleistophoridae Family Encephalitozoonidae Family Abelsporidae Family Tuzetiidae Family Microfilidae Family Unikaryonidae - Family Glugeidae - Family Pleistophoridae - Family Encephalitozoonidae - Family Abelsporidae - Family Tuzetiidae - Family Microfilidae - Family Unikaryonidae - Order Chyridiopsida Family Chytridiopsida Family Buxtehudiidae Family Enterocytozoonidae Family Burkeidae - Family Chytridiopsida Family Buxtehudiidae Family Enterocytozoonidae Family Burkeidae - Family Chytridiopsida - Family Buxtehudiidae - Family Enterocytozoonidae - Family Burkeidae # Microsporidia causing human disease Although phylum microsporidia have more than 1000 species and over 100 genres, Only 14 species were associated with human disease. - Anncaliia (formerly Brachiola) A. algerae, A. connori, A. vesicularum - A. algerae, A. connori, A. vesicularum - Encephalitozoon E. cuniculi, E. hellem, E. intestinalis (formerly Septata intestinalis) - E. cuniculi, E. hellem, E. intestinalis (formerly Septata intestinalis) - Enterocytozoon E. bieneusi - E. bieneusi - Microsporidium M. ceylonensis, M. africanum - M. ceylonensis, M. africanum - Nosema N. ocularum - N. ocularum - Pleistophora sp. - Trachipleistophora T. hominis, T. anthropophthera - T. hominis, T. anthropophthera - Vittaforma V. corneae. - V. corneae. - Tubulinosema T. acridophagus - T. acridophagus # Diseases caused by the different species The clinical manifestations vary according to the causative species with diarrhea being the most common presentation. *Two reports of E. bieneusi in respiratory samples have also been published, one in 1992 and the other in 1997.	Microsporidia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Microsporidia are parasites of animals, now considered to be extremely reduced fungi. Most infect insects, but they are also responsible for common diseases of crustaceans and fish, and have been found in most other animal groups, including humans and other mammals which can be parasitized by species of Encephalitozoon. Replication takes place within the host's cells, which are infected by means of unicellular spores. These vary from 1-40 μm, making them some of the smallest eukaryotes. They also have the shortest eukaryotic genomes. Microsporidia are unusual in lacking mitochondria and in having mitosomes. They also lack motile structures such as flagella. The spores are protected by a layered wall including proteins and chitin. Their interior is dominated by a unique coiled structure called a polar tube (not to be confused with the polar filaments of Myxozoa). In most cases there are two closely associated nuclei, forming a diplokaryon, but sometimes there is only one. During infection, the polar tube penetrates the host cell (the process has been compared by Patrick J. Keeling to "turning a garden hose inside out"), and the contents of the spore are pumped through it. Keeling likens the system to a combination of "harpoon and hypodermic syringe", adding that it is "one of the most sophisticated infection mechanisms in biology". Once inside the host cell, the sporoplasm grows, dividing or forming a multinucleate plasmodium before producing new spores. The life cycle varies considerably. Some have a simple asexual life cycle, while others have a complex life cycle involving multiple hosts and both asexual and sexual reproduction. Different types of spores may be produced at different stages, probably with different functions including autoinfection (transmission within a single host). The Microsporidia often cause chronic, debilitating diseases rather than lethal infections. Effects on the host include reduced longevity, fertility, weight, and general vigor. Vertical transmission of microsporidia is frequently reported. In the case of insect hosts, vertical transmission often occurs as transovarial transmission, where the microsporidian parasites pass from the ovaries of the female host into eggs and eventually multiply in the infected larvae. Amblyospora salinaria n. sp. which infects the mosquito Culex salinarius Coquillett, and Amblyospora californica which infects the mosquito Culex tarsalis Coquillett, provide typical examples of transovarial transmission of microsporidia (Andreadis and Hall 1979a,b; Jahn et al. 1986; Becnel and Andreadis 1998). Because they are unicellular, Microsporidia were traditionally treated as protozoa, and like other amitochondriate eukaryotes were considered to have diverged very early on. However, other genes place them alongside or within the Fungi, and this is supported by several chemical and morphological features. In particular, they appear to be allied with the Zygomycota or Ascomycota. Microsporidium was once the vernacular name for a member of the class Microsporea (Corliss and Levine 1963). # Classification - Subclass: Dihaplophasea Order: Meiodihaplophasida Superfamily Thelohanioidea Family Thelohaniidae Family Duboscqiidae Family Janacekiidae Family Pereziidae Family Striatosporidae Family Cylindrosporidae Superfamily Burenelloidea Family Burenellidae Superfamily Amblyosporoidae Family Amblyosporidae Order Dissociodihaplophasida Superfamily Nosematoidea Family Nosematidae Family Ichthyosporidiidae Family Caudosporidae Family Pseudopleistophoridae Family Mrazekiidae Superfamily Culicosporoidea Family Culicosporidae Family Culicosporellidae Family Golbergiidae Family Spragueidae Superfamily Ovavesiculoidea Family Ovavesiculidae Family Tetramicridae - Order: Meiodihaplophasida Superfamily Thelohanioidea Family Thelohaniidae Family Duboscqiidae Family Janacekiidae Family Pereziidae Family Striatosporidae Family Cylindrosporidae Superfamily Burenelloidea Family Burenellidae Superfamily Amblyosporoidae Family Amblyosporidae - Superfamily Thelohanioidea Family Thelohaniidae Family Duboscqiidae Family Janacekiidae Family Pereziidae Family Striatosporidae Family Cylindrosporidae - Family Thelohaniidae - Family Duboscqiidae - Family Janacekiidae - Family Pereziidae - Family Striatosporidae - Family Cylindrosporidae - Superfamily Burenelloidea Family Burenellidae - Family Burenellidae - Superfamily Amblyosporoidae Family Amblyosporidae - Family Amblyosporidae - Order Dissociodihaplophasida Superfamily Nosematoidea Family Nosematidae Family Ichthyosporidiidae Family Caudosporidae Family Pseudopleistophoridae Family Mrazekiidae Superfamily Culicosporoidea Family Culicosporidae Family Culicosporellidae Family Golbergiidae Family Spragueidae Superfamily Ovavesiculoidea Family Ovavesiculidae Family Tetramicridae - Superfamily Nosematoidea Family Nosematidae Family Ichthyosporidiidae Family Caudosporidae Family Pseudopleistophoridae Family Mrazekiidae - Family Nosematidae - Family Ichthyosporidiidae - Family Caudosporidae - Family Pseudopleistophoridae - Family Mrazekiidae - Superfamily Culicosporoidea Family Culicosporidae Family Culicosporellidae Family Golbergiidae Family Spragueidae - Family Culicosporidae - Family Culicosporellidae - Family Golbergiidae - Family Spragueidae - Superfamily Ovavesiculoidea Family Ovavesiculidae Family Tetramicridae - Family Ovavesiculidae - Family Tetramicridae - Subclass Haplophasea Order Glugeida Family Glugeidae Family Pleistophoridae Family Encephalitozoonidae Family Abelsporidae Family Tuzetiidae Family Microfilidae Family Unikaryonidae Order Chyridiopsida Family Chytridiopsida Family Buxtehudiidae Family Enterocytozoonidae Family Burkeidae - Order Glugeida Family Glugeidae Family Pleistophoridae Family Encephalitozoonidae Family Abelsporidae Family Tuzetiidae Family Microfilidae Family Unikaryonidae - Family Glugeidae Family Pleistophoridae Family Encephalitozoonidae Family Abelsporidae Family Tuzetiidae Family Microfilidae Family Unikaryonidae - Family Glugeidae - Family Pleistophoridae - Family Encephalitozoonidae - Family Abelsporidae - Family Tuzetiidae - Family Microfilidae - Family Unikaryonidae - Order Chyridiopsida Family Chytridiopsida Family Buxtehudiidae Family Enterocytozoonidae Family Burkeidae - Family Chytridiopsida Family Buxtehudiidae Family Enterocytozoonidae Family Burkeidae - Family Chytridiopsida - Family Buxtehudiidae - Family Enterocytozoonidae - Family Burkeidae # Microsporidia causing human disease Although phylum microsporidia have more than 1000 species and over 100 genres, Only 14 species were associated with human disease. - Anncaliia (formerly Brachiola)[2] A. algerae, A. connori, A. vesicularum - A. algerae, A. connori, A. vesicularum - Encephalitozoon E. cuniculi, E. hellem, E. intestinalis (formerly Septata intestinalis) - E. cuniculi, E. hellem, E. intestinalis (formerly Septata intestinalis) - Enterocytozoon E. bieneusi - E. bieneusi - Microsporidium M. ceylonensis, M. africanum - M. ceylonensis, M. africanum - Nosema N. ocularum - N. ocularum - Pleistophora sp. - Trachipleistophora T. hominis, T. anthropophthera - T. hominis, T. anthropophthera - Vittaforma V. corneae. - V. corneae. - Tubulinosema T. acridophagus - T. acridophagus # Diseases caused by the different species The clinical manifestations vary according to the causative species with diarrhea being the most common presentation.[3] *Two reports of E. bieneusi in respiratory samples have also been published, one in 1992 and the other in 1997.	https://www.wikidoc.org/index.php/Microsporidia
1730d4940339202bd5c71771ff19d6262abed21c	wikidoc	Mimosa pudica	Mimosa pudica The Sensitive plant (Mimosa pudica L.) is a creeping annual or perennial herb often grown for its curiosity value: the compound leaves fold inward and droop when touched, re-opening within minutes. Mimosa pudica is native to Brazil, but is now a pantropical weed. Other names given to this curious plant are Humble plant, TickleMe Plant, Shame plant, Sleeping grass, Prayer Plant, Touch-me-not, Makahiya (Philippines, meaning "shy"), Mori Vivi (West Indies), mate-loi (false death) (Tonga). The Chinese name for this plant translates to "shyness grass". The species epithet, pudica, is Latin for "bashful" or "shrinking", because of its curious nature and easy procreation. Its Sinhala name is Nidikumba, where 'nidi' means 'sleep'. The seeds are currently marketed to children under the name "TickleMe Plant". The stem is erect in young plants, but becomes creeping or trailing with age. The stem is slender, branching, and sparsely to densely prickly, growing to a length of 1.5 m (5 ft). The leaves are bipinnately compound, with one or two pinnae pairs, and 10-26 leaflets per pinna. The petioles are also prickly. Pedunculate (stalked) pale pink or purple flower heads arise from the leaf axils. The globose to ovoid heads are 8-10 mm in diameter (excluding the stamens). On close examination, it is seen that the floret petals are red in their upper part and the filaments are pink to lavender. The fruit consists of clusters of 2-8 pods from 1-2 cm long each, these prickly on the margins. The pods break into 2-5 segments and contain pale brown seeds some 2.5 mm long. # Plant movement Mimosa pudica is well known for its rapid plant movement. In the evening the leaflets will fold together and the whole leaf droops downward. It then re-opens at sunrise. This type of motion has been termed nyctinastic movement. The leaves also close up under various other stimuli, such as touching, warming, or shaking. The stimulus can also be transmitted to neighbouring leaves. These types of movements have been termed seismonastic movements. The cause is a loss of turgor pressure. The movement is caused by "a rapid loss of pressure in strategically situated cells that cause the leaves to droop right before one’s eyes". # Medicinal Properties The plant lajjalu described in Ayurveda has been identified as Mimosa pudica. This plant has several alternate Sanskrit common names, including Namaskari, and Rakta Paadi. In Ayurveda, the plant is described as a plant which folds itself when touched and spreads its leaves once again after a while. It is said to have a bitter and astringent taste, and has a history of use for the treatment of various ailments. Most commonly used is the root, but leaves, flowers, bark, and fruit can also be implemented. ## Ayurvedan Properties (guna) of Lajjalu - Has tikta and kashaya rasa (bitter and astringent taste). - Has property of cold (sheetha). - Balances kapha, pitta. - Shushrutha has placed this plant in Priyangwambhastaadi gana. # Cultivation In cultivation, this plant is most often grown as an indoor annual, but is also grown for groundcover. Propagation is generally by seed. - Mimosa pudica with leaves open Mimosa pudica with leaves open - Mimosa pudica with leaves closed Mimosa pudica with leaves closed	Mimosa pudica The Sensitive plant (Mimosa pudica L.) is a creeping annual or perennial herb often grown for its curiosity value: the compound leaves fold inward and droop when touched, re-opening within minutes. Mimosa pudica is native to Brazil, but is now a pantropical weed. Other names given to this curious plant are Humble plant, TickleMe Plant, Shame plant, Sleeping grass, Prayer Plant, Touch-me-not, Makahiya (Philippines, meaning "shy"), Mori Vivi (West Indies), mate-loi (false death) (Tonga). The Chinese name for this plant translates to "shyness grass". The species epithet, pudica, is Latin for "bashful" or "shrinking", because of its curious nature and easy procreation. Its Sinhala name is Nidikumba, where 'nidi' means 'sleep'. The seeds are currently marketed to children under the name "TickleMe Plant"[1]. The stem is erect in young plants, but becomes creeping or trailing with age. The stem is slender, branching, and sparsely to densely prickly, growing to a length of 1.5 m (5 ft). The leaves are bipinnately compound, with one or two pinnae pairs, and 10-26 leaflets per pinna. The petioles are also prickly. Pedunculate (stalked) pale pink or purple flower heads arise from the leaf axils. The globose to ovoid heads are 8-10 mm in diameter (excluding the stamens). On close examination, it is seen that the floret petals are red in their upper part and the filaments are pink to lavender. The fruit consists of clusters of 2-8 pods from 1-2 cm long each, these prickly on the margins. The pods break into 2-5 segments and contain pale brown seeds some 2.5 mm long. # Plant movement Mimosa pudica is well known for its rapid plant movement. In the evening the leaflets will fold together and the whole leaf droops downward. It then re-opens at sunrise. This type of motion has been termed nyctinastic movement. The leaves also close up under various other stimuli, such as touching, warming, or shaking. The stimulus can also be transmitted to neighbouring leaves. These types of movements have been termed seismonastic movements. The cause is a loss of turgor pressure. The movement is caused by "a rapid loss of pressure in strategically situated cells that cause the leaves to droop right before one’s eyes".[2] # Medicinal Properties The plant lajjalu described in Ayurveda has been identified as Mimosa pudica. This plant has several alternate Sanskrit common names, including Namaskari, and Rakta Paadi. In Ayurveda, the plant is described as a plant which folds itself when touched and spreads its leaves once again after a while. It is said to have a bitter and astringent taste, and has a history of use for the treatment of various ailments. Most commonly used is the root, but leaves, flowers, bark, and fruit can also be implemented. ## Ayurvedan Properties (guna) of Lajjalu - Has tikta and kashaya rasa (bitter and astringent taste). - Has property of cold (sheetha). - Balances kapha, pitta. - Shushrutha has placed this plant in Priyangwambhastaadi gana. # Cultivation In cultivation, this plant is most often grown as an indoor annual, but is also grown for groundcover. Propagation is generally by seed. - Mimosa pudica with leaves open Mimosa pudica with leaves open - Mimosa pudica with leaves closed Mimosa pudica with leaves closed # External links - Sensitive Plant by Dr. T. Ombrello - Nyctinasty and Mimosa leaf movement by John Hewitson - Videos of the sensitive plant 1 2 - Streaming video of plant. [3] - Sensitive Plant Seeds and Experiments. [4] zh-min-nan:Kiàn-siàu-chháu de:Mimose to:Mateloi hsb:Mimoza lt:Jautrioji mimoza ml:തൊട്ടാവാടി ms:Pokok Semalu nl:Kruidje-roer-me-niet to:mateloi Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Mimosa_pudica
db5b31e408b8268ce038e454b7d12443ac260016	wikidoc	Mind at Large	Mind at Large Mind at Large is a concept from The Doors of Perception and Heaven and Hell by Aldous Huxley. Psychedelic drugs are thought to disable filters which block or suppress signals related to mundane functions from reaching the conscious mind. In this book, Huxley explores the idea that the human mind filters reality, partly because handling the details of all of the impressions and images coming in would be unbearable, partly because it has been taught to do so. He believes that psychotropic drugs can partly remove this filter, which leaves the drug user exposed to Mind at Large. Huxley was administered mescaline, and had an interviewer prompt him to comment on various stimuli around him, such as books and flowers. The conversation was recorded and the book mainly concerns Huxley's thoughts on what he says in the recordings. He observed that everyday objects lose their functionality and suddenly exist "as such." Space and dimension become irrelevant, and perceptions seem to be enlarged and at times even overwhelming. According to The Doors of Perception by Aldous Huxley, In Prometheus Rising, Robert Anton Wilson stated: "Mind" is a tool invented by the universe to see itself; but it can never see all of itself, for much the same reason that you can’t see your own back (without mirrors). Or as Alan Watts liked to say, because the tongue ultimately cannot taste the tongue. If the "mind" can be expanded to what Huxley called "Mind at Large", then perhaps the "mind" in this state is seeing the entire universe. In The Doors of Perception, Huxley also stated: In the final stage of egolessness there is an "obscure knowledge" that All is in all—that All is actually each. This is as near, I take it, as a finite mind can ever come to "perceiving everything that is happening everywhere in the universe."	Mind at Large Mind at Large is a concept from The Doors of Perception and Heaven and Hell by Aldous Huxley. Psychedelic drugs are thought to disable filters which block or suppress signals related to mundane functions from reaching the conscious mind. In this book, Huxley explores the idea that the human mind filters reality, partly because handling the details of all of the impressions and images coming in would be unbearable, partly because it has been taught to do so. He believes that psychotropic drugs can partly remove this filter, which leaves the drug user exposed to Mind at Large. Huxley was administered mescaline, and had an interviewer prompt him to comment on various stimuli around him, such as books and flowers. The conversation was recorded and the book mainly concerns Huxley's thoughts on what he says in the recordings. He observed that everyday objects lose their functionality and suddenly exist "as such." Space and dimension become irrelevant, and perceptions seem to be enlarged and at times even overwhelming. According to The Doors of Perception by Aldous Huxley, In Prometheus Rising, Robert Anton Wilson stated: "Mind" is a tool invented by the universe to see itself; but it can never see all of itself, for much the same reason that you can’t see your own back (without mirrors). Or as Alan Watts liked to say, because the tongue ultimately cannot taste the tongue. If the "mind" can be expanded to what Huxley called "Mind at Large", then perhaps the "mind" in this state is seeing the entire universe. In The Doors of Perception, Huxley also stated: In the final stage of egolessness there is an "obscure knowledge" that All is in all—that All is actually each. This is as near, I take it, as a finite mind can ever come to "perceiving everything that is happening everywhere in the universe."	https://www.wikidoc.org/index.php/Mind_at_Large
0ff344a0182781a93b0e0e3e6ddf3a4d3ed95a67	wikidoc	Mineral water	Mineral water # Overview Mineral water is water containing minerals or other dissolved substances that alter its taste or give it therapeutic value. Salts, sulfur compounds, and gases are among the substances that can be dissolved in the water. Mineral water can often be effervescent. Mineral water can be prepared or can occur naturally. Traditionally mineral waters would be used or consumed at their source, often referred to as taking the waters or taking the cure, and such sites were referred to as spas, baths or wells. Spa would be used when the water was consumed and bathed in, bath when the water was not generally consumed, and well when the water was not generally bathed in. Often an active tourist centre would grow up around a mineral water site (even in ancient times; see Bath). Such tourist development resulted in spa towns and hydropathic hotels (often shortened to Hydros). In modern times, it is far more common for mineral waters to be bottled at source for distributed consumption. Travelling to the mineral water site for direct access to the water is now uncommon, and in many cases not possible (because of exclusive commercial ownership rights). There are over 3000 brands of mineral water available commercially worldwide. The U.S. FDA classifies mineral water as water containing at least 250 parts per million total dissolved solids (TDS), and is also water coming from a source tapped at one or more bore holes or spring, originating from a geologically and physically protected underground water source. No minerals may be added to this water.	Mineral water # Overview Mineral water is water containing minerals or other dissolved substances that alter its taste or give it therapeutic value. Salts, sulfur compounds, and gases are among the substances that can be dissolved in the water. Mineral water can often be effervescent. Mineral water can be prepared or can occur naturally. Traditionally mineral waters would be used or consumed at their source, often referred to as taking the waters or taking the cure, and such sites were referred to as spas, baths or wells. Spa would be used when the water was consumed and bathed in, bath when the water was not generally consumed, and well when the water was not generally bathed in. Often an active tourist centre would grow up around a mineral water site (even in ancient times; see Bath). Such tourist development resulted in spa towns and hydropathic hotels (often shortened to Hydros). In modern times, it is far more common for mineral waters to be bottled at source for distributed consumption. Travelling to the mineral water site for direct access to the water is now uncommon, and in many cases not possible (because of exclusive commercial ownership rights). There are over 3000 brands of mineral water available commercially worldwide.[1] The U.S. FDA classifies mineral water as water containing at least 250 parts per million total dissolved solids (TDS), and is also water coming from a source tapped at one or more bore holes or spring, originating from a geologically and physically protected underground water source. No minerals may be added to this water. # External links - List of mineral water brands by country - process description mineral water	https://www.wikidoc.org/index.php/Mineral_springs
0bceaeeaca164bb856dba3c07955ca4f4a64dbab	wikidoc	Mirror neuron	Mirror neuron A mirror neuron is a neuron which fires both when an animal acts and when the animal observes the same action performed by another (especially conspecific) animal. Thus, the neuron "mirrors" the behavior of another animal, as though the observer were itself acting. These neurons have been directly observed in primates, and are believed to exist in humans and in some birds. In humans, brain activity consistent with mirror neurons has been found in the premotor cortex and the inferior parietal cortex. Some scientists consider mirror neurons one of the most important findings of neuroscience in the last decade. Among them is V.S. Ramachandran, who believes they might be very important in imitation and language acquisition. However, despite the popularity of this field, to date no plausible neural or computational models have been put forward to describe how mirror neuron activity supports cognitive functions such as imitation. # Introduction In the macaque monkey, mirror neurons are found in the ventral premotor cortex (probably the equivalent of the inferior frontal gyrus in humans) and in the anterior inferior parietal lobule. These neurons are active when the monkeys perform certain tasks, but they also fire when the monkeys watch or hear someone else perform the same specific task. Researchers using fMRI, TMS, and EEG have found evidence of a similar system (matching observations with actions), in the human brain. The function of the mirror system is a subject of much speculation. These neurons may be important for understanding the actions of other people, and for learning new skills by imitation. Some researchers also speculate that mirror systems may simulate observed actions, and thus contribute to our theory of mind skills, while others relate mirror neurons to language abilities. It has also been proposed that problems with the mirror system may underlie cognitive disorders, in particular autism. Research into all of these possibilities is ongoing. # Discovery In the 1980s and 1990s, Giacomo Rizzolatti was working with Luciano Fadiga, Leonardo Fogassi and Vittorio Gallese at the university in Parma, Italy. These scientists had placed electrodes in the inferior frontal cortex of the macaque monkey to study neurons specialised for the control of hand actions, for example, grabbing objects, picking items up etc. During each experiment, they recorded from a single neuron in the monkey's brain while the monkey was allowed to reach for pieces of food, so the researchers could measure the neuron's response to certain movements. This work has since been published and confirmed with mirror neurons found in both inferior frontal and inferior parietal regions of the brain. Recently, evidence from fMRI, TMS and EEG and behavioral strongly suggest the presence of similar systems in humans, where brain regions which respond during both action and the observation of action have been identified. Not surprisingly, these brain regions closely match those found in the macaque monkey . More recently Keysers and colleagues have shown that both in humans and monkeys, the mirror system also responds to the sound of actions # Mirror neurons in monkeys The only animal where mirror neurons have been studied individually is the macaque monkey. In these monkeys, mirror neurons are found in the inferior frontal gyrus (region F5) and the inferior parietal lobule Mirror neurons are believed to mediate the understanding of other animal's behavior. For example, a mirror neuron which fires when the monkey rips a piece of paper would also fire when the monkey sees a person rip paper, or hears paper ripping (without visual information). These properties have led researchers to believe that mirror neurons encode abstract concepts of actions like 'ripping paper', whether the action is performed by the monkey or another animal. . The function of mirror neurons in macaques is not known. Adult macaques do not seem to learn by imitation. Recent experiments suggest that infant macaqes can imitate a human's face movements, only as neonates and during a limited temporal window. However, it is not known if mirror neurons underlie this behaviour. In adult monkeys, mirror neurons may enable the monkey to understand what another monkey is doing, or to recognise the other monkey's action. # The mirror neuron system in humans It is not normally possible to study single neurons in the human brain, so scientists can not be certain that humans have mirror neurons. However, the results of brain imaging experiments have shown that the human inferior frontal cortex and superior parietal lobule is active when the person performs an action and also when the person sees another individual performing an action. Therefore, these brain regions are likely to contain mirror neurons and have been defined as the human mirror neuron system. Human infant data suggest that the mirror neuron system develops before 12 months of age, and that this system helps human infants understand other people's actions. # Possible functions of the mirror neuron system Many different functions for the mirror neuron system have been suggested. These include: ## Understanding Intentions Many studies link mirror neurons to understanding goals and intentions. Fogassi et al. (2005) recorded the activity of 41 mirror neurons in the inferior parietal lobe (IPL) of two rhesus macaques. The IPL has long been recognized as an association cortex that integrates sensory information. The monkeys watched an experimenter either grasp an apple and bring it to his mouth or grasp an object and place it in a cup. In total, 15 mirror neurons fired vigorously when the monkey observed the "grasp-to-eat" motion, but registered no activity while exposed to the "grasp-to-place" condition. For four other mirror neurons, the reverse held true: they activated in response to the experimenter eventually placing the apple in the cup but not to eating it. Only the type of action, and not the kinematic force with which models manipulated objects, determined neuron activity. Significantly, neurons fired before the monkey observed the human model starting the second motor act (bringing the object to the mouth or placing it in a cup). Therefore, IPL neurons "code the same act (grasping) in a different way according to the final goal of the action in which the act is embedded" (664). They may furnish a neural basis for predicting another individual’s subsequent actions and inferring intention. ## Empathy Mirror neurons have been linked to empathy, because certain brain regions (in particular the anterior insula and inferior frontal cortex) are active when a person experiences an emotion (disgust, happiness, pain etc) and when they see another person experience an emotion. However, these brain regions are not quite the same as the ones which mirror hand actions, and mirror neurons for emotional states or empathy have not yet been described in monkeys. More recently, Keysers and colleagues have shown that people that are more empathic according to self-report questionnaires have stronger activations both in the mirror system for hand actions and the mirror system for emotions providing more direct support to the idea that the mirror system is linked to empathy. ## Language In humans, mirror neurons have been found in the inferior frontal cortex, close to Broca's area, a language region. This has led to suggestions that human language evolved from a gesture performance/understanding system implemented in mirror neurons. Mirror neurons certainly have the potential to provide a mechanism for action understanding, imitation learning, and the simulation of other people's behaviour. However, like many theories of language evolution, there is little direct evidence either way. ## Autism Some researchers claim there is a link between mirror neuron deficiency and autism. In typical children, EEG recordings from motor areas are suppressed when the child watches another person move, and this is believed to be an index of mirror neuron activity. However, this suppression is not seen in children with autism . Also, children with autism have less activity in mirror neuron regions of the brain when imitating . Finally, anatomical differences have been found in the mirror neuron related brain areas in adults with autism spectrum disorders, compared to non-autistic adults. All these cortical areas were thinner and the degree of thinning was correlated with autism symptom severity, a correlation nearly restricted to these brain regions. Based on these results, some researchers claim that autism is caused by a lack of mirror neurons, leading to disabilities in social skills, imitation, empathy and theory of mind. This is just one of many theories of autism and it has not yet been proven. ## Theory of Mind In Philosophy of mind, mirror neurons have become the primary rallying call of simulation theorists concerning our 'theory of mind.' 'Theory of mind' refers to our ability to infer another person's mental state (i.e., beliefs and desires) from their experiences or their behavior. For example, if you see a person reaching into a jar labelled 'cookies,' you might assume that he wants a cookie (even if you know the jar is empty) and that he believes there are cookies in the jar. There are several competing models which attempt to account for our theory of mind; the most notable in relation to mirror neurons is simulation theory. According to simulation theory, theory of mind is available because we subconsciously put ourselves in the shoes of the person we're observing and, accounting for relevant differences, imagine what we would desire and believe in that scenario. Mirror neurons have been interpreted as the mechanism by which we simulate others in order to better understand them, and therefore their discovery has been taken by some as a validation of simulation theory (which appeared a decade before the discovery of mirror neurons). ## Gender differences Stronger MEG responses related to the mirror neuron system have been recorded in women compared to men . This finding is consistent with the idea that women tend to be more empathetic, that the mirror neuron system is related to empathy, and that weak responses in the mirror neuron system could be linked to an extreme male brain theory of autism . However, these ideas have not been tested in full. # Footnotes - ↑ V.S. Ramachandran, "Mirror Neurons and imitation learning as the driving force behind "the great leap forward" in human evolution". Edge Foundation. Retrieved 2006-11-16..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} - ↑ Christian Keysers and Valeria Gazzola, Progress in Brain Research, 2006, - ↑ Michael Arbib, The Mirror System Hypothesis. Linking Language to Theory of Mind, 2005, retrieved 2006-02-17 - ↑ Hugo Théoret, Alvaro Pascual-Leone, Language Acquisition: Do As You Hear, Current Biology, Vol. 12, No. 21, pp. R736-R737, 2002-10-29 - ↑ Oberman LM, Hubbard EM, McCleery JP, Altschuler EL, Ramachandran VS, Pineda JA., EEG evidence for mirror neuron dysfunction in autism spectral disorders, Brain Res Cogn Brain Res.; 24(2):190-8, 2005-06 - ↑ Mirella Dapretto, Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders, Nature Neuroscience, Vol. 9, No. 1, pp. 28-30, 2006-01 - ↑ Giacomo Rizzolatti et al. (1996). Premotor cortex and the recognition of motor actions, Cognitive Brain Research 3 131-141 - ↑ Gallese et al, Action recognition in the premotor cortex, Brain, 1996 - ↑ Fogassi et al, Parietal Lobe: From Action Organization to Intention Understanding, Science, 2005 - ↑ Rizzolatti G., Craighero L., The mirror-neuron system, Annual Review of Neuroscience. 2004;27:169-92 - ↑ Kohler et al., Science, 2002 - ↑ Gazzola et al., Current Biology, 2006 - ↑ Rizzolatti G., Craighero L., The mirror-neuron system, Annual Review of Neuroscience. 2004;27:169-92 - ↑ Giacomo Rizzolatti and Laila Craighero Annu. Rev. Neurosci. 2004. 27:169–92 - ↑ Ferrari PF, Visalberghi E, Paukner A, Fogassi L, Ruggiero A, et al. (2006) Neonatal Imitation in Rhesus Macaques. PLoS Biol 4(9): e302 - ↑ Giacomo Rizzolatti and Michael A. Arbib, Language within our grasp, Trends in neurosciences, Vol. 21, No. 5, 1998 - ↑ Marco Iacoboni, Roger P. Woods, Marcel Brass, Harold Bekkering, John C. Mazziotta, Giacomo Rizzolatti, Cortical Mechanisms of Human Imitation, Science 286:5449 (1999) - ↑ Terje Falck-Ytter, Gustaf Gredebäck & Claes von Hofsten, Infants predict other people's action goals, Nature Neuroscience 9 (2006) - ↑ Fogassi, Leonardo, Pier Francesco Ferrari, Benno Gesierich, Stefano Rozzi, Fabian Chersi, Giacomo Rizzolatti. 2005. Parietal lobe: from action organization to intention understanding. Science 308: 662-667. - ↑ Wicker et al., Neuron, 2003 - ↑ Singer et al., Science, 2004 - ↑ Jabbi, Swart and Keysers, NeuroImage, 2006 - ↑ Gazzola, Aziz-Zadeh and Keysers, Current Biology, 2006 - ↑ Jabbi, Swart and Keysers, NeuroImage, 2006 - ↑ Skoyles, John R., Gesture, Language Origins, and Right Handedness, Psycoloquy: 11,#24, 2000 - ↑ Oberman LM, Hubbard EM, McCleery JP, Altschuler EL, Ramachandran VS, Pineda JA., EEG evidence for mirror neuron dysfunction in autism spectral disorders, Brain Res Cogn Brain Res.; 24(2):190-8, 2005-06 - ↑ Mirella Dapretto, Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders, Nature Neuroscience, Vol. 9, No. 1, pp. 28-30, 2006-01 - ↑ Hadjikhani; et al. "Anatomical Differences in the Mirror Neuron System and Social Cognition Network in Autism". Cerebral Cortex. PMID 16306324.CS1 maint: Explicit use of et al. (link) - ↑ Gordon, R. (1986). Folk psychology as simulation. Mind and Language 1: 158-171 - ↑ Goldman, A. (1989). Interpretation psychologized. Mind and Language 4: 161–185 - ↑ Gallese, V., and Goldman, A. (1998). Mirror neurons and the simulation theory of mindreading. Trends in Cognitive Sciences. 2: 493–501 - ↑ Cheng, Y. W., Tzeng, O. J. L., Decety, J., Imada, T., Hsieh, J. C. 2006. Gender differences in the human mirror system: a magnetoencephalography study. Neuroreport. 2006 Jul 31;17(11):1115-9 - ↑ Baron-Cohen, S. 2003. The Essential Difference: The Truth about the Male and Female Brain. NY: Basic Books	Mirror neuron A mirror neuron is a neuron which fires both when an animal acts and when the animal observes the same action performed by another (especially conspecific) animal. Thus, the neuron "mirrors" the behavior of another animal, as though the observer were itself acting. These neurons have been directly observed in primates, and are believed to exist in humans and in some birds. In humans, brain activity consistent with mirror neurons has been found in the premotor cortex and the inferior parietal cortex. Some scientists consider mirror neurons one of the most important findings of neuroscience in the last decade. Among them is V.S. Ramachandran[1], who believes they might be very important in imitation and language acquisition. However, despite the popularity of this field, to date no plausible neural or computational models have been put forward to describe how mirror neuron activity supports cognitive functions such as imitation. # Introduction In the macaque monkey, mirror neurons are found in the ventral premotor cortex (probably the equivalent of the inferior frontal gyrus in humans) and in the anterior inferior parietal lobule. These neurons are active when the monkeys perform certain tasks, but they also fire when the monkeys watch or hear someone else perform the same specific task. Researchers using fMRI, TMS, and EEG have found evidence of a similar system (matching observations with actions), in the human brain. The function of the mirror system is a subject of much speculation. These neurons may be important for understanding the actions of other people, and for learning new skills by imitation. Some researchers also speculate that mirror systems may simulate observed actions, and thus contribute to our theory of mind skills, [2] [3] while others relate mirror neurons to language abilities.[4] It has also been proposed that problems with the mirror system may underlie cognitive disorders, in particular autism.[5][6] Research into all of these possibilities is ongoing. # Discovery In the 1980s and 1990s, Giacomo Rizzolatti was working with Luciano Fadiga, Leonardo Fogassi and Vittorio Gallese at the university in Parma, Italy. These scientists had placed electrodes in the inferior frontal cortex of the macaque monkey to study neurons specialised for the control of hand actions, for example, grabbing objects, picking items up etc. During each experiment, they recorded from a single neuron in the monkey's brain while the monkey was allowed to reach for pieces of food, so the researchers could measure the neuron's response to certain movements.[7] This work has since been published [8] and confirmed [9] with mirror neurons found in both inferior frontal and inferior parietal regions of the brain. Recently, evidence from fMRI, TMS and EEG and behavioral strongly suggest the presence of similar systems in humans, where brain regions which respond during both action and the observation of action have been identified. Not surprisingly, these brain regions closely match those found in the macaque monkey [10]. More recently Keysers and colleagues have shown that both in humans and monkeys, the mirror system also responds to the sound of actions [11] [12] # Mirror neurons in monkeys The only animal where mirror neurons have been studied individually is the macaque monkey. In these monkeys, mirror neurons are found in the inferior frontal gyrus (region F5) and the inferior parietal lobule [13] Mirror neurons are believed to mediate the understanding of other animal's behavior. For example, a mirror neuron which fires when the monkey rips a piece of paper would also fire when the monkey sees a person rip paper, or hears paper ripping (without visual information). These properties have led researchers to believe that mirror neurons encode abstract concepts of actions like 'ripping paper', whether the action is performed by the monkey or another animal. [14]. The function of mirror neurons in macaques is not known. Adult macaques do not seem to learn by imitation. Recent experiments suggest that infant macaqes can imitate a human's face movements, only as neonates and during a limited temporal window[15]. However, it is not known if mirror neurons underlie this behaviour. In adult monkeys, mirror neurons may enable the monkey to understand what another monkey is doing, or to recognise the other monkey's action.[16] # The mirror neuron system in humans It is not normally possible to study single neurons in the human brain, so scientists can not be certain that humans have mirror neurons. However, the results of brain imaging experiments have shown that the human inferior frontal cortex and superior parietal lobule is active when the person performs an action and also when the person sees another individual performing an action. Therefore, these brain regions are likely to contain mirror neurons and have been defined as the human mirror neuron system.[17] Human infant data suggest that the mirror neuron system develops before 12 months of age, and that this system helps human infants understand other people's actions.[18] # Possible functions of the mirror neuron system Many different functions for the mirror neuron system have been suggested. These include: ## Understanding Intentions Many studies link mirror neurons to understanding goals and intentions. Fogassi et al. (2005)[19] recorded the activity of 41 mirror neurons in the inferior parietal lobe (IPL) of two rhesus macaques. The IPL has long been recognized as an association cortex that integrates sensory information. The monkeys watched an experimenter either grasp an apple and bring it to his mouth or grasp an object and place it in a cup. In total, 15 mirror neurons fired vigorously when the monkey observed the "grasp-to-eat" motion, but registered no activity while exposed to the "grasp-to-place" condition. For four other mirror neurons, the reverse held true: they activated in response to the experimenter eventually placing the apple in the cup but not to eating it. Only the type of action, and not the kinematic force with which models manipulated objects, determined neuron activity. Significantly, neurons fired before the monkey observed the human model starting the second motor act (bringing the object to the mouth or placing it in a cup). Therefore, IPL neurons "code the same act (grasping) in a different way according to the final goal of the action in which the act is embedded" (664). They may furnish a neural basis for predicting another individual’s subsequent actions and inferring intention. ## Empathy Mirror neurons have been linked to empathy, because certain brain regions (in particular the anterior insula and inferior frontal cortex) are active when a person experiences an emotion (disgust, happiness, pain etc) and when they see another person experience an emotion. [20] [21] [22] However, these brain regions are not quite the same as the ones which mirror hand actions, and mirror neurons for emotional states or empathy have not yet been described in monkeys. More recently, Keysers and colleagues have shown that people that are more empathic according to self-report questionnaires have stronger activations both in the mirror system for hand actions [23] and the mirror system for emotions [24] providing more direct support to the idea that the mirror system is linked to empathy. ## Language In humans, mirror neurons have been found in the inferior frontal cortex, close to Broca's area, a language region. This has led to suggestions that human language evolved from a gesture performance/understanding system implemented in mirror neurons. Mirror neurons certainly have the potential to provide a mechanism for action understanding, imitation learning, and the simulation of other people's behaviour.[25] However, like many theories of language evolution, there is little direct evidence either way. ## Autism Some researchers claim there is a link between mirror neuron deficiency and autism. In typical children, EEG recordings from motor areas are suppressed when the child watches another person move, and this is believed to be an index of mirror neuron activity. However, this suppression is not seen in children with autism [26]. Also, children with autism have less activity in mirror neuron regions of the brain when imitating [27]. Finally, anatomical differences have been found in the mirror neuron related brain areas in adults with autism spectrum disorders, compared to non-autistic adults. All these cortical areas were thinner and the degree of thinning was correlated with autism symptom severity, a correlation nearly restricted to these brain regions.[28] Based on these results, some researchers claim that autism is caused by a lack of mirror neurons, leading to disabilities in social skills, imitation, empathy and theory of mind. This is just one of many theories of autism and it has not yet been proven. ## Theory of Mind In Philosophy of mind, mirror neurons have become the primary rallying call of simulation theorists concerning our 'theory of mind.' 'Theory of mind' refers to our ability to infer another person's mental state (i.e., beliefs and desires) from their experiences or their behavior. For example, if you see a person reaching into a jar labelled 'cookies,' you might assume that he wants a cookie (even if you know the jar is empty) and that he believes there are cookies in the jar. There are several competing models which attempt to account for our theory of mind; the most notable in relation to mirror neurons is simulation theory. According to simulation theory, theory of mind is available because we subconsciously put ourselves in the shoes of the person we're observing and, accounting for relevant differences, imagine what we would desire and believe in that scenario. [29][30] Mirror neurons have been interpreted as the mechanism by which we simulate others in order to better understand them, and therefore their discovery has been taken by some as a validation of simulation theory (which appeared a decade before the discovery of mirror neurons).[31] ## Gender differences Stronger MEG responses related to the mirror neuron system have been recorded in women compared to men [32]. This finding is consistent with the idea that women tend to be more empathetic, that the mirror neuron system is related to empathy, and that weak responses in the mirror neuron system could be linked to an extreme male brain theory of autism [33]. However, these ideas have not been tested in full. # Footnotes - ↑ V.S. Ramachandran, "Mirror Neurons and imitation learning as the driving force behind "the great leap forward" in human evolution". Edge Foundation. Retrieved 2006-11-16..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} - ↑ Christian Keysers and Valeria Gazzola, Progress in Brain Research, 2006, [1] - ↑ Michael Arbib, The Mirror System Hypothesis. Linking Language to Theory of Mind, 2005, retrieved 2006-02-17 - ↑ Hugo Théoret, Alvaro Pascual-Leone, Language Acquisition: Do As You Hear, Current Biology, Vol. 12, No. 21, pp. R736-R737, 2002-10-29 - ↑ Oberman LM, Hubbard EM, McCleery JP, Altschuler EL, Ramachandran VS, Pineda JA., EEG evidence for mirror neuron dysfunction in autism spectral disorders, Brain Res Cogn Brain Res.; 24(2):190-8, 2005-06 - ↑ Mirella Dapretto, Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders, Nature Neuroscience, Vol. 9, No. 1, pp. 28-30, 2006-01 - ↑ Giacomo Rizzolatti et al. (1996). Premotor cortex and the recognition of motor actions, Cognitive Brain Research 3 131-141 - ↑ Gallese et al, Action recognition in the premotor cortex, Brain, 1996 - ↑ Fogassi et al, Parietal Lobe: From Action Organization to Intention Understanding, Science, 2005 - ↑ Rizzolatti G., Craighero L., The mirror-neuron system, Annual Review of Neuroscience. 2004;27:169-92 - ↑ Kohler et al., Science, 2002 [2] - ↑ Gazzola et al., Current Biology, 2006 [3] - ↑ Rizzolatti G., Craighero L., The mirror-neuron system, Annual Review of Neuroscience. 2004;27:169-92 - ↑ Giacomo Rizzolatti and Laila Craighero Annu. Rev. Neurosci. 2004. 27:169–92 - ↑ Ferrari PF, Visalberghi E, Paukner A, Fogassi L, Ruggiero A, et al. (2006) Neonatal Imitation in Rhesus Macaques. PLoS Biol 4(9): e302 - ↑ Giacomo Rizzolatti and Michael A. Arbib, Language within our grasp, Trends in neurosciences, Vol. 21, No. 5, 1998 - ↑ Marco Iacoboni, Roger P. Woods, Marcel Brass, Harold Bekkering, John C. Mazziotta, Giacomo Rizzolatti, Cortical Mechanisms of Human Imitation, Science 286:5449 (1999) - ↑ Terje Falck-Ytter, Gustaf Gredebäck & Claes von Hofsten, Infants predict other people's action goals, Nature Neuroscience 9 (2006) - ↑ Fogassi, Leonardo, Pier Francesco Ferrari, Benno Gesierich, Stefano Rozzi, Fabian Chersi, Giacomo Rizzolatti. 2005. Parietal lobe: from action organization to intention understanding. Science 308: 662-667. - ↑ Wicker et al., Neuron, 2003 [4] - ↑ Singer et al., Science, 2004 [5] - ↑ Jabbi, Swart and Keysers, NeuroImage, 2006 [6] - ↑ Gazzola, Aziz-Zadeh and Keysers, Current Biology, 2006 [7] - ↑ Jabbi, Swart and Keysers, NeuroImage, 2006 [8] - ↑ Skoyles, John R., Gesture, Language Origins, and Right Handedness, Psycoloquy: 11,#24, 2000 - ↑ Oberman LM, Hubbard EM, McCleery JP, Altschuler EL, Ramachandran VS, Pineda JA., EEG evidence for mirror neuron dysfunction in autism spectral disorders, Brain Res Cogn Brain Res.; 24(2):190-8, 2005-06 - ↑ Mirella Dapretto, Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders, Nature Neuroscience, Vol. 9, No. 1, pp. 28-30, 2006-01 - ↑ Hadjikhani; et al. "Anatomical Differences in the Mirror Neuron System and Social Cognition Network in Autism". Cerebral Cortex. PMID 16306324.CS1 maint: Explicit use of et al. (link) - ↑ Gordon, R. (1986). Folk psychology as simulation. Mind and Language 1: 158-171 - ↑ Goldman, A. (1989). Interpretation psychologized. Mind and Language 4: 161–185 - ↑ Gallese, V., and Goldman, A. (1998). Mirror neurons and the simulation theory of mindreading. Trends in Cognitive Sciences. 2: 493–501 - ↑ Cheng, Y. W., Tzeng, O. J. L., Decety, J., Imada, T., Hsieh, J. C. 2006. Gender differences in the human mirror system: a magnetoencephalography study. Neuroreport. 2006 Jul 31;17(11):1115-9 - ↑ Baron-Cohen, S. 2003. The Essential Difference: The Truth about the Male and Female Brain. NY: Basic Books	https://www.wikidoc.org/index.php/Mirror_neuron
5293c768f34c35e324353060ed8bdf75d0870dcd	wikidoc	Mitochondrion	Mitochondrion # Overview In cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 1–10 micrometers (μm) in size. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. Mitochondria have been implicated in several human diseases and may play a role in the aging process. The word mitochondrion comes from the Greek μίτος or mitos, thread + χονδρίον or khondrion, granule. Their ancestry is not fully understood, but, according to the endosymbiotic theory, mitochondria are descended from ancient bacteria, which were engulfed by the ancestors of eukaryotic cells more than a billion years ago. Several characteristics make mitochondria unique. The number of mitochondria in a cell varies widely by organism and tissue type. Many cells have only a single mitochondrion, whereas others can contain several thousand mitochondria. The organelle is composed of compartments that carry out specialized functions. These compartments or regions include the outer membrane, the intermembrane space, the inner membrane, and the cristae and matrix. In humans, mitochondria contain about 615 distinct types of proteins, depending on the tissue of origin. Although most of a cell's DNA is contained in the cell nucleus, the mitochondrion has its own independent genome. Further, its DNA shows substantial similarity to bacterial genomes. # Structure A mitochondrion contains inner and outer membranes composed of phospholipid bilayers and proteins. The two membranes, however, have different properties. Because of this double-membraned organization, there are five distinct compartments within the mitochondrion. There is the outer mitochondrial membrane, the intermembrane space (the space between the outer and inner membranes), the inner mitochondrial membrane, the cristae space (formed by infoldings of the inner membrane), and the matrix (space within the inner membrane). ## Outer membrane The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to that of the eukaryotic plasma membrane (about 1:1 by weight). It contains large numbers of integral proteins called porins. These porins form channels that allow molecules 5000 Daltons or less in molecular weight to freely diffuse from one side of the membrane to the other. Larger proteins can also enter the mitochondrion if a signaling sequence at their N-terminus binds to a large multisubunit protein called translocase of the outer membrane, which then actively moves them across the membrane. Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death. ## Intermembrane space The intermembrane space is the space between the outer membrane and the inner membrane. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules such as ions and sugars in the intermembrane space is the same as the cytosol. However, as large proteins must have a specific signaling sequence to be transported across the outer membrane, the protein composition of this space is different than the protein composition of the cytosol. One protein that is localized to the intermembrane space in this way is cytochrome c. ## Inner membrane The inner mitochondrial membrane contains proteins with four types of functions: - Those that perform the redox reactions of oxidative phosphorylation - ATP synthase, which generates ATP in the matrix - Specific transport proteins that regulate metabolite passage into and out of the matrix - Protein import machinery. It contains more than 100 different polypeptides, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1 protein for 15 phospholipids). The inner membrane is home to around 1/5 of the total protein in a mitochondrion. In addition, the inner membrane is rich in an unusual phospholipid, cardiolipin. This phospholipid was originally discovered in beef hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes. Cardiolipin contains four fatty acids rather than two and may help to make the inner membrane impermeable. Unlike the outer membrane, the inner membrane does not contain porins and is highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exit the matrix. Proteins are ferried into the matrix via the translocase of the inner membrane (TIM) complex or via Oxa1. In addition, there is a membrane potential across the inner membrane formed by the action of the enzymes of the electron transport chain. ### Cristae The inner mitochondrial membrane is compartmentalized into numerous cristae, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. These are not simple random folds but rather invaginations of the inner membrane, which can affect overall chemiosmotic function. In typical liver mitochondria, for example, the surface area, including cristae, is about five times that of the outer membrane. Mitochondria of cells that have greater demand for ATP, such as muscle cells, contain more cristae than typical liver mitochondria. ## Matrix The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion. The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly-concentrated mixture of hundreds of enzymes, special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle. Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins (see: protein biosynthesis). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total genes, 24 tRNA and rRNA genes and 13 peptide genes. The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus. # Organization and distribution Mitochondria are found in nearly all eukaryotes. They vary in number and location according to cell type. Substantial numbers of mitochondria are in the liver, with about 1000–2000 mitochondria per cell making up 1/5th of the cell volume. The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum. Often they form a complex 3D branching network inside the cell with the cytoskeleton. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well. Recent evidence suggests vimentin, one of the components of the cytoskeleton, is critical to the association with the cytoskeleton. # Function The most prominent roles of the mitochondrion are its production of ATP and regulation of cellular metabolism. The central set of reactions involved in ATP production are collectively known as the citric acid cycle. However, the mitochondrion has many other functions in addition to the production of ATP. ## Energy conversion A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of glycolysis, pyruvate, and NADH, which are produced in the cytosol. This process of cellular respiration, also known as aerobic respiration, is dependent on the presence of oxygen. When oxygen is limited, the glycolytic products will be metabolized by anaerobic respiration, a process that is independent of the mitochondria. The production of ATP from glucose has an approximately 13-fold higher yield during aerobic respiration compared to anaerobic respiration. ### Pyruvate: the citric acid cycle Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane, and into the matrix where it is oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH. The acetyl-CoA is the primary substrate to enter the citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle. The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception of succinate dehydrogenase, which is bound to the inner mitochondrial membrane as part of Complex II. The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of NADH and one molecule of FADH2) that are a source of electrons for the electron transport chain, and a molecule of GTP (that is readily converted to an ATP). ### NADH and FADH2: the electron transport chain The redox energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transport chain. These energy-rich molecules are produced within the matrix via the citric acid cycle but are also produced in the cytoplasm by glycolysis. Reducing equivalents from the cytoplasm can be imported via the malate-aspartate shuttle system of antiporter proteins or feed into the electron transport chain using a glycerol phosphate shuttle. Protein complexes in the inner membrane (NADH dehydrogenase, cytochrome c reductase, and cytochrome c oxidase) perform the transfer and the incremental release of energy is used to pump protons (H+) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as superoxide. This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process. As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is established across the inner membrane. The protons can return to the matrix through the ATP synthase complex, and their potential energy is used to synthesize ATP from ADP and inorganic phosphate (Pi). This process is called chemiosmosis, and was first described by Peter Mitchell who was awarded the 1978 Nobel Prize in Chemistry for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their clarification of the working mechanism of ATP synthase. ### Heat production Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as proton leak or mitochondrial uncoupling and is due to the facilitated diffusion of protons into the matrix. The process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat. The process is mediated by a proton channel called thermogenin, or UCP1. Thermogenin is a 33kDa protein first discovered in 1973. Thermogenin is primarily found in brown adipose tissue, or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age. ## Storage of calcium ions The concentrations of free calcium in the cell can regulate an array of reactions and is important for signal transduction in the cell. Mitochondria can transiently store calcium, a contributing process for the cell's homeostasis of calcium. In fact, their ability to rapidly take in calcium for later release makes them very good "cytosolic buffers" for calcium. The endoplasmic reticulum (ER) is the most significant storage site of calcium, and there is a significant interplay between the mitochondrion and ER with regard to calcium. The calcium is taken up into the matrix by a calcium uniporter on the inner mitochondrial membrane. It is primarily driven by the mitochondrial membrane potential. Release of this calcium back into the cell's interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways. This can initiate calcium spikes or calcium waves with large changes in the membrane potential. These can activate a series of second messenger system proteins that can coordinate processes such as neurotransmitter release in nerve cells and release of hormones in endocrine cells. ## Additional functions Mitochondria play a central role in many other metabolic tasks, such as: - Regulation of the membrane potential - Apoptosis-programmed cell death - Glutamate-mediated excitotoxic neuronal injury - Cellular proliferation regulation - Regulation of cellular metabolism - Certain heme synthesis reactions (see also: porphyrin) - Steroid synthesis Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cells contain enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. A mutation in the genes regulating any of these functions can result in mitochondrial diseases. # Origin Mitochondria have many features in common with prokaryotes. As a result, they are believed to be originally derived from endosymbiotic prokaryotes. Mitochondria contain DNA which is formed only during the division of other mitochondria within the cell. This DNA contains genes for ribosomes, and the twenty-one tRNA's necessary for the translation of messenger RNAs into protein. The DNA is often circular, as is most bacterial DNA, and employs a variant genetic code similar to that of Proteobacteria. This suggests that their ancestor, the so-called proto-mitochondrion, was a member of the Proteobacteria. In particular, the proto-mitochondrion was probably related to the rickettsia. However, the exact relationship of the ancestor of mitochondria to the alpha-proteobacteria remains controversial. The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure. They closely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes which are coded for by nuclear DNA. The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis. The endosymbiotic hypothesis suggests that mitochondria descended from bacteria that somehow survived endocytosis by another cell, and became incorporated into the cytoplasm. The ability of these bacteria to conduct respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. In a similar manner, host cells with symbiotic bacteria capable of photosynthesis would also have had an advantage. The incorporation of symbiotes would have increased the number of environments in which the cells could survive. This symbiotic relationship probably developed 1.7-2 billion years ago. A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae. These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, suggesting that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long-branch attraction – they are derived groups and retain genes or organelles derived from mitochondria (e.g., mitosomes and hydrogenosomes). # Genome The human mitochondrial genome is a circular DNA molecule of about 16 kilobases. It encodes 37 genes: 13 for subunits of respiratory complexes I, III, IV, and V, 22 for mitochondrial tRNA, and 2 for rRNA. One mitochondrion can contain 2–10 copies of its DNA. As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats. Mitochondrial genes are transcribed as multigenic transcripts, which are cleaved and polyadenylated to yield mature mRNAs. Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome; most are coded by genes in the cell nucleus and imported to the mitochondrion. The exact number of genes encoded by the nucleus and the mitochondrial genome differs between species. In general, mitochondrial genomes are circular, although exceptions have been reported. Also, in general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome; however, introns have been observed in some eukaryotic mitochondrial DNA, such as that of yeast and protists, including Dictyostelium discoideum. While slight variations on the standard code had been predicted earlier, none was discovered until 1979, when researchers studying human mitochondrial genes determined that they used an alternative code. Many slight variants have been discovered since, including various alternative mitochondrial codes. Further, the AUA, AUC, and AUU codons are all allowable start codons. Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of RNA editing, which is common in mitochondria. In higher plants, it was thought that CGG encoded for tryptophan and not arginine; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the universal genetic code for tryptophan. Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine. Mitochondrial genomes have far fewer genes than the eubacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus, such as the respiratory complex II protein subunits. This is thought to be relatively common over evolutionary time. A few organisms, such as the Cryptosporidium, actually have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred. In Cryptosporidium, the mitochondria have an altered ATP generation system that renders the parasite resistant to many classical mitochondrial inhibitors such as cyanide, azide, and atovaquone. # Replication and inheritance Mitochondria replicate their DNA and divide mainly in response to the energy needs of the cell. In other words, their growth and division is not linked to the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When the energy use is low, mitochondria are destroyed or become inactive. At cell division, mitochondria are distributed to the daughter cells essentially randomly during the division of the cytoplasm. Mitochondria divide by binary fission similar to bacterial cell division; unlike bacteria, however, mitochondria can also fuse with other mitochondria. Mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an egg cell by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus. In contrast, the mitochondria, and therefore the mitochondrial DNA, usually comes from the egg only. The sperm's mitochondria enters the egg but does not contribute genetic information to the embryo. Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo. The egg cell contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism. Mitochondria are, therefore, in most cases inherited down the female line, known as maternal inheritance. This mode is seen in most organisms including all animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain coniferous plants, although not in pine trees and yew trees. It has also been suggested that it occurs at a very low level in humans. Uniparental inheritance leads to little opportunity for genetic recombination between different lineages of mitochondria, although a single mitochondrion can contain 2–10 copies of its DNA. For this reason, mitochondrial DNA usually is thought to reproduce by binary fission. What recombination does take place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells. Further, evidence suggests that animal mitochondria can undergo recombination. The data are a bit more controversial in humans, although indirect evidence of recombination exists. If recombination does not occur, the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the evolutionary history of populations. # Population genetic studies The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for scientists involved in population genetics and evolutionary biology. Because all the mitochondrial DNA is inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a recent date for mitochondrial Eve. This is often interpreted as strong support for a recent modern human expansion out of Africa. Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively-large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for lack of interbreeding between Neanderthals and anatomically-modern humans. However, mitochondrial DNA reflects the history of only females in a population and so may not represent the history of the population as a whole. This can be partially overcome by the use of paternal genetic sequences, such as the non-recombining region of the Y-chromosome. In a broader sense, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population. # Dysfunction and disease ## Mitochondrial diseases With their central place in cell metabolism, damage - and subsequent dysfunction - in mitochondria is an important factor in a wide range of human diseases. Mitochondrial disorders often present as neurological disorders, but can manifest as myopathy, diabetes, multiple endocrinopathy, or a variety of other systemic manifestations. Diseases caused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy. In the vast majority of cases, these diseases are transmitted by a female to her children, as the zygote derives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, Pearson's syndrome, and progressive external ophthalmoplegia are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF), and others are due to point mutations in mtDNA. In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in Friedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease. These diseases are inherited in a dominance relationship, as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as coenzyme Q10 deficiency and Barth syndrome. Environmental influences may also interact with hereditary predispositions and cause mitochondrial disease. For example, there may be a link between pesticide exposure and the later onset of Parkinson's disease. Other diseases not directly linked to mitochondrial enzymes may feature dysfunction of mitochondria. These include schizophrenia, bipolar disorder, dementia, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, cardiovascular disease, retinitis pigmentosa, and diabetes mellitus. The common thread linking these seemingly-unrelated conditions is cellular damage causing oxidative stress and the accumulation of reactive oxygen species. These oxidants then damage the mitochondrial DNA, resulting in mitochondrial dysfunction and cell death. ## Possible relationships to aging Given the role of mitochondria as the cell's powerhouse, there may be some leakage of the high-energy electrons in the respiratory chain to form reactive oxygen species. This can result in significant oxidative stress in the mitochondria with high mutation rates of mitochondrial DNA. A vicious cycle is thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress. A number of changes occur to mitochondria during the aging process. Tissues from elderly patients show a decrease in enzymatic activity of the proteins of the respiratory chain. Large deletions in the mitochondrial genome can lead to high levels of oxidative stress and neuronal death in Parkinson's disease. Hypothesized links between aging and oxidative stress are not new and were proposed over 50 years ago; however, there is much debate over whether mitochondrial changes are causes of aging or merely characteristics of aging. One notable study in mice demonstrated no increase in reactive oxygen species despite increasing mitochondrial DNA mutations, suggesting that the aging process is not due to oxidative stress. As a result, the exact relationships between mitochondria, oxidative stress, and aging have not yet been settled.	Mitochondrion Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview In cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed organelle found in most eukaryotic cells.[1] These organelles range from 1–10 micrometers (μm) in size. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth.[2] Mitochondria have been implicated in several human diseases and may play a role in the aging process. The word mitochondrion comes from the Greek μίτος or mitos, thread + χονδρίον or khondrion, granule. Their ancestry is not fully understood, but, according to the endosymbiotic theory, mitochondria are descended from ancient bacteria, which were engulfed by the ancestors of eukaryotic cells more than a billion years ago. Several characteristics make mitochondria unique. The number of mitochondria in a cell varies widely by organism and tissue type. Many cells have only a single mitochondrion, whereas others can contain several thousand mitochondria.[3][4] The organelle is composed of compartments that carry out specialized functions. These compartments or regions include the outer membrane, the intermembrane space, the inner membrane, and the cristae and matrix. In humans, mitochondria contain about 615 distinct types of proteins, depending on the tissue of origin.[5] Although most of a cell's DNA is contained in the cell nucleus, the mitochondrion has its own independent genome. Further, its DNA shows substantial similarity to bacterial genomes. # Structure Template:Mitochondrion imagemap A mitochondrion contains inner and outer membranes composed of phospholipid bilayers and proteins.[3] The two membranes, however, have different properties. Because of this double-membraned organization, there are five distinct compartments within the mitochondrion. There is the outer mitochondrial membrane, the intermembrane space (the space between the outer and inner membranes), the inner mitochondrial membrane, the cristae space (formed by infoldings of the inner membrane), and the matrix (space within the inner membrane). ## Outer membrane The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to that of the eukaryotic plasma membrane (about 1:1 by weight). It contains large numbers of integral proteins called porins. These porins form channels that allow molecules 5000 Daltons or less in molecular weight to freely diffuse from one side of the membrane to the other.[3] Larger proteins can also enter the mitochondrion if a signaling sequence at their N-terminus binds to a large multisubunit protein called translocase of the outer membrane, which then actively moves them across the membrane.[6] Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death.[7] ## Intermembrane space The intermembrane space is the space between the outer membrane and the inner membrane. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules such as ions and sugars in the intermembrane space is the same as the cytosol.[3] However, as large proteins must have a specific signaling sequence to be transported across the outer membrane, the protein composition of this space is different than the protein composition of the cytosol. One protein that is localized to the intermembrane space in this way is cytochrome c.[7] ## Inner membrane The inner mitochondrial membrane contains proteins with four types of functions:[3] - Those that perform the redox reactions of oxidative phosphorylation - ATP synthase, which generates ATP in the matrix - Specific transport proteins that regulate metabolite passage into and out of the matrix - Protein import machinery. It contains more than 100 different polypeptides, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1 protein for 15 phospholipids). The inner membrane is home to around 1/5 of the total protein in a mitochondrion.[3] In addition, the inner membrane is rich in an unusual phospholipid, cardiolipin. This phospholipid was originally discovered in beef hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes.[8] Cardiolipin contains four fatty acids rather than two and may help to make the inner membrane impermeable.[3] Unlike the outer membrane, the inner membrane does not contain porins and is highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exit the matrix. Proteins are ferried into the matrix via the translocase of the inner membrane (TIM) complex or via Oxa1.[6] In addition, there is a membrane potential across the inner membrane formed by the action of the enzymes of the electron transport chain. ### Cristae The inner mitochondrial membrane is compartmentalized into numerous cristae, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. These are not simple random folds but rather invaginations of the inner membrane, which can affect overall chemiosmotic function.[9] In typical liver mitochondria, for example, the surface area, including cristae, is about five times that of the outer membrane. Mitochondria of cells that have greater demand for ATP, such as muscle cells, contain more cristae than typical liver mitochondria.[3] ## Matrix The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion.[3] The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly-concentrated mixture of hundreds of enzymes, special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.[3] Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins (see: protein biosynthesis). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total genes, 24 tRNA and rRNA genes and 13 peptide genes.[10] The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus. # Organization and distribution Mitochondria are found in nearly all eukaryotes. They vary in number and location according to cell type. Substantial numbers of mitochondria are in the liver, with about 1000–2000 mitochondria per cell making up 1/5th of the cell volume.[3] The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum.[3] Often they form a complex 3D branching network inside the cell with the cytoskeleton. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well.[11] Recent evidence suggests vimentin, one of the components of the cytoskeleton, is critical to the association with the cytoskeleton.[12] # Function The most prominent roles of the mitochondrion are its production of ATP and regulation of cellular metabolism.[4] The central set of reactions involved in ATP production are collectively known as the citric acid cycle. However, the mitochondrion has many other functions in addition to the production of ATP. ## Energy conversion A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of glycolysis, pyruvate, and NADH, which are produced in the cytosol.[4] This process of cellular respiration, also known as aerobic respiration, is dependent on the presence of oxygen. When oxygen is limited, the glycolytic products will be metabolized by anaerobic respiration, a process that is independent of the mitochondria.[4] The production of ATP from glucose has an approximately 13-fold higher yield during aerobic respiration compared to anaerobic respiration.[13] ### Pyruvate: the citric acid cycle Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane, and into the matrix where it is oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH.[4] The acetyl-CoA is the primary substrate to enter the citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle. The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception of succinate dehydrogenase, which is bound to the inner mitochondrial membrane as part of Complex II.[14] The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of NADH and one molecule of FADH2) that are a source of electrons for the electron transport chain, and a molecule of GTP (that is readily converted to an ATP).[4] ### NADH and FADH2: the electron transport chain The redox energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transport chain. These energy-rich molecules are produced within the matrix via the citric acid cycle but are also produced in the cytoplasm by glycolysis. Reducing equivalents from the cytoplasm can be imported via the malate-aspartate shuttle system of antiporter proteins or feed into the electron transport chain using a glycerol phosphate shuttle.[4] Protein complexes in the inner membrane (NADH dehydrogenase, cytochrome c reductase, and cytochrome c oxidase) perform the transfer and the incremental release of energy is used to pump protons (H+) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as superoxide.[4] This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.[15] As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is established across the inner membrane. The protons can return to the matrix through the ATP synthase complex, and their potential energy is used to synthesize ATP from ADP and inorganic phosphate (Pi).[4] This process is called chemiosmosis, and was first described by Peter Mitchell[16][17] who was awarded the 1978 Nobel Prize in Chemistry for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their clarification of the working mechanism of ATP synthase.[18] ### Heat production Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as proton leak or mitochondrial uncoupling and is due to the facilitated diffusion of protons into the matrix. The process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat.[4] The process is mediated by a proton channel called thermogenin, or UCP1.[19] Thermogenin is a 33kDa protein first discovered in 1973.[20] Thermogenin is primarily found in brown adipose tissue, or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.[19] ## Storage of calcium ions The concentrations of free calcium in the cell can regulate an array of reactions and is important for signal transduction in the cell. Mitochondria can transiently store calcium, a contributing process for the cell's homeostasis of calcium.[21] In fact, their ability to rapidly take in calcium for later release makes them very good "cytosolic buffers" for calcium.[22] The endoplasmic reticulum (ER) is the most significant storage site of calcium, and there is a significant interplay between the mitochondrion and ER with regard to calcium.[23] The calcium is taken up into the matrix by a calcium uniporter on the inner mitochondrial membrane.[24] It is primarily driven by the mitochondrial membrane potential.[21] Release of this calcium back into the cell's interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways.[24] This can initiate calcium spikes or calcium waves with large changes in the membrane potential. These can activate a series of second messenger system proteins that can coordinate processes such as neurotransmitter release in nerve cells and release of hormones in endocrine cells. ## Additional functions Mitochondria play a central role in many other metabolic tasks, such as: - Regulation of the membrane potential[4] - Apoptosis-programmed cell death[25] - Glutamate-mediated excitotoxic neuronal injury[26] - Cellular proliferation regulation[27] - Regulation of cellular metabolism[27] - Certain heme synthesis reactions[28] (see also: porphyrin) - Steroid synthesis[22] Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cells contain enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. A mutation in the genes regulating any of these functions can result in mitochondrial diseases. # Origin Mitochondria have many features in common with prokaryotes. As a result, they are believed to be originally derived from endosymbiotic prokaryotes. Mitochondria contain DNA which is formed only during the division of other mitochondria within the cell. This DNA contains genes for ribosomes, and the twenty-one tRNA's necessary for the translation of messenger RNAs into protein. The DNA is often circular, as is most bacterial DNA, and employs a variant genetic code similar to that of Proteobacteria.[29] This suggests that their ancestor, the so-called proto-mitochondrion, was a member of the Proteobacteria.[30] In particular, the proto-mitochondrion was probably related to the rickettsia.[31] However, the exact relationship of the ancestor of mitochondria to the alpha-proteobacteria remains controversial. The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.[32] They closely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes which are coded for by nuclear DNA. The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis.[33] The endosymbiotic hypothesis suggests that mitochondria descended from bacteria that somehow survived endocytosis by another cell, and became incorporated into the cytoplasm. The ability of these bacteria to conduct respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. In a similar manner, host cells with symbiotic bacteria capable of photosynthesis would also have had an advantage. The incorporation of symbiotes would have increased the number of environments in which the cells could survive. This symbiotic relationship probably developed 1.7[34]-2[35] billion years ago. A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae.[36] These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, suggesting that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long-branch attraction – they are derived groups and retain genes or organelles derived from mitochondria (e.g., mitosomes and hydrogenosomes).[1] # Genome The human mitochondrial genome is a circular DNA molecule of about 16 kilobases.[37] It encodes 37 genes: 13 for subunits of respiratory complexes I, III, IV, and V, 22 for mitochondrial tRNA, and 2 for rRNA.[37] One mitochondrion can contain 2–10 copies of its DNA.[38] As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats. Mitochondrial genes are transcribed as multigenic transcripts, which are cleaved and polyadenylated to yield mature mRNAs. Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome; most are coded by genes in the cell nucleus and imported to the mitochondrion.[39] The exact number of genes encoded by the nucleus and the mitochondrial genome differs between species. In general, mitochondrial genomes are circular, although exceptions have been reported.[40] Also, in general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome;[39] however, introns have been observed in some eukaryotic mitochondrial DNA,[41] such as that of yeast[42] and protists,[43] including Dictyostelium discoideum.[44] While slight variations on the standard code had been predicted earlier,[45] none was discovered until 1979, when researchers studying human mitochondrial genes determined that they used an alternative code.[46] Many slight variants have been discovered since,[47] including various alternative mitochondrial codes.[48] Further, the AUA, AUC, and AUU codons are all allowable start codons. Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of RNA editing, which is common in mitochondria. In higher plants, it was thought that CGG encoded for tryptophan and not arginine; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the universal genetic code for tryptophan.[49] Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.[50] Mitochondrial genomes have far fewer genes than the eubacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus, such as the respiratory complex II protein subunits.[37] This is thought to be relatively common over evolutionary time. A few organisms, such as the Cryptosporidium, actually have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred.[51] In Cryptosporidium, the mitochondria have an altered ATP generation system that renders the parasite resistant to many classical mitochondrial inhibitors such as cyanide, azide, and atovaquone.[51] # Replication and inheritance Template:Seealso Mitochondria replicate their DNA and divide mainly in response to the energy needs of the cell. In other words, their growth and division is not linked to the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When the energy use is low, mitochondria are destroyed or become inactive. At cell division, mitochondria are distributed to the daughter cells essentially randomly during the division of the cytoplasm. Mitochondria divide by binary fission similar to bacterial cell division; unlike bacteria, however, mitochondria can also fuse with other mitochondria.[37][52] Mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an egg cell by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus. In contrast, the mitochondria, and therefore the mitochondrial DNA, usually comes from the egg only. The sperm's mitochondria enters the egg but does not contribute genetic information to the embryo.[53] Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.[54] The egg cell contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism. Mitochondria are, therefore, in most cases inherited down the female line, known as maternal inheritance. This mode is seen in most organisms including all animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain coniferous plants, although not in pine trees and yew trees.[55] It has also been suggested that it occurs at a very low level in humans.[56] Uniparental inheritance leads to little opportunity for genetic recombination between different lineages of mitochondria, although a single mitochondrion can contain 2–10 copies of its DNA.[38] For this reason, mitochondrial DNA usually is thought to reproduce by binary fission. What recombination does take place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells.[57] Further, evidence suggests that animal mitochondria can undergo recombination.[58] The data are a bit more controversial in humans, although indirect evidence of recombination exists.[59][60] If recombination does not occur, the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the evolutionary history of populations. # Population genetic studies The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for scientists involved in population genetics and evolutionary biology.[61] Because all the mitochondrial DNA is inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a recent date for mitochondrial Eve.[62][63] This is often interpreted as strong support for a recent modern human expansion out of Africa.[64] Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively-large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for lack of interbreeding between Neanderthals and anatomically-modern humans.[65] However, mitochondrial DNA reflects the history of only females in a population and so may not represent the history of the population as a whole. This can be partially overcome by the use of paternal genetic sequences, such as the non-recombining region of the Y-chromosome.[64] In a broader sense, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population.[66] # Dysfunction and disease ## Mitochondrial diseases With their central place in cell metabolism, damage - and subsequent dysfunction - in mitochondria is an important factor in a wide range of human diseases. Mitochondrial disorders often present as neurological disorders, but can manifest as myopathy, diabetes, multiple endocrinopathy, or a variety of other systemic manifestations.[67] Diseases caused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy.[68] In the vast majority of cases, these diseases are transmitted by a female to her children, as the zygote derives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, Pearson's syndrome, and progressive external ophthalmoplegia are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF), and others are due to point mutations in mtDNA.[67] In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in Friedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease.[69] These diseases are inherited in a dominance relationship, as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as coenzyme Q10 deficiency and Barth syndrome.[67] Environmental influences may also interact with hereditary predispositions and cause mitochondrial disease. For example, there may be a link between pesticide exposure and the later onset of Parkinson's disease.[70][71] Other diseases not directly linked to mitochondrial enzymes may feature dysfunction of mitochondria. These include schizophrenia, bipolar disorder, dementia, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, cardiovascular disease, retinitis pigmentosa, and diabetes mellitus.[72][73] The common thread linking these seemingly-unrelated conditions is cellular damage causing oxidative stress and the accumulation of reactive oxygen species. These oxidants then damage the mitochondrial DNA, resulting in mitochondrial dysfunction and cell death.[73] ## Possible relationships to aging Given the role of mitochondria as the cell's powerhouse, there may be some leakage of the high-energy electrons in the respiratory chain to form reactive oxygen species. This can result in significant oxidative stress in the mitochondria with high mutation rates of mitochondrial DNA.[74] A vicious cycle is thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress. A number of changes occur to mitochondria during the aging process. Tissues from elderly patients show a decrease in enzymatic activity of the proteins of the respiratory chain.[75] Large deletions in the mitochondrial genome can lead to high levels of oxidative stress and neuronal death in Parkinson's disease.[76] Hypothesized links between aging and oxidative stress are not new and were proposed over 50 years ago;[77] however, there is much debate over whether mitochondrial changes are causes of aging or merely characteristics of aging. One notable study in mice demonstrated no increase in reactive oxygen species despite increasing mitochondrial DNA mutations, suggesting that the aging process is not due to oxidative stress.[78] As a result, the exact relationships between mitochondria, oxidative stress, and aging have not yet been settled.	https://www.wikidoc.org/index.php/Mitochondria
9e0ec2f396a6019ebf4b0a0b5dd95d4a13fbd6e8	wikidoc	Mittelschmerz	Mittelschmerz # Overview Mittelschmerz (German: "middle pain") is a medical term for "ovulation pain" or "midcycle pain". About 20% of women experience mittelschmerz, some every cycle, some intermittently. # Symptoms and diagnosis Mittelschmerz is characterised by lower abdominal and pelvic pain that occurs roughly midway through a woman's menstrual cycle. The pain can appear suddenly and usually subsides within hours, although it may sometimes last two or three days. In some women, the mittelschmerz is localized enough so that they can tell which of their two ovaries provided the egg in a given month. Because ovulation occurs on a random ovary each cycle, the pain may switch sides or stay on the same side from one cycle to another. Diagnosis of mittelschmerz is generally made if a woman is mid-cycle and a pelvic examination shows no abnormalities. If the pain is prolonged and/or severe, other diagnostic procedures such as an abdominal ultrasound may be performed to rule out other causes of abdominal pain. The pain of mittelschmerz is sometimes mistaken for appendicitis and is one of the differential diagnoses for appendicitis in women of child-bearing age. # Treatment The pain is not harmful and does not signify the presence of disease. No treatment is usually necessary. Pain relievers (analgesics) may be needed in cases of prolonged or intense pain. Hormonal forms of contraception can be taken to prevent ovulation -- and therefore ovulatory pain -- but otherwise there is no known prevention. # Causes Mittelschmerz is believed to have a variety of causes: - The swelling of follicles in the ovaries prior to ovulation. While only one or two eggs mature to the point of being released, a number of follicles grow during the follicular phase of the menstrual cycle (non-dominant follicles atrophy prior to ovulation). Because follicles develop on both sides, this theory explains mittelschmerz that occurs simultaneously on both sides of the abdomen. - The ovaries have no openings; at ovulation the egg breaks through the ovary's wall. This may make ovulation itself painful for some women. - At the time of ovulation, blood or other fluid is released from the ruptured egg follicle. This fluid may cause irritation of the abdominal lining. - After ovulation, the fallopian tubes contract (similar to peristalsis of the esophagus), which may cause pain in some women. - At ovulation, this pain may be related to smooth muscle cell contraction in the ovary as well as in its ligaments. These contractions are in response to an increased level of prostaglandin F2-alpha mediated by the surge of leutinizing hormone (LH). # Usefulness Women charting with some form of fertility awareness may find mittelschmerz to be a helpful secondary sign in detecting ovulation. Because normal sperm life is up to five days, however, mittelschmerz alone does not provide sufficient advance warning to avoid pregnancy. Because other causes of minor abdominal pain are common, mittelschmerz alone also cannot be used to confirm the beginning of the post-ovulatory infertile period. # Other ovulation symptoms Women may notice other physical symptoms associated with their mittelschmerz, or near ovulation. The most common sign is the appearance of fertile cervical mucus in the days leading up to ovulation. Cervical mucus is one of the primary signs used by various fertility awareness methods. Other symptoms are sometimes called secondary fertility signs to distinguish from the three primary signs. - Mid-cycle or ovulatory bleeding is thought to result from the sudden drop in estrogen that occurs just before ovulation. This drop in hormones can trigger withdrawal bleeding in the same way that switching from active to placebo birth control pills does. The rise in hormones that occurs after ovulation prevents such mid-cycle spotting from becoming as heavy or long lasting as a typical menstruation. Spotting is more common in longer cycles. - A woman's vulva may swell just prior to ovulation, especially the side on which ovulation will occur. - One of the groin lymph nodes (on the side on which ovulation will occur) will swell to about the size of a pea, and may become tender.	Mittelschmerz For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Mittelschmerz (German: "middle pain") is a medical term for "ovulation pain" or "midcycle pain". About 20% of women experience mittelschmerz, some every cycle, some intermittently. # Symptoms and diagnosis Mittelschmerz is characterised by lower abdominal and pelvic pain that occurs roughly midway through a woman's menstrual cycle. The pain can appear suddenly and usually subsides within hours, although it may sometimes last two or three days.[1] In some women, the mittelschmerz is localized enough so that they can tell which of their two ovaries provided the egg in a given month. Because ovulation occurs on a random ovary each cycle, the pain may switch sides or stay on the same side from one cycle to another. Diagnosis of mittelschmerz is generally made if a woman is mid-cycle and a pelvic examination shows no abnormalities. If the pain is prolonged and/or severe, other diagnostic procedures such as an abdominal ultrasound may be performed to rule out other causes of abdominal pain. The pain of mittelschmerz is sometimes mistaken for appendicitis and is one of the differential diagnoses for appendicitis in women of child-bearing age. # Treatment The pain is not harmful and does not signify the presence of disease. No treatment is usually necessary. Pain relievers (analgesics) may be needed in cases of prolonged or intense pain. Hormonal forms of contraception can be taken to prevent ovulation -- and therefore ovulatory pain -- but otherwise there is no known prevention. # Causes Mittelschmerz is believed to have a variety of causes: - The swelling of follicles in the ovaries prior to ovulation. While only one or two eggs mature to the point of being released, a number of follicles grow during the follicular phase of the menstrual cycle (non-dominant follicles atrophy prior to ovulation). Because follicles develop on both sides, this theory explains mittelschmerz that occurs simultaneously on both sides of the abdomen.[2] - The ovaries have no openings; at ovulation the egg breaks through the ovary's wall. This may make ovulation itself painful for some women.[2] - At the time of ovulation, blood or other fluid is released from the ruptured egg follicle. This fluid may cause irritation of the abdominal lining.[1][2] - After ovulation, the fallopian tubes contract (similar to peristalsis of the esophagus), which may cause pain in some women.[1] - At ovulation, this pain may be related to smooth muscle cell contraction in the ovary as well as in its ligaments. These contractions are in response to an increased level of prostaglandin F2-alpha mediated by the surge of leutinizing hormone (LH).[3] # Usefulness Women charting with some form of fertility awareness may find mittelschmerz to be a helpful secondary sign in detecting ovulation. Because normal sperm life is up to five days, however, mittelschmerz alone does not provide sufficient advance warning to avoid pregnancy. Because other causes of minor abdominal pain are common, mittelschmerz alone also cannot be used to confirm the beginning of the post-ovulatory infertile period.[1][2] # Other ovulation symptoms Women may notice other physical symptoms associated with their mittelschmerz, or near ovulation. The most common sign is the appearance of fertile cervical mucus in the days leading up to ovulation. Cervical mucus is one of the primary signs used by various fertility awareness methods. Other symptoms are sometimes called secondary fertility signs to distinguish from the three primary signs.[2] - Mid-cycle or ovulatory bleeding is thought to result from the sudden drop in estrogen that occurs just before ovulation. This drop in hormones can trigger withdrawal bleeding in the same way that switching from active to placebo birth control pills does. The rise in hormones that occurs after ovulation prevents such mid-cycle spotting from becoming as heavy or long lasting as a typical menstruation. Spotting is more common in longer cycles.[2] - A woman's vulva may swell just prior to ovulation, especially the side on which ovulation will occur.[2] - One of the groin lymph nodes (on the side on which ovulation will occur) will swell to about the size of a pea, and may become tender.[2]	https://www.wikidoc.org/index.php/Mittelschmerz
f0e26bab6d1562d0356c196725a1c44ec2e904f5	wikidoc	Mobile health	Mobile health # Overview Mobile health, also called mHealth, is a component of eHealth. “To date, no standardized definition of mHealth has been established...the Global Observatory for eHealth (GOe) defined mHealth or mobile health as medical and public health practice supported by mobile devices, such as mobile phones, patient monitoring devices, personal digital assistants (PDAs), and other wireless devices. mHealth involves the use and capitalization on a mobile phone’s core utility of voice and short messaging service (SMS) as well as more complex functionalities and applications including general packet radio service (GPRS), third and fourth generation mobile telecommunications (3G and 4G systems), global positioning system (GPS), and Bluetooth technology”. In an age where technology plays a significant role in all aspects of our lives, it seems reasonable to believe that mHealth will become an integral part of our healthcare. One observational study showed that the vast majority of the patients have a smartphone and have an interest in utilizing it to improve their health, even in a population with lower socioeconomic status where access may be of concern. A possible limitation is accuracy of the accelerometer of smartphones to estimate energy expenditure by the wearer. Usability and functionality of apps has been questioned. Effectiveness may be helped by gamification. # Effectiveness Complex trials are being started. ## Patient compliance Regarding medication compliance: Mobile phone strategies may or may not improve medicine adherence: - Regarding primary prevention of cardiovascular disease, mobile phone-based interventions have low-quality evidence of increasing compliance with medications - Regarding medication adherence, text messaging approximately doubles the odds of adherence according to a meta analysis of 16 randomized control trials of patients with chronic disease. The review concluded that this intervention improved adherence rates from 50% to 67.8% or an absolute increase of 17.8%. More recent trails confirm benefit. - Regarding physical activity, a 2018 proof of concept randomized controlled trial found fitness trackers target behavioral changes to including goal setting, and social support and comparison as motivators within the concept of social cognitive therapy allowing planning, problem solving and behavioral practice. Counseling with motivational interviewing is necessary in addition to the fitness tracker to increase behaviors. These results are similar to a prior systematic review of overweight people. ## Patient engagement mHealth may increase patient engagement. One prospective randomized control trial found that the participants utilizing a mobile application to track their chronic disease had improvement in health self-management as compared to the the control participants who were not utilizing a mobile application. ## Patient outcomes There is not yet strong evidence that mobile phone messaging interventions improve health outcomes, but they may improve a patient’s ability to self-manage their disease. - A Cochrane Review published in 2012 of four studies that utilized mobile phone messaging interventions in the management of chronic diseases (diabetes mellitus, hypertension, and asthma) demonstrated that there was no significant difference in glycemic control, blood pressure control or FVC/FEV1 values between intervention and control groups. The reviewed study that focused on asthma did however find that there was a significant difference in the pooled asthma symptom score, favoring the text messaging intervention over usual care. All four reviewed studies showed evidence of either improved disease self-monitoring or better medication adherence with the utilization of mobile phone messaging interventions. Regarding coronary artery disease, a randomized controlled trial found reduction of risk factors associated with using mobile health. Regarding hypertension, a randomized controlled trial found no benefit. Meta-analyses published in 2019, including a review of randomized trials published through May, 2017 and an AHRQ technical brief of any study design published through July, 2017 found benefit from mHealth when augmented by health care providers or study personnel, - A trial omitted from the above reviews also found greater hemoglobin A1c decline. - A ore recent trail also found reduction in HbA1c ### Physical activity mHealth increases physical activity per a systematic review in 2020 and earlier in 2016. Text messaging may give short term improvement. Performance feedback provided from mobile devices about progress towards goals may increase motivation according to trials and reviews. ### Weight loss and obesity A systematic review for the Community Guide found that electronic activity monitors increase physical activity. Regarding MyFitnessPal, a randomized control trial in 2014 of 212 patients with a body mass index >25 kg/m^2 aimed at evaluating the efficacy of the application MyFitnessPal for weight loss in the primary care setting demonstrated that the application did not result in increased weight loss compared to usual care. Although it must be noted that most participants didn’t use the application after the first month of the study; 94 participants logged on in the first month compared to only 34 in the sixth month. A second randomized controlled trial was also negative. A pilot randomized control trial in 2013 found that a smartphone app may improve adherence and total weight loss after 6 months when compared to a website monitoring group. 128 overweight individuals were randomized to receive a weight management intervention delivered by smartphone app, website, or paper diary. The smartphone app intervention, My Meal Mate (MMM), was developed by the research team using an evidence-based behavioral approach. - Trial retention was 93% in the smartphone group, 55% in the website group, and 53% in the paper diary group at 6 months. - Adherence means were 92 days in the smartphone group, 35 days in the website group, and 29 days in the paper diary group. - Mean weight loss and BMI reduction, respectively, at 6 months were -4.6 kg and -1.6 kg/m2 in the smartphone group, -2.9 kg and -1.0 kg/m2 in the paper diary group, and -1.3 kg and -0.5 kg/m2 in the website group. # Diagnostic assistance A smartphone camera may be able to use photoplethysmography to detect atrial fibrillation according to initial research.	Mobile health Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Stephanie Peters; Sierra Foster; Monica Khurana; Ross Miller; Matt Greenstein; Lauren Schuessler # Overview Mobile health, also called mHealth, is a component of eHealth. “To date, no standardized definition of mHealth has been established...the Global Observatory for eHealth (GOe) defined mHealth or mobile health as medical and public health practice supported by mobile devices, such as mobile phones, patient monitoring devices, personal digital assistants (PDAs), and other wireless devices. mHealth involves the use and capitalization on a mobile phone’s core utility of voice and short messaging service (SMS) as well as more complex functionalities and applications including general packet radio service (GPRS), third and fourth generation mobile telecommunications (3G and 4G systems), global positioning system (GPS), and Bluetooth technology”[1]. In an age where technology plays a significant role in all aspects of our lives, it seems reasonable to believe that mHealth will become an integral part of our healthcare. One observational study showed that the vast majority of the patients have a smartphone and have an interest in utilizing it to improve their health, even in a population with lower socioeconomic status where access may be of concern[2]. A possible limitation is accuracy of the accelerometer of smartphones to estimate energy expenditure by the wearer[3]. Usability and functionality of apps has been questioned[4]. Effectiveness may be helped by gamification[5]. # Effectiveness Complex trials are being started[6]. ## Patient compliance Regarding medication compliance: Mobile phone strategies may or may not improve medicine adherence: - Regarding primary prevention of cardiovascular disease, mobile phone-based interventions have low-quality evidence of increasing compliance with medications[7] - Regarding medication adherence, text messaging approximately doubles the odds of adherence according to a meta analysis of 16 randomized control trials of patients with chronic disease. The review concluded that this intervention improved adherence rates from 50% to 67.8% or an absolute increase of 17.8%[8]. More recent trails confirm benefit[9]. - Regarding physical activity, a 2018 proof of concept randomized controlled trial found fitness trackers target behavioral changes to including goal setting, and social support and comparison as motivators within the concept of social cognitive therapy allowing planning, problem solving and behavioral practice. Counseling with motivational interviewing is necessary in addition to the fitness tracker to increase behaviors[10]. These results are similar to a prior systematic review of overweight people[11]. ## Patient engagement mHealth may increase patient engagement. One prospective randomized control trial found that the participants utilizing a mobile application to track their chronic disease had improvement in health self-management as compared to the the control participants who were not utilizing a mobile application[12]. ## Patient outcomes There is not yet strong evidence that mobile phone messaging interventions improve health outcomes, but they may improve a patient’s ability to self-manage their disease. - A Cochrane Review published in 2012 of four studies that utilized mobile phone messaging interventions in the management of chronic diseases (diabetes mellitus, hypertension, and asthma) demonstrated that there was no significant difference in glycemic control, blood pressure control or FVC/FEV1 values between intervention and control groups. The reviewed study that focused on asthma did however find that there was a significant difference in the pooled asthma symptom score, favoring the text messaging intervention over usual care. All four reviewed studies showed evidence of either improved disease self-monitoring or better medication adherence with the utilization of mobile phone messaging interventions[13]. Regarding coronary artery disease, a randomized controlled trial found reduction of risk factors associated with using mobile health[14]. Regarding hypertension, a randomized controlled trial found no benefit[15]. Meta-analyses published in 2019[16], including a review of randomized trials published through May, 2017[17] and an AHRQ technical brief of any study design published through July, 2017[18][19] found benefit from mHealth when augmented by health care providers or study personnel, - A trial omitted from the above reviews also found greater hemoglobin A1c decline[20]. - A ore recent trail also found reduction in HbA1c[21] ### Physical activity mHealth increases physical activity per a systematic review in 2020[22] and earlier in 2016[11][23]. Text messaging may give short term improvement[24]. Performance feedback provided from mobile devices about progress towards goals may increase motivation according to trials[25][26] and reviews[27][28]. ### Weight loss and obesity A systematic review for the Community Guide found that electronic activity monitors increase physical activity[11][29]. Regarding MyFitnessPal, a randomized control trial in 2014 of 212 patients with a body mass index >25 kg/m^2 aimed at evaluating the efficacy of the application MyFitnessPal for weight loss in the primary care setting demonstrated that the application did not result in increased weight loss compared to usual care. Although it must be noted that most participants didn’t use the application after the first month of the study; 94 participants logged on in the first month compared to only 34 in the sixth month[30][11]. A second randomized controlled trial was also negative[31]. A pilot randomized control trial in 2013 found that a smartphone app may improve adherence and total weight loss after 6 months when compared to a website monitoring group[32]. 128 overweight individuals were randomized to receive a weight management intervention delivered by smartphone app, website, or paper diary. The smartphone app intervention, My Meal Mate (MMM), was developed by the research team using an evidence-based behavioral approach[32]. - Trial retention was 93% in the smartphone group, 55% in the website group, and 53% in the paper diary group at 6 months. - Adherence means were 92 days in the smartphone group, 35 days in the website group, and 29 days in the paper diary group. - Mean weight loss and BMI reduction, respectively, at 6 months were -4.6 kg and -1.6 kg/m2 in the smartphone group, -2.9 kg and -1.0 kg/m2 in the paper diary group, and -1.3 kg and -0.5 kg/m2 in the website group. # Diagnostic assistance A smartphone camera may be able to use photoplethysmography to detect atrial fibrillation according to initial research[33].	https://www.wikidoc.org/index.php/Mobile_health
e1423f142307f8239c75b44405d4ca1eaa573905	wikidoc	Mogamulizumab	Mogamulizumab # 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 Mogamulizumab is a CC chemokine receptor type 4 (CCR4)-directed monoclonal antibody that is FDA approved for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy. Common adverse reactions include rash, infusion reactions, fatigue, diarrhea, musculoskeletal pain, and upper respiratory tract infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Mogamulizumab is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. Dosage - The recommended dose of mogamulizumab is 1 mg/kg administered as an intravenous infusion over at least 60 minutes. Administer on days 1, 8, 15, and 22 of the first 28-day cycle, then on days 1 and 15 of each subsequent 28-day cycle until disease progression or unacceptable toxicity. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding mogamulizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding mogamulizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of mogamulizumab in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding mogamulizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding mogamulizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Fatal and life-threatening skin adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have occurred in recipients of mogamulizumab. Rash (drug eruption) is one of the most common adverse reactions associated with mogamulizumab. In Trial 1, 25% (80/319) of patients treated with mogamulizumab had an adverse reaction of drug eruption, with 18% of these cases being severe (Grade 3) and 82% of these cases being Grade 1 or 2. Of 528 patients treated with mogamulizumab in clinical trials, Grade 3 skin adverse reactions were reported in 3.6%, Grade 4 skin adverse reactions in <1%, and SJS in <1%. - The onset of drug eruption is variable, and the affected areas and appearance vary. In Trial 1, the median time to onset was 15 weeks, with 25% of cases occurring after 31 weeks. The more common presentations reported included papular or maculopapular rash, lichenoid, spongiotic or granulomatous dermatitis, and morbilliform rash. Other presentations included scaly plaques, pustular eruption, folliculitis, non-specific dermatitis, and psoriasiform dermatitis. - Monitor patients for rash throughout the treatment course. Management of dermatologic toxicity includes topical corticosteroids and interruption or permanent cessation of mogamulizumab. Consider skin biopsy to help distinguish drug eruption from disease progression. - Discontinue mogamulizumab permanently for SJS or TEN or for any life-threatening (Grade 4) reaction. For possible SJS or TEN, interrupt mogamulizumab and do not restart unless SJS or TEN is ruled out and the cutaneous reaction has resolved to Grade 1 or less. - Fatal and life-threatening infusion reactions have been reported in patients treated with mogamulizumab. In Trial 1, infusion reactions occurred in 35% (112/319) of patients treated with mogamulizumab, with 8% of these reactions being severe (Grade 3). Most reactions (approximately 90%) occur during or shortly after the first infusion. Infusion reactions can also occur with subsequent infusions. The most commonly reported signs include chills, nausea, fever, tachycardia, rigors, headache, and vomiting. - Consider premedication (such as diphenhydramine and acetaminophen) for the first infusion of mogamulizumab in all patients. Whether premedication reduces the risk or severity of these reactions is not established. In Trial 1, infusion reactions occurred in 42% of patients without premedication and 32% of patients with premedication. Monitor patients closely for signs and symptoms of infusion reactions and interrupt the infusion for any grade reaction and treat promptly. - Fatal and life-threatening infections have occurred in patients treated with mogamulizumab, including sepsis, pneumonia, and skin infection. In Trial 1, 18% (34/184) of patients randomized to mogamulizumab had Grade 3 or higher infection or an infection-related serious adverse reaction. Monitor patients for signs and symptoms of infection and treat promptly. - Fatal and life-threatening immune-mediated complications have been reported in recipients of mogamulizumab. Grade 3 or higher immune-mediated or possibly immune-mediated reactions have included myositis, myocarditis, polymyositis, hepatitis, pneumonitis, and a variant of Guillain-Barré syndrome. Use of systemic immunosuppressants for immune-mediated reactions was reported in 1.9% (6/319) of recipients of mogamulizumab in Trial 1, including for a case of Grade 2 polymyalgia rheumatica. New-onset hypothyroidism (Grade 1 or 2) was reported in 1.3% of patients and managed with observation or levothyroxine. Interrupt or permanently discontinue mogamulizumab as appropriate for suspected immune-mediated adverse reactions. Consider the benefit/risk of mogamulizumab in patients with a history of autoimmune disease. - Increased risks of transplant complications have been reported in patients who receive allogeneic HSCT after mogamulizumab including severe (Grade 3 or 4) acute graft-versus-host disease (GVHD), steroid-refractory GVHD, and transplant-related death. Among recipients of pre-transplantation mogamulizumab, a higher risk of transplant complications has been reported if mogamulizumab is given within a shorter time frame (approximately 50 days) before HSCT. Follow patients closely for early evidence of transplant-related complications. # 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. Trial 1 - The data described below reflect exposure to mogamulizumab in a randomized, open-label, actively controlled clinical trial for adult patients with MF or SS who received at least one prior systemic therapy. Of 370 patients treated, 184 (57% with MF, 43% with SS) received mogamulizumab as randomized treatment and 186 (53% with MF, 47% with SS) received vorinostat. In the vorinostat arm, 135 patients (73%) subsequently crossed over to mogamulizumab for a total of 319 patients treated with mogamulizumab. - Mogamulizumab was administered at 1 mg/kg intravenously over at least 60 minutes on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of subsequent 28-day cycles. Premedication (diphenhydramine, acetaminophen) was optional and administered to 65% of randomized patients for the first infusion. The comparator group received vorinostat 400 mg orally once daily, given continuously in 28-day cycles. Treatment continued until unacceptable toxicity or progressive disease. - The median age was 64 years (range, 25 to 101 years), 58% of patients were male, 70% were white, and 99% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients had a median of 3 prior systemic therapies. The trial required an absolute neutrophil count (ANC) ≥1500/µL (≥1000/µL if bone marrow was involved), platelet count ≥100,000/µL (≥75,000/µL if bone marrow was involved), creatinine clearance >50 mL/min or serum creatinine ≤1.5 mg/dL, and hepatic transaminases ≤2.5 times upper limit of normal (ULN) (≤5 times ULN if lymphomatous liver infiltration). Patients with active autoimmune disease, active infection, autologous HSCT within 90 days, or prior allogeneic HSCT were excluded. - During randomized treatment, the median duration of exposure to mogamulizumab was 5.6 months, with 48% (89/184) of patients with at least 6 months of exposure and 23% (43/184) with at least 12 months of exposure. The median duration of exposure to vorinostat was 2.8 months, with 22% (41/186) of patients with at least 6 months of exposure. - Fatal adverse reactions within 90 days of the last dose occurred in 2.2% (7/319) of patients who received mogamulizumab as randomized or crossover treatment. - Serious adverse reactions were reported in 36% (66/184) of patients randomized to mogamulizumab and most often involved infection (16% of patients; 30/184). Serious adverse reactions reported in >2% of patients randomized to mogamulizumab were pneumonia (5%), sepsis (4%), pyrexia (4%), and skin infection (3%); other serious adverse reactions, each reported in 2% of patients, included hepatitis, pneumonitis, rash, infusion related reaction, lower respiratory tract infection, and renal insufficiency. Mogamulizumab was discontinued for adverse reactions in 18% of randomized patients, most often due to rash or drug eruption (7.1%). Common Adverse Reactions - The most common adverse reactions (reported in ≥20% of patients randomized to mogamulizumab) were rash (including drug eruption), infusion related reactions, fatigue, diarrhea, upper respiratory tract infection and musculoskeletal pain. Other common adverse reactions (reported in ≥10% of patients randomized to mogamulizumab) included skin infection, pyrexia, nausea, edema, thrombocytopenia, headache, constipation, mucositis, anemia, cough and hypertension. Table 1 summarizes common adverse reactions having a ≥2% higher incidence with mogamulizumab than with vorinostat in Trial 1. - Other Common Adverse Reactions in ≥10% of mogamulizumab Arm General disorders: fatigue (31%), edema (16%) Gastrointestinal disorders: diarrhea (28%), nausea (16%), constipation (13%) Blood and lymphatic system disorders: thrombocytopenia (14%), anemia (12%) Nervous system disorders: headache (14%) Vascular disorders: hypertension (10%) Respiratory disorders: cough (11%) - General disorders: fatigue (31%), edema (16%) - Gastrointestinal disorders: diarrhea (28%), nausea (16%), constipation (13%) - Blood and lymphatic system disorders: thrombocytopenia (14%), anemia (12%) - Nervous system disorders: headache (14%) - Vascular disorders: hypertension (10%) - Respiratory disorders: cough (11%) - Adverse Reactions in ≥5% but <10% of mogamulizumab Arm Infections: candidiasis (9%), urinary tract infection (9%), folliculitis (8%), pneumonia (6%), otitis (5%), herpesvirus infection (5%) Investigations: renal insufficiency (9%), hyperglycemia (9%), hyperuricemia (8%), weight increase (8%), weight decrease (6%), hypomagnesemia (6%) Psychiatric disorders: insomnia (9%), depression (7%) Skin and subcutaneous disorders: xerosis (8%), alopecia (7%) Nervous system disorders: dizziness (8%), peripheral neuropathy (7%) Metabolism and nutrition disorders: decreased appetite (8%) Respiratory disorders: dyspnea (7%) General disorders: chills (7%) Gastrointestinal disorders: vomiting (7%), abdominal pain (5%) Injury, poisoning and procedural complications: fall (6%) Musculoskeletal disorders: muscle spasms (5%) Cardiovascular disorders: arrhythmia (5%) Eye disorders: conjunctivitis (5%) - Infections: candidiasis (9%), urinary tract infection (9%), folliculitis (8%), pneumonia (6%), otitis (5%), herpesvirus infection (5%) - Investigations: renal insufficiency (9%), hyperglycemia (9%), hyperuricemia (8%), weight increase (8%), weight decrease (6%), hypomagnesemia (6%) - Psychiatric disorders: insomnia (9%), depression (7%) - Skin and subcutaneous disorders: xerosis (8%), alopecia (7%) - Nervous system disorders: dizziness (8%), peripheral neuropathy (7%) - Metabolism and nutrition disorders: decreased appetite (8%) - Respiratory disorders: dyspnea (7%) - General disorders: chills (7%) - Gastrointestinal disorders: vomiting (7%), abdominal pain (5%) - Injury, poisoning and procedural complications: fall (6%) - Musculoskeletal disorders: muscle spasms (5%) - Cardiovascular disorders: arrhythmia (5%) - Eye disorders: conjunctivitis (5%) - Selected Other Adverse Reactions Tumor lysis syndrome (<1%) Myocardial ischemia or infarction (<1%) Cardiac failure (<1%) - Tumor lysis syndrome (<1%) - Myocardial ischemia or infarction (<1%) - Cardiac failure (<1%) - Table 2 summarizes common treatment-emergent laboratory abnormalities having a ≥2% higher incidence with mogamulizumab than with vorinostat. - Other common treatment-emergent laboratory abnormalities in the mogamulizumab arm included hyperglycemia (52%; 4% Grade 3-4), anemia (35%; 2% Grade 3-4), thrombocytopenia (29%, none Grade 3-4), aspartate transaminase (AST) increased (25%; 2% Grade 3-4), alanine transaminase (ALT) increased (18%; 1% Grade 3-4), alkaline phosphatase increased (17%; 0% Grade 3-4), and neutropenia (10%; 2% Grade 3-4). Grade 4 treatment-emergent laboratory abnormalities observed in ≥1% of the mogamulizumab arm included lymphopenia (5%), leukopenia (1%), and hypophosphatemia (1%). ## Immunogenicity - As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to mogamulizumab with the incidences of antibodies in other studies or to other products may be misleading. - Among 258 patients treated with mogamulizumab in Trial 1, 10 (3.9%) tested positive for treatment-emergent (treatment-induced or treatment-boosted) anti-mogamulizumab antibodies by an electrochemiluminescent assay. There were no positive neutralizing antibody responses. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of mogamulizumab. 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. Infections: Hepatitis B virus reactivation Cardiac disorders: Stress cardiomyopathy - Infections: Hepatitis B virus reactivation - Cardiac disorders: Stress cardiomyopathy # Drug Interactions There is limited information regarding Mogamulizumab Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There are no available data on mogamulizumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of mogamulizumab to pregnant cynomolgus monkeys from the start of organogenesis through delivery did not show a potential for adverse developmental outcomes at maternal systemic exposures 27 times the exposure in patients at the recommended dose, based on AUC. In general, IgG molecules are known to cross the placental barrier and in the monkey reproduction study mogamulizumab was detected in fetal plasma. Therefore, mogamulizumab has the potential to be transmitted from the mother to the developing fetus. Mogamulizumab is not recommended during pregnancy or in women of childbearing potential not using contraception. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Animal Data - The effects of mogamulizumab on embryo-fetal development were evaluated in 12 pregnant cynomolgus monkeys that received mogamulizumab once weekly by intravenous administration from the start of organogenesis through delivery at an exposure level 27 times higher than the clinical dose. Mogamulizumab administration did not show a potential for embryo-fetal lethality, teratogenicity, or fetal growth retardation and did not result in spontaneous abortion or increased fetal death. In surviving fetuses (10 of 12 compared with 11 of 12 in the control group) of cynomolgus monkeys treated with mogamulizumab, a decrease in CCR4-expressing lymphocytes due to the pharmacological activity of mogamulizumab was noted; there were no apparent mogamulizumab -related external, visceral, or skeletal abnormalities. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mogamulizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mogamulizumab during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of mogamulizumab in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for mogamulizumab and any potential adverse effects on the breastfed child from mogamulizumab or from the underlying maternal condition. ### Pediatric Use - The safety and effectiveness of mogamulizumab in pediatric patients have not been established. ### Geriatic Use - Of 319 patients with MF or SS who received mogamulizumab in Trial 1, 162 (51%) were ≥65 years. No overall differences in effectiveness were observed between these patients and younger patients. In patients aged ≥65, Grade 3 or higher adverse reactions were reported in 45% and serious adverse reactions in 36%, whereas in patients aged <65, Grade 3 or higher adverse reactions were reported in 36% and serious adverse reactions in 29%. ### Gender There is no FDA guidance on the use of Mogamulizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mogamulizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mogamulizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mogamulizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Mogamulizumab is not recommended during pregnancy or in women of childbearing potential not using contraception. Pregnancy Testing - For females of reproductive potential, verify pregnancy status prior to initiating mogamulizumab. Contraception - Advise females of reproductive potential to use effective contraception during treatment with mogamulizumab and for at least 3 months following the last dose of mogamulizumab. ### Immunocompromised Patients There is no FDA guidance one the use of Mogamulizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended dose of mogamulizumab is 1 mg/kg administered as an intravenous infusion over at least 60 minutes. Administer on days 1, 8, 15, and 22 of the first 28-day cycle, then on days 1 and 15 of each subsequent 28-day cycle until disease progression or unacceptable toxicity. - Administer mogamulizumab within 2 days of the scheduled dose. If a dose is missed, administer the next dose as soon as possible and resume dosing schedule. - Do not administer mogamulizumab subcutaneously or by rapid intravenous administration. Recommended Premedications - Administer premedication with diphenhydramine and acetaminophen for the first mogamulizumab infusion. Preparation - Visually inspect drug product solution for particulate matter and discoloration prior to administration. Mogamulizumab is a clear to slightly opalescent colorless solution. Discard the vial if cloudiness, discoloration, or particulates are observed. - Calculate the dose (mg/kg) and number of vials of mogamulizumab needed to prepare the infusion solution based on patient weight. - Aseptically withdraw the required volume of mogamulizumab into the syringe and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP. The final concentration of the diluted solution should be between 0.1 mg/mL to 3.0 mg/mL. - Mix diluted solution by gentle inversion. Do not shake. - Discard any unused portion left in the vial. - The diluted solution is compatible with polyvinyl chloride (PVC) or polyolefin (PO) infusion bags. Administration - Administer infusion solution over at least 60 minutes through an intravenous line containing a sterile, low protein binding, 0.22 micron (or equivalent) in-line filter. - Do not mix mogamulizumab with other drugs. - Do not co-administer other drugs through the same intravenous line. Storage of Diluted Solution - After preparation, infuse the mogamulizumab solution immediately, or store under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 4 hours from the time of infusion preparation. - Do not freeze. Do not shake. ### Monitoring Dermatologic Toxicity - Permanently discontinue mogamulizumab for life-threatening (Grade 4) rash or for any Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). If SJS or TEN is suspected, stop mogamulizumab and do not resume unless SJS or TEN has been excluded and the cutaneous reaction has resolved to Grade 1 or less. - If moderate or severe (Grades 2 or 3) rash occurs, interrupt mogamulizumab and administer at least 2 weeks of topical corticosteroids. If rash improves to Grade 1 or less, mogamulizumab may be resumed. - If mild (Grade 1) rash occurs, consider topical corticosteroids. Infusion Reactions - Permanently discontinue mogamulizumab for a life-threatening (Grade 4) infusion reaction. - Temporarily interrupt the infusion of mogamulizumab for mild to severe (Grades 1 to 3) infusion reactions and treat symptoms. Reduce the infusion rate by at least 50% when restarting the infusion after symptoms resolve. If reaction recurs and is unmanageable, discontinue infusion. - If an infusion reaction occurs, administer premedication (such as diphenhydramine and acetaminophen) for subsequent mogamulizumab infusions. # IV Compatibility - Mogamulizumab is administered as an intravenous infusion. # Overdosage There is limited information regarding Mogamulizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Mogamulizumab is a defucosylated, humanized IgG1 kappa monoclonal antibody that binds to CCR4, a G protein-coupled receptor for CC chemokines that is involved in the trafficking of lymphocytes to various organs. Non-clinical in vitro studies demonstrate mogamulizumab binding targets a cell for antibody-dependent cellular cytotoxicity (ADCC) resulting in depletion of the target cells. CCR4 is expressed on the surface of some T-cell malignancies and is expressed on regulatory T-cells (Treg) and a subset of Th2 T-cells. ## Structure There is limited information regarding Mogamulizumab Structure in the drug label. ## Pharmacodynamics - Mogamulizumab exposure-response relationships and the time course of pharmacodynamics response are unknown. ## Pharmacokinetics - Mogamulizumab pharmacokinetics (PK) was evaluated in patients with T-cell malignancies. Parameters are presented as the geometric mean unless otherwise specified. Mogamulizumab concentrations increased proportionally with dose over the dose range of 0.01 to 1.0 mg/kg (0.01 to 1 times the approved recommended dosage). - Following repeated dosing of the approved recommended dosage, steady state concentrations were reached after 8 doses (12 weeks), and the systemic accumulation was 1.6-fold. At steady state, the peak concentration (Cmax,ss) is 32 (68%) µg/mL, the trough concentration (Cmin,ss) is 11 (239%) µg/mL, and AUCss is 5577 (125%) µg∙hr/mL. Distribution - The central volume of distribution is 3.6 L (20%). Elimination - The terminal half-life is 17 days (66%), and the clearance is 12 mL/h (84%). Specific Populations: - No clinically significant changes in the PK of mogamulizumab were observed based on age (range: 22 to 101 years), sex, ethnicity, renal impairment (creatinine clearance 1.5 to 3 times ULN and any AST) hepatic impairment, disease subtype (MF or SS), degree of CCR4 expression, or ECOG status. The effect of severe hepatic impairment (total bilirubin >3 times ULN and any AST) on mogamulizumab PK is unknown. Drug Interaction Studies - No drug interaction studies have been conducted with mogamulizumab. ## Nonclinical Toxicology - No carcinogenicity or genotoxicity studies have been conducted with mogamulizumab. - No specific studies have been conducted to evaluate potential effects of mogamulizumab on fertility. No mogamulizumab -related toxic effects in the male and female reproductive organs were observed in sexually mature monkeys in repeat-dose toxicology studies up to 26 weeks in duration. # Clinical Studies Trial 1 - A randomized, open-label, multicenter trial (Study 0761-010; NCT01728805) evaluated the efficacy of mogamulizumab in adult patients with MF or SS after at least one prior systemic therapy. The trial randomized 372 patients 1:1 to either mogamulizumab (186 patients; 56% with MF, 44% with SS) or vorinostat (186 patients; 53% with MF, 47% with SS). The trial included patients regardless of tumor CCR4 expression status and excluded patients with histologic transformation, prior allogeneic HSCT, autologous HSCT within 90 days, active autoimmune disease, or active infection. The trial required patients to have ANC ≥1500/µL (≥1000/µL if bone marrow was involved), platelet count ≥100,000/µL (≥75,000/µL if bone marrow was involved), creatinine clearance >50 mL/min or serum creatinine ≤1.5 mg/dL and hepatic transaminases ≤2.5 times ULN (≤5 times ULN if lymphomatous liver infiltration). - The dose of mogamulizumab was 1 mg/kg administered intravenously over at least 60 minutes on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of each subsequent cycle. Vorinostat was dosed at 400 mg orally once daily, continuously for 28-day cycles. Treatment continued until disease progression or unacceptable toxicity. Vorinostat-treated patients with disease progression or unacceptable toxicities were permitted to cross over to mogamulizumab. - The median age was 64 years (range: 25 to 101), 58% of patients were male, and 70% were white. At study baseline, 38% had stage IB-II disease, 10% stage III, and 52% stage IV. The median number of prior systemic therapies was 3. In the mogamulizumab arm, baseline CCR4 expression status by immunohistochemistry was available in 140 patients (75%), of whom all had CCR4 detected on ≥1% of lymphocytes on skin biopsy, and 134/140 (96%) had CCR4 detected on ≥10% of the lymphocytes. CCR4 expression status was similar in the vorinostat arm. - During randomized treatment, the median duration of exposure to mogamulizumab was 5.6 months (range: <1 to 45.3 months), with 48% of patients with at least 6 months of exposure and 23% with at least 12 months of exposure. The median duration of exposure to vorinostat was 2.8 months (range: <1 to 34.8 months), with 22% of patients with at least 6 months of exposure. - Efficacy was based on investigator-assessed progression-free survival (PFS), which was defined as the time from the date of randomization until documented progression of disease or death. Other efficacy measures included overall response rate (ORR) based on global composite response criteria that combine measures from each disease compartment (skin, blood, lymph nodes and viscera). Responses required confirmation at two successive disease assessments, which included the modified Severity Weighted Assessment Tool, skin photographs, central flow cytometry, and computed tomography. - The trial demonstrated that mogamulizumab significantly prolonged PFS compared to vorinostat (Table 3). The Kaplan-Meier curve for PFS by Investigator is shown in Figure 1. The estimated median follow-up for investigator-assessed PFS was 13 months in the mogamulizumab arm and 10.4 months in the vorinostat arm. By independent review committee assessment, the estimated median PFS was 6.7 months (95% CI, 5.6 to 9.4) in the mogamulizumab arm and 3.8 months (95% CI, 3.0 to 4.7) in the vorinostat arm (hazard ratio 0.64; 95% CI: 0.49, 0.84). - Table 3 also summarizes investigator-assessed confirmed response rates, overall and by disease compartment. The trial demonstrated improvement in ORR with mogamulizumab. # How Supplied - Mogamulizumab injection is a sterile, preservative-free, clear to slightly opalescent colorless solution supplied in a carton containing one 20 mg/5 mL (4 mg/mL), single-dose glass vial (NDC 42747-761-01). ## Storage - Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original package to protect from light until time of use. Do not freeze. Do not shake. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Patient Information). - Inform patients of the risk of the following adverse reactions that may require additional treatment and/or withholding or discontinuation of mogamulizumab including: Dermatological Toxicity: Advise patients to contact their healthcare provider immediately for new or worsening skin rash. Advise patients that the rash can happen at any time while receiving mogamulizumab. Infusion Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions. Infections: Advise patients to contact their health care provider for fever or other evidence of infection. Autoimmune Complications: Advise patients to notify their healthcare provider of any history of autoimmune disease. Complications of Allogeneic HSCT after mogamulizumab: Advise patients of potential risk of post-transplant complications. Females of Reproductive Potential: Advise use of effective contraception during treatment with mogamulizumab and for at least 3 months following the last dose of mogamulizumab. - Dermatological Toxicity: Advise patients to contact their healthcare provider immediately for new or worsening skin rash. Advise patients that the rash can happen at any time while receiving mogamulizumab. - Infusion Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions. - Infections: Advise patients to contact their health care provider for fever or other evidence of infection. - Autoimmune Complications: Advise patients to notify their healthcare provider of any history of autoimmune disease. - Complications of Allogeneic HSCT after mogamulizumab: Advise patients of potential risk of post-transplant complications. - Females of Reproductive Potential: Advise use of effective contraception during treatment with mogamulizumab and for at least 3 months following the last dose of mogamulizumab. # Precautions with Alcohol Alcohol-Mogamulizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Poteligeo # Look-Alike Drug Names There is limited information regarding Mogamulizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Mogamulizumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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 Mogamulizumab is a CC chemokine receptor type 4 (CCR4)-directed monoclonal antibody that is FDA approved for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy. Common adverse reactions include rash, infusion reactions, fatigue, diarrhea, musculoskeletal pain, and upper respiratory tract infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Mogamulizumab is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. Dosage - The recommended dose of mogamulizumab is 1 mg/kg administered as an intravenous infusion over at least 60 minutes. Administer on days 1, 8, 15, and 22 of the first 28-day cycle, then on days 1 and 15 of each subsequent 28-day cycle until disease progression or unacceptable toxicity. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding mogamulizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding mogamulizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of mogamulizumab in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding mogamulizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding mogamulizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Fatal and life-threatening skin adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have occurred in recipients of mogamulizumab. Rash (drug eruption) is one of the most common adverse reactions associated with mogamulizumab. In Trial 1, 25% (80/319) of patients treated with mogamulizumab had an adverse reaction of drug eruption, with 18% of these cases being severe (Grade 3) and 82% of these cases being Grade 1 or 2. Of 528 patients treated with mogamulizumab in clinical trials, Grade 3 skin adverse reactions were reported in 3.6%, Grade 4 skin adverse reactions in <1%, and SJS in <1%. - The onset of drug eruption is variable, and the affected areas and appearance vary. In Trial 1, the median time to onset was 15 weeks, with 25% of cases occurring after 31 weeks. The more common presentations reported included papular or maculopapular rash, lichenoid, spongiotic or granulomatous dermatitis, and morbilliform rash. Other presentations included scaly plaques, pustular eruption, folliculitis, non-specific dermatitis, and psoriasiform dermatitis. - Monitor patients for rash throughout the treatment course. Management of dermatologic toxicity includes topical corticosteroids and interruption or permanent cessation of mogamulizumab. Consider skin biopsy to help distinguish drug eruption from disease progression. - Discontinue mogamulizumab permanently for SJS or TEN or for any life-threatening (Grade 4) reaction. For possible SJS or TEN, interrupt mogamulizumab and do not restart unless SJS or TEN is ruled out and the cutaneous reaction has resolved to Grade 1 or less. - Fatal and life-threatening infusion reactions have been reported in patients treated with mogamulizumab. In Trial 1, infusion reactions occurred in 35% (112/319) of patients treated with mogamulizumab, with 8% of these reactions being severe (Grade 3). Most reactions (approximately 90%) occur during or shortly after the first infusion. Infusion reactions can also occur with subsequent infusions. The most commonly reported signs include chills, nausea, fever, tachycardia, rigors, headache, and vomiting. - Consider premedication (such as diphenhydramine and acetaminophen) for the first infusion of mogamulizumab in all patients. Whether premedication reduces the risk or severity of these reactions is not established. In Trial 1, infusion reactions occurred in 42% of patients without premedication and 32% of patients with premedication. Monitor patients closely for signs and symptoms of infusion reactions and interrupt the infusion for any grade reaction and treat promptly. - Fatal and life-threatening infections have occurred in patients treated with mogamulizumab, including sepsis, pneumonia, and skin infection. In Trial 1, 18% (34/184) of patients randomized to mogamulizumab had Grade 3 or higher infection or an infection-related serious adverse reaction. Monitor patients for signs and symptoms of infection and treat promptly. - Fatal and life-threatening immune-mediated complications have been reported in recipients of mogamulizumab. Grade 3 or higher immune-mediated or possibly immune-mediated reactions have included myositis, myocarditis, polymyositis, hepatitis, pneumonitis, and a variant of Guillain-Barré syndrome. Use of systemic immunosuppressants for immune-mediated reactions was reported in 1.9% (6/319) of recipients of mogamulizumab in Trial 1, including for a case of Grade 2 polymyalgia rheumatica. New-onset hypothyroidism (Grade 1 or 2) was reported in 1.3% of patients and managed with observation or levothyroxine. Interrupt or permanently discontinue mogamulizumab as appropriate for suspected immune-mediated adverse reactions. Consider the benefit/risk of mogamulizumab in patients with a history of autoimmune disease. - Increased risks of transplant complications have been reported in patients who receive allogeneic HSCT after mogamulizumab including severe (Grade 3 or 4) acute graft-versus-host disease (GVHD), steroid-refractory GVHD, and transplant-related death. Among recipients of pre-transplantation mogamulizumab, a higher risk of transplant complications has been reported if mogamulizumab is given within a shorter time frame (approximately 50 days) before HSCT. Follow patients closely for early evidence of transplant-related complications. # 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. Trial 1 - The data described below reflect exposure to mogamulizumab in a randomized, open-label, actively controlled clinical trial for adult patients with MF or SS who received at least one prior systemic therapy. Of 370 patients treated, 184 (57% with MF, 43% with SS) received mogamulizumab as randomized treatment and 186 (53% with MF, 47% with SS) received vorinostat. In the vorinostat arm, 135 patients (73%) subsequently crossed over to mogamulizumab for a total of 319 patients treated with mogamulizumab. - Mogamulizumab was administered at 1 mg/kg intravenously over at least 60 minutes on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of subsequent 28-day cycles. Premedication (diphenhydramine, acetaminophen) was optional and administered to 65% of randomized patients for the first infusion. The comparator group received vorinostat 400 mg orally once daily, given continuously in 28-day cycles. Treatment continued until unacceptable toxicity or progressive disease. - The median age was 64 years (range, 25 to 101 years), 58% of patients were male, 70% were white, and 99% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients had a median of 3 prior systemic therapies. The trial required an absolute neutrophil count (ANC) ≥1500/µL (≥1000/µL if bone marrow was involved), platelet count ≥100,000/µL (≥75,000/µL if bone marrow was involved), creatinine clearance >50 mL/min or serum creatinine ≤1.5 mg/dL, and hepatic transaminases ≤2.5 times upper limit of normal (ULN) (≤5 times ULN if lymphomatous liver infiltration). Patients with active autoimmune disease, active infection, autologous HSCT within 90 days, or prior allogeneic HSCT were excluded. - During randomized treatment, the median duration of exposure to mogamulizumab was 5.6 months, with 48% (89/184) of patients with at least 6 months of exposure and 23% (43/184) with at least 12 months of exposure. The median duration of exposure to vorinostat was 2.8 months, with 22% (41/186) of patients with at least 6 months of exposure. - Fatal adverse reactions within 90 days of the last dose occurred in 2.2% (7/319) of patients who received mogamulizumab as randomized or crossover treatment. - Serious adverse reactions were reported in 36% (66/184) of patients randomized to mogamulizumab and most often involved infection (16% of patients; 30/184). Serious adverse reactions reported in >2% of patients randomized to mogamulizumab were pneumonia (5%), sepsis (4%), pyrexia (4%), and skin infection (3%); other serious adverse reactions, each reported in 2% of patients, included hepatitis, pneumonitis, rash, infusion related reaction, lower respiratory tract infection, and renal insufficiency. Mogamulizumab was discontinued for adverse reactions in 18% of randomized patients, most often due to rash or drug eruption (7.1%). Common Adverse Reactions - The most common adverse reactions (reported in ≥20% of patients randomized to mogamulizumab) were rash (including drug eruption), infusion related reactions, fatigue, diarrhea, upper respiratory tract infection and musculoskeletal pain. Other common adverse reactions (reported in ≥10% of patients randomized to mogamulizumab) included skin infection, pyrexia, nausea, edema, thrombocytopenia, headache, constipation, mucositis, anemia, cough and hypertension. Table 1 summarizes common adverse reactions having a ≥2% higher incidence with mogamulizumab than with vorinostat in Trial 1. - Other Common Adverse Reactions in ≥10% of mogamulizumab Arm General disorders: fatigue (31%), edema (16%) Gastrointestinal disorders: diarrhea (28%), nausea (16%), constipation (13%) Blood and lymphatic system disorders: thrombocytopenia (14%), anemia (12%) Nervous system disorders: headache (14%) Vascular disorders: hypertension (10%) Respiratory disorders: cough (11%) - General disorders: fatigue (31%), edema (16%) - Gastrointestinal disorders: diarrhea (28%), nausea (16%), constipation (13%) - Blood and lymphatic system disorders: thrombocytopenia (14%), anemia (12%) - Nervous system disorders: headache (14%) - Vascular disorders: hypertension (10%) - Respiratory disorders: cough (11%) - Adverse Reactions in ≥5% but <10% of mogamulizumab Arm Infections: candidiasis (9%), urinary tract infection (9%), folliculitis (8%), pneumonia (6%), otitis (5%), herpesvirus infection (5%) Investigations: renal insufficiency (9%), hyperglycemia (9%), hyperuricemia (8%), weight increase (8%), weight decrease (6%), hypomagnesemia (6%) Psychiatric disorders: insomnia (9%), depression (7%) Skin and subcutaneous disorders: xerosis (8%), alopecia (7%) Nervous system disorders: dizziness (8%), peripheral neuropathy (7%) Metabolism and nutrition disorders: decreased appetite (8%) Respiratory disorders: dyspnea (7%) General disorders: chills (7%) Gastrointestinal disorders: vomiting (7%), abdominal pain (5%) Injury, poisoning and procedural complications: fall (6%) Musculoskeletal disorders: muscle spasms (5%) Cardiovascular disorders: arrhythmia (5%) Eye disorders: conjunctivitis (5%) - Infections: candidiasis (9%), urinary tract infection (9%), folliculitis (8%), pneumonia (6%), otitis (5%), herpesvirus infection (5%) - Investigations: renal insufficiency (9%), hyperglycemia (9%), hyperuricemia (8%), weight increase (8%), weight decrease (6%), hypomagnesemia (6%) - Psychiatric disorders: insomnia (9%), depression (7%) - Skin and subcutaneous disorders: xerosis (8%), alopecia (7%) - Nervous system disorders: dizziness (8%), peripheral neuropathy (7%) - Metabolism and nutrition disorders: decreased appetite (8%) - Respiratory disorders: dyspnea (7%) - General disorders: chills (7%) - Gastrointestinal disorders: vomiting (7%), abdominal pain (5%) - Injury, poisoning and procedural complications: fall (6%) - Musculoskeletal disorders: muscle spasms (5%) - Cardiovascular disorders: arrhythmia (5%) - Eye disorders: conjunctivitis (5%) - Selected Other Adverse Reactions Tumor lysis syndrome (<1%) Myocardial ischemia or infarction (<1%) Cardiac failure (<1%) - Tumor lysis syndrome (<1%) - Myocardial ischemia or infarction (<1%) - Cardiac failure (<1%) - Table 2 summarizes common treatment-emergent laboratory abnormalities having a ≥2% higher incidence with mogamulizumab than with vorinostat. - Other common treatment-emergent laboratory abnormalities in the mogamulizumab arm included hyperglycemia (52%; 4% Grade 3-4), anemia (35%; 2% Grade 3-4), thrombocytopenia (29%, none Grade 3-4), aspartate transaminase (AST) increased (25%; 2% Grade 3-4), alanine transaminase (ALT) increased (18%; 1% Grade 3-4), alkaline phosphatase increased (17%; 0% Grade 3-4), and neutropenia (10%; 2% Grade 3-4). Grade 4 treatment-emergent laboratory abnormalities observed in ≥1% of the mogamulizumab arm included lymphopenia (5%), leukopenia (1%), and hypophosphatemia (1%). ## Immunogenicity - As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to mogamulizumab with the incidences of antibodies in other studies or to other products may be misleading. - Among 258 patients treated with mogamulizumab in Trial 1, 10 (3.9%) tested positive for treatment-emergent (treatment-induced or treatment-boosted) anti-mogamulizumab antibodies by an electrochemiluminescent assay. There were no positive neutralizing antibody responses. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of mogamulizumab. 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. Infections: Hepatitis B virus reactivation Cardiac disorders: Stress cardiomyopathy - Infections: Hepatitis B virus reactivation - Cardiac disorders: Stress cardiomyopathy # Drug Interactions There is limited information regarding Mogamulizumab Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There are no available data on mogamulizumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of mogamulizumab to pregnant cynomolgus monkeys from the start of organogenesis through delivery did not show a potential for adverse developmental outcomes at maternal systemic exposures 27 times the exposure in patients at the recommended dose, based on AUC. In general, IgG molecules are known to cross the placental barrier and in the monkey reproduction study mogamulizumab was detected in fetal plasma. Therefore, mogamulizumab has the potential to be transmitted from the mother to the developing fetus. Mogamulizumab is not recommended during pregnancy or in women of childbearing potential not using contraception. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Animal Data - The effects of mogamulizumab on embryo-fetal development were evaluated in 12 pregnant cynomolgus monkeys that received mogamulizumab once weekly by intravenous administration from the start of organogenesis through delivery at an exposure level 27 times higher than the clinical dose. Mogamulizumab administration did not show a potential for embryo-fetal lethality, teratogenicity, or fetal growth retardation and did not result in spontaneous abortion or increased fetal death. In surviving fetuses (10 of 12 compared with 11 of 12 in the control group) of cynomolgus monkeys treated with mogamulizumab, a decrease in CCR4-expressing lymphocytes due to the pharmacological activity of mogamulizumab was noted; there were no apparent mogamulizumab -related external, visceral, or skeletal abnormalities. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mogamulizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mogamulizumab during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of mogamulizumab in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for mogamulizumab and any potential adverse effects on the breastfed child from mogamulizumab or from the underlying maternal condition. ### Pediatric Use - The safety and effectiveness of mogamulizumab in pediatric patients have not been established. ### Geriatic Use - Of 319 patients with MF or SS who received mogamulizumab in Trial 1, 162 (51%) were ≥65 years. No overall differences in effectiveness were observed between these patients and younger patients. In patients aged ≥65, Grade 3 or higher adverse reactions were reported in 45% and serious adverse reactions in 36%, whereas in patients aged <65, Grade 3 or higher adverse reactions were reported in 36% and serious adverse reactions in 29%. ### Gender There is no FDA guidance on the use of Mogamulizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mogamulizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mogamulizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mogamulizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Mogamulizumab is not recommended during pregnancy or in women of childbearing potential not using contraception. Pregnancy Testing - For females of reproductive potential, verify pregnancy status prior to initiating mogamulizumab. Contraception - Advise females of reproductive potential to use effective contraception during treatment with mogamulizumab and for at least 3 months following the last dose of mogamulizumab. ### Immunocompromised Patients There is no FDA guidance one the use of Mogamulizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended dose of mogamulizumab is 1 mg/kg administered as an intravenous infusion over at least 60 minutes. Administer on days 1, 8, 15, and 22 of the first 28-day cycle, then on days 1 and 15 of each subsequent 28-day cycle until disease progression or unacceptable toxicity. - Administer mogamulizumab within 2 days of the scheduled dose. If a dose is missed, administer the next dose as soon as possible and resume dosing schedule. - Do not administer mogamulizumab subcutaneously or by rapid intravenous administration. Recommended Premedications - Administer premedication with diphenhydramine and acetaminophen for the first mogamulizumab infusion. Preparation - Visually inspect drug product solution for particulate matter and discoloration prior to administration. Mogamulizumab is a clear to slightly opalescent colorless solution. Discard the vial if cloudiness, discoloration, or particulates are observed. - Calculate the dose (mg/kg) and number of vials of mogamulizumab needed to prepare the infusion solution based on patient weight. - Aseptically withdraw the required volume of mogamulizumab into the syringe and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP. The final concentration of the diluted solution should be between 0.1 mg/mL to 3.0 mg/mL. - Mix diluted solution by gentle inversion. Do not shake. - Discard any unused portion left in the vial. - The diluted solution is compatible with polyvinyl chloride (PVC) or polyolefin (PO) infusion bags. Administration - Administer infusion solution over at least 60 minutes through an intravenous line containing a sterile, low protein binding, 0.22 micron (or equivalent) in-line filter. - Do not mix mogamulizumab with other drugs. - Do not co-administer other drugs through the same intravenous line. Storage of Diluted Solution - After preparation, infuse the mogamulizumab solution immediately, or store under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 4 hours from the time of infusion preparation. - Do not freeze. Do not shake. ### Monitoring Dermatologic Toxicity - Permanently discontinue mogamulizumab for life-threatening (Grade 4) rash or for any Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). If SJS or TEN is suspected, stop mogamulizumab and do not resume unless SJS or TEN has been excluded and the cutaneous reaction has resolved to Grade 1 or less. - If moderate or severe (Grades 2 or 3) rash occurs, interrupt mogamulizumab and administer at least 2 weeks of topical corticosteroids. If rash improves to Grade 1 or less, mogamulizumab may be resumed. - If mild (Grade 1) rash occurs, consider topical corticosteroids. Infusion Reactions - Permanently discontinue mogamulizumab for a life-threatening (Grade 4) infusion reaction. - Temporarily interrupt the infusion of mogamulizumab for mild to severe (Grades 1 to 3) infusion reactions and treat symptoms. Reduce the infusion rate by at least 50% when restarting the infusion after symptoms resolve. If reaction recurs and is unmanageable, discontinue infusion. - If an infusion reaction occurs, administer premedication (such as diphenhydramine and acetaminophen) for subsequent mogamulizumab infusions. # IV Compatibility - Mogamulizumab is administered as an intravenous infusion. # Overdosage There is limited information regarding Mogamulizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Mogamulizumab is a defucosylated, humanized IgG1 kappa monoclonal antibody that binds to CCR4, a G protein-coupled receptor for CC chemokines that is involved in the trafficking of lymphocytes to various organs. Non-clinical in vitro studies demonstrate mogamulizumab binding targets a cell for antibody-dependent cellular cytotoxicity (ADCC) resulting in depletion of the target cells. CCR4 is expressed on the surface of some T-cell malignancies and is expressed on regulatory T-cells (Treg) and a subset of Th2 T-cells. ## Structure There is limited information regarding Mogamulizumab Structure in the drug label. ## Pharmacodynamics - Mogamulizumab exposure-response relationships and the time course of pharmacodynamics response are unknown. ## Pharmacokinetics - Mogamulizumab pharmacokinetics (PK) was evaluated in patients with T-cell malignancies. Parameters are presented as the geometric mean [% coefficient of variation (%CV)] unless otherwise specified. Mogamulizumab concentrations increased proportionally with dose over the dose range of 0.01 to 1.0 mg/kg (0.01 to 1 times the approved recommended dosage). - Following repeated dosing of the approved recommended dosage, steady state concentrations were reached after 8 doses (12 weeks), and the systemic accumulation was 1.6-fold. At steady state, the peak concentration (Cmax,ss) is 32 (68%) µg/mL, the trough concentration (Cmin,ss) is 11 (239%) µg/mL, and AUCss is 5577 (125%) µg∙hr/mL. Distribution - The central volume of distribution is 3.6 L (20%). Elimination - The terminal half-life is 17 days (66%), and the clearance is 12 mL/h (84%). Specific Populations: - No clinically significant changes in the PK of mogamulizumab were observed based on age (range: 22 to 101 years), sex, ethnicity, renal impairment (creatinine clearance <90 mL/min, estimated by Cockcroft-Gault), mild (total bilirubin ≤ ULN and AST <ULN, or total bilirubin <1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment, disease subtype (MF or SS), degree of CCR4 expression, or ECOG status. The effect of severe hepatic impairment (total bilirubin >3 times ULN and any AST) on mogamulizumab PK is unknown. Drug Interaction Studies - No drug interaction studies have been conducted with mogamulizumab. ## Nonclinical Toxicology - No carcinogenicity or genotoxicity studies have been conducted with mogamulizumab. - No specific studies have been conducted to evaluate potential effects of mogamulizumab on fertility. No mogamulizumab -related toxic effects in the male and female reproductive organs were observed in sexually mature monkeys in repeat-dose toxicology studies up to 26 weeks in duration. # Clinical Studies Trial 1 - A randomized, open-label, multicenter trial (Study 0761-010; NCT01728805) evaluated the efficacy of mogamulizumab in adult patients with MF or SS after at least one prior systemic therapy. The trial randomized 372 patients 1:1 to either mogamulizumab (186 patients; 56% with MF, 44% with SS) or vorinostat (186 patients; 53% with MF, 47% with SS). The trial included patients regardless of tumor CCR4 expression status and excluded patients with histologic transformation, prior allogeneic HSCT, autologous HSCT within 90 days, active autoimmune disease, or active infection. The trial required patients to have ANC ≥1500/µL (≥1000/µL if bone marrow was involved), platelet count ≥100,000/µL (≥75,000/µL if bone marrow was involved), creatinine clearance >50 mL/min or serum creatinine ≤1.5 mg/dL and hepatic transaminases ≤2.5 times ULN (≤5 times ULN if lymphomatous liver infiltration). - The dose of mogamulizumab was 1 mg/kg administered intravenously over at least 60 minutes on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of each subsequent cycle. Vorinostat was dosed at 400 mg orally once daily, continuously for 28-day cycles. Treatment continued until disease progression or unacceptable toxicity. Vorinostat-treated patients with disease progression or unacceptable toxicities were permitted to cross over to mogamulizumab. - The median age was 64 years (range: 25 to 101), 58% of patients were male, and 70% were white. At study baseline, 38% had stage IB-II disease, 10% stage III, and 52% stage IV. The median number of prior systemic therapies was 3. In the mogamulizumab arm, baseline CCR4 expression status by immunohistochemistry was available in 140 patients (75%), of whom all had CCR4 detected on ≥1% of lymphocytes on skin biopsy, and 134/140 (96%) had CCR4 detected on ≥10% of the lymphocytes. CCR4 expression status was similar in the vorinostat arm. - During randomized treatment, the median duration of exposure to mogamulizumab was 5.6 months (range: <1 to 45.3 months), with 48% of patients with at least 6 months of exposure and 23% with at least 12 months of exposure. The median duration of exposure to vorinostat was 2.8 months (range: <1 to 34.8 months), with 22% of patients with at least 6 months of exposure. - Efficacy was based on investigator-assessed progression-free survival (PFS), which was defined as the time from the date of randomization until documented progression of disease or death. Other efficacy measures included overall response rate (ORR) based on global composite response criteria that combine measures from each disease compartment (skin, blood, lymph nodes and viscera). Responses required confirmation at two successive disease assessments, which included the modified Severity Weighted Assessment Tool, skin photographs, central flow cytometry, and computed tomography. - The trial demonstrated that mogamulizumab significantly prolonged PFS compared to vorinostat (Table 3). The Kaplan-Meier curve for PFS by Investigator is shown in Figure 1. The estimated median follow-up for investigator-assessed PFS was 13 months in the mogamulizumab arm and 10.4 months in the vorinostat arm. By independent review committee assessment, the estimated median PFS was 6.7 months (95% CI, 5.6 to 9.4) in the mogamulizumab arm and 3.8 months (95% CI, 3.0 to 4.7) in the vorinostat arm (hazard ratio 0.64; 95% CI: 0.49, 0.84). - Table 3 also summarizes investigator-assessed confirmed response rates, overall and by disease compartment. The trial demonstrated improvement in ORR with mogamulizumab. # How Supplied - Mogamulizumab injection is a sterile, preservative-free, clear to slightly opalescent colorless solution supplied in a carton containing one 20 mg/5 mL (4 mg/mL), single-dose glass vial (NDC 42747-761-01). ## Storage - Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original package to protect from light until time of use. Do not freeze. Do not shake. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Patient Information). - Inform patients of the risk of the following adverse reactions that may require additional treatment and/or withholding or discontinuation of mogamulizumab including: Dermatological Toxicity: Advise patients to contact their healthcare provider immediately for new or worsening skin rash. Advise patients that the rash can happen at any time while receiving mogamulizumab. Infusion Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions. Infections: Advise patients to contact their health care provider for fever or other evidence of infection. Autoimmune Complications: Advise patients to notify their healthcare provider of any history of autoimmune disease. Complications of Allogeneic HSCT after mogamulizumab: Advise patients of potential risk of post-transplant complications. Females of Reproductive Potential: Advise use of effective contraception during treatment with mogamulizumab and for at least 3 months following the last dose of mogamulizumab. - Dermatological Toxicity: Advise patients to contact their healthcare provider immediately for new or worsening skin rash. Advise patients that the rash can happen at any time while receiving mogamulizumab. - Infusion Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions. - Infections: Advise patients to contact their health care provider for fever or other evidence of infection. - Autoimmune Complications: Advise patients to notify their healthcare provider of any history of autoimmune disease. - Complications of Allogeneic HSCT after mogamulizumab: Advise patients of potential risk of post-transplant complications. - Females of Reproductive Potential: Advise use of effective contraception during treatment with mogamulizumab and for at least 3 months following the last dose of mogamulizumab. # Precautions with Alcohol Alcohol-Mogamulizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Poteligeo # Look-Alike Drug Names There is limited information regarding Mogamulizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Mogamulizumab
210a2435f8f09552ad1326f065aa50aefbf20b4f	wikidoc	Molar (tooth)	Molar (tooth) # Overview Molars are the rearmost and most complicated kind of tooth in most mammals. In many mammals they grind food; hence the Latin name mola, "millstone". # Human molars Adult humans have twelve molars, in four groups of three at the back of the mouth. The third (rearmost) molar in each group is called a wisdom tooth. It is the last tooth to appear, breaking through the surface of the gum at about the age of twenty, although this varies by ethnicity. The types of molars in the human mouth are: - maxillary first molars, maxillary second molars, and maxillary third molars - mandibular first molars, mandibular second molars, and mandibular third molars # Molars among species Molars differ considerably from one species to another, so there are many terms describing them: - Tribosphenic: This kind is found in insectivores and young platypuses (adults have no teeth). Upper molars look like three-pointed mountain ranges; lowers look like two peaks and a third off to the side. - Quadrate: This kind is found in humans and various other species. Four cusps are arranged in a rectangle; there may be a fifth. - Bunodont: The cusps, instead of being sharp peaks, are rounded hills. The entire tooth is covered in enamel, and is most common among omnivores such as the pig, the bear and humans. - Hypsodont: There is a lot of enamel and dentine above the gumline and the top of the pulp. This kind of molar is found in mammals that wear their teeth a lot, such as the horse. - Zalambdodont: The tooth has two ridges that meet at an angle, forming the letter lambda. - Dilambdodont: Like zalambdodont, but there are two lambdas on one tooth. - Lophodont: The tooth has a few ridges perpendicular to the jaw. - Selenodont: The tooth has a crescent-shaped ridge or ridges. - Loxodont: The tooth has several parallel oblique ridges on its surface. The elephant Loxodonta is named for this feature. # Tribosphenic molar The molar design that is considered one of the most important characteristics of mammals is a three-cusped shape called a tribosphenic molar. This design of molar has two important features: the trigonoid, or shearing end, and the talinoid, or crushing heel. With the exception of Jurassic mammal Shuotherium, the talinoid is posterior the triginoid. The tribosphenic design appears in all species of mammals. In monotremes, it seems to have developed independently, rather than from common ancestry with marsupials and placentals. # Additional images - Molar 47 (left), molar 46 and premolar 45(right) Molar 47 (left), molar 46 and premolar 45(right) - Mouth (oral cavity) - Left maxilla. Outer surface. - Base of skull. Inferior surface. - The permanent teeth, viewed from the right.	Molar (tooth) Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Molars are the rearmost and most complicated kind of tooth in most mammals. In many mammals they grind food; hence the Latin name mola, "millstone". # Human molars Adult humans have twelve molars, in four groups of three at the back of the mouth. The third (rearmost) molar in each group is called a wisdom tooth. It is the last tooth to appear, breaking through the surface of the gum at about the age of twenty, although this varies by ethnicity. The types of molars in the human mouth are: - maxillary first molars, maxillary second molars, and maxillary third molars - mandibular first molars, mandibular second molars, and mandibular third molars # Molars among species Molars differ considerably from one species to another, so there are many terms describing them: - Tribosphenic: This kind is found in insectivores and young platypuses (adults have no teeth). Upper molars look like three-pointed mountain ranges; lowers look like two peaks and a third off to the side. - Quadrate: This kind is found in humans and various other species. Four cusps are arranged in a rectangle; there may be a fifth. - Bunodont: The cusps, instead of being sharp peaks, are rounded hills. The entire tooth is covered in enamel, and is most common among omnivores such as the pig, the bear and humans. - Hypsodont: There is a lot of enamel and dentine above the gumline and the top of the pulp. This kind of molar is found in mammals that wear their teeth a lot, such as the horse. - Zalambdodont: The tooth has two ridges that meet at an angle, forming the letter lambda. - Dilambdodont: Like zalambdodont, but there are two lambdas on one tooth. - Lophodont: The tooth has a few ridges perpendicular to the jaw. - Selenodont: The tooth has a crescent-shaped ridge or ridges. - Loxodont: The tooth has several parallel oblique ridges on its surface. The elephant Loxodonta is named for this feature. # Tribosphenic molar The molar design that is considered one of the most important characteristics of mammals is a three-cusped shape called a tribosphenic molar. This design of molar has two important features: the trigonoid, or shearing end, and the talinoid, or crushing heel. With the exception of Jurassic mammal Shuotherium, the talinoid is posterior the triginoid. The tribosphenic design appears in all species of mammals. In monotremes, it seems to have developed independently, rather than from common ancestry with marsupials and placentals. # Additional images - Molar 47 (left), molar 46 and premolar 45(right) Molar 47 (left), molar 46 and premolar 45(right) - Mouth (oral cavity) - Left maxilla. Outer surface. - Base of skull. Inferior surface. - The permanent teeth, viewed from the right. # External links For pictures of various molars see The Diversity of Cheek Teeth. Template:Head and neck general cs:Stolička da:Kindtand de:Molar (Zahn) eo:Vangodento#Molaro he:שן טוחנת it:Molare nl:Kies nds-nl:Koeze no:Jeksel sr:Кутњаци fi:Poskihammas sv:Molarer Template:WH Template:WS	https://www.wikidoc.org/index.php/Molar_(tooth)
41ea130ecd784ecea47810302fa5c2e54e650725	wikidoc	Mole fraction	Mole fraction In chemistry, the mole fraction of a component in a mixture is the relative proportion of molecules belonging to the component to those in the mixture, by number of molecules. It is one way of measuring concentration. It provides the most symmetrical way of representing thermodynamic functions of mixtures. For each component i, the mole fraction x_i is the number of moles n_i divided by the total number of moles in the system, n. where The sum is over all components, including the solvent in the case of a chemical solution. As indicated above, the same ratio is obtained using the number of molecules of i, N_i, and the total number of molecules of all kinds, N. where N_A is Avogadro's number ≈ 6.022 x 1023. By definition, the sum of the mole fractions equals one, a normalization property. Mole fractions are one way of representing the concentrations of the various chemical species. They are an ideal-mixture approximation to the effect of concentration on the equilbrium or rate of a reaction. In practice (except for very dilute solutions or for gasses at atmospheric pressure), all measures of concentration must be multiplied by correction factors called activity coefficients in order to yield accurate results. The mole fraction is sometimes denoted by the lower case Greek letter \chi (chi) instead of a Roman x. Mole fractions are dimensionless numbers. Other ways of representing concentrations, e.g., molarity and molality, yield dimensional quantities (per litre, per kilogram, etc.). When chemical formulas seem to be taking the logarithms of dimensional quantities, there is an implied ratio, and such expressions can always be rearranged so that the arguments of the logarithms are dimensionless numbers, as they must be. As an example, if a mixture is obtained by dissolving 10 moles of NaCl in 90 moles of water, the mole fraction of NaCl in that mixture is 0.1. For mixtures of molecules of differing sizes, see: volume fraction.	Mole fraction In chemistry, the mole fraction of a component in a mixture is the relative proportion of molecules belonging to the component to those in the mixture, by number of molecules. It is one way of measuring concentration. It provides the most symmetrical way of representing thermodynamic functions of mixtures. For each component <math>i</math>, the mole fraction <math>x_i</math> is the number of moles <math>n_i</math> divided by the total number of moles in the system, <math>n</math>. where The sum is over all components, including the solvent in the case of a chemical solution. As indicated above, the same ratio is obtained using the number of molecules of <math>i</math>, <math>N_i</math>, and the total number of molecules of all kinds, <math>N</math>. where <math>N_A</math> is Avogadro's number ≈ 6.022 x 1023. By definition, the sum of the mole fractions equals one, a normalization property. Mole fractions are one way of representing the concentrations of the various chemical species. They are an ideal-mixture approximation to the effect of concentration on the equilbrium or rate of a reaction. In practice (except for very dilute solutions or for gasses at atmospheric pressure), all measures of concentration must be multiplied by correction factors called activity coefficients in order to yield accurate results. The mole fraction is sometimes denoted by the lower case Greek letter <math>\chi</math> (chi) instead of a Roman <math>x</math>. Mole fractions are dimensionless numbers. Other ways of representing concentrations, e.g., molarity and molality, yield dimensional quantities (per litre, per kilogram, etc.). When chemical formulas seem to be taking the logarithms of dimensional quantities, there is an implied ratio, and such expressions can always be rearranged so that the arguments of the logarithms are dimensionless numbers, as they must be. As an example, if a mixture is obtained by dissolving 10 moles of NaCl in 90 moles of water, the mole fraction of NaCl in that mixture is 0.1. For mixtures of molecules of differing sizes, see: volume fraction.	https://www.wikidoc.org/index.php/Mole_fraction
3c1de1e0a23ad1cb4adb148d99bfa57338cf9310	wikidoc	Motor protein	Motor protein # Overview Motor proteins are a class of molecular motors that are able to move along the surface of a suitable substrate. They are powered by the hydrolysis of ATP and convert chemical energy into mechanical work. # Cellular functions The most prominent example of a motor protein is the muscle protein myosin which "motors" the contraction of muscle fibers in animals. Motor proteins are the driving force behind most active transport of proteins and vesicles in the cytoplasm. Kinesins and dyneins play essential roles in intracellular transport such as axonal transport and in the formation of the spindle apparatus and the separation of the chromosomes during mitosis and meiosis. Dynein is found in flagella and is crucial to cell motility, for example in spermatozoa. # Diseases associated with motor protein defects The importance of motor proteins in cells becomes evident when they fail to fulfill their function. For example, kinesin deficiencies have been identified as cause for Charcot-Marie-Tooth disease and some kidney diseases. Dynein deficiencies can lead to chronic infections of the respiratory tract as cilia fail to function without dynein. Defects in muscular myosin predictably cause myopathies, whereas defects in unconventional myosin are the cause for Usher syndrome and deafness. # Structure Most eukaryotic motor proteins consist of two distinct domains: A motor head domain with ATPase function and a tail domain that can either form fibers (muscle myosin) or attach to a cargo such as for example chromosomes during anaphase of mitosis (kinesin) or vesicles during endocytosis (dynein). The head domain of the proteins carries out the movement by binding to a specific site on the substrate and changing conformation depending on ATP hydrolysis. The tail end of the molecule normally binds adaptor proteins that allow for stable interactions with the cargo to be moved along the substrate. These motor proteins typically form a complex of longer "heavy chains" with motor head domains and shorter "light chains" for stabilization. # Cytoskeletal motor proteins Motor proteins utilizing the cytoskeleton for movement fall into two categories based on their substrates: Actin motors such as myosin move along microfilaments through interaction with actin. Microtubule motors such as dynein and kinesin move along microtubules through interaction with tubulin. There are two basic types of microtubule motors: plus-end motors and minus-end motors, depending on the direction in which they "walk" along the microtubule cables within the cell. ## Actin motors ### Myosin Myosins are actin motors and form myosin complexes consisting of two heavy chains with motor heads and two light chains. Derived from the Greek word for muscle, myosin is the protein responsible for generating muscle contraction. By non-processively walking along actin filaments, many molecules of myosin generate enough force to contract muscle tissue. Myosins are also vital in the process of cell division. They are also involved in cytoplasmic streaming, wherein movement along microfilament networks in the cell allows organelles and cytoplasm to stream in a particular direction. Eighteen different classes of myosins are known. Genomic representation of myosin motors: - Fungi (yeast): 5 - Plants (Arabidopsis): 17 - Insects (Drosophila): 13 - Mammals (human): 40 ## Microtubule motors ### Kinesin Kinesins are a group of related motor proteins that use a microtubule track along which to "walk." They are vital to movement of chromosomes during mitosis and are also responsible for shuttling mitochondria, Golgi bodies, and vesicles within eukaryotic cells. Kinesins typically contain two heavy chains with motor heads which move along microtubules via a pseudo-processive asymmetric walking motion, that can be towards the plus-end or the minus-end, depending on the type of kinesin. Fourteen distinct kinesin families are known, with some additional kinesin-like proteins that cannot be classified into these families. Genomic representation of kinesin motors: - Fungi (yeast): 6 - Plants (Arabidopsis): 61 - Insects (Drosophila): 25 - Mammals (human): 45 ### Dynein Dyneins are microtubule motors capable of a sliding movement. Dynein complexes are much larger and more complex than kinesin and myosin motors. Dynein facilitates the movement of cilia and flagella. Compared to 15 types of dynein for this function, only two cytoplasmic forms are known. Genomic representation of dynein motors: - Fungi (yeast): 1 - Plants (Arabidopsis): 0 - Insects (Drosophila): 13 - Mammals (human): 14-15 ## Plant-specific motors In contrast to animals, fungi and non-vascular plants, the cells of flowering plants lack dynein motors. However, they contain a larger number of different kinesins. Many of these plant-specific kinesin groups are specialized for functions during plant cell mitosis. Plant cells differ from animal cells in that they have a cell wall. During mitosis, the new cell wall is built by the formation of a cell plate starting in the center of the cell. This process is facilitated by a phragmoplast, a microtubule array unique to plant cell mitosis. The building of cell plate and ultimately the new cell wall requires kinesin-like motor proteins. Another motor protein essential for plant cell division is kinesin-like calmodulin-binding protein (KCBP), which is unique to plants and part kinesin and part myosin. # Other molecular motors Besides the motor proteins above, there are many more types of proteins capable of generating forces and torque in the cell. Among the processes regulated by force-generating proteins are: - transcription of RNA - DNA replication - chromatin remodeling - chromosome condensation by SMC proteins - Helicases Many of the molecular motors that regulate these processes are ubiquitous in both prokaryotic and eukaryotic cells, although some, like those involved with cytoskeletal elements or chromatin, are unique to eukaryotes.	Motor protein # Overview Motor proteins are a class of molecular motors that are able to move along the surface of a suitable substrate. They are powered by the hydrolysis of ATP and convert chemical energy into mechanical work. # Cellular functions The most prominent example of a motor protein is the muscle protein myosin which "motors" the contraction of muscle fibers in animals. Motor proteins are the driving force behind most active transport of proteins and vesicles in the cytoplasm. Kinesins and dyneins play essential roles in intracellular transport such as axonal transport and in the formation of the spindle apparatus and the separation of the chromosomes during mitosis and meiosis. Dynein is found in flagella and is crucial to cell motility, for example in spermatozoa. # Diseases associated with motor protein defects The importance of motor proteins in cells becomes evident when they fail to fulfill their function. For example, kinesin deficiencies have been identified as cause for Charcot-Marie-Tooth disease and some kidney diseases. Dynein deficiencies can lead to chronic infections of the respiratory tract as cilia fail to function without dynein. Defects in muscular myosin predictably cause myopathies, whereas defects in unconventional myosin are the cause for Usher syndrome and deafness.[1] # Structure Most eukaryotic motor proteins consist of two distinct domains: A motor head domain with ATPase function and a tail domain that can either form fibers (muscle myosin) or attach to a cargo such as for example chromosomes during anaphase of mitosis (kinesin) or vesicles during endocytosis (dynein). The head domain of the proteins carries out the movement by binding to a specific site on the substrate and changing conformation depending on ATP hydrolysis. The tail end of the molecule normally binds adaptor proteins that allow for stable interactions with the cargo to be moved along the substrate.[2] These motor proteins typically form a complex of longer "heavy chains" with motor head domains and shorter "light chains" for stabilization. # Cytoskeletal motor proteins Motor proteins utilizing the cytoskeleton for movement fall into two categories based on their substrates: Actin motors such as myosin move along microfilaments through interaction with actin. Microtubule motors such as dynein and kinesin move along microtubules through interaction with tubulin. There are two basic types of microtubule motors: plus-end motors and minus-end motors, depending on the direction in which they "walk" along the microtubule cables within the cell. ## Actin motors ### Myosin Myosins are actin motors and form myosin complexes consisting of two heavy chains with motor heads and two light chains. Derived from the Greek word for muscle, myosin is the protein responsible for generating muscle contraction. By non-processively walking along actin filaments, many molecules of myosin generate enough force to contract muscle tissue. Myosins are also vital in the process of cell division. They are also involved in cytoplasmic streaming, wherein movement along microfilament networks in the cell allows organelles and cytoplasm to stream in a particular direction. Eighteen different classes of myosins are known.[3] Genomic representation of myosin motors: [4] - Fungi (yeast): 5 - Plants (Arabidopsis): 17 - Insects (Drosophila): 13 - Mammals (human): 40 ## Microtubule motors ### Kinesin Kinesins are a group of related motor proteins that use a microtubule track along which to "walk." They are vital to movement of chromosomes during mitosis and are also responsible for shuttling mitochondria, Golgi bodies, and vesicles within eukaryotic cells. Kinesins typically contain two heavy chains with motor heads which move along microtubules via a pseudo-processive asymmetric walking motion, that can be towards the plus-end or the minus-end, depending on the type of kinesin. Fourteen distinct kinesin families are known, with some additional kinesin-like proteins that cannot be classified into these families.[5] Genomic representation of kinesin motors: [4] - Fungi (yeast): 6 - Plants (Arabidopsis): 61 - Insects (Drosophila): 25 - Mammals (human): 45 ### Dynein Dyneins are microtubule motors capable of a sliding movement. Dynein complexes are much larger and more complex than kinesin and myosin motors. Dynein facilitates the movement of cilia and flagella. Compared to 15 types of dynein for this function, only two cytoplasmic forms are known.[6] Genomic representation of dynein motors: [4] - Fungi (yeast): 1 - Plants (Arabidopsis): 0 - Insects (Drosophila): 13 - Mammals (human): 14-15 ## Plant-specific motors In contrast to animals, fungi and non-vascular plants, the cells of flowering plants lack dynein motors. However, they contain a larger number of different kinesins. Many of these plant-specific kinesin groups are specialized for functions during plant cell mitosis.[7] Plant cells differ from animal cells in that they have a cell wall. During mitosis, the new cell wall is built by the formation of a cell plate starting in the center of the cell. This process is facilitated by a phragmoplast, a microtubule array unique to plant cell mitosis. The building of cell plate and ultimately the new cell wall requires kinesin-like motor proteins.[8] Another motor protein essential for plant cell division is kinesin-like calmodulin-binding protein (KCBP), which is unique to plants and part kinesin and part myosin.[9] # Other molecular motors Besides the motor proteins above, there are many more types of proteins capable of generating forces and torque in the cell. Among the processes regulated by force-generating proteins are: - transcription of RNA - DNA replication - chromatin remodeling - chromosome condensation by SMC proteins[10] - Helicases Many of the molecular motors that regulate these processes are ubiquitous in both prokaryotic and eukaryotic cells, although some, like those involved with cytoskeletal elements or chromatin, are unique to eukaryotes.	https://www.wikidoc.org/index.php/Molecular_motors
2585eb391c27b3637d5255c8a45736e385dfb717	wikidoc	Monoglyceride	Monoglyceride A monoglyceride, more correctly known as a monoacylglycerol, is a glyceride consisting of one fatty acid chain covalently bonded to a glycerol molecule through an ester linkage. Monoacylglycerol can be broadly divided into two groups; 1-monoacylglycerols and 2-monoacylglycerols, depending on the position of the ester bond on the glycerol moiety. Monoacylglycerols can be formed by both industrial chemical and biological processes. They are formed biochemically via release of a fatty acid from diacylglycerol by diacylglycerol lipase or hormone sensitive lipase. Monoacylglycerols are broken down by monoacylglycerol lipase. Mono- and Diglycerides are commonly added to commercial food products in small quantities. They act as emulsifiers, helping to mix ingredients such as oil and water that would not otherwise blend well. The commercial source may be either animal (cow- or hog-derived) or vegetable, and they may be synthetically made as well. They are often found in bakery products, beverages, ice cream, chewing gum, shortening, whipped toppings, margarine, and confections. One special monoacylglycerol, 2-arachidonoylglycerol, is a full agonist of the cannabinoid receptors and thus classified as an endocannabinoid. he:מונוגליצריד	Monoglyceride A monoglyceride, more correctly known as a monoacylglycerol, is a glyceride consisting of one fatty acid chain covalently bonded to a glycerol molecule through an ester linkage. Monoacylglycerol can be broadly divided into two groups; 1-monoacylglycerols and 2-monoacylglycerols, depending on the position of the ester bond on the glycerol moiety. Monoacylglycerols can be formed by both industrial chemical and biological processes. They are formed biochemically via release of a fatty acid from diacylglycerol by diacylglycerol lipase or hormone sensitive lipase. Monoacylglycerols are broken down by monoacylglycerol lipase. Mono- and Diglycerides are commonly added to commercial food products in small quantities. They act as emulsifiers, helping to mix ingredients such as oil and water that would not otherwise blend well. The commercial source may be either animal (cow- or hog-derived) or vegetable, and they may be synthetically made as well. They are often found in bakery products, beverages, ice cream, chewing gum, shortening, whipped toppings, margarine, and confections. One special monoacylglycerol, 2-arachidonoylglycerol, is a full agonist of the cannabinoid receptors and thus classified as an endocannabinoid. Template:Glycerides Template:Ester-stub he:מונוגליצריד Template:WH Template:WS	https://www.wikidoc.org/index.php/Monoglyceride
d4d824616464cf50394f099c07f8482c7cab0331	wikidoc	Monterey Pine	Monterey Pine Pinus radiata (family Pinaceae) is known in English as Monterey Pine in some parts of the world (mainly in the USA, Canada and the British Isles), and Radiata Pine in others (primarily Australia, New Zealand). It is a species of pine native to coastal California in three very limited areas in Santa Cruz, Monterey and San Luis Obispo Counties, and (as the variety Pinus radiata var. binata, Guadalupe Pine) on Guadalupe Island and (possibly separable as var./ssp. cedrosensis) Cedros Island off the west coast of Baja California, Mexico. It is also extensively cultivated in many other warm temperate parts of the world. P. radiata grows to between 15-30 m in height in the wild, but up to 60 m in cultivation in optimum conditions, with upward pointing branches and a rounded top. The leaves ('needles') are bright green, in clusters of three (two in var. binata), slender, 8-15 cm long and with a blunt tip. The cones are 7-17 cm long, brown, ovoid (egg-shaped), and usually set asymmetrically on a branch, attached at an oblique angle. The bark is fissured and dark grey to brown. It is closely related to Bishop Pine and Knobcone Pine, hybridizing readily with both species; it is distinguished from the former by needles in threes (not pairs), and from both by the cones not having a sharp spine on the scales. ## Ecology and status The forests associated with Monterey Pine are associated with other flora and fauna of note. In particular, the pine forest in Monterey, California was the discovery site for Hickman's potentilla, an endangered species. Piperia yadonii, a rare species of orchid is endemic to the same pine forest adjacent to Pebble Beach. Nearby in a remnant pine forest of Pacific Grove, is a prime wintering habitat of the Monarch butterfly . In the wild, the Monterey Pine proper is seriously threatened in California by an introduced fungal disease, Pine Pitch Canker, caused by Fusarium circinatum. On Guadalupe Island, var. binata is critically endangered. Most of the population was destroyed as a consequence of tens of thousands of feral goats eating each and every seedling that germinated since the mid-19th century, the old plants dying off by and by. The population stood at a low of maybe 100 in 2001-02. With the removal of goats essentially complete after 2005, the tree population can now recover; hundreds of young Guadalupe Pines have started to grow up in habitat fenced after 2001, the first time this has happened in 150 years or so. Accidental introduction of Pitch Pine Canker to Guadalupe is considered the biggest threat to the population's survival at present. ## Cultivation and uses It is a fast-growing tree, adaptable to a broad range of soil types and climates, though does not tolerate temperatures below about -15°C. Its fast growth makes it ideal for forestry; in a good situation, P. radiata can reach its full height in 40 years or so. It was first introduced into New Zealand in the 1850s; today, over 90% of the country's plantation forests are of this species. This includes the Kaingaroa Forest on the central plateau of the North Island which is the largest planted forest in the world. Australia also has massive Radiata Pine plantations; so much so that many Australians are concerned by the resulting loss of native wildlife habitat. A few native animals, however, thrive on P. radiata, notably the Yellow-tailed Black Cockatoo which, although deprived of much of its natural diet by massive habitat alteration, feeds on P. radiata seeds. P. radiata has also been introduced to the Valdivian temperate rain forests of southern Chile, where vast plantations have been planted for timber, again displacing the native forests. In areas such as New Zealand this tree has become naturalized, and is considered an invasive weed where it has escaped from plantations. - Detail of bark Detail of bark - Needles and spikes Needles and spikes - Pine cone on forest floor Pine cone on forest floor - Monterey Pine plantation, Australia Monterey Pine plantation, Australia # Footnotes - ↑ Junak et al. (2003), León de la Luz et al. (2003)	Monterey Pine Pinus radiata (family Pinaceae) is known in English as Monterey Pine in some parts of the world (mainly in the USA, Canada and the British Isles), and Radiata Pine in others (primarily Australia, New Zealand). It is a species of pine native to coastal California in three very limited areas in Santa Cruz, Monterey and San Luis Obispo Counties, and (as the variety Pinus radiata var. binata, Guadalupe Pine) on Guadalupe Island and (possibly separable as var./ssp. cedrosensis) Cedros Island off the west coast of Baja California, Mexico. It is also extensively cultivated in many other warm temperate parts of the world. P. radiata grows to between 15-30 m in height in the wild, but up to 60 m in cultivation in optimum conditions, with upward pointing branches and a rounded top. The leaves ('needles') are bright green, in clusters of three (two in var. binata), slender, 8-15 cm long and with a blunt tip. The cones are 7-17 cm long, brown, ovoid (egg-shaped), and usually set asymmetrically on a branch, attached at an oblique angle. The bark is fissured and dark grey to brown. It is closely related to Bishop Pine and Knobcone Pine, hybridizing readily with both species; it is distinguished from the former by needles in threes (not pairs), and from both by the cones not having a sharp spine on the scales. ## Ecology and status The forests associated with Monterey Pine are associated with other flora and fauna of note. In particular, the pine forest in Monterey, California was the discovery site for Hickman's potentilla, an endangered species. Piperia yadonii, a rare species of orchid is endemic to the same pine forest adjacent to Pebble Beach. Nearby in a remnant pine forest of Pacific Grove, is a prime wintering habitat of the Monarch butterfly [1]. In the wild, the Monterey Pine proper is seriously threatened in California by an introduced fungal disease, Pine Pitch Canker, caused by Fusarium circinatum. On Guadalupe Island, var. binata is critically endangered. Most of the population was destroyed as a consequence of tens of thousands of feral goats eating each and every seedling that germinated since the mid-19th century, the old plants dying off by and by. The population stood at a low of maybe 100 in 2001-02. With the removal of goats essentially complete after 2005, the tree population can now recover; hundreds of young Guadalupe Pines have started to grow up in habitat fenced after 2001, the first time this has happened in 150 years or so. Accidental introduction of Pitch Pine Canker to Guadalupe is considered the biggest threat to the population's survival at present.[1] ## Cultivation and uses It is a fast-growing tree, adaptable to a broad range of soil types and climates, though does not tolerate temperatures below about -15°C. Its fast growth makes it ideal for forestry; in a good situation, P. radiata can reach its full height in 40 years or so. It was first introduced into New Zealand in the 1850s; today, over 90% of the country's plantation forests are of this species. This includes the Kaingaroa Forest on the central plateau of the North Island which is the largest planted forest in the world. Australia also has massive Radiata Pine plantations; so much so that many Australians are concerned by the resulting loss of native wildlife habitat. A few native animals, however, thrive on P. radiata, notably the Yellow-tailed Black Cockatoo which, although deprived of much of its natural diet by massive habitat alteration, feeds on P. radiata seeds. P. radiata has also been introduced to the Valdivian temperate rain forests of southern Chile, where vast plantations have been planted for timber, again displacing the native forests. In areas such as New Zealand this tree has become naturalized, and is considered an invasive weed where it has escaped from plantations. - Detail of bark Detail of bark - Needles and spikes Needles and spikes - Pine cone on forest floor Pine cone on forest floor - Monterey Pine plantation, Australia Monterey Pine plantation, Australia # Footnotes - ↑ Junak et al. (2003), León de la Luz et al. (2003)	https://www.wikidoc.org/index.php/Monterey_Pine
dbc963e5737aa86890629a843af7e997b2c8c0d5	wikidoc	Pinus radiata	Pinus radiata # Overview The Monterey Pine, Pinus radiata, family Pinaceae, also known as the Insignis Pine or Radiata Pine is a species of pine native to the Central Coast of California. It is the most widely planted pine in the world, valued for rapid growth and desirable lumber and pulp qualities. Although Pinus radiata is extensively cultivated as a plantation timber in many temperate parts of the world, it faces serious threats in its natural range. # Distribution It is native to three very limited areas located in Santa Cruz, Monterey Peninsula, and San Luis Obispo Counties. It is also found as the variety Pinus radiata var. binata or Guadalupe Pine on Guadalupe Island, and a possibly separable P. radiata var./subspecies—ssp. cedrosensis on Cedros Island, both in the Pacific Ocean off the west coast of the northern Baja California Peninsula in Mexico. In Australia, New Zealand, and Spain it is the leading introduced tree and in Argentina, Chile, Uruguay, Kenya, and South Africa it is a major plantation species. # Description It is closely related to Bishop Pine and Knobcone Pine, hybridizing readily with both species; it is distinguished from the former by needles in threes (not pairs), and from both by the cones not having a sharp spine on the scales. The modern tree is vastly different from the native tree of Monterey. In plantations the tree is commonly planted at 3m x 3m spacing on a wide variety of landscapes from flat to moderatly steep hills.Because of selective breeding and more recently the extensive use of Growth Factor seedlings, forests planted since the 1990s are of superior wood with very straight tall trunks without the problem of twin leaders. The trees are pruned in 3 lifts so that the lower 2/3 of a mature tree is branch- ( and hence knot-) free. In its natural state, the wood is poor quality: twisted, knotty and full of sap/resin only really suitable for firewood, but the modern product is very different. # Ecology Monterey Pine is a species adapted to cope with stand-killing fire disturbance. Its cones are serotinous, i.e. they remain closed until opened by the heat of a forest fire; the abundant seeds are then discharged to regenerate on the burned forest floor. The cones may also burst open in hot weather. In its native range, Monterey Pine is associated with a characteristic flora and fauna. It is the co-dominant canopy tree together with Cupressus macrocarpa which naturally occurs only in coastal Monterey County. Furthermore, one of the pine forests in Monterey, California, was the discovery site for Hickman's potentilla, an endangered species. Piperia yadonii, a rare species of orchid is endemic to the same pine forest adjacent to Pebble Beach. In its native range, Monterey Pine is a principal host for the dwarf mistletoe Arceuthobium littorum. A remnant Monterey Pine stand in Pacific Grove is a prime wintering habitat of the Monarch butterfly. # Conservation status ## California The three remaining wild stands of var. radiata (Monterey Pine proper) are infected and under threat of extirpation from Pine Pitch Canker caused by Fusarium circinatum, a fungal disease native to the southeast United States and found (in 1986) to have been introduced to California. When trees begin to die of the disease, they attract bark beetles which provide a pathway for infection of other trees. In some stands, 80–90% of trees are infected. If the disease is introduced in agroforestry areas dependent upon Monterey Pine, such as New Zealand, it could have catastrophic effects in those countries as well. ## Baja California On Guadalupe Island, var. binata is critically endangered. Most of the population was destroyed as tens of thousands of feral goats ate binata seedlings and caused soil erosion from the mid-19th century until just a few years ago. The older trees gradually died off until by 2001–2002 the population stood at only one hundred. With a program to remove the goats essentially complete by 2005, hundreds of young Guadalupe Pines have started to grow up in habitat fenced after 2001, the first significant new growth in about 150 years. Possible accidental introduction of Pine Pitch Canker is considered the biggest threat at present to the survival of the Guadalupe Island pine population. The University of California's Russell Reservation forestry research station hosts an orchard planted with 73 Pinus radiata seedlings from Guadalupe Island and plays an important role in conserving the binata variety. # Cultivation ## Australia Australia has large P. radiata plantations (though they are less than 2% of the total forested area); so much so that many Australians are concerned by the resulting loss of native wildlife habitat. A few native animals, however, thrive on them, notably the Yellow-tailed Black Cockatoo which, although deprived of much of its natural diet by massive habitat alteration through clearing for agriculture, feeds on P. radiata seeds. They are also the most common tree used for Christmas trees in Australia. ## Chile P. radiata has also been introduced to the Valdivian temperate rain forests, where vast plantations have been planted for timber, again displacing the native forests. ## New Zealand The Monterey Pine (always called Pinus radiata in New Zealand) was first introduced into New Zealand in 1859 and today 89% of the country's plantation forests are of this species. This includes the Kaingaroa Forest on the central plateau of the North Island which is the largest planted forest in the world. Mass plantings became common from 1900 in the Rotorua area where prison labour was used. In some areas it is considered an invasive species (termed a wilding conifer or more commonly wilding pine) where it has escaped from plantations. It is the most extensively used wood in New Zealand. A 1995 change to the New Zealand building regulations no longer required boron treatment of radiata pine to be used for framing houses, a key factor in the subsequent expensive leaky homes crisis. From 2003 onward a series of changes have now improved the regulations. ## United States The Monterey Pine is widely used in private gardens and public landscapes in temperate California, and similar climates around the world. It is a fast-growing tree, adaptable to a broad range of soil types and climates, though does not tolerate temperatures below about −15 °C (Expression error: Missing operand for *. ). Its fast growth makes it ideal for landscapes and forestry; in a good situation, P. radiata can reach its full height in 40 years or so. ## United Kingdom P. radiata is grown as an ornamental tree in parks and gardens, and has gained the Royal Horticultural Society's Award of Garden Merit. # Uses As timber Radiata is suitable for a wide variety of uses. It holds screws and nails well and takes paint and stain without difficulty - and modern kiln dried timber is very easy to work. It is about 1/3 heavier than dried western Red cedar and about the same weight as New Zealand and Fijian Kauri. It is brittle when bent, so does not have the same load bearing features as Oregon pine (Douglas fir, Pseudotsuga). Radiata is used in house construction as weatherboards, posts, beams or plywood, in fencing, retaining walls, for concrete formers - and to a limited extent in boat building where untreated ply is sometimes used, but must be encased in epoxy resin to exclude moisture. The wood is normally kiln dried to 12% moisture in 6m long, clear lengths. It is available treated with a range of chemical salts, or untreated. Chemical salt treatment is well proven and such timber is frequently used in the ground as posts and poles as part of structures such as retaining walls and pole houses. The name applied to this treatment is tanalized wood. H1 and H2 treatment is suited to indoor use. H3 is the standard house timber and this grade is used for fence palings. H4 and H5 are the standard for inground use. Lower grade timber is converted to pulp to make newsprint. Higher grade timber is used in house construction. Radiata is used chipped to make particle board sheets, commonly used in flooring. Other sheet products are hardboard, softboard and ply. Plywood is peeled from logs in long sheets. Most ply is structural and available in 7-22mm sizes. A small amount of higher grade ply is used to produce thinner (4 and 7mm) ply suitable for furniture, cabinet work and boat building. This is knot and crack free and glued with resorcinol waterproof glue. Since the 1990s finger jointed joinery grade wood has become available in up to 6m lengths in a wide range of profiles. In 1958, boat designer Des Townson started building 186 eleven-foot, cold-moulded Zepher class yachts, using Pinus radiata. In 2011 these hand built boats fetch very high prices and are generally in excellent condition.	Pinus radiata Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Monterey Pine, Pinus radiata, family Pinaceae, also known as the Insignis Pine[1] or Radiata Pine is a species of pine native to the Central Coast of California. It is the most widely planted pine in the world, valued for rapid growth and desirable lumber and pulp qualities. Although Pinus radiata is extensively cultivated as a plantation timber in many temperate parts of the world,[2] it faces serious threats in its natural range.[3] # Distribution It is native to three very limited areas located in Santa Cruz, Monterey Peninsula, and San Luis Obispo Counties. It is also found as the variety Pinus radiata var. binata or Guadalupe Pine on Guadalupe Island, and a possibly separable P. radiata var./subspecies—ssp. cedrosensis on Cedros Island, both in the Pacific Ocean off the west coast of the northern Baja California Peninsula in Mexico. In Australia, New Zealand, and Spain it is the leading introduced tree[citation needed] and in Argentina, Chile, Uruguay, Kenya, and South Africa it is a major plantation species. # Description It is closely related to Bishop Pine and Knobcone Pine, hybridizing readily with both species; it is distinguished from the former by needles in threes (not pairs), and from both by the cones not having a sharp spine on the scales. The modern tree is vastly different from the native tree of Monterey. In plantations the tree is commonly planted at 3m x 3m spacing on a wide variety of landscapes from flat to moderatly steep hills.Because of selective breeding and more recently the extensive use of Growth Factor seedlings, forests planted since the 1990s are of superior wood with very straight tall trunks without the problem of twin leaders. The trees are pruned in 3 lifts so that the lower 2/3 of a mature tree is branch- ( and hence knot-) free. In its natural state, the wood is poor quality: twisted, knotty and full of sap/resin only really suitable for firewood, but the modern product is very different. # Ecology Monterey Pine is a species adapted to cope with stand-killing fire disturbance. Its cones are serotinous, i.e. they remain closed until opened by the heat of a forest fire; the abundant seeds are then discharged to regenerate on the burned forest floor. The cones may also burst open in hot weather.[4] In its native range, Monterey Pine is associated with a characteristic flora and fauna. It is the co-dominant canopy tree together with Cupressus macrocarpa which naturally occurs only in coastal Monterey County.[5] Furthermore, one of the pine forests in Monterey, California, was the discovery site for Hickman's potentilla, an endangered species. Piperia yadonii, a rare species of orchid is endemic to the same pine forest adjacent to Pebble Beach. In its native range, Monterey Pine is a principal host for the dwarf mistletoe Arceuthobium littorum.[6] A remnant Monterey Pine stand in Pacific Grove is a prime wintering habitat of the Monarch butterfly.[7] # Conservation status ## California The three remaining wild stands of var. radiata (Monterey Pine proper) are infected and under threat of extirpation from Pine Pitch Canker caused by Fusarium circinatum, a fungal disease native to the southeast United States and found (in 1986) to have been introduced to California. When trees begin to die of the disease, they attract bark beetles which provide a pathway for infection of other trees. In some stands, 80–90% of trees are infected. If the disease is introduced in agroforestry areas dependent upon Monterey Pine, such as New Zealand, it could have catastrophic effects in those countries as well.[2] ## Baja California On Guadalupe Island, var. binata is critically endangered. Most of the population was destroyed as tens of thousands of feral goats ate binata seedlings and caused soil erosion from the mid-19th century until just a few years ago. The older trees gradually died off until by 2001–2002 the population stood at only one hundred. With a program to remove the goats essentially complete by 2005, hundreds of young Guadalupe Pines have started to grow up in habitat fenced after 2001, the first significant new growth in about 150 years. Possible accidental introduction of Pine Pitch Canker is considered the biggest threat at present to the survival of the Guadalupe Island pine population.[8] The University of California's Russell Reservation forestry research station hosts an orchard planted with 73 Pinus radiata seedlings from Guadalupe Island and plays an important role in conserving the binata variety.[9] # Cultivation ## Australia Australia has large P. radiata plantations (though they are less than 2% of the total forested area); so much so that many Australians are concerned by the resulting loss of native wildlife habitat. A few native animals, however, thrive on them, notably the Yellow-tailed Black Cockatoo which, although deprived of much of its natural diet by massive habitat alteration through clearing for agriculture, feeds on P. radiata seeds. They are also the most common tree used for Christmas trees in Australia. ## Chile P. radiata has also been introduced to the Valdivian temperate rain forests, where vast plantations have been planted for timber, again displacing the native forests.[10] ## New Zealand The Monterey Pine (always called Pinus radiata in New Zealand) was first introduced into New Zealand in 1859[11][12] and today 89% of the country's plantation forests are of this species.[13] This includes the Kaingaroa Forest on the central plateau of the North Island which is the largest planted forest in the world. Mass plantings became common from 1900 in the Rotorua area where prison labour was used. In some areas it is considered an invasive species (termed a wilding conifer or more commonly wilding pine) where it has escaped from plantations. It is the most extensively used wood in New Zealand. A 1995 change to the New Zealand building regulations no longer required boron treatment of radiata pine to be used for framing houses,[14] a key factor in the subsequent expensive[15] leaky homes crisis. From 2003[16] onward a series of changes have now improved the regulations. ## United States The Monterey Pine is widely used in private gardens and public landscapes in temperate California, and similar climates around the world. It is a fast-growing tree, adaptable to a broad range of soil types and climates, though does not tolerate temperatures below about −15 °C (Expression error: Missing operand for *. ). Its fast growth makes it ideal for landscapes and forestry; in a good situation, P. radiata can reach its full height in 40 years or so. ## United Kingdom P. radiata is grown as an ornamental tree in parks and gardens, and has gained the Royal Horticultural Society's Award of Garden Merit.[17] # Uses As timber Radiata is suitable for a wide variety of uses.[18] It holds screws and nails well and takes paint and stain without difficulty - and modern kiln dried timber is very easy to work.[19] It is about 1/3 heavier than dried western Red cedar and about the same weight as New Zealand and Fijian Kauri. It is brittle when bent, so does not have the same load bearing features as Oregon pine (Douglas fir, Pseudotsuga). Radiata is used in house construction as weatherboards, posts, beams or plywood, in fencing, retaining walls, for concrete formers - and to a limited extent in boat building where untreated ply is sometimes used, but must be encased in epoxy resin to exclude moisture. The wood is normally kiln dried to 12% moisture in 6m long, clear lengths. It is available treated with a range of chemical salts, or untreated. Chemical salt treatment is well proven and such timber is frequently used in the ground as posts and poles as part of structures such as retaining walls and pole houses. The name applied to this treatment is tanalized wood. H1 and H2 treatment is suited to indoor use. H3 is the standard house timber and this grade is used for fence palings. H4 and H5 are the standard for inground use. Lower grade timber is converted to pulp to make newsprint.[20] Higher grade timber is used in house construction. Radiata is used chipped to make particle board sheets, commonly used in flooring. Other sheet products are hardboard, softboard and ply. Plywood is peeled from logs in long sheets.[clarification needed] Most ply is structural and available in 7-22mm sizes. A small amount of higher grade ply is used to produce thinner (4 and 7mm) ply suitable for furniture, cabinet work and boat building. This is knot and crack free and glued with resorcinol waterproof glue. Since the 1990s finger jointed joinery grade wood has become available in up to 6m lengths in a wide range of profiles. In 1958, boat designer Des Townson started building 186 eleven-foot, cold-moulded Zepher class yachts, using Pinus radiata. In 2011 these hand built boats fetch very high prices and are generally in excellent condition.	https://www.wikidoc.org/index.php/Monteroy_pine_tree
a29ab25f774c6f1914635e0f28e6b77eb3566dc3	wikidoc	Mood disorder	Mood disorder # Overview A mood disorder is a condition whereby the prevailing emotional mood is distorted or inappropriate to the circumstances. The two major types of mood disorders are depression (or unipolar depression) and bipolar disorder. - Depression (or unipolar depression), including subtypes: Major Depression Major Depression (Recurrent) Major Depression with psychotic symptoms (psychotic depression) Dysthymia ( similar but milder form of MDD) Postpartum depression - Major Depression - Major Depression (Recurrent) - Major Depression with psychotic symptoms (psychotic depression) - Dysthymia ( similar but milder form of MDD) - Postpartum depression - Bipolar disorder, a mood disorder formerly known as "manic depression" and described by alternating periods of mania and depression (and in some cases rapid cycling, mixed states, and psychotic symptoms). Subtypes include: Bipolar I Bipolar II Cyclothymia ( similar but milder form of BD) - Bipolar I - Bipolar II - Cyclothymia ( similar but milder form of BD) de:Affektive Störung et:Meeleoluhäire nl:Stemmingsstoornis fi:Mielialahäiriö	Mood disorder Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate editor-in-Chief: Christeen Henen # Overview A mood disorder is a condition whereby the prevailing emotional mood is distorted or inappropriate to the circumstances. The two major types of mood disorders are depression (or unipolar depression) and bipolar disorder. - Depression (or unipolar depression), including subtypes: Major Depression Major Depression (Recurrent) Major Depression with psychotic symptoms (psychotic depression) Dysthymia ( similar but milder form of MDD) Postpartum depression - Major Depression - Major Depression (Recurrent) - Major Depression with psychotic symptoms (psychotic depression) - Dysthymia ( similar but milder form of MDD) - Postpartum depression - Bipolar disorder, a mood disorder formerly known as "manic depression" and described by alternating periods of mania and depression (and in some cases rapid cycling, mixed states, and psychotic symptoms). Subtypes include: Bipolar I Bipolar II Cyclothymia ( similar but milder form of BD) - Bipolar I - Bipolar II - Cyclothymia ( similar but milder form of BD) de:Affektive Störung et:Meeleoluhäire nl:Stemmingsstoornis fi:Mielialahäiriö Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Mood_Disorder
4597a17802807069d064803d7a601732176c99dd	wikidoc	Morning glory	Morning glory Morning glory is a common name for over 1,000 species of flowering plants in the family the Convolvulaceae, belonging to the following genera: - Calystegia - Convolvulus - Ipomoea - Merremia - Rivea As the name implies, morning glory flowers, which are funnel-shaped, open in the morning, allowing them to be pollinated by hummingbirds, butterflies, bees, and other daytime insects and birds as well as Hawkmoth at dusk for longer blooming variants. The flower typically lasts for a single morning and dies in the afternoon. New flowers bloom each day. The flowers usually start to fade a couple of hours before the petals start showing visible curling. They prefer full sun throughout the day and mesic soils. In cultivation, most are treated as perennial plants in tropical areas and as annual plants in colder climates, but some species tolerate winter cold. Morning glories are a close relative of Moon flowers which open at night to be pollinated by moths. # Cultivation Morning glory is also called asagao (in Japanese, a compound of 朝 asa "morning" and 顔 kao "face"). A rare brownish-coloured variant known as Danjuro is very popular. It was first known in China for its medicinal uses, due to the laxative properties of its seeds. It was introduced to the Japanese in the 9th century, and they were first to cultivate it as an ornament. During the Edo Period, it became a very popular ornamental flower. Aztec priests in Mexico were also known to use the plant's hallucinogenic properties. (see Rivea corymbosa). Ancient Mesoamerican civilizations used the morning glory species Ipomoea alba to convert the latex from the Castilla elastica tree and also the guayule plant to produce bouncing rubber balls. The sulfur in the morning glory's juice served to vulcanize the rubber, a process pre-dating Charles Goodyear's discovery by at least 3,000 years. Because of their fast growth, twining habit, attractive flowers, and tolerance for poor, dry soils, some morning glories are excellent vines for creating summer shade on building walls when trellised, thus keeping the building cooler and reducing heating and cooling costs. In some places such as Australian bushland morning glories develop thick roots and tend to grow in dense thickets. They can quickly spread by way of long creeping stems. By crowding out, blanketing and smothering other plants, morning glory has turned into a serious invasive weed problem. # Culinary uses ### Sweet potato Ipomoea batatas is the Sweet Potato, a familiar food crop. ### Water spinach Ipomoea aquatica, known as water spinach, water morning-glory, water convolvulus, Ong-Choy, Kang-kung, or swamp cabbage, is popularly used as a green vegetable especially in East and Southeast Asian cuisines. It is a Federal Noxious Weed, however, and technically it is illegal to grow, import, possess, or sell. See: USDA weed factsheet. The fact that it is goes by so many names means that it easily slips through import inspections, and it is often available in Asian or specialty produce markets. # Recreational use The seeds of many species of morning glory contain d-lysergic acid amide, ergoline alkaloids better known as LSA. Seeds of I. tricolor and I. corymbosa (syn. R. corymbosa) are used as hallucinogens. They are about 5% to 10% as potent as LSD, and produce a similar effect when taken in the hundreds. They should not be taken by people with a history of liver disorders or hepatitis. They should not be taken by pregnant women due to uterine contraction which can lead to miscarriage. Individuals with a history of cardiovascular disease (Heart attack, blood clot, and stroke) or a family history of such problems, and the elderly should avoid consuming these seeds due to the vasoconstrictive effects. # Gallery - Blue Morning Glories Blue Morning Glories - A fully open blue and purple morning glory A fully open blue and purple morning glory - A fully open pink morning glory A fully open pink morning glory - Side view of a partially curled morning glory in early afternoon Side view of a partially curled morning glory in early afternoon - The top of partially curled morning glory in early afternoon The top of partially curled morning glory in early afternoon - The leaves of a morning glory The leaves of a morning glory	Morning glory Morning glory is a common name for over 1,000 species of flowering plants in the family the Convolvulaceae, belonging to the following genera: - Calystegia - Convolvulus - Ipomoea - Merremia - Rivea As the name implies, morning glory flowers, which are funnel-shaped, open in the morning, allowing them to be pollinated by hummingbirds, butterflies, bees, and other daytime insects and birds as well as Hawkmoth at dusk for longer blooming variants. The flower typically lasts for a single morning and dies in the afternoon. New flowers bloom each day. The flowers usually start to fade a couple of hours before the petals start showing visible curling. They prefer full sun throughout the day and mesic soils. In cultivation, most are treated as perennial plants in tropical areas and as annual plants in colder climates, but some species tolerate winter cold. Morning glories are a close relative of Moon flowers which open at night to be pollinated by moths. # Cultivation Morning glory is also called asagao (in Japanese, a compound of 朝 asa "morning" and 顔 kao "face"). A rare brownish-coloured variant known as Danjuro is very popular. It was first known in China for its medicinal uses, due to the laxative properties of its seeds. It was introduced to the Japanese in the 9th century, and they were first to cultivate it as an ornament. During the Edo Period, it became a very popular ornamental flower. Aztec priests in Mexico were also known to use the plant's hallucinogenic properties. (see Rivea corymbosa). Ancient Mesoamerican civilizations used the morning glory species Ipomoea alba to convert the latex from the Castilla elastica tree and also the guayule plant to produce bouncing rubber balls. The sulfur in the morning glory's juice served to vulcanize the rubber, a process pre-dating Charles Goodyear's discovery by at least 3,000 years.[1] Because of their fast growth, twining habit, attractive flowers, and tolerance for poor, dry soils, some morning glories are excellent vines for creating summer shade on building walls when trellised, thus keeping the building cooler and reducing heating and cooling costs. In some places such as Australian bushland morning glories develop thick roots and tend to grow in dense thickets. They can quickly spread by way of long creeping stems. By crowding out, blanketing and smothering other plants, morning glory has turned into a serious invasive weed problem. # Culinary uses ### Sweet potato Ipomoea batatas is the Sweet Potato, a familiar food crop. ### Water spinach Ipomoea aquatica, known as water spinach, water morning-glory, water convolvulus, Ong-Choy, Kang-kung, or swamp cabbage, is popularly used as a green vegetable especially in East and Southeast Asian cuisines. It is a Federal Noxious Weed, however, and technically it is illegal to grow, import, possess, or sell. See: USDA weed factsheet. The fact that it is goes by so many names means that it easily slips through import inspections, and it is often available in Asian or specialty produce markets. # Recreational use The seeds of many species of morning glory contain d-lysergic acid amide, ergoline alkaloids better known as LSA. Seeds of I. tricolor and I. corymbosa (syn. R. corymbosa) are used as hallucinogens. They are about 5% to 10% as potent as LSD, and produce a similar effect when taken in the hundreds. They should not be taken by people with a history of liver disorders or hepatitis. They should not be taken by pregnant women due to uterine contraction which can lead to miscarriage. Individuals with a history of cardiovascular disease (Heart attack, blood clot, and stroke) or a family history of such problems, and the elderly should avoid consuming these seeds due to the vasoconstrictive effects. [2][3][4] # Gallery - Blue Morning Glories Blue Morning Glories - A fully open blue and purple morning glory A fully open blue and purple morning glory - A fully open pink morning glory A fully open pink morning glory - Side view of a partially curled morning glory in early afternoon Side view of a partially curled morning glory in early afternoon - The top of partially curled morning glory in early afternoon The top of partially curled morning glory in early afternoon - The leaves of a morning glory The leaves of a morning glory # External links Template:Wiktionarypar - Morning Glories: Naturally Occurring Psychedelics Related to LSD - Erowid Morning Glory Vault - section from Erowid's vast reference site. Template:Hallucinogenic lysergamides	https://www.wikidoc.org/index.php/Morning_glory
f471f946966298499eee4c4f3519cf8adc0e6934	wikidoc	Morphometrics	Morphometrics Generally, morphometrics (from the Greek: "morph," meaning shape or form, and "metron”, meaning measurement) comprises methods of extracting measurements from shapes. In most cases applied to biological topics in the widest sense. Morphometrics studies the "form follows function" aspect of biology, mapping the changes in an organism's shape in regards to its function. Schools of morphometrics are characterized by what aspects of biological "form" they are concerned with, what they choose to measure, and what kinds of questions they ask of the measurements once they are made. In many cases involves calculating angles, areas, volumes and other quantitative data from landmark and segmentation data. The term is also used in geosciences to describe measurements of terrain. Geomorphometry or more generally topography is the field specializing in this measurement. # Bibliography - Cadrin, Steven X. (2000). "Advances in morphometric identification of fishery stocks". Reviews in Fish Biology and Fisheries. 10: 91–112..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} - McLellan, Tracy (June 1998). "The Relative Success of Some Methods for Measuring and Describing the Shape of Complex Objects". Systematic Biology. Society of Systematic Biologists. 47 (2): 264–281. Retrieved 2007-03-22. Unknown parameter \|coauthors= ignored (help) - Swiderski, Donald L. (July 1998). "Why Morphometrics is not Special: Coding Quantitative Data for Phylogenetic Analysis". Systematic Biology. Society of Systematic Biologists. 47 (3): 508–519. Unknown parameter \|coauthors= ignored (help)	Morphometrics Generally, morphometrics (from the Greek: "morph," meaning shape or form, and "metron”, meaning measurement) comprises methods of extracting measurements from shapes. In most cases applied to biological topics in the widest sense. Morphometrics studies the "form follows function" aspect of biology, mapping the changes in an organism's shape in regards to its function. Schools of morphometrics are characterized by what aspects of biological "form" they are concerned with, what they choose to measure, and what kinds of questions they ask of the measurements once they are made. In many cases involves calculating angles, areas, volumes and other quantitative data from landmark and segmentation data. The term is also used in geosciences to describe measurements of terrain. Geomorphometry or more generally topography is the field specializing in this measurement. # Bibliography - Cadrin, Steven X. (2000). "Advances in morphometric identification of fishery stocks". Reviews in Fish Biology and Fisheries. 10: 91–112..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} - McLellan, Tracy (June 1998). "The Relative Success of Some Methods for Measuring and Describing the Shape of Complex Objects". Systematic Biology. Society of Systematic Biologists. 47 (2): 264–281. Retrieved 2007-03-22. Unknown parameter \|coauthors= ignored (help) - Swiderski, Donald L. (July 1998). "Why Morphometrics is not Special: Coding Quantitative Data for Phylogenetic Analysis". Systematic Biology. Society of Systematic Biologists. 47 (3): 508–519. Unknown parameter \|coauthors= ignored (help)	https://www.wikidoc.org/index.php/Morphometrics
677c6caf19217aa04040b6ea45620a3651847c16	wikidoc	Mother liquor	Mother liquor Mother Liquor is a chemical name for the part of a solution that is left over after crystallization. It is also an important process in the creation of cigarettes. After reprocessing of unsold cigarettes, introduction of new tobacco, and a chemical process to bring this mix down to a liquid, it is sent to a large tank that creates the Mother Liquor. Later this concoction is sprayed -n paper for introduction to new cigarettes.	Mother liquor Mother Liquor is a chemical name for the part of a solution that is left over after crystallization. It is also an important process in the creation of cigarettes. After reprocessing of unsold cigarettes, introduction of new tobacco, and a chemical process to bring this mix down to a liquid, it is sent to a large tank that creates the Mother Liquor. Later this concoction is sprayed on paper for introduction to new cigarettes. Template:Chem-stub	https://www.wikidoc.org/index.php/Mother_liquor
c5756bc62ef06cd7376cd717be3379ce7f5cd2f7	wikidoc	Mpemba effect	Mpemba effect The Mpemba effect is the observation that, in certain specific circumstances, warmer water freezes faster than colder water. New Scientist recommends starting the experiment with containers at 35°C and 5°C to maximise the effect. # Origin The effect is named for the Tanzanian high-school student Erasto B. Mpemba. Mpemba first encountered the phenomenon in 1963 in Form 3 of Magamba Secondary School, Tanzania when freezing hot ice cream mix in cookery classes and noticing that they froze before cold mixes. After passing his O-level examinations, he became a student at Mkwawa Secondary (formerly High) School, Iringa, Tanzania. The headmaster invited Dr. Denis G. Osborne from the University College in Dar Es Salaam to give a lecture on physics. After the lecture, Erasto Mpemba asked him the question "If you take two similar containers with equal volumes of water, one at 35°C and the other at 100°C, and put them into a refrigerator, the one that started at 100°C freezes first. Why?" only to be ridiculed by his classmates. After initial consternation, Dr. Osborne confirmed Erasto's finding and they published the results together in 1969. Erasto Mpemba currently works for the African Forestry and Wildlife Commission. # Causes At first sight, the behaviour seems contrary to thermodynamics. However, the Mpemba effect can be explained with standard physical theory. Many effects can contribute to the observation, depending on the experimental set-up: - Definition of frozen: Is it the physical definition of the point at which water forms a visible surface layer of ice, or the point at which the entire volume of water becomes a solid block of ice? - Evaporation: Reducing the volume to be frozen. Evaporation is endothermic. - Convection: Accelerating heat transfers. Reduction of water density below 4°C tends to suppress the convection currents cooling the lower part of the liquid mass; the lower density of hot water would reduce this effect, perhaps sustaining the more rapid initial cooling. - Frost: Has insulating effects. The lower temperature water will tend to freeze from the top, reducing further heat loss by radiation and air convection, while the warmer water will tend to freeze from the bottom and sides because of water convection. This is disputed as there are experiments which account for this factor. - Supercooling: It is hypothesized that cold water, when placed in a freezing environment, supercools more than hot water in the same environment, thus solidifying slower than hot water. However, supercooling tends to be less significant where there are particles that act as nuclei for ice crystals, thus precipitating rapid freezing. - Solutes: The effects of calcium, magnesium carbonate among others. - The effect of heating on dissolved gases. ## Scalar functionality According to an article by Monwhea Jeng: "Analysis of the situation is now quite complex, since we are no longer considering a single parameter, but a scalar function, and computational fluid dynamics (CFD) is notoriously difficult." This effect is a heat transfer problem, and therefore well suited to be studied from a transport phenomena viewpoint, based on continuum mechanics. When heat transfer is analyzed in terms of partial differential equations, whose solutions depend on a number of conditions, it becomes clear that measuring only a few lumped parameters, such as the water average temperature is generally insufficient to define the system behaviour, since conditions such as geometry, fluid properties and temperature and flow fields play an important role. The counterintuitiveness of the effect, if analyzed only in terms of simplified thermodynamics illustrates the need to include all the relevant variables and use the best available theoretical tools when approaching a physical problem. # Recent view of the Mpemba effect A reviewer for Physics World writes, "Even if the Mpemba effect is real - if hot water can sometimes freeze more quickly than cold - it is not clear whether the explanation would be trivial or illuminating." # Historical observations Similar behavior may have been observed by ancient scientists such as Aristotle, and Early Modern scientists such as Francis Bacon and René Descartes. Aristotle's explanation involved an erroneous property he called antiperistasis, defined as "the supposed increase in the intensity of a quality as a result of being surrounded by its contrary quality".	Mpemba effect The Mpemba effect is the observation that, in certain specific circumstances, warmer water freezes faster than colder water. New Scientist recommends starting the experiment with containers at 35°C and 5°C to maximise the effect.[1] # Origin The effect is named for the Tanzanian high-school student Erasto B. Mpemba. Mpemba first encountered the phenomenon in 1963 in Form 3 of Magamba Secondary School, Tanzania when freezing hot ice cream mix in cookery classes and noticing that they froze before cold mixes. After passing his O-level examinations, he became a student at Mkwawa Secondary (formerly High) School, Iringa, Tanzania. The headmaster invited Dr. Denis G. Osborne from the University College in Dar Es Salaam to give a lecture on physics. After the lecture, Erasto Mpemba asked him the question "If you take two similar containers with equal volumes of water, one at 35°C and the other at 100°C, and put them into a refrigerator, the one that started at 100°C freezes first. Why?" only to be ridiculed by his classmates. After initial consternation, Dr. Osborne confirmed Erasto's finding and they published the results together in 1969.[2][3] Erasto Mpemba currently works for the African Forestry and Wildlife Commission.[4] # Causes At first sight, the behaviour seems contrary to thermodynamics. However, the Mpemba effect can be explained with standard physical theory. Many effects can contribute to the observation, depending on the experimental set-up: - Definition of frozen: Is it the physical definition of the point at which water forms a visible surface layer of ice, or the point at which the entire volume of water becomes a solid block of ice? - Evaporation: Reducing the volume to be frozen.[5] Evaporation is endothermic. - Convection: Accelerating heat transfers. Reduction of water density below 4°C tends to suppress the convection currents cooling the lower part of the liquid mass; the lower density of hot water would reduce this effect, perhaps sustaining the more rapid initial cooling. - Frost: Has insulating effects. The lower temperature water will tend to freeze from the top, reducing further heat loss by radiation and air convection, while the warmer water will tend to freeze from the bottom and sides because of water convection. This is disputed as there are experiments which account for this factor. - Supercooling: It is hypothesized that cold water, when placed in a freezing environment, supercools more than hot water in the same environment, thus solidifying slower than hot water.[6] However, supercooling tends to be less significant where there are particles that act as nuclei for ice crystals, thus precipitating rapid freezing. - Solutes: The effects of calcium, magnesium carbonate among others.[7] - The effect of heating on dissolved gases. ## Scalar functionality According to an article by Monwhea Jeng: "Analysis of the situation is now quite complex, since we are no longer considering a single parameter, but a scalar function, and computational fluid dynamics (CFD) is notoriously difficult."[8] This effect is a heat transfer problem,[9][10][11][12] and therefore well suited to be studied from a transport phenomena viewpoint, based on continuum mechanics. When heat transfer is analyzed in terms of partial differential equations, whose solutions depend on a number of conditions, it becomes clear that measuring only a few lumped parameters, such as the water average temperature is generally insufficient to define the system behaviour, since conditions such as geometry, fluid properties and temperature and flow fields play an important role. The counterintuitiveness of the effect, if analyzed only in terms of simplified thermodynamics illustrates the need to include all the relevant variables and use the best available theoretical tools when approaching a physical problem.[9][10][12][11] # Recent view of the Mpemba effect A reviewer for Physics World writes, "Even if the Mpemba effect is real - if hot water can sometimes freeze more quickly than cold - it is not clear whether the explanation would be trivial or illuminating."[13] # Historical observations Similar behavior may have been observed by ancient scientists such as Aristotle[14], and Early Modern scientists such as Francis Bacon[15] and René Descartes[16]. Aristotle's explanation involved an erroneous property he called antiperistasis, defined as "the supposed increase in the intensity of a quality as a result of being surrounded by its contrary quality".	https://www.wikidoc.org/index.php/Mpemba_effect
8b0a1465b2deca081025e83a6220b7f67b8e65c6	wikidoc	Mucoid plaque	Mucoid plaque Mucoid plaque or mucoid rope is a term coined by a naturopath and entrepreneur, purporting to describe a harmful coating of mucus-like material existing in the gastrointestinal tracts of most people. The existence of mucoid plaque has not been reported in the medical literature, and it has been variously described as "a complete fabrication without any anatomical basis", a "non-credible concept", and "a bold lie". An article from the Division of Complementary Medicine of the University of Exeter described mucoid plaque and other claims of "colonic autointoxication" as "a triumph of ignorance over science", based on "old bogus claims and the impressive power of vested interests." Despite the absence of scientific evidence, mucoid plaque is discussed outside the medical community, especially within holistic health circles and in anecdotal accounts of colon hydrotherapy procedures. The idea of huge accumulations of fecal material in the bowel has acquired urban legend status. # Background The concept of mucoid plaque was coined by Richard Anderson, a naturopath and seller of products which purport to remove mucoid plaque. Anderson claims that mucoid plaque is created when the body produces mucus to protect itself from potentially toxic substances. Anderson further claims that mucoid plaque acts as a health threat by reducing the absorption of nutrients, impairing digestion, providing a haven for parasitic microorganisms, behaving as a reservoir of toxins, promoting the development of cancer, causing skin conditions and allergies, and reducing bowel transit time. Anderson further claims that removing this allegedly protective layer is beneficial to health. These claims are not supported by scientific or medical research. # Criticism The major criticisms of the concept of mucoid plaque are that it has never been described in the scientific or medical literature and that medical doctors report that it has never been found in their patients. The existence of mucoid plaque is promoted primarily by people and organizations in the business of selling books and products aimed at remedying it. Edward Uthman, a practicing pathologist and Adjunct Professor of Pathology at the University of Texas School of Medicine, has said on the basis of having examined several thousand intestinal biopsies: "This is a complete fabrication with no anatomic basis." Another practicing pathologist, Ed Friedlander at Brown University, states, "As a pathologist, I have opened hundreds of colons and never seen anything like 'toxic bowel settlement'." Furthermore, in reference to purported photos of expelled mucoid plaque, he writes, "Sites they have shared include one depicting what I recognize to be a blood clot." It has also been proposed that the bentonite clay found in many popular cleansing products, combined with normal fecal matter during its passage through the intestines, accounts for the consistency of many of these alleged plaques. A 2004 paper by Soergel, Tse and Slaughter on the relationship between lay and medical language uses "mucoid plaque" as an example of "non-credible concepts" used by healthcare consumers. An editorial in the Journal of Clinical Gastroenterology described the concept of mucoid plaque and "colonic autointoxication" in general as characterized by "...false claims, a lack of evidence, big money, aggressive advertising, disregard of risk." # The John Wayne and Elvis Presley Myth Advertisements for some products marketed to cleanse the colon of mucoid plaque claim that an autopsy of John Wayne revealed that the actor had over 40 pounds of plaque/fecal material accumulated in his colon. In fact, an autopsy was never performed on John Wayne. Similar false claims are made about singer Elvis Presley.	Mucoid plaque Mucoid plaque or mucoid rope is a term coined by a naturopath and entrepreneur, purporting to describe a harmful coating of mucus-like material existing in the gastrointestinal tracts of most people. The existence of mucoid plaque has not been reported in the medical literature,[1][2] and it has been variously described as "a complete fabrication without any anatomical basis",[3] a "non-credible concept",[4] and "a bold lie".[5] An article from the Division of Complementary Medicine of the University of Exeter described mucoid plaque and other claims of "colonic autointoxication" as "a triumph of ignorance over science", based on "old bogus claims and the impressive power of vested interests."[6] Despite the absence of scientific evidence, mucoid plaque is discussed outside the medical community, especially within holistic health circles and in anecdotal accounts of colon hydrotherapy procedures.[7][8] The idea of huge accumulations of fecal material in the bowel has acquired urban legend status.[9] # Background The concept of mucoid plaque was coined by Richard Anderson, a naturopath and seller of products which purport to remove mucoid plaque. Anderson claims that mucoid plaque is created when the body produces mucus to protect itself from potentially toxic substances. Anderson further claims that mucoid plaque acts as a health threat by reducing the absorption of nutrients, impairing digestion, providing a haven for parasitic microorganisms, behaving as a reservoir of toxins, promoting the development of cancer, causing skin conditions and allergies, and reducing bowel transit time. Anderson further claims that removing this allegedly protective layer is beneficial to health.[10] These claims are not supported by scientific or medical research. # Criticism The major criticisms of the concept of mucoid plaque are that it has never been described in the scientific or medical literature[1][2] and that medical doctors report that it has never been found in their patients.[3] The existence of mucoid plaque is promoted primarily by people and organizations in the business of selling books and products aimed at remedying it. Edward Uthman, a practicing pathologist and Adjunct Professor of Pathology at the University of Texas School of Medicine, has said on the basis of having examined several thousand intestinal biopsies: "This is a complete fabrication with no anatomic basis."[3] Another practicing pathologist, Ed Friedlander at Brown University, states, "As a pathologist, I have opened hundreds of colons and never seen anything like 'toxic bowel settlement'." Furthermore, in reference to purported photos of expelled mucoid plaque, he writes, "Sites they have shared include one depicting what I recognize to be a blood clot."[5] It has also been proposed that the bentonite clay found in many popular cleansing products, combined with normal fecal matter during its passage through the intestines, accounts for the consistency of many of these alleged plaques. A 2004 paper by Soergel, Tse and Slaughter on the relationship between lay and medical language uses "mucoid plaque" as an example of "non-credible concepts" used by healthcare consumers.[4] An editorial in the Journal of Clinical Gastroenterology described the concept of mucoid plaque and "colonic autointoxication" in general as characterized by "...false claims, a lack of evidence, big money, aggressive advertising, [and] disregard of risk."[6] # The John Wayne and Elvis Presley Myth Advertisements for some products marketed to cleanse the colon of mucoid plaque claim that an autopsy of John Wayne revealed that the actor had over 40 pounds of plaque/fecal material accumulated in his colon. In fact, an autopsy was never performed on John Wayne. Similar false claims are made about singer Elvis Presley.[9]	https://www.wikidoc.org/index.php/Mucoid_plaque
ade540fee16c463cc53a809ba412fc5d0414477f	wikidoc	Mucolipidosis	Mucolipidosis # Overview Mucolipidoses (ML) are a group of inherited metabolic diseases that affect the body’s ability to carry out the normal turnover of various materials within cells. In ML, abnormal amounts of carbohydrates or fatty materials (lipids) accumulate in cells. Because our cells are not able to handle such large amounts of these substances, damage to the cells occurs, causing symptoms that range from mild learning disabilities to severe mental retardation and skeletal deformities. Symptoms of ML can be congenital (present at birth) or begin in early childhood or adolescence. Early symptoms can include vision problems and developmental delays. Over time, many children with ML develop poor mental capacities, have difficulty reaching normal developmental milestones, and, in many cases, eventually die of the disease. # Cause The MLs are classified as lysosomal storage diseases because they involve increased storage of substances in the lysosomes, which are specialized sac-like components within most cells. Lysosomes play a critical role in the metabolic function of our bodies. One of their primary roles is to pick up substances such as carbohydrates and lipids and break them down into smaller molecules so that they can be used again in the metabolic process. This process is possible because lysosomes contain enzymes, which are proteins that help the body’s chemistry work better and faster. Working continuously, enzymes break down carbohydrates and lipids and assist in the transfer of their byproducts throughout the rest of the cell for the production of energy or excretion. Patients with ML are born with a genetic defect in which their bodies either do not produce enough enzymes or, in some instances, produce ineffective forms of enzymes. Without functioning enzymes, which are proteins, lysosomes cannot break down carbohydrates and lipids and transport them to their normal destination. The molecules then accumulate in the cells of various tissues in the body, leading to swelling and damage of organs. In patients with ML, the molecules accumulate in nerve, liver, and muscle tissue as well as in bone marrow, and this abnormal storage causes the various symptoms associated with ML. For example, excess storage of these molecules in nerve tissues can cause mental retardation, accumulation in the tissues of the spleen and liver can cause poor functioning of these vital organs, and excess storage in the bone marrow can damage bones, leading to skeletal deformities. The accumulation of carbohydrates and lipids in tissue is not the result of just one deficient enzyme. Lysosomes contain as many as 40 or 50 different enzymes, each responsible for a highly specialized function. Therefore, a deficiency in one particular enzyme or activator protein causes symptoms that may be somewhat different from the symptoms caused by the deficiency of another type of enzyme. There are four types of ML and each is classified according to the enzyme(s) or other protein that is deficient or mutated (altered). Symptoms can range from mild to severe. The MLs are similar to another group of lysosomal storage diseases known as the mucopolysaccharidoses. While both conditions produce similar symptoms and are caused by the lack of enzymes necessary to break down and transport carbohydrates and lipids, the mucopolysaccharidoses result in an excess of sugars, known as mucopolysaccharides, in the urine. Mucopolysaccharides are not seen in urine of patients with ML, therefore screening of the urine can help doctors distinguish between the two groups of disorders. # Types The four types of ML are sialidosis (sometimes referred to as ML I), and types II, III, and IV. ## ML I Mucolipidosis type I (ML I) or sialidosis results from a deficiency in one of the digestive enzymes known as sialidase. ## ML II and III Mucolipidosis types II and III (ML II and ML III) result from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase. Just as luggage in an airport is tagged to direct it to the correct destination, enzymes are often "tagged." In ML II and ML III, the deficient enzyme is supposed to tag other enzymes (activator proteins) so that they can initiate certain metabolic processes in the cell. Because the activator proteins are not properly tagged, they escape into spaces outside the cell and therefore cannot do their usual work of breaking down substances inside the cells. ## ML IV Mucolipidosis type IV (ML IV) is caused by harmful alterations of a protein in the cell that is believed to be involved in the movement of molecules such as calcium across cell membranes. # Genetics The mucolipidoses are inherited in an autosomal recessive manner, that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry a defective gene, each of their children faces a one in four chance of developing one of the MLs. At the same time, each child also faces a one in two chance of inheriting only one copy of the defective gene. People who have only one defective gene are known as carriers. These individuals do not develop the disease but they can pass the defective gene on to their own children. Because the defective genes involved in certain forms of ML are known, tests can identify people who are carriers in some instances. # Diagnosis The diagnosis of ML is based on clinical symptoms, a complete medical history, and certain laboratory tests. Diagnosis of ML I, II, and III can be confirmed by a blood test that measures enzyme activity in the patient's white blood cells. Activity levels that are lower than normal indicate specific enzyme deficiencies. Another way to confirm the diagnosis is through skin biopsy. A small sample of skin is taken from the patient and grown in a cell culture. The activity of a particular enzyme in the cultured skin cells is then measured. ML IV is suspected when cells that are easily obtained by conjunctival swabbing are found to have numerous inclusions. In addition, measurement of the level of gastrin in the blood, which is significantly increased in ML IV patients, helps to confirm the diagnosis. Scientists have identified the genes responsible for all four types of MLs. In 2000, scientists at NINDS laboratories and other research institutions identified the gene responsible for ML IV. This gene, MCOLN1, makes the protein mucolipin-1. Due to mutations in the gene, mucolipin-1 is missing or dysfunctional in people with ML IV. This important genetic finding allows for the accurate diagnosis of patients as well as prenatal (before birth) diagnosis and the screening of carriers of the disease. Prenatal diagnosis for ML is accomplished using a procedure known as chorionic villus sampling, or CVS. It is usually done around the 8th or 10th week of pregnancy and involves removing and testing a very small sample of the placenta. For ML types I, II, and III, placental cells called amniocytes are grown in culture and then tested to measure enzyme activity levels. For ML IV, no culture is required. DNA is obtained directly from the amniocytes and analyzed to find if mutations consistent with ML IV have occurred in the DNA. This technique is called genotyping. Genetic testing for ML IV is available at specialized laboratories. Genetic counselors can help explain how the MLs are inherited and the effect of these diseases on patients and their families. Counselors can also help adults who might have a defective gene decide whether or not they wish to have children. Psychological counseling and support groups for people with genetic diseases may also help patients and their families cope with ML. # Treatment No cure for ML currently exists. Therapies are generally geared toward treating symptoms and providing supportive care to the child. For individuals with corneal clouding, surgery to remove the thin layer over the eye has been shown to reduce the cloudiness in the eye. However, this improvement is only temporary. Physical and occupational therapy may help children with motor delays. Children with language delays may benefit from speech therapy. Care also should be taken to maintain the overall health of patients with ML. For example, children at risk for failure to thrive (growth failure) may need nutritional supplements, especially iron and vitamin B12 for patients with ML IV. Respiratory infections should be treated immediately and fully with antibiotics. # Sources - Template:NINDS	Mucolipidosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Mucolipidoses (ML) are a group of inherited metabolic diseases that affect the body’s ability to carry out the normal turnover of various materials within cells. In ML, abnormal amounts of carbohydrates or fatty materials (lipids) accumulate in cells. Because our cells are not able to handle such large amounts of these substances, damage to the cells occurs, causing symptoms that range from mild learning disabilities to severe mental retardation and skeletal deformities. Symptoms of ML can be congenital (present at birth) or begin in early childhood or adolescence. Early symptoms can include vision problems and developmental delays. Over time, many children with ML develop poor mental capacities, have difficulty reaching normal developmental milestones, and, in many cases, eventually die of the disease. # Cause The MLs are classified as lysosomal storage diseases because they involve increased storage of substances in the lysosomes, which are specialized sac-like components within most cells. Lysosomes play a critical role in the metabolic function of our bodies. One of their primary roles is to pick up substances such as carbohydrates and lipids and break them down into smaller molecules so that they can be used again in the metabolic process. This process is possible because lysosomes contain enzymes, which are proteins that help the body’s chemistry work better and faster. Working continuously, enzymes break down carbohydrates and lipids and assist in the transfer of their byproducts throughout the rest of the cell for the production of energy or excretion. Patients with ML are born with a genetic defect in which their bodies either do not produce enough enzymes or, in some instances, produce ineffective forms of enzymes. Without functioning enzymes, which are proteins, lysosomes cannot break down carbohydrates and lipids and transport them to their normal destination. The molecules then accumulate in the cells of various tissues in the body, leading to swelling and damage of organs. In patients with ML, the molecules accumulate in nerve, liver, and muscle tissue as well as in bone marrow, and this abnormal storage causes the various symptoms associated with ML. For example, excess storage of these molecules in nerve tissues can cause mental retardation, accumulation in the tissues of the spleen and liver can cause poor functioning of these vital organs, and excess storage in the bone marrow can damage bones, leading to skeletal deformities. The accumulation of carbohydrates and lipids in tissue is not the result of just one deficient enzyme. Lysosomes contain as many as 40 or 50 different enzymes, each responsible for a highly specialized function. Therefore, a deficiency in one particular enzyme or activator protein causes symptoms that may be somewhat different from the symptoms caused by the deficiency of another type of enzyme. There are four types of ML and each is classified according to the enzyme(s) or other protein that is deficient or mutated (altered). Symptoms can range from mild to severe. The MLs are similar to another group of lysosomal storage diseases known as the mucopolysaccharidoses. While both conditions produce similar symptoms and are caused by the lack of enzymes necessary to break down and transport carbohydrates and lipids, the mucopolysaccharidoses result in an excess of sugars, known as mucopolysaccharides, in the urine. Mucopolysaccharides are not seen in urine of patients with ML, therefore screening of the urine can help doctors distinguish between the two groups of disorders. # Types The four types of ML are sialidosis (sometimes referred to as ML I), and types II, III, and IV. ## ML I Mucolipidosis type I (ML I) or sialidosis results from a deficiency in one of the digestive enzymes known as sialidase. ## ML II and III Mucolipidosis types II and III (ML II and ML III) result from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase. Just as luggage in an airport is tagged to direct it to the correct destination, enzymes are often "tagged." In ML II and ML III, the deficient enzyme is supposed to tag other enzymes (activator proteins) so that they can initiate certain metabolic processes in the cell. Because the activator proteins are not properly tagged, they escape into spaces outside the cell and therefore cannot do their usual work of breaking down substances inside the cells. ## ML IV Mucolipidosis type IV (ML IV) is caused by harmful alterations of a protein in the cell that is believed to be involved in the movement of molecules such as calcium across cell membranes. # Genetics The mucolipidoses are inherited in an autosomal recessive manner, that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry a defective gene, each of their children faces a one in four chance of developing one of the MLs. At the same time, each child also faces a one in two chance of inheriting only one copy of the defective gene. People who have only one defective gene are known as carriers. These individuals do not develop the disease but they can pass the defective gene on to their own children. Because the defective genes involved in certain forms of ML are known, tests can identify people who are carriers in some instances. # Diagnosis The diagnosis of ML is based on clinical symptoms, a complete medical history, and certain laboratory tests. Diagnosis of ML I, II, and III can be confirmed by a blood test that measures enzyme activity in the patient's white blood cells. Activity levels that are lower than normal indicate specific enzyme deficiencies. Another way to confirm the diagnosis is through skin biopsy. A small sample of skin is taken from the patient and grown in a cell culture. The activity of a particular enzyme in the cultured skin cells is then measured. ML IV is suspected when cells that are easily obtained by conjunctival swabbing are found to have numerous inclusions. In addition, measurement of the level of gastrin in the blood, which is significantly increased in ML IV patients, helps to confirm the diagnosis. Scientists have identified the genes responsible for all four types of MLs. In 2000, scientists at NINDS laboratories and other research institutions identified the gene responsible for ML IV. This gene, MCOLN1, makes the protein mucolipin-1. Due to mutations in the gene, mucolipin-1 is missing or dysfunctional in people with ML IV. This important genetic finding allows for the accurate diagnosis of patients as well as prenatal (before birth) diagnosis and the screening of carriers of the disease. Prenatal diagnosis for ML is accomplished using a procedure known as chorionic villus sampling, or CVS. It is usually done around the 8th or 10th week of pregnancy and involves removing and testing a very small sample of the placenta. For ML types I, II, and III, placental cells called amniocytes are grown in culture and then tested to measure enzyme activity levels. For ML IV, no culture is required. DNA is obtained directly from the amniocytes and analyzed to find if mutations consistent with ML IV have occurred in the DNA. This technique is called genotyping. Genetic testing for ML IV is available at specialized laboratories. Genetic counselors can help explain how the MLs are inherited and the effect of these diseases on patients and their families. Counselors can also help adults who might have a defective gene decide whether or not they wish to have children. Psychological counseling and support groups for people with genetic diseases may also help patients and their families cope with ML. # Treatment No cure for ML currently exists. Therapies are generally geared toward treating symptoms and providing supportive care to the child. For individuals with corneal clouding, surgery to remove the thin layer over the eye has been shown to reduce the cloudiness in the eye. However, this improvement is only temporary. Physical and occupational therapy may help children with motor delays. Children with language delays may benefit from speech therapy. Care also should be taken to maintain the overall health of patients with ML. For example, children at risk for failure to thrive (growth failure) may need nutritional supplements, especially iron and vitamin B12 for patients with ML IV. Respiratory infections should be treated immediately and fully with antibiotics. # Sources - Template:NINDS Template:Metabolic pathology Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Mucolipidoses
eb176423017e6732da87ab4bf0d5b3384761ad4c	wikidoc	Muromonab-CD3	Muromonab-CD3 # 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 Muromonab-CD3 is a monoclonal antibody that is FDA approved for the treatment of acute allograft rejection in renal transplant patients, steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema , hypotension, tachycardia, rash, diarrhea, nausea, vomiting, headache, tremor, fever, shivering. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ORTHOCLONE OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients. - ORTHOCLONE OKT3 is indicated for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. - The dosage of other immunosuppressive agents used in conjunction with ORTHOCLONE OKT3 should be reduced to the lowest level compatible with an effective therapeutic response. - The recommended dose of ORTHOCLONE OKT3 for the treatment of acute renal, steroid-resistant cardiac, or steroid-resistant hepatic allograft rejection is 5 mg per day in a single (bolus) intravenous injection in less than one minute for 10 to 14 days. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant cardiac or hepatic allograft rejection, treatment should begin when the treating physician deems a rejection has not been reversed by an adequate course of corticosteroid therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Muromonab-CD3 in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Muromonab-CD3 in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The initial recommended dose is 2.5 mg per day in pediatric patients weighing less than or equal to 30 kg and 5 mg per day in pediatric patients weighing greater than 30 kg in a single (bolus) intravenous injection in less than one minute for 10 to 14 days. Daily increases in ORTHOCLONE OKT3 doses (i.e., 2.5 mg increments) may be required to achieve depletion of CD3 positive cells ( 800 ng/mL). Pediatric patients may require augmentation of the ORTHOCLONE OKT3 dose. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant cardiac or hepatic allograft rejection, treatment should begin when the treating physician deems a rejection has not been reversed by an adequate course of corticosteroid therapy. - For the first few doses, patients should be monitored in a facility equipped and staffed for cardiopulmonary resuscitation (CPR). Patients receiving subsequent doses of ORTHOCLONE OKT3, should also be monitored in a facility equipped and staffed for CPR. Vital signs should be monitored frequently. Patients receiving ORTHOCLONE OKT3 should also be carefully monitored for signs and symptoms of Cytokine Release Syndrome, particularly after the first few doses but also after a treatment hiatus with resumption of therapy. The patient's temperature should be lowered to <37.8°C (100°F) before the administration of any dose of ORTHOCLONE OKT3. - Prior to administration of ORTHOCLONE OKT3, the patient's volume status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload, uncontrolled hypertension, or uncompensated heart failure. Patients should have a clear chest X-ray and should not weigh more than 3% above their minimum weight during the week prior to injection. - To decrease the incidence and severity of Cytokine Release Syndrome, associated with the first dose of ORTHOCLONE OKT3, it is strongly recommended that methylprednisolone sodium succinate 8.0 mg/kg be administered intravenously 1 to 4 hours prior to the initial dose of ORTHOCLONE OKT3. - Acetaminophen and antihistamines given concomitantly with ORTHOCLONE OKT3 may also help to reduce some early reactions. - When using concomitant immunosuppressive drugs, the dose of each should be reduced to the lowest level compatible with an effective therapeutic response in order to reduce the potential for malignancy and infections. Maintenance immunosuppression should be resumed approximately three days prior to the cessation of ORTHOCLONE OKT®3 therapy. - Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. - Before administration, ORTHOCLONE OKT3 should be inspected for particulate matter and discoloration. Because ORTHOCLONE OKT3 is a protein solution, it may develop fine translucent particles (shown not to affect potency). - No bacteriostatic agent is present in this product. Adherence to aseptic technique is advised. Once the ampule is opened, use immediately and discard the unused portion. - Prepare ORTHOCLONE OKT3 for injection by drawing solution into a syringe through a low protein-binding 0.2 or 0.22 micrometer (µm) filter. Detach filter and attach a new needle for a single intravenous (bolus) injection. - Because no data is available on compatibility of ORTHOCLONE OKT3 with other intravenous substances or additives, other medications/substances should not be added or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed with saline before and after injection of ORTHOCLONE OKT3. - Administer ORTHOCLONE OKT3 as a single intravenous (bolus) injection in less than one minute. Do not administer by intravenous infusion or in conjunction with other drug solutions.Pediatric Patients - The initial recommended dose is 2.5 mg per day in pediatric patients weighing less than or equal to 30 kg and 5 mg per day in pediatric patients weighing greater than 30 kg in a single (bolus) intravenous injection in less than one minute for 10 to 14 days. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant cardiac or hepatic allograft rejection, treatment should begin when the treating physician deems a rejection has not been reversed by an adequate course of corticosteroid therapy. - For the first few doses, patients should be monitored in a facility equipped and staffed for cardiopulmonary resuscitation (CPR). Patients receiving subsequent doses of ORTHOCLONE OKT3, should also be monitored in a facility equipped and staffed for CPR. Vital signs should be monitored frequently. Patients receiving ORTHOCLONE OKT3 should also be carefully monitored for signs and symptoms of Cytokine Release Syndrome, particularly after the first few doses but also after a treatment hiatus with resumption of therapy. The patient's temperature should be lowered to <37.8°C (100°F) before the administration of any dose of ORTHOCLONE OKT3. - Prior to administration of ORTHOCLONE OKT3, the patient's volume status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload, uncontrolled hypertension, or uncompensated heart failure. Patients should have a clear chest X-ray and should not weigh more than 3% above their minimum weight during the week prior to injection. - To decrease the incidence and severity of Cytokine Release Syndrome, associated with the first dose of ORTHOCLONE OKT3, it is strongly recommended that methylprednisolone sodium succinate 8.0 mg/kg be administered intravenously 1 to 4 hours prior to the initial dose of ORTHOCLONE OKT3. - Acetaminophen and antihistamines given concomitantly with ORTHOCLONE OKT3 may also help to reduce some early reactions. - When using concomitant immunosuppressive drugs, the dose of each should be reduced to the lowest level compatible with an effective therapeutic response in order to reduce the potential for malignancy and infections. Maintenance immunosuppression should be resumed approximately three days prior to the cessation of ORTHOCLONE OKT®3 therapy. - Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. - Before administration, ORTHOCLONE OKT3 should be inspected for particulate matter and discoloration. Because ORTHOCLONE OKT3 is a protein solution, it may develop fine translucent particles (shown not to affect potency). - No bacteriostatic agent is present in this product. Adherence to aseptic technique is advised. Once the ampule is opened, use immediately and discard the unused portion. - Prepare ORTHOCLONE OKT3 for injection by drawing solution into a syringe through a low protein-binding 0.2 or 0.22 micrometer (µm) filter. Detach filter and attach a new needle for a single intravenous (bolus) injection. - Because no data is available on compatibility of ORTHOCLONE OKT3 with other intravenous substances or additives, other medications/substances should not be added or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed with saline before and after injection of ORTHOCLONE OKT3. - Administer ORTHOCLONE OKT3 as a single intravenous (bolus) injection in less than one minute. Do not administer by intravenous infusion or in conjunction with other drug solutions.Pediatric Patients - The initial recommended dose is 2.5 mg per day in pediatric patients weighing less than or equal to 30 kg and 5 mg per day in pediatric patients weighing greater than 30 kg in a single (bolus) intravenous injection in less than one minute for 10 to 14 days. Daily increases in ORTHOCLONE OKT3 doses (i.e., 2.5 mg increments) may be required to achieve depletion of CD3 positive cells ( 800 ng/mL). Pediatric patients may require augmentation of the ORTHOCLONE OKT3 dose. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant cardiac or hepatic allograft rejection, treatment should begin when the treating physician deems a rejection has not been reversed by an adequate course of corticosteroid therapy. - For the first few doses, patients should be monitored in a facility equipped and staffed for cardiopulmonary resuscitation (CPR). Patients receiving subsequent doses of ORTHOCLONE OKT3, should also be monitored in a facility equipped and staffed for CPR. Vital signs should be monitored frequently. Patients receiving ORTHOCLONE OKT3 should also be carefully monitored for signs and symptoms of Cytokine Release Syndrome, particularly after the first few doses but also after a treatment hiatus with resumption of therapy. The patient's temperature should be lowered to <37.8°C (100°F) before the administration of any dose of ORTHOCLONE OKT3. - Prior to administration of ORTHOCLONE OKT3, the patient's volume status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload, uncontrolled hypertension, or uncompensated heart failure. Patients should have a clear chest X-ray and should not weigh more than 3% above their minimum weight during the week prior to injection. - To decrease the incidence and severity of Cytokine Release Syndrome, associated with the first dose of ORTHOCLONE OKT3, it is strongly recommended that methylprednisolone sodium succinate 8.0 mg/kg be administered intravenously 1 to 4 hours prior to the initial dose of ORTHOCLONE OKT3. - Acetaminophen and antihistamines given concomitantly with ORTHOCLONE OKT3 may also help to reduce some early reactions. - When using concomitant immunosuppressive drugs, the dose of each should be reduced to the lowest level compatible with an effective therapeutic response in order to reduce the potential for malignancy and infections. Maintenance immunosuppression should be resumed approximately three days prior to the cessation of ORTHOCLONE OKT®3 therapy. - Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. - Before administration, ORTHOCLONE OKT3 should be inspected for particulate matter and discoloration. Because ORTHOCLONE OKT3 is a protein solution, it may develop fine translucent particles (shown not to affect potency). - No bacteriostatic agent is present in this product. Adherence to aseptic technique is advised. Once the ampule is opened, use immediately and discard the unused portion. - Prepare ORTHOCLONE OKT3 for injection by drawing solution into a syringe through a low protein-binding 0.2 or 0.22 micrometer (µm) filter. Detach filter and attach a new needle for a single intravenous (bolus) injection. - Because no data is available on compatibility of ORTHOCLONE OKT3 with other intravenous substances or additives, other medications/substances should not be added or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed with saline before and after injection of ORTHOCLONE OKT3. - Administer ORTHOCLONE OKT3 as a single intravenous (bolus) injection in less than one minute. Do not administer by intravenous infusion or in conjunction with other drug solutions. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Muromonab-CD3 in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Muromonab-CD3 in pediatric patients. # Contraindications - ORTHOCLONE OKT3 should not be given to patients who: - are hypersensitive to this or any other product of murine origin; have anti-mouse antibody titers ≥1:1000; - are in (uncompensated) heart failure or in fluid overload, as evidenced by chest X-ray or a greater than 3 percent weight gain within the week prior to planned ORTHOCLONE OKT3 administration; - have uncontrolled hypertension; - have a history of seizures, or are predisposed to seizures; - are determined or suspected to be pregnant, or who are breast-feeding. # Warnings - Most patients develop an acute clinical syndrome that has been attributed to the release of cytokines by activated lymphocytes or monocytes and is temporally associated with the administration of the first few doses of ORTHOCLONE OKT®3 (particularly, the first two to three doses). This clinical syndrome has ranged from a more frequently reported mild, self-limited, "flu-like" illness to a less frequently reported severe, life-threatening shock-like reaction, which may include serious cardiovascular and central nervous system manifestations. The syndrome typically begins approximately 30 to 60 minutes after administration of a dose of ORTHOCLONE OKT3 (but may occur later) and may persist for several hours. The frequency and severity of this symptom complex is usually greatest with the first dose. With each successive dose of ORTHOCLONE OKT3, both the frequency and severity of the Cytokine Release Syndrome tends to diminish. Increasing the amount of ORTHOCLONE OKT3 or resuming treatment after a hiatus may result in a reappearance of the CRS. - Common clinical manifestations of CRS may include: high fever (often spiking, up to 107°F), chills/rigors, headache, tremor, nausea/vomiting, diarrhea, abdominal pain, malaise, muscle/joint aches and pains, and generalized weakness. Less frequently reported adverse experiences include: minor dermatologic reactions (e.g., rash, pruritus, etc.) and a spectrum of often serious, occasionally fatal, cardiorespiratory and central nervous system adverse experiences. - Cardiorespiratory findings may include: dyspnea, shortness of breath, bronchospasm/wheezing, tachypnea, respiratory arrest/failure/distress, cardiovascular collapse, cardiac arrest, angina/myocardial infarction, chest pain/tightness, tachycardia (including ventricular), hypertension, hemodynamic instability, hypotension including profound shock, heart failure, pulmonary edema (cardiogenic and non-cardiogenic), adult respiratory distress syndrome, hypoxemia, apnea, and arrhythmias. - In the initial studies of renal allograft rejection, potentially fatal, severe pulmonary edema occurred in 5% of the initial 107 patients. Fluid overload was present before treatment in all of these cases. It occurred in none of the subsequent 311 patients treated with first-dose volume/weight restrictions. In subsequent trials and in post-marketing experience, severe pulmonary edema has occurred in patients who appeared to be euvolemic. The pathogenesis of pulmonary edema may involve all or some of the following: volume overload; increased pulmonary vascular permeability; and/or reduced left ventricular compliance/contractility. During the first 1 to 3 days of ORTHOCLONE OKT3 therapy, some patients have experienced an acute and transient decline in the glomerular filtration rate (GFR) and diminished urine output with a resulting increase in the level of serum creatinine. - Massive release of cytokines appears to lead to reversible renal functional impairment and/or delayed renal allograft function. Similarly, transient elevations in hepatic transaminases have been reported following administration of the first few doses of ORTHOCLONE OKT3. - Patients at risk for more serious complications of CRS may include those with the following conditions: unstable angina; recent myocardial infarction or symptomatic ischemic heart disease; heart failure of any etiology; pulmonary edema of any etiology; any form of chronic obstructive pulmonary disease; intravascular volume overload or depletion of any etiology (e.g., excessive dialysis, recent intensive diuresis, blood loss, etc.); cerebrovascular disease; patients with advanced symptomatic vascular disease or neuropathy; a history of seizures; and septic shock. Efforts should be made to correct or stabilize background conditions prior to the initiation of therapy. - Prior to administration of ORTHOCLONE OKT3, the patient's volume (fluid) status and a chest X-ray should be assessed to rule out volume overload, uncontrolled hypertension, or uncompensated heart failure. Patients should not weigh >3% above their minimum weight during the week prior to injection. - The Cytokine Release Syndrome is associated with increased serum levels of cytokines (e.g., TNF-α, IL-2, IL-6, IFN-γ) that peak between 1 and 4 hours following administration of ORTHOCLONE OKT3. The serum levels of cytokines and the manifestations of CRS may be reduced by pretreatment with 8 mg/kg of methylprednisolone (i.e., high-dose steroids), given 1 to 4 hours prior to administration of the first dose of ORTHOCLONE OKT3, and by closely following recommendations for dosage and treatment duration. It is not known if corticosteroid pretreatment decreases organ damage and sequelae associated with CRS. For example, increased intracranial pressure and cerebral herniation have occurred despite pretreatment with currently recommended doses and schedules of methylprednisolone. - If any of the more serious presentations of the Cytokine Release Syndrome occur, intensive treatment including oxygen, intravenous fluids, corticosteroids, pressor amines, antihistamines, intubation, etc., may be required. - Seizures, encephalopathy, cerebral edema, aseptic meningitis, and headache have been reported, even following the first dose, during therapy with ORTHOCLONE OKT®3. Seizures, some accompanied by loss of consciousness or cardiorespiratory arrest, or death, have occurred independently or in conjunction with any of the neurologic syndromes described below. - A few cases of fatal cerebral herniations subsequent to cerebral edema have been reported. All patients, particularly pediatric patients, must be carefully evaluated for fluid retention and hypertension before the initiation of ORTHOCLONE OKT3 therapy. Close monitoring for neurologic symptoms must be performed during the first twenty - four (24) hours following each of the first few doses of ORTHOCLONE OKT3 injection. - Patients should be closely monitored for convulsions and manifestations of encephalopathy, including: impaired cognition, confusion, obtundation, altered mental status, disorientation, auditory/visual hallucinations, psychosis (delirium, paranoia), mood changes (e.g., mania, agitation, combativeness, etc.), diffuse hypotonus, hyperreflexia, myoclonus, tremor, asterixis, involuntary movements, major motor seizures, lethargy/stupor/coma, and diffuse weakness. Approximately one-third of patients with a diagnosis of encephalopathy may have had coexisting aseptic meningitis syndrome. - Signs and symptoms of the aseptic meningitis syndrome described in association with the use of ORTHOCLONE OKT3 have included: fever, headache, meningismus (stiff neck), and photophobia. Diagnosis is confirmed by cerebrospinal fluid (CSF) analysis demonstrating leukocytosis with pleocytosis, elevated protein and normal or decreased glucose, with negative viral, bacterial, and fungal cultures. The possibility of infection should be evaluated in any immunosuppressed transplant patient with clinical findings suggesting meningitis. Approximately one-third of the patients with a diagnosis of aseptic meningitis had coexisting signs and symptoms of encephalopathy. Most patients with the aseptic meningitis syndrome had a benign course and recovered without any permanent sequelae during therapy or subsequent to its completion or discontinuation. However, because meningitis is a frequent infection encountered in pediatric allograft recipients, and the immunosuppression associated with transplantation increases the risk of opportunistic infection, pediatric patients with signs or symptoms suggestive of meningeal irritation while receiving ORTHOCLONE OKT3 should have lumbar punctures performed to rule out an infectious etiology. - Signs or symptoms of encephalopathy, meningitis, seizures, and cerebral edema, with or without headache, typically have been reversible. Headache, aseptic meningitis, seizures, and less severe forms of encephalopathy resolved in most patients despite continued treatment with ORTHOCLONE OKT3. However, some events resulted in permanent neurologic impairment. - The following additional central nervous system events have each been reported: irreversible blindness, impaired vision, quadri-or paraparesis/plegia, cerebrovascular accident (hemiparesis/plegia), aphasia, transient ischemic attack, subarachnoid hemorrhage, palsy of the VI cranial nerve, hearing decrease, and deafness. - Patients who may be at greater risk for CNS adverse experiences include those: with known or suspected CNS disorders (e.g., history of seizure disorder, etc.); with cerebrovascular disease (small or large vessel); with conditions having associated neurologic problems (e.g., head trauma, uremia, infection, fluid and electrolyte disturbance, etc.); with underlying vascular diseases; or who are receiving a medication concomitantly that may, by itself, affect the central nervous system. - Serious and occasionally fatal, immediate (usually within 10 minutes) hypersensitivity (anaphylactic) reactions have been reported in patients treated with ORTHOCLONE OKT3. Manifestations of anaphylaxis may appear similar to manifestations of the Cytokine Release Syndrome (described above). It may be impossible to determine the mechanism responsible for any systemic reaction(s). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release. Acute hypersensitivity reactions may be characterized by: cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, hypotension/shock, tachycardia, tingling, angioedema (including laryngeal, pharyngeal, or facial edema), airway obstruction, bronchospasm, dyspnea, urticaria, and pruritus. - Serious allergic events, including anaphylactic or anaphylactoid reactions, have been reported in patients re-exposed to ORTHOCLONE OKT3 subsequent to their initial course of therapy. Pretreatment with antihistamines and/or steroids may not reliably prevent anaphylaxis in this setting. Possible allergic hazards of retreatment should be weighed against expected therapeutic benefits and alternatives. If a patient is retreated with ORTHOCLONE OKT3, it is particularly important that epinephrine and other emergency life-support equipment should be immediately available. - If hypersensitivity is suspected, discontinue the drug immediately; do not resume therapy or re-expose the patient to ORTHOCLONE OKT3. Serious acute hypersensitivity reactions may require emergency treatment with 0.3 mL to 0.5 mL aqueous epinephrine (1:1000 dilution) subcutaneously and other resuscitative measures including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. - Serious and sometimes fatal infections and neoplasias have been reported in association with all immunosuppressive therapies, including those regimens containing ORTHOCLONE OKT®3. - ORTHOCLONE OKT3 is usually added to immunosuppressive therapeutic regimens, thereby augmenting the degree of immunosuppression. This increase in the total amount of immunosuppression may alter the spectrum of infections observed and increase the risk, the severity, and the morbidity of infectious complications. During the first month post-transplant, patients are at greatest risk for the following infections: (1) those present prior to transplant, perhaps exacerbated by post-transplant immunosuppression; (2) infection conveyed by the donor organ; and (3) the usual post-operative urinary tract, intravenous line related, wound, or pulmonary infections due to bacterial pathogens. - Approximately one to six months post-transplant, patients are at risk for viral infections which produce serious systemic disease and which also increase the overall state of immunosuppression. - Reactivation (1 to 4 months post-transplant) of EBV and CMV has been reported. When administration of an anti-lymphocyte antibody, including ORTHOCLONE OKT3, is followed by an immunosuppressive regimen including cyclosporine, there is an increased risk of reactivating CMV and impaired ability to limit its proliferation, resulting in symptomatic and disseminated disease. EBV infection, either primary or reactivated, may play an important role in the development of post-transplant lymphoproliferative disorders. - In the pediatric transplant population, viral infections often include pathogens uncommon in adults, such as varicella zoster virus (VZV), adenovirus, and respiratory syncytial virus (RSV). A large proportion of pediatric patients have not been infected with the herpes viruses prior to transplantation and, therefore, are susceptible to developing primary infections from the grafted organ and/or blood products. - Geriatric patients may have a reduced capability to overcome infections during intense immunosuppression. There is no information on the use of OKT3 in geriatric patients. In an age-stratification analysis, no overall difference in the safety of OKT3 was noted between older (51 to 64 years) and younger (≤30 years) patients. Caution should be used when prescribing immunosuppressive agents to elderly patients. - Anti-infective prophylaxis may reduce the morbidity associated with certain potential pathogens and should be considered for pediatric and other high-risk patients. Judicious use of immunosuppressive drugs, including type, dosage, and duration, may limit the risk and seriousness of some opportunistic infections. It is also possible to reduce the risk of serious CMV or EBV infection by avoiding transplantation of a CMV-seropositive (donor) and/or EBV-seropositive (donor) organ into a seronegative patient. - As a result of depressed cell-mediated immunity from immunosuppressive agents, organ transplant patients have an increased risk of developing malignancies. This risk is evidenced almost exclusively by the occurrence of lymphoproliferative disorders, squamous cell carcinomas of the skin and lip, and sarcomas. In immunosuppressed patients, T cell cytotoxicity is impaired allowing for transformation and proliferation of EBV-infected B lymphocytes. - Transformed B lymphocytes are thought to initiate oncogenesis, which ultimately culminates in the development of most post-transplant lymphoproliferative disorders. Patients, especially pediatric patients, with primary EBV infection may be at a higher risk for the development of EBV-associated lymphoproliferative disorders. Data support an association between the development of lymphoproliferative disorders at the time of active EBV infection and ORTHOCLONE OKT3 administration in pediatric liver allograft recipients. - Following the initiation of ORTHOCLONE OKT3 therapy, patients should be continuously monitored for evidence of lymphoproliferative disorders through physical examination and histological evaluation of any suspect lymphoid tissue. Close surveillance is advised, since early detection with subsequent reduction of total immunosuppression may result in regression of some of these lymphoproliferative disorders. Since the potential for the development of lymphoproliferative disorders is related to the duration and extent (intensity) of total immunosuppression, physicians are advised: to adhere to the recommended dosage and duration of ORTHOCLONE OKT3 therapy; to limit the number of courses of ORTHOCLONE OKT3 and other anti- T lymphocyte antibody preparations administered within a short period of time; and, if appropriate, to reduce the dosage(s) of immunosuppressive drugs used concomitantly to the lowest level compatible with an effective therapeutic response. - A recent study examined the incidence of non-Hodgkin's lymphoma (NHL) among 45,000 kidney transplant recipients and over 7,500 heart transplant recipients. This study suggested that all transplant patients, regardless of the immunosuppressive regimen employed, are at increased risk of NHL over the general population. The relative risk was highest among those receiving the most aggressive regimens. - The long-term risk of neoplastic events in patients being treated with ORTHOCLONE OKT3 has not been determined. # Adverse Reactions ## Clinical Trials Experience - In controlled clinical trials for treatment of acute renal allograft rejection, patients treated with ORTHOCLONE OKT3 plus concomitant low-dose immunosuppressive therapy (primarily azathioprine and corticosteroids) were observed to have an increased incidence of adverse experiences during the first two days of treatment, as compared with the group of patients receiving azathioprine and high-dose steroid therapy. During this period the majority of patients experienced pyrexia (90%), of which 19% were 40.0°C (104°F) or above, and chills (59%). In addition, other adverse experiences occurring in 8% or more of the patients during the first two days of ORTHOCLONE OKT3 therapy included: dyspnea (21%), nausea (19%), vomiting (19%), chest pain (14%), diarrhea (14%), tremor (13%), wheezing (13%), headache (11%), tachycardia (10%), rigor (8%), and hypertension (8%). A similar spectrum of clinical manifestations has been observed in open clinical studies and in post-marketing experience involving patients treated with ORTHOCLONE OKT3 for rejection following renal, cardiac, and hepatic transplantation. - Additional serious and occasionally fatal cardiorespiratory manifestations have been reported following any of the first few doses. - In the acute renal allograft rejection trials, potentially fatal pulmonary edema had been reported following the first two doses in less than 2% of the patients treated with ORTHOCLONE OKT3. Pulmonary edema was usually associated with fluid overload. However, post-marketing experience revealed that pulmonary edema has occurred in patients who appeared to be euvolemic, presumably as a consequence of cytokine-mediated increased vascular permeability ("leaky capillaries") and/or reduced myocardial contractility/compliance (i.e., left ventricular dysfunction). - In the controlled randomized renal allograft rejection trial conducted before cyclosporine was marketed, the most common infections during the first 45 days of ORTHOCLONE OKT3 therapy were due to herpes simplex virus (27%) and cytomegalovirus (19%). Other severe and life-threatening infections were Staphylococcus epidermidis (5%), Pneumocystis carinii (3%), Legionella (2%), Cryptococcus (2%), Serratia (2%) and gram-negative bacteria (2%). The incidence of infections was similar in patients treated with ORTHOCLONE OKT3 and in patients treated with high-dose steroids. - In a clinical trial of acute hepatic allograft rejection, refractory to conventional treatment, the most common infections reported in patients treated with ORTHOCLONE OKT3 during the first 45 days of the study were cytomegalovirus (16% of patients, of which 43% of infections were severe), fungal infections (15% of patients, of which 30% were severe), and herpes simplex virus (8% of patients, of which 10% were severe). Other severe and life-threatening infections were gram-positive infections (9% of patients), gram-negative infections (8% of patients), viral infections (2% of patients), and Legionella (1% of patients). In another trial studying the use of ORTHOCLONE OKT®3 in patients with hepatic allografts, the incidence of fungal infections was 34% and infections with the herpes simplex virus was 31%. - In a clinical trial studying the use of ORTHOCLONE OKT3 in patients with acute cardiac rejection refractory to conventional treatment, the most common infections in the ORTHOCLONE OKT3 group reported during the first 45 days of the study were herpes simplex virus (5% of patients, of which 20% were severe), fungal infections (4% of patients, of which 75% were severe), and cytomegalovirus (3% of patients, of which 33% were severe). No other severe or life-threatening infections were reported during this period. - In a retrospective analysis of pediatric patients treated for acute hepatic rejection, the most common infections reported in patients treated with ORTHOCLONE OKT3 therapy were due to bacterial infections (47%), fungal infections (21%), cytomegalovirus (19%), herpes simplex virus (15%), adenovirus (8%), and Epstein-Barr virus (8%). The overall rates of viral, fungal, and bacterial infections were similar in patients treated with ORTHOCLONE OKT3 (n = 53) and in patients whose rejection was treated with steroids alone (n = 27). In another study of 149 pediatric liver allograft patients where 59 episodes of steroid-resistant rejection were treated with ORTHOCLONE OKT3, the incidence of invasive cytomegalovirus infection was higher in patients receiving ORTHOCLONE OKT3 than in those receiving steroids alone. - Clinically significant infections (e.g., pneumonia, sepsis, etc.) due to the following pathogens have been reported: - In patients treated with ORTHOCLONE OKT3, post-transplant lymphoproliferative disorders have ranged from lymphadenopathy or benign polyclonal B cell hyperplasias to malignant and often fatal monoclonal B cell lymphomas. In post-marketing experience, approximately one-third of the lymphoproliferations reported were benign and two-thirds were malignant. Lymphoma types included: B cell, large cell, polyclonal, non-Hodgkin's, lymphocytic, T cell, Burkitt's. The majority were not histologically classified. Malignant lymphomas appear to develop early after transplantation, the majority within the first four months post-treatment. - Many of these have been rapidly progressive. Some were fulminant, involving the allografted organ and were widely disseminated at the time of diagnosis. - Carcinomas of the skin included: basal cell, squamous cell, sarcoma, melanoma, and keratoacanthoma. Other neoplasms infrequently reported include: multiple myeloma, leukemia, carcinoma of the breast, adenocarcinoma, cholangiocarcinoma, and recurrences of pre-existing hepatoma and renal cell carcinoma. - Reported adverse reactions resulting from the formation of antibodies to ORTHOCLONE OKT3 have included antigen-antibody (immune complex) mediated syndromes and IgE-mediated reactions. Hypersensitivity reactions have ranged from a mild, self-limited rash or pruritus to severe, life-threatening anaphylactic reactions/shock or angioedema (including: swelling of lips, eyelids, laryngeal spasm and airway obstruction with hypoxia). - Other hypersensitivity reactions have included - Ineffectiveness of treatment, serum sickness, arthritis, allergic interstitial nephritis, immune complex deposition resulting in glomerulonephritis, vasculitis (including temporal and retinal), and eosinophilia. - Adverse events reported in greater than or equal to 1% of clinical trial patients treated with ORTHOCLONE OKT3 (n=393) are shown in Table 1: ## Postmarketing Experience - Body as a Whole, General Disorders: Fever (including spiking temperatures as high as 107°F), Flu-like Syndrome. - Cardiovascular Disorders: Cardiovascular Collapse, Hemodynamic Instability, Left Ventricular Dysfunction. - Central and Peripheral Nervous System Disorders: Agitation, Aphasia, Asterixis, Cerebritis, Cerebral Edema, Cerebral Herniation, Cerebrovascular Accident, CNS Infection, CNS Malignancy, Cranial Nerve VI Palsy, Encephalitis, Hyperreflexia, Involuntary Movements, Intracranial Hemorrhage, Impaired Cognition, Myoclonus, Obnubilation, Paresis/plegia including quadriparesis/plegia, Status Epilepticus, Stupor, Transient Ischemic Attack, Vertigo. - In a post-marketing survey involving 214 renal transplant patients, the incidence of aseptic meningitis syndrome was 6%. Fever (89%), headache (44%), neck stiffness (14%), and photophobia (10%) were the most commonly reported symptoms; a combination of these four symptoms occurred in 5% of patients. - Between 1987 and 1992, 75 post-marketing reports have described seizures, averaging about 12 per year, and including 23 fatalities. More than two-thirds of these reports (53) were of domestic spontaneous origin, and their age and sex distributions were broad. Post-licensure reports generally provide insufficient data to allow accurate estimation of risk or of incidence. - Gastrointestinal Disorders: Bowel Infarction. - Hematopoietic Disorders: Aplastic anemia, Arterial, Venous and Capillary Thrombosis of allografts and other vascular beds e.g., heart, lung, brain and bowel etc., Disseminated Intravascular Coagulation, Microangiopathic Changes (e.g., platelet microthrombi), Microangiopathic Hemolytic Anemia, Neutropenia, Pancytopenia. - Hepatobiliary: Hepatitis or Hepato/splenomegaly, usually secondary to viral infection or lymphoma. - Reactivation of viral hepatitis including CMV, EBV, Hepatitis B virus (HBV), and Hepatitis C virus (HCV). - Musculoskeletal Disorders: Arthritis, Stiffness/Aches/Pains. - Renal Disorders: Azotemia, Abnormal Urinary Cytology including exfoliation of damaged lymphocytes, collecting duct cells and cellular casts, Delayed Graft Function, Renal Insufficiency/Renal Failure, usually transient and reversible and occasionally in association with Cytokine Release Syndrome. - Respiratory System Disorders: Adult Respiratory Distress Syndrome, Respiratory Arrest, Respiratory Failure. - Skin and Appendages: Erythema, Flushing, Stevens-Johnson Syndrome, Urticaria. - Special Senses: Blindness, Blurred Vision, Deafness, Diplopia, Otitis Media, Nasal and Ear Stuffiness, Papilledema. # Drug Interactions # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproductive studies have not been conducted with ORTHOCLONE OKT3. It is also not known whether ORTHOCLONE OKT3 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. - However, ORTHOCLONE OKT3 is an IgG antibody and may cross the human placenta. The effect on the fetus of the release of cytokines and/or immunosuppression after treatment with ORTHOCLONE OKT3 is not known. ORTHOCLONE OKT3 should be given to a pregnant woman only if clearly needed. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Muromonab-CD3 in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Muromonab-CD3 during labor and delivery. ### Nursing Mothers - It is not known whether ORTHOCLONE OKT3 is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse events/oncogenesis shown for ORTHOCLONE OKT3 in human studies, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness have been established in infants (1 mo. up to 2 yr.); children (2 yr. up to 12 yr.); and adolescents (12 yr. up to 16 yr.). Use of ORTHOCLONE OKT3 in these age groups is supported by clinical studies that included adults and pediatric patients. In those studies, the safety and efficacy of ORTHOCLONE OKT3 in pediatric patients receiving renal or hepatic transplants was similar to that in the overall cohort. There were insufficient data to compare the safety and efficacy of ORTHOCLONE OKT3 in pediatric patients in a study of patients receiving cardiac transplants. Additional pharmacokinetic, pharmacodynamic, and clinical studies in infants, children, and adolescents have been reported in published literature. - Pediatric patients are known to have higher CD3 lymphocyte counts than adults; therefore, progressively higher doses of ORTHOCLONE OKT3 are often required to achieve therapeutic levels of lymphocyte clearance. Specific Safety Concerns in Pediatric Patients - The postmarketing data base indicates that pediatric patients may be at increased risk of developing cerebral edema with or without herniation compared to adults. In the period between 1986 and 1996, twenty-five cases (6 in pediatric patients) of cerebral edema were identified with subsequent cerebral herniation and death in five cases (4 in pediatric patients). Herniation in the pediatric patients and one 19 year old subject occurred within a few hours to one day after the first dose (2.5 or 5 mg) of ORTHOCLONE OKT3 administered in the investigational setting for prophylaxis of renal allograft rejection. All pediatric patients and especially those receiving a renal allograft must be carefully evaluated for fluid retention and hypertension before the initiation of ORTHOCLONE OKT3 therapy. Patients should be closely monitored for neurologic symptoms during the first twenty four (24) hours following each of the first few doses of ORTHOCLONE OKT3 injection. - Other significant neurologic complications reported in pediatric transplant recipients receiving ORTHOCLONE OKT3 include status epilepticus, cerebral edema, diffuse encephalopathy, cerebritis, seizures, cortical dysfunction, and intracranial hemorrhage. Permanent neurologic impairments (e.g., blindness, deafness, paralysis) have been reported rarely. Because meningitis is a frequent infection encountered in pediatric allograft recipients, and the immunosuppression associated with transplantation increases the risk of opportunistic infection, patients with meningeal irritation following treatment with ORTHOCLONE OKT3 therapy should be evaluated with lumbar puncture as early as possible to rule out an infectious etiology. - The overall incidence of infections appeared to be similar in pediatric patients compared to the overall population studied. In the pediatric population, viral infections often include pathogens uncommon in adults, such as varicella zoster virus (VZV), adenovirus, enterovirus, parainfluenza virus, and respiratory syncytial virus (RSV). In addition, many viral diseases often manifest differently in pediatric patients than they do in adults. Because a large proportion of pediatric patients have not been infected by herpes viruses (e.g., EBV, HSV, CMV) prior to transplantation they may be more susceptible to acquiring primary infections from the grafted organ and/or blood products when immunosuppressed. Antiviral prophylactic therapy may be particularly useful in these high risk pediatric patients. - Patients with primary EBV infection may be at higher risk for the development of EBV-associated lymphoproliferative disorders. There are data to support an association between the development of lymphoproliferative disorders at the time of active EBV infection and ORTHOCLONE OKT®3 administration in pediatric liver allograft recipients. Antiviral prophylactic therapy may be particularly useful in these high risk pediatric patients. - Parenteral hydration may be required for gastrointestinal fluid loss secondary to diarrhea and/or vomiting resulting from the "Cytokine Release Syndrome." - Pediatric patients may be at an increased risk of thrombosis. Pediatric patients weighing less than 15 kg are at high-risk for hepatic artery thrombosis. Thrombosis has been reported in pediatric transplant recipients treated with ORTHOCLONE OKT3. A number of factors, including surgical technique, the presence of a hypercoaguable state, and the absence of prior dialysis experience may be relevant to the pathophysiology of the increased risk of thrombosis. ### Geriatic Use There is no information on the use of OKT3 in geriatric patients. Caution should be used when prescribing immunosuppressive agents to elderly patients. ### Gender There is no FDA guidance on the use of Muromonab-CD3 with respect to specific gender populations. ### Race There is no FDA guidance on the use of Muromonab-CD3 with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Muromonab-CD3 in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Muromonab-CD3 in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Muromonab-CD3 in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Muromonab-CD3 in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - Patients should be closely monitored for neurologic symptoms during the first twenty four (24) hours following each of the first few doses of ORTHOCLONE OKT3 injection. - Patients should be closely monitored for convulsions and manifestations of encephalopathy, including: impaired cognition, confusion, obtundation, altered mental status, disorientation, auditory/visual hallucinations, psychosis (delirium, paranoia), mood changes (e.g., mania, agitation, combativeness, etc.), diffuse hypotonus, hyperreflexia, myoclonus, tremor, asterixis, involuntary movements, major motor seizures, lethargy/stupor/coma, and diffuse weakness. - Vital signs should be monitored frequently. Patients receiving ORTHOCLONE OKT3 should also be carefully monitored for signs and symptoms of Cytokine Release Syndrome, particularly after the first few doses but also after a treatment hiatus with resumption of therapy. - Following the initiation of ORTHOCLONE OKT3 therapy, patients should be continuously monitored for evidence of lymphoproliferative disorders through physical examination and histological evaluation of any suspect lymphoid tissue. - The following tests should be monitored prior to and during ORTHOCLONE OKT®3 therapy: - Renal: BUN, serum creatinine, etc.; - Hepatic: transaminases, alkaline phosphatase, bilirubin; - Hematopoietic: WBCs and differential, platelet count, etc.; - Chest X-ray within 24 hours before initiating ORTHOCLONE OKT3 treatment to rule out heart failure or fluid overload. - Blood Tests: Periodic assessment of organ system functions (renal, hepatic, and hematopoietic) should be performed. # IV Compatibility There is limited information regarding IV Compatibility of Muromonab-CD3 in the drug label. # Overdosage - Symptoms of overdosage with ORTHOCLONE OKT®3 may include hyperthermia, severe chills, myalgia, vomiting, diarrhea, edema, oliguria, pulmonary edema, and acute renal failure. A high incidence (5%) of microangiopathic hemolytic anemia/HUS syndrome in patients receiving 10 mg per day of ORTHOCLONE OKT3 was also reported. In the event of acute overdosage with ORTHOCLONE OKT3, the patient should be carefully observed and given symptomatic and supportive treatment. # Pharmacology ## Mechanism of Action - ORTHOCLONE OKT3 reverses graft rejection, probably by blocking the function of T cells which play a major role in acute allograft rejection. OTHOCLONE OKT3 reacts with and blocks the function of a 20,000 dalton molecule (CD3) in the membrane of human T cells that has been associated in vitro with the antigen recognition structure of T cells and is essential for signal transduction. In in vitro cytolytic assays, ORTHOCLONE OKT3 blocks both the generation and function of effector cells. Binding of ORTHOCLONE OKT3 to T lymphocytes results in early activation of T cells, which leads to cytokine release, followed by blocking T cell functions. After termination of ORTHOCLONE OKT3 therapy, T cell function usually returns to normal within one week. - In vivo, ORTHOCLONE OKT3 reacts with most peripheral blood T cells and T cells in body tissues, but has not been found to react with other hematopoietic elements or other tissues of the body. - A rapid and concomitant decrease in the number of circulating CD3 positive cells, including those that are CD2, CD4, or CD8 positive has been observed in patients studied within minutes after the administration of ORTHOCLONE OKT3. This decrease in the number of CD3 positive T cells results from the specific interaction between ORTHOCLONE OKT3 and the CD3 antigen on the surface of all T lymphocytes. T cell activation results in the release of numerous cytokines/lymphokines, which are felt to be responsible for many of the acute clinical manifestations seen following ORTHOCLONE OKT3 administration ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Muromonab-CD3 in the drug label. ## Pharmacokinetics - While CD3 positive cells are not detectable between days two and seven, increasing numbers of circulating CD2, CD4, and CD8 positive cells have been observed. The presence of these CD2, CD4, and CD8 positive cells has not been shown to affect reversal of rejection. After termination of ORTHOCLONE OKT3 therapy, CD3 positive cells reappear rapidly and reach pre-treatment levels within a week. In some patients however, increasing numbers of CD3 positive cells have been observed prior to termination of ORTHOCLONE OKT3 therapy. This reappearance of CD3 positive cells has been attributed to the development of neutralizing antibodies to ORTHOCLONE OKT3, which in turn block its ability to bind to the CD3 antigen on T lymphocytes. - Pediatric patients are known to have higher CD3 lymphocyte counts than adults. Pediatric patients receiving ORTHOCLONE OKT®3 therapy often require progressively higher doses of ORTHOCLONE OKT3 to achieve depletion of CD3 positive cells (800 ng/mL). - Serum levels of ORTHOCLONE OKT3 are measurable using an enzyme-linked immunosorbent assay (ELISA). During the initial clinical trials in renal allograft rejection, in patients treated with 5 mg per day for 14 days, mean serum trough levels of the drug rose over the first three days and then averaged 900 ng/mL on days 3 to 14. Serum concentrations measured daily during treatment with ORTHOCLONE OKT3 in renal, hepatic, and cardiac allograft recipients revealed that pediatric patients less than 10 years of age have higher levels than patients 10–50 years of age. Subsequent clinical experience has demonstrated that serum levels greater than or equal to 800 ng/mL of ORTHOCLONE OKT3 blocks the function of cytotoxic T cells in vitro and in vivo. Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. - Following administration of ORTHOCLONE OKT3 in vivo, leukocytes have been observed in cerebrospinal and peritoneal fluids. The mechanism for this effect is not completely understood, but probably is related to cytokines altering membrane permeability, rather than an active inflammatory process. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Muromonab-CD3 in the drug label. # Clinical Studies - In a controlled randomized clinical trial, ORTHOCLONE OKT3 was compared with conventional high-dose steroid therapy in reversing acute renal allograft rejection. In this trial, 122 evaluable patients undergoing acute rejection of cadaveric renal transplants were treated either with ORTHOCLONE OKT3 daily for a mean of 14 days, with concomitant lowering of the dosage of azathioprine and maintenance steroids (62 patients), or with conventional high-dose steroids (60 patients). ORTHOCLONE OKT3 reversed 94% of the rejections compared to a 75% reversal rate obtained with conventional high-dose steroid treatment (p=0.006). The one year Kaplan-Meier (actuarial) estimates of graft survival rates for these patients who had acute rejection were 62% and 45% for ORTHOCLONE OKT3 and steroid-treated patients, respectively (p=0.04). At two years the rates were 56% and 42%, respectively (p=0.06). - One- and two-year patient survivals were not significantly different between the two groups, being 85% and 75% for ORTHOCLONE OKT3 treated patients and 90% and 85% for steroid-treated patients. - In additional open clinical trials, the observed rate of reversal of acute renal allograft rejection was 92% (n=126) for ORTHOCLONE OKT3 therapy. ORTHOCLONE OKT3 was also effective in reversing acute renal allograft rejections in 65% (n=225) of cases where steroids and lymphocyte immune globulin preparations were contraindicated or were not successful. - The effectiveness of ORTHOCLONE OKT3 for prophylaxis of renal allograft rejection has not been established. - ORTHOCLONE OKT3 was studied for use in reversing acute cardiac and hepatic allograft rejection in patients who are unresponsive to high-doses of steroids. The rate of reversal in acute cardiac allograft rejection was 90% (n = 61) and was 83% for hepatic allograft rejection (n = 124) in patients unresponsive to treatment with steroids. - Controlled randomized trials have not been conducted to evaluate the effectiveness of ORTHOCLONE OKT3 compared to conventional therapy as first line treatment for acute cardiac and hepatic allograft rejection. # How Supplied - ORTHOCLONE OKT3 is supplied as a sterile solution in packages of 5 ampules (NDC 59676-101-01). Each 5 mL ampule contains 5 mg of muromonab-CD3. ## Storage Storage Store in a refrigerator at 2° to 8°C (36° to 46°F). DO NOT FREEZE OR SHAKE. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Muromonab-CD3 in the drug label. # Precautions with Alcohol - Alcohol-Muromonab-CD3 interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - OKT3 ® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Muromonab-CD3 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Muromonab-CD3 is a monoclonal antibody that is FDA approved for the treatment of acute allograft rejection in renal transplant patients, steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema , hypotension, tachycardia, rash, diarrhea, nausea, vomiting, headache, tremor, fever, shivering. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ORTHOCLONE OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients. - ORTHOCLONE OKT3 is indicated for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. - The dosage of other immunosuppressive agents used in conjunction with ORTHOCLONE OKT3 should be reduced to the lowest level compatible with an effective therapeutic response. - The recommended dose of ORTHOCLONE OKT3 for the treatment of acute renal, steroid-resistant cardiac, or steroid-resistant hepatic allograft rejection is 5 mg per day in a single (bolus) intravenous injection in less than one minute for 10 to 14 days. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant cardiac or hepatic allograft rejection, treatment should begin when the treating physician deems a rejection has not been reversed by an adequate course of corticosteroid therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Muromonab-CD3 in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Muromonab-CD3 in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The initial recommended dose is 2.5 mg per day in pediatric patients weighing less than or equal to 30 kg and 5 mg per day in pediatric patients weighing greater than 30 kg in a single (bolus) intravenous injection in less than one minute for 10 to 14 days. Daily increases in ORTHOCLONE OKT3 doses (i.e., 2.5 mg increments) may be required to achieve depletion of CD3 positive cells (<25 cells/mm3) and ensure therapeutic ORTHOCLONE OKT3 serum concentrations (> 800 ng/mL). Pediatric patients may require augmentation of the ORTHOCLONE OKT3 dose. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant cardiac or hepatic allograft rejection, treatment should begin when the treating physician deems a rejection has not been reversed by an adequate course of corticosteroid therapy. - For the first few doses, patients should be monitored in a facility equipped and staffed for cardiopulmonary resuscitation (CPR). Patients receiving subsequent doses of ORTHOCLONE OKT3, should also be monitored in a facility equipped and staffed for CPR. Vital signs should be monitored frequently. Patients receiving ORTHOCLONE OKT3 should also be carefully monitored for signs and symptoms of Cytokine Release Syndrome, particularly after the first few doses but also after a treatment hiatus with resumption of therapy. The patient's temperature should be lowered to <37.8°C (100°F) before the administration of any dose of ORTHOCLONE OKT3. - Prior to administration of ORTHOCLONE OKT3, the patient's volume status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload, uncontrolled hypertension, or uncompensated heart failure. Patients should have a clear chest X-ray and should not weigh more than 3% above their minimum weight during the week prior to injection. - To decrease the incidence and severity of Cytokine Release Syndrome, associated with the first dose of ORTHOCLONE OKT3, it is strongly recommended that methylprednisolone sodium succinate 8.0 mg/kg be administered intravenously 1 to 4 hours prior to the initial dose of ORTHOCLONE OKT3. - Acetaminophen and antihistamines given concomitantly with ORTHOCLONE OKT3 may also help to reduce some early reactions. - When using concomitant immunosuppressive drugs, the dose of each should be reduced to the lowest level compatible with an effective therapeutic response in order to reduce the potential for malignancy and infections. Maintenance immunosuppression should be resumed approximately three days prior to the cessation of ORTHOCLONE OKT®3 therapy. - Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. - Before administration, ORTHOCLONE OKT3 should be inspected for particulate matter and discoloration. Because ORTHOCLONE OKT3 is a protein solution, it may develop fine translucent particles (shown not to affect potency). - No bacteriostatic agent is present in this product. Adherence to aseptic technique is advised. Once the ampule is opened, use immediately and discard the unused portion. - Prepare ORTHOCLONE OKT3 for injection by drawing solution into a syringe through a low protein-binding 0.2 or 0.22 micrometer (µm) filter. Detach filter and attach a new needle for a single intravenous (bolus) injection. - Because no data is available on compatibility of ORTHOCLONE OKT3 with other intravenous substances or additives, other medications/substances should not be added or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed with saline before and after injection of ORTHOCLONE OKT3. - Administer ORTHOCLONE OKT3 as a single intravenous (bolus) injection in less than one minute. Do not administer by intravenous infusion or in conjunction with other drug solutions.Pediatric Patients - The initial recommended dose is 2.5 mg per day in pediatric patients weighing less than or equal to 30 kg and 5 mg per day in pediatric patients weighing greater than 30 kg in a single (bolus) intravenous injection in less than one minute for 10 to 14 days. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant cardiac or hepatic allograft rejection, treatment should begin when the treating physician deems a rejection has not been reversed by an adequate course of corticosteroid therapy. - For the first few doses, patients should be monitored in a facility equipped and staffed for cardiopulmonary resuscitation (CPR). Patients receiving subsequent doses of ORTHOCLONE OKT3, should also be monitored in a facility equipped and staffed for CPR. Vital signs should be monitored frequently. Patients receiving ORTHOCLONE OKT3 should also be carefully monitored for signs and symptoms of Cytokine Release Syndrome, particularly after the first few doses but also after a treatment hiatus with resumption of therapy. The patient's temperature should be lowered to <37.8°C (100°F) before the administration of any dose of ORTHOCLONE OKT3. - Prior to administration of ORTHOCLONE OKT3, the patient's volume status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload, uncontrolled hypertension, or uncompensated heart failure. Patients should have a clear chest X-ray and should not weigh more than 3% above their minimum weight during the week prior to injection. - To decrease the incidence and severity of Cytokine Release Syndrome, associated with the first dose of ORTHOCLONE OKT3, it is strongly recommended that methylprednisolone sodium succinate 8.0 mg/kg be administered intravenously 1 to 4 hours prior to the initial dose of ORTHOCLONE OKT3. - Acetaminophen and antihistamines given concomitantly with ORTHOCLONE OKT3 may also help to reduce some early reactions. - When using concomitant immunosuppressive drugs, the dose of each should be reduced to the lowest level compatible with an effective therapeutic response in order to reduce the potential for malignancy and infections. Maintenance immunosuppression should be resumed approximately three days prior to the cessation of ORTHOCLONE OKT®3 therapy. - Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. - Before administration, ORTHOCLONE OKT3 should be inspected for particulate matter and discoloration. Because ORTHOCLONE OKT3 is a protein solution, it may develop fine translucent particles (shown not to affect potency). - No bacteriostatic agent is present in this product. Adherence to aseptic technique is advised. Once the ampule is opened, use immediately and discard the unused portion. - Prepare ORTHOCLONE OKT3 for injection by drawing solution into a syringe through a low protein-binding 0.2 or 0.22 micrometer (µm) filter. Detach filter and attach a new needle for a single intravenous (bolus) injection. - Because no data is available on compatibility of ORTHOCLONE OKT3 with other intravenous substances or additives, other medications/substances should not be added or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed with saline before and after injection of ORTHOCLONE OKT3. - Administer ORTHOCLONE OKT3 as a single intravenous (bolus) injection in less than one minute. Do not administer by intravenous infusion or in conjunction with other drug solutions.Pediatric Patients - The initial recommended dose is 2.5 mg per day in pediatric patients weighing less than or equal to 30 kg and 5 mg per day in pediatric patients weighing greater than 30 kg in a single (bolus) intravenous injection in less than one minute for 10 to 14 days. Daily increases in ORTHOCLONE OKT3 doses (i.e., 2.5 mg increments) may be required to achieve depletion of CD3 positive cells (<25 cells/mm3) and ensure therapeutic ORTHOCLONE OKT3 serum concentrations (> 800 ng/mL). Pediatric patients may require augmentation of the ORTHOCLONE OKT3 dose. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant cardiac or hepatic allograft rejection, treatment should begin when the treating physician deems a rejection has not been reversed by an adequate course of corticosteroid therapy. - For the first few doses, patients should be monitored in a facility equipped and staffed for cardiopulmonary resuscitation (CPR). Patients receiving subsequent doses of ORTHOCLONE OKT3, should also be monitored in a facility equipped and staffed for CPR. Vital signs should be monitored frequently. Patients receiving ORTHOCLONE OKT3 should also be carefully monitored for signs and symptoms of Cytokine Release Syndrome, particularly after the first few doses but also after a treatment hiatus with resumption of therapy. The patient's temperature should be lowered to <37.8°C (100°F) before the administration of any dose of ORTHOCLONE OKT3. - Prior to administration of ORTHOCLONE OKT3, the patient's volume status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload, uncontrolled hypertension, or uncompensated heart failure. Patients should have a clear chest X-ray and should not weigh more than 3% above their minimum weight during the week prior to injection. - To decrease the incidence and severity of Cytokine Release Syndrome, associated with the first dose of ORTHOCLONE OKT3, it is strongly recommended that methylprednisolone sodium succinate 8.0 mg/kg be administered intravenously 1 to 4 hours prior to the initial dose of ORTHOCLONE OKT3. - Acetaminophen and antihistamines given concomitantly with ORTHOCLONE OKT3 may also help to reduce some early reactions. - When using concomitant immunosuppressive drugs, the dose of each should be reduced to the lowest level compatible with an effective therapeutic response in order to reduce the potential for malignancy and infections. Maintenance immunosuppression should be resumed approximately three days prior to the cessation of ORTHOCLONE OKT®3 therapy. - Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. - Before administration, ORTHOCLONE OKT3 should be inspected for particulate matter and discoloration. Because ORTHOCLONE OKT3 is a protein solution, it may develop fine translucent particles (shown not to affect potency). - No bacteriostatic agent is present in this product. Adherence to aseptic technique is advised. Once the ampule is opened, use immediately and discard the unused portion. - Prepare ORTHOCLONE OKT3 for injection by drawing solution into a syringe through a low protein-binding 0.2 or 0.22 micrometer (µm) filter. Detach filter and attach a new needle for a single intravenous (bolus) injection. - Because no data is available on compatibility of ORTHOCLONE OKT3 with other intravenous substances or additives, other medications/substances should not be added or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed with saline before and after injection of ORTHOCLONE OKT3. - Administer ORTHOCLONE OKT3 as a single intravenous (bolus) injection in less than one minute. Do not administer by intravenous infusion or in conjunction with other drug solutions. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Muromonab-CD3 in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Muromonab-CD3 in pediatric patients. # Contraindications - ORTHOCLONE OKT3 should not be given to patients who: - are hypersensitive to this or any other product of murine origin; have anti-mouse antibody titers ≥1:1000; - are in (uncompensated) heart failure or in fluid overload, as evidenced by chest X-ray or a greater than 3 percent weight gain within the week prior to planned ORTHOCLONE OKT3 administration; - have uncontrolled hypertension; - have a history of seizures, or are predisposed to seizures; - are determined or suspected to be pregnant, or who are breast-feeding. # Warnings - Most patients develop an acute clinical syndrome [i.e., Cytokine Release Syndrome (CRS)] that has been attributed to the release of cytokines by activated lymphocytes or monocytes and is temporally associated with the administration of the first few doses of ORTHOCLONE OKT®3 (particularly, the first two to three doses). This clinical syndrome has ranged from a more frequently reported mild, self-limited, "flu-like" illness to a less frequently reported severe, life-threatening shock-like reaction, which may include serious cardiovascular and central nervous system manifestations. The syndrome typically begins approximately 30 to 60 minutes after administration of a dose of ORTHOCLONE OKT3 (but may occur later) and may persist for several hours. The frequency and severity of this symptom complex is usually greatest with the first dose. With each successive dose of ORTHOCLONE OKT3, both the frequency and severity of the Cytokine Release Syndrome tends to diminish. Increasing the amount of ORTHOCLONE OKT3 or resuming treatment after a hiatus may result in a reappearance of the CRS. - Common clinical manifestations of CRS may include: high fever (often spiking, up to 107°F), chills/rigors, headache, tremor, nausea/vomiting, diarrhea, abdominal pain, malaise, muscle/joint aches and pains, and generalized weakness. Less frequently reported adverse experiences include: minor dermatologic reactions (e.g., rash, pruritus, etc.) and a spectrum of often serious, occasionally fatal, cardiorespiratory and central nervous system adverse experiences. - Cardiorespiratory findings may include: dyspnea, shortness of breath, bronchospasm/wheezing, tachypnea, respiratory arrest/failure/distress, cardiovascular collapse, cardiac arrest, angina/myocardial infarction, chest pain/tightness, tachycardia (including ventricular), hypertension, hemodynamic instability, hypotension including profound shock, heart failure, pulmonary edema (cardiogenic and non-cardiogenic), adult respiratory distress syndrome, hypoxemia, apnea, and arrhythmias. - In the initial studies of renal allograft rejection, potentially fatal, severe pulmonary edema occurred in 5% of the initial 107 patients. Fluid overload was present before treatment in all of these cases. It occurred in none of the subsequent 311 patients treated with first-dose volume/weight restrictions. In subsequent trials and in post-marketing experience, severe pulmonary edema has occurred in patients who appeared to be euvolemic. The pathogenesis of pulmonary edema may involve all or some of the following: volume overload; increased pulmonary vascular permeability; and/or reduced left ventricular compliance/contractility. During the first 1 to 3 days of ORTHOCLONE OKT3 therapy, some patients have experienced an acute and transient decline in the glomerular filtration rate (GFR) and diminished urine output with a resulting increase in the level of serum creatinine. - Massive release of cytokines appears to lead to reversible renal functional impairment and/or delayed renal allograft function. Similarly, transient elevations in hepatic transaminases have been reported following administration of the first few doses of ORTHOCLONE OKT3. - Patients at risk for more serious complications of CRS may include those with the following conditions: unstable angina; recent myocardial infarction or symptomatic ischemic heart disease; heart failure of any etiology; pulmonary edema of any etiology; any form of chronic obstructive pulmonary disease; intravascular volume overload or depletion of any etiology (e.g., excessive dialysis, recent intensive diuresis, blood loss, etc.); cerebrovascular disease; patients with advanced symptomatic vascular disease or neuropathy; a history of seizures; and septic shock. Efforts should be made to correct or stabilize background conditions prior to the initiation of therapy. - Prior to administration of ORTHOCLONE OKT3, the patient's volume (fluid) status and a chest X-ray should be assessed to rule out volume overload, uncontrolled hypertension, or uncompensated heart failure. Patients should not weigh >3% above their minimum weight during the week prior to injection. - The Cytokine Release Syndrome is associated with increased serum levels of cytokines (e.g., TNF-α, IL-2, IL-6, IFN-γ) that peak between 1 and 4 hours following administration of ORTHOCLONE OKT3. The serum levels of cytokines and the manifestations of CRS may be reduced by pretreatment with 8 mg/kg of methylprednisolone (i.e., high-dose steroids), given 1 to 4 hours prior to administration of the first dose of ORTHOCLONE OKT3, and by closely following recommendations for dosage and treatment duration. It is not known if corticosteroid pretreatment decreases organ damage and sequelae associated with CRS. For example, increased intracranial pressure and cerebral herniation have occurred despite pretreatment with currently recommended doses and schedules of methylprednisolone. - If any of the more serious presentations of the Cytokine Release Syndrome occur, intensive treatment including oxygen, intravenous fluids, corticosteroids, pressor amines, antihistamines, intubation, etc., may be required. - Seizures, encephalopathy, cerebral edema, aseptic meningitis, and headache have been reported, even following the first dose, during therapy with ORTHOCLONE OKT®3. Seizures, some accompanied by loss of consciousness or cardiorespiratory arrest, or death, have occurred independently or in conjunction with any of the neurologic syndromes described below. - A few cases of fatal cerebral herniations subsequent to cerebral edema have been reported. All patients, particularly pediatric patients, must be carefully evaluated for fluid retention and hypertension before the initiation of ORTHOCLONE OKT3 therapy. Close monitoring for neurologic symptoms must be performed during the first twenty - four (24) hours following each of the first few doses of ORTHOCLONE OKT3 injection. - Patients should be closely monitored for convulsions and manifestations of encephalopathy, including: impaired cognition, confusion, obtundation, altered mental status, disorientation, auditory/visual hallucinations, psychosis (delirium, paranoia), mood changes (e.g., mania, agitation, combativeness, etc.), diffuse hypotonus, hyperreflexia, myoclonus, tremor, asterixis, involuntary movements, major motor seizures, lethargy/stupor/coma, and diffuse weakness. Approximately one-third of patients with a diagnosis of encephalopathy may have had coexisting aseptic meningitis syndrome. - Signs and symptoms of the aseptic meningitis syndrome described in association with the use of ORTHOCLONE OKT3 have included: fever, headache, meningismus (stiff neck), and photophobia. Diagnosis is confirmed by cerebrospinal fluid (CSF) analysis demonstrating leukocytosis with pleocytosis, elevated protein and normal or decreased glucose, with negative viral, bacterial, and fungal cultures. The possibility of infection should be evaluated in any immunosuppressed transplant patient with clinical findings suggesting meningitis. Approximately one-third of the patients with a diagnosis of aseptic meningitis had coexisting signs and symptoms of encephalopathy. Most patients with the aseptic meningitis syndrome had a benign course and recovered without any permanent sequelae during therapy or subsequent to its completion or discontinuation. However, because meningitis is a frequent infection encountered in pediatric allograft recipients, and the immunosuppression associated with transplantation increases the risk of opportunistic infection, pediatric patients with signs or symptoms suggestive of meningeal irritation while receiving ORTHOCLONE OKT3 should have lumbar punctures performed to rule out an infectious etiology. - Signs or symptoms of encephalopathy, meningitis, seizures, and cerebral edema, with or without headache, typically have been reversible. Headache, aseptic meningitis, seizures, and less severe forms of encephalopathy resolved in most patients despite continued treatment with ORTHOCLONE OKT3. However, some events resulted in permanent neurologic impairment. - The following additional central nervous system events have each been reported: irreversible blindness, impaired vision, quadri-or paraparesis/plegia, cerebrovascular accident (hemiparesis/plegia), aphasia, transient ischemic attack, subarachnoid hemorrhage, palsy of the VI cranial nerve, hearing decrease, and deafness. - Patients who may be at greater risk for CNS adverse experiences include those: with known or suspected CNS disorders (e.g., history of seizure disorder, etc.); with cerebrovascular disease (small or large vessel); with conditions having associated neurologic problems (e.g., head trauma, uremia, infection, fluid and electrolyte disturbance, etc.); with underlying vascular diseases; or who are receiving a medication concomitantly that may, by itself, affect the central nervous system. - Serious and occasionally fatal, immediate (usually within 10 minutes) hypersensitivity (anaphylactic) reactions have been reported in patients treated with ORTHOCLONE OKT3. Manifestations of anaphylaxis may appear similar to manifestations of the Cytokine Release Syndrome (described above). It may be impossible to determine the mechanism responsible for any systemic reaction(s). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release. Acute hypersensitivity reactions may be characterized by: cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, hypotension/shock, tachycardia, tingling, angioedema (including laryngeal, pharyngeal, or facial edema), airway obstruction, bronchospasm, dyspnea, urticaria, and pruritus. - Serious allergic events, including anaphylactic or anaphylactoid reactions, have been reported in patients re-exposed to ORTHOCLONE OKT3 subsequent to their initial course of therapy. Pretreatment with antihistamines and/or steroids may not reliably prevent anaphylaxis in this setting. Possible allergic hazards of retreatment should be weighed against expected therapeutic benefits and alternatives. If a patient is retreated with ORTHOCLONE OKT3, it is particularly important that epinephrine and other emergency life-support equipment should be immediately available. - If hypersensitivity is suspected, discontinue the drug immediately; do not resume therapy or re-expose the patient to ORTHOCLONE OKT3. Serious acute hypersensitivity reactions may require emergency treatment with 0.3 mL to 0.5 mL aqueous epinephrine (1:1000 dilution) subcutaneously and other resuscitative measures including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. - Serious and sometimes fatal infections and neoplasias have been reported in association with all immunosuppressive therapies, including those regimens containing ORTHOCLONE OKT®3. - ORTHOCLONE OKT3 is usually added to immunosuppressive therapeutic regimens, thereby augmenting the degree of immunosuppression. This increase in the total amount of immunosuppression may alter the spectrum of infections observed and increase the risk, the severity, and the morbidity of infectious complications. During the first month post-transplant, patients are at greatest risk for the following infections: (1) those present prior to transplant, perhaps exacerbated by post-transplant immunosuppression; (2) infection conveyed by the donor organ; and (3) the usual post-operative urinary tract, intravenous line related, wound, or pulmonary infections due to bacterial pathogens. - Approximately one to six months post-transplant, patients are at risk for viral infections [e.g., cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), etc.] which produce serious systemic disease and which also increase the overall state of immunosuppression. - Reactivation (1 to 4 months post-transplant) of EBV and CMV has been reported. When administration of an anti-lymphocyte antibody, including ORTHOCLONE OKT3, is followed by an immunosuppressive regimen including cyclosporine, there is an increased risk of reactivating CMV and impaired ability to limit its proliferation, resulting in symptomatic and disseminated disease. EBV infection, either primary or reactivated, may play an important role in the development of post-transplant lymphoproliferative disorders. - In the pediatric transplant population, viral infections often include pathogens uncommon in adults, such as varicella zoster virus (VZV), adenovirus, and respiratory syncytial virus (RSV). A large proportion of pediatric patients have not been infected with the herpes viruses prior to transplantation and, therefore, are susceptible to developing primary infections from the grafted organ and/or blood products. - Geriatric patients may have a reduced capability to overcome infections during intense immunosuppression. There is no information on the use of OKT3 in geriatric patients. In an age-stratification analysis, no overall difference in the safety of OKT3 was noted between older (51 to 64 years) and younger (≤30 years) patients. Caution should be used when prescribing immunosuppressive agents to elderly patients. - Anti-infective prophylaxis may reduce the morbidity associated with certain potential pathogens and should be considered for pediatric and other high-risk patients. Judicious use of immunosuppressive drugs, including type, dosage, and duration, may limit the risk and seriousness of some opportunistic infections. It is also possible to reduce the risk of serious CMV or EBV infection by avoiding transplantation of a CMV-seropositive (donor) and/or EBV-seropositive (donor) organ into a seronegative patient. - As a result of depressed cell-mediated immunity from immunosuppressive agents, organ transplant patients have an increased risk of developing malignancies. This risk is evidenced almost exclusively by the occurrence of lymphoproliferative disorders, squamous cell carcinomas of the skin and lip, and sarcomas. In immunosuppressed patients, T cell cytotoxicity is impaired allowing for transformation and proliferation of EBV-infected B lymphocytes. * Transformed B lymphocytes are thought to initiate oncogenesis, which ultimately culminates in the development of most post-transplant lymphoproliferative disorders. Patients, especially pediatric patients, with primary EBV infection may be at a higher risk for the development of EBV-associated lymphoproliferative disorders. Data support an association between the development of lymphoproliferative disorders at the time of active EBV infection and ORTHOCLONE OKT3 administration in pediatric liver allograft recipients. - Following the initiation of ORTHOCLONE OKT3 therapy, patients should be continuously monitored for evidence of lymphoproliferative disorders through physical examination and histological evaluation of any suspect lymphoid tissue. Close surveillance is advised, since early detection with subsequent reduction of total immunosuppression may result in regression of some of these lymphoproliferative disorders. Since the potential for the development of lymphoproliferative disorders is related to the duration and extent (intensity) of total immunosuppression, physicians are advised: to adhere to the recommended dosage and duration of ORTHOCLONE OKT3 therapy; to limit the number of courses of ORTHOCLONE OKT3 and other anti- T lymphocyte antibody preparations administered within a short period of time; and, if appropriate, to reduce the dosage(s) of immunosuppressive drugs used concomitantly to the lowest level compatible with an effective therapeutic response. - A recent study examined the incidence of non-Hodgkin's lymphoma (NHL) among 45,000 kidney transplant recipients and over 7,500 heart transplant recipients. This study suggested that all transplant patients, regardless of the immunosuppressive regimen employed, are at increased risk of NHL over the general population. The relative risk was highest among those receiving the most aggressive regimens. - The long-term risk of neoplastic events in patients being treated with ORTHOCLONE OKT3 has not been determined. # Adverse Reactions ## Clinical Trials Experience - In controlled clinical trials for treatment of acute renal allograft rejection, patients treated with ORTHOCLONE OKT3 plus concomitant low-dose immunosuppressive therapy (primarily azathioprine and corticosteroids) were observed to have an increased incidence of adverse experiences during the first two days of treatment, as compared with the group of patients receiving azathioprine and high-dose steroid therapy. During this period the majority of patients experienced pyrexia (90%), of which 19% were 40.0°C (104°F) or above, and chills (59%). In addition, other adverse experiences occurring in 8% or more of the patients during the first two days of ORTHOCLONE OKT3 therapy included: dyspnea (21%), nausea (19%), vomiting (19%), chest pain (14%), diarrhea (14%), tremor (13%), wheezing (13%), headache (11%), tachycardia (10%), rigor (8%), and hypertension (8%). A similar spectrum of clinical manifestations has been observed in open clinical studies and in post-marketing experience involving patients treated with ORTHOCLONE OKT3 for rejection following renal, cardiac, and hepatic transplantation. - Additional serious and occasionally fatal cardiorespiratory manifestations have been reported following any of the first few doses. - In the acute renal allograft rejection trials, potentially fatal pulmonary edema had been reported following the first two doses in less than 2% of the patients treated with ORTHOCLONE OKT3. Pulmonary edema was usually associated with fluid overload. However, post-marketing experience revealed that pulmonary edema has occurred in patients who appeared to be euvolemic, presumably as a consequence of cytokine-mediated increased vascular permeability ("leaky capillaries") and/or reduced myocardial contractility/compliance (i.e., left ventricular dysfunction). - In the controlled randomized renal allograft rejection trial conducted before cyclosporine was marketed, the most common infections during the first 45 days of ORTHOCLONE OKT3 therapy were due to herpes simplex virus (27%) and cytomegalovirus (19%). Other severe and life-threatening infections were Staphylococcus epidermidis (5%), Pneumocystis carinii (3%), Legionella (2%), Cryptococcus (2%), Serratia (2%) and gram-negative bacteria (2%). The incidence of infections was similar in patients treated with ORTHOCLONE OKT3 and in patients treated with high-dose steroids. - In a clinical trial of acute hepatic allograft rejection, refractory to conventional treatment, the most common infections reported in patients treated with ORTHOCLONE OKT3 during the first 45 days of the study were cytomegalovirus (16% of patients, of which 43% of infections were severe), fungal infections (15% of patients, of which 30% were severe), and herpes simplex virus (8% of patients, of which 10% were severe). Other severe and life-threatening infections were gram-positive infections (9% of patients), gram-negative infections (8% of patients), viral infections (2% of patients), and Legionella (1% of patients). In another trial studying the use of ORTHOCLONE OKT®3 in patients with hepatic allografts, the incidence of fungal infections was 34% and infections with the herpes simplex virus was 31%. - In a clinical trial studying the use of ORTHOCLONE OKT3 in patients with acute cardiac rejection refractory to conventional treatment, the most common infections in the ORTHOCLONE OKT3 group reported during the first 45 days of the study were herpes simplex virus (5% of patients, of which 20% were severe), fungal infections (4% of patients, of which 75% were severe), and cytomegalovirus (3% of patients, of which 33% were severe). No other severe or life-threatening infections were reported during this period. - In a retrospective analysis of pediatric patients treated for acute hepatic rejection, the most common infections reported in patients treated with ORTHOCLONE OKT3 therapy were due to bacterial infections (47%), fungal infections (21%), cytomegalovirus (19%), herpes simplex virus (15%), adenovirus (8%), and Epstein-Barr virus (8%). The overall rates of viral, fungal, and bacterial infections were similar in patients treated with ORTHOCLONE OKT3 (n = 53) and in patients whose rejection was treated with steroids alone (n = 27). In another study of 149 pediatric liver allograft patients where 59 episodes of steroid-resistant rejection were treated with ORTHOCLONE OKT3, the incidence of invasive cytomegalovirus infection was higher in patients receiving ORTHOCLONE OKT3 than in those receiving steroids alone. - Clinically significant infections (e.g., pneumonia, sepsis, etc.) due to the following pathogens have been reported: - In patients treated with ORTHOCLONE OKT3, post-transplant lymphoproliferative disorders have ranged from lymphadenopathy or benign polyclonal B cell hyperplasias to malignant and often fatal monoclonal B cell lymphomas. In post-marketing experience, approximately one-third of the lymphoproliferations reported were benign and two-thirds were malignant. Lymphoma types included: B cell, large cell, polyclonal, non-Hodgkin's, lymphocytic, T cell, Burkitt's. The majority were not histologically classified. Malignant lymphomas appear to develop early after transplantation, the majority within the first four months post-treatment. - Many of these have been rapidly progressive. Some were fulminant, involving the allografted organ and were widely disseminated at the time of diagnosis. * Carcinomas of the skin included: basal cell, squamous cell, sarcoma, melanoma, and keratoacanthoma. Other neoplasms infrequently reported include: multiple myeloma, leukemia, carcinoma of the breast, adenocarcinoma, cholangiocarcinoma, and recurrences of pre-existing hepatoma and renal cell carcinoma. - Reported adverse reactions resulting from the formation of antibodies to ORTHOCLONE OKT3 have included antigen-antibody (immune complex) mediated syndromes and IgE-mediated reactions. Hypersensitivity reactions have ranged from a mild, self-limited rash or pruritus to severe, life-threatening anaphylactic reactions/shock or angioedema (including: swelling of lips, eyelids, laryngeal spasm and airway obstruction with hypoxia). - Other hypersensitivity reactions have included - Ineffectiveness of treatment, serum sickness, arthritis, allergic interstitial nephritis, immune complex deposition resulting in glomerulonephritis, vasculitis (including temporal and retinal), and eosinophilia. - Adverse events reported in greater than or equal to 1% of clinical trial patients treated with ORTHOCLONE OKT3 (n=393) are shown in Table 1: ## Postmarketing Experience - Body as a Whole, General Disorders: Fever (including spiking temperatures as high as 107°F), Flu-like Syndrome. - Cardiovascular Disorders: Cardiovascular Collapse, Hemodynamic Instability, Left Ventricular Dysfunction. - Central and Peripheral Nervous System Disorders: Agitation, Aphasia, Asterixis, Cerebritis, Cerebral Edema, Cerebral Herniation, Cerebrovascular Accident, CNS Infection, CNS Malignancy, Cranial Nerve VI Palsy, Encephalitis, Hyperreflexia, Involuntary Movements, Intracranial Hemorrhage, Impaired Cognition, Myoclonus, Obnubilation, Paresis/plegia including quadriparesis/plegia, Status Epilepticus, Stupor, Transient Ischemic Attack, Vertigo. - In a post-marketing survey involving 214 renal transplant patients, the incidence of aseptic meningitis syndrome was 6%. Fever (89%), headache (44%), neck stiffness (14%), and photophobia (10%) were the most commonly reported symptoms; a combination of these four symptoms occurred in 5% of patients. - Between 1987 and 1992, 75 post-marketing reports have described seizures, averaging about 12 per year, and including 23 fatalities. More than two-thirds of these reports (53) were of domestic spontaneous origin, and their age and sex distributions were broad. Post-licensure reports generally provide insufficient data to allow accurate estimation of risk or of incidence. - Gastrointestinal Disorders: Bowel Infarction. - Hematopoietic Disorders: Aplastic anemia, Arterial, Venous and Capillary Thrombosis of allografts and other vascular beds e.g., heart, lung, brain and bowel etc., Disseminated Intravascular Coagulation, Microangiopathic Changes (e.g., platelet microthrombi), Microangiopathic Hemolytic Anemia, Neutropenia, Pancytopenia. - Hepatobiliary: Hepatitis or Hepato/splenomegaly, usually secondary to viral infection or lymphoma. - Reactivation of viral hepatitis including CMV, EBV, Hepatitis B virus (HBV), and Hepatitis C virus (HCV). - Musculoskeletal Disorders: Arthritis, Stiffness/Aches/Pains. - Renal Disorders: Azotemia, Abnormal Urinary Cytology including exfoliation of damaged lymphocytes, collecting duct cells and cellular casts, Delayed Graft Function, Renal Insufficiency/Renal Failure, usually transient and reversible and occasionally in association with Cytokine Release Syndrome. - Respiratory System Disorders: Adult Respiratory Distress Syndrome, Respiratory Arrest, Respiratory Failure. - Skin and Appendages: Erythema, Flushing, Stevens-Johnson Syndrome, Urticaria. - Special Senses: Blindness, Blurred Vision, Deafness, Diplopia, Otitis Media, Nasal and Ear Stuffiness, Papilledema. # Drug Interactions - # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproductive studies have not been conducted with ORTHOCLONE OKT3. It is also not known whether ORTHOCLONE OKT3 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. - However, ORTHOCLONE OKT3 is an IgG antibody and may cross the human placenta. The effect on the fetus of the release of cytokines and/or immunosuppression after treatment with ORTHOCLONE OKT3 is not known. ORTHOCLONE OKT3 should be given to a pregnant woman only if clearly needed. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Muromonab-CD3 in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Muromonab-CD3 during labor and delivery. ### Nursing Mothers - It is not known whether ORTHOCLONE OKT3 is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse events/oncogenesis shown for ORTHOCLONE OKT3 in human studies, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness have been established in infants (1 mo. up to 2 yr.); children (2 yr. up to 12 yr.); and adolescents (12 yr. up to 16 yr.). Use of ORTHOCLONE OKT3 in these age groups is supported by clinical studies that included adults and pediatric patients. In those studies, the safety and efficacy of ORTHOCLONE OKT3 in pediatric patients receiving renal or hepatic transplants was similar to that in the overall cohort. There were insufficient data to compare the safety and efficacy of ORTHOCLONE OKT3 in pediatric patients in a study of patients receiving cardiac transplants. Additional pharmacokinetic, pharmacodynamic, and clinical studies in infants, children, and adolescents have been reported in published literature. - Pediatric patients are known to have higher CD3 lymphocyte counts than adults; therefore, progressively higher doses of ORTHOCLONE OKT3 are often required to achieve therapeutic levels of lymphocyte clearance. Specific Safety Concerns in Pediatric Patients - The postmarketing data base indicates that pediatric patients may be at increased risk of developing cerebral edema with or without herniation compared to adults. In the period between 1986 and 1996, twenty-five cases (6 in pediatric patients) of cerebral edema were identified with subsequent cerebral herniation and death in five cases (4 in pediatric patients). Herniation in the pediatric patients and one 19 year old subject occurred within a few hours to one day after the first dose (2.5 or 5 mg) of ORTHOCLONE OKT3 administered in the investigational setting for prophylaxis of renal allograft rejection. All pediatric patients and especially those receiving a renal allograft must be carefully evaluated for fluid retention and hypertension before the initiation of ORTHOCLONE OKT3 therapy. Patients should be closely monitored for neurologic symptoms during the first twenty four (24) hours following each of the first few doses of ORTHOCLONE OKT3 injection. - Other significant neurologic complications reported in pediatric transplant recipients receiving ORTHOCLONE OKT3 include status epilepticus, cerebral edema, diffuse encephalopathy, cerebritis, seizures, cortical dysfunction, and intracranial hemorrhage. Permanent neurologic impairments (e.g., blindness, deafness, paralysis) have been reported rarely. Because meningitis is a frequent infection encountered in pediatric allograft recipients, and the immunosuppression associated with transplantation increases the risk of opportunistic infection, patients with meningeal irritation following treatment with ORTHOCLONE OKT3 therapy should be evaluated with lumbar puncture as early as possible to rule out an infectious etiology. - The overall incidence of infections appeared to be similar in pediatric patients compared to the overall population studied. In the pediatric population, viral infections often include pathogens uncommon in adults, such as varicella zoster virus (VZV), adenovirus, enterovirus, parainfluenza virus, and respiratory syncytial virus (RSV). In addition, many viral diseases often manifest differently in pediatric patients than they do in adults. Because a large proportion of pediatric patients have not been infected by herpes viruses (e.g., EBV, HSV, CMV) prior to transplantation they may be more susceptible to acquiring primary infections from the grafted organ and/or blood products when immunosuppressed. Antiviral prophylactic therapy may be particularly useful in these high risk pediatric patients. - Patients with primary EBV infection may be at higher risk for the development of EBV-associated lymphoproliferative disorders. There are data to support an association between the development of lymphoproliferative disorders at the time of active EBV infection and ORTHOCLONE OKT®3 administration in pediatric liver allograft recipients. Antiviral prophylactic therapy may be particularly useful in these high risk pediatric patients. - Parenteral hydration may be required for gastrointestinal fluid loss secondary to diarrhea and/or vomiting resulting from the "Cytokine Release Syndrome." - Pediatric patients may be at an increased risk of thrombosis. Pediatric patients weighing less than 15 kg are at high-risk for hepatic artery thrombosis. Thrombosis has been reported in pediatric transplant recipients treated with ORTHOCLONE OKT3. A number of factors, including surgical technique, the presence of a hypercoaguable state, and the absence of prior dialysis experience may be relevant to the pathophysiology of the increased risk of thrombosis. ### Geriatic Use There is no information on the use of OKT3 in geriatric patients. Caution should be used when prescribing immunosuppressive agents to elderly patients. ### Gender There is no FDA guidance on the use of Muromonab-CD3 with respect to specific gender populations. ### Race There is no FDA guidance on the use of Muromonab-CD3 with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Muromonab-CD3 in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Muromonab-CD3 in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Muromonab-CD3 in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Muromonab-CD3 in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - Patients should be closely monitored for neurologic symptoms during the first twenty four (24) hours following each of the first few doses of ORTHOCLONE OKT3 injection. - Patients should be closely monitored for convulsions and manifestations of encephalopathy, including: impaired cognition, confusion, obtundation, altered mental status, disorientation, auditory/visual hallucinations, psychosis (delirium, paranoia), mood changes (e.g., mania, agitation, combativeness, etc.), diffuse hypotonus, hyperreflexia, myoclonus, tremor, asterixis, involuntary movements, major motor seizures, lethargy/stupor/coma, and diffuse weakness. - Vital signs should be monitored frequently. Patients receiving ORTHOCLONE OKT3 should also be carefully monitored for signs and symptoms of Cytokine Release Syndrome, particularly after the first few doses but also after a treatment hiatus with resumption of therapy. - Following the initiation of ORTHOCLONE OKT3 therapy, patients should be continuously monitored for evidence of lymphoproliferative disorders through physical examination and histological evaluation of any suspect lymphoid tissue. - The following tests should be monitored prior to and during ORTHOCLONE OKT®3 therapy: - Renal: BUN, serum creatinine, etc.; - Hepatic: transaminases, alkaline phosphatase, bilirubin; - Hematopoietic: WBCs and differential, platelet count, etc.; - Chest X-ray within 24 hours before initiating ORTHOCLONE OKT3 treatment to rule out heart failure or fluid overload. - Blood Tests: Periodic assessment of organ system functions (renal, hepatic, and hematopoietic) should be performed. # IV Compatibility There is limited information regarding IV Compatibility of Muromonab-CD3 in the drug label. # Overdosage - Symptoms of overdosage with ORTHOCLONE OKT®3 may include hyperthermia, severe chills, myalgia, vomiting, diarrhea, edema, oliguria, pulmonary edema, and acute renal failure. A high incidence (5%) of microangiopathic hemolytic anemia/HUS syndrome in patients receiving 10 mg per day of ORTHOCLONE OKT3 was also reported. In the event of acute overdosage with ORTHOCLONE OKT3, the patient should be carefully observed and given symptomatic and supportive treatment. # Pharmacology ## Mechanism of Action - ORTHOCLONE OKT3 reverses graft rejection, probably by blocking the function of T cells which play a major role in acute allograft rejection. OTHOCLONE OKT3 reacts with and blocks the function of a 20,000 dalton molecule (CD3) in the membrane of human T cells that has been associated in vitro with the antigen recognition structure of T cells and is essential for signal transduction. In in vitro cytolytic assays, ORTHOCLONE OKT3 blocks both the generation and function of effector cells. Binding of ORTHOCLONE OKT3 to T lymphocytes results in early activation of T cells, which leads to cytokine release, followed by blocking T cell functions. After termination of ORTHOCLONE OKT3 therapy, T cell function usually returns to normal within one week. - In vivo, ORTHOCLONE OKT3 reacts with most peripheral blood T cells and T cells in body tissues, but has not been found to react with other hematopoietic elements or other tissues of the body. - A rapid and concomitant decrease in the number of circulating CD3 positive cells, including those that are CD2, CD4, or CD8 positive has been observed in patients studied within minutes after the administration of ORTHOCLONE OKT3. This decrease in the number of CD3 positive T cells results from the specific interaction between ORTHOCLONE OKT3 and the CD3 antigen on the surface of all T lymphocytes. T cell activation results in the release of numerous cytokines/lymphokines, which are felt to be responsible for many of the acute clinical manifestations seen following ORTHOCLONE OKT3 administration ## Structure - ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Muromonab-CD3 in the drug label. ## Pharmacokinetics - While CD3 positive cells are not detectable between days two and seven, increasing numbers of circulating CD2, CD4, and CD8 positive cells have been observed. The presence of these CD2, CD4, and CD8 positive cells has not been shown to affect reversal of rejection. After termination of ORTHOCLONE OKT3 therapy, CD3 positive cells reappear rapidly and reach pre-treatment levels within a week. In some patients however, increasing numbers of CD3 positive cells have been observed prior to termination of ORTHOCLONE OKT3 therapy. This reappearance of CD3 positive cells has been attributed to the development of neutralizing antibodies to ORTHOCLONE OKT3, which in turn block its ability to bind to the CD3 antigen on T lymphocytes. - Pediatric patients are known to have higher CD3 lymphocyte counts than adults. Pediatric patients receiving ORTHOCLONE OKT®3 therapy often require progressively higher doses of ORTHOCLONE OKT3 to achieve depletion of CD3 positive cells (<25 cells/mm3) and ensure therapeutic ORTHOCLONE OKT3 serum concentrations (>800 ng/mL). - Serum levels of ORTHOCLONE OKT3 are measurable using an enzyme-linked immunosorbent assay (ELISA). During the initial clinical trials in renal allograft rejection, in patients treated with 5 mg per day for 14 days, mean serum trough levels of the drug rose over the first three days and then averaged 900 ng/mL on days 3 to 14. Serum concentrations measured daily during treatment with ORTHOCLONE OKT3 in renal, hepatic, and cardiac allograft recipients revealed that pediatric patients less than 10 years of age have higher levels than patients 10–50 years of age. Subsequent clinical experience has demonstrated that serum levels greater than or equal to 800 ng/mL of ORTHOCLONE OKT3 blocks the function of cytotoxic T cells in vitro and in vivo. Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. - Following administration of ORTHOCLONE OKT3 in vivo, leukocytes have been observed in cerebrospinal and peritoneal fluids. The mechanism for this effect is not completely understood, but probably is related to cytokines altering membrane permeability, rather than an active inflammatory process. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Muromonab-CD3 in the drug label. # Clinical Studies - In a controlled randomized clinical trial, ORTHOCLONE OKT3 was compared with conventional high-dose steroid therapy in reversing acute renal allograft rejection. In this trial, 122 evaluable patients undergoing acute rejection of cadaveric renal transplants were treated either with ORTHOCLONE OKT3 daily for a mean of 14 days, with concomitant lowering of the dosage of azathioprine and maintenance steroids (62 patients), or with conventional high-dose steroids (60 patients). ORTHOCLONE OKT3 reversed 94% of the rejections compared to a 75% reversal rate obtained with conventional high-dose steroid treatment (p=0.006). The one year Kaplan-Meier (actuarial) estimates of graft survival rates for these patients who had acute rejection were 62% and 45% for ORTHOCLONE OKT3 and steroid-treated patients, respectively (p=0.04). At two years the rates were 56% and 42%, respectively (p=0.06). - One- and two-year patient survivals were not significantly different between the two groups, being 85% and 75% for ORTHOCLONE OKT3 treated patients and 90% and 85% for steroid-treated patients. - In additional open clinical trials, the observed rate of reversal of acute renal allograft rejection was 92% (n=126) for ORTHOCLONE OKT3 therapy. ORTHOCLONE OKT3 was also effective in reversing acute renal allograft rejections in 65% (n=225) of cases where steroids and lymphocyte immune globulin preparations were contraindicated or were not successful. - The effectiveness of ORTHOCLONE OKT3 for prophylaxis of renal allograft rejection has not been established. - ORTHOCLONE OKT3 was studied for use in reversing acute cardiac and hepatic allograft rejection in patients who are unresponsive to high-doses of steroids. The rate of reversal in acute cardiac allograft rejection was 90% (n = 61) and was 83% for hepatic allograft rejection (n = 124) in patients unresponsive to treatment with steroids. - Controlled randomized trials have not been conducted to evaluate the effectiveness of ORTHOCLONE OKT3 compared to conventional therapy as first line treatment for acute cardiac and hepatic allograft rejection. # How Supplied - ORTHOCLONE OKT3 is supplied as a sterile solution in packages of 5 ampules (NDC 59676-101-01). Each 5 mL ampule contains 5 mg of muromonab-CD3. ## Storage Storage Store in a refrigerator at 2° to 8°C (36° to 46°F). DO NOT FREEZE OR SHAKE. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Muromonab-CD3 in the drug label. # Precautions with Alcohol - Alcohol-Muromonab-CD3 interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - OKT3 ®[1] # Look-Alike Drug Names - A® — B®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Muromonab
054f7781409ec8d2e829299b1fd4ef9d96cfa6b4	wikidoc	Muscle memory	Muscle memory Muscle memory is a common term for neuromuscular facilitation, which is the process of the neuromuscular system memorizing motor skills. # Overview When an active person repeatedly trains movement, often of the same activity, in an effort to stimulate the mind’s adaptation process, the outcome is to induce physiological changes which attain increased levels of accuracy through repetition. Even though the process is really brain-muscle memory or motor memory, the colloquial expression "muscle memory" is commonly used. Individuals rely upon the mind’s ability to assimilate a given activity and adapt to the training. As the brain and muscle adapts to training, the subsequent changes are a form or representation of its muscle memory. There are two types of motor skills involved in muscle memory: fine and gross. Fine motor skills are very minute and small skills we perform with our hands such as brushing teeth, combing hair, using a pencil or pen to write, touch typing or even playing video games. Gross motor skills are those actions that require large body parts and large body movements as in the throwing sports such as bowling, American football, and baseball, sports such as archery, basketball, golfing, judo, swimming, and tennis, and activities such as driving a car (especially one with a manual transmission), playing a musical instrument, and marksmanship. Muscle memory is fashioned over time through repetition of a given suite of motor skills and the ability through brain activity to inculcate and instill it such it they become automatic. Activities such as brushing the teeth, combing the hair, or even driving a vehicle are not as easy as they look to the beginner. As one reinforces those movements through repetition, the neural system learns those fine and gross motor skills to the degree that one no longer needs to think about them, but merely to react and perform appropriately. In this sense the muscle memory process is an example of automating an OODA Loop insofar as one learns to Observe, Orient, Decide, and Act. When one picks up a hair brush, one automatically has a certain motion, style, number of strokes, and amount of pressure as the hair is brushed without requiring conscious thought about each movement. Other forms of rather elaborate motions that have become automatic include speech. As one speaks, one usually does not consciously think about the complex tongue movements, synchronisation with vocal cords and various lip movements that are required to produce phonemes, because of muscle memory. In speaking a language that is not one's native language, one typically speaks with an accent, because one's muscle memory is tuned to forming the phonemes of one's native language, rather than those of the language one is speaking. An accent can be eliminated only by carefully retraining the muscle memory. # Physiology Muscle memory starts with a visual cue. A classic example are chords while playing instruments such as the piano or guitar. The beginner must think and interpret these chords, but after repetition, the letters and symbols on the page become cues to the muscle movements. As the brain processes the information about the desired activity and motion such as a golf swing, one then commits to that motion thought as correct. Over time, the accuracy and skills in performing the swing or movement improve. Muscle memory is the control center of the movement. In maximizing muscle memory to learn a new motion, practicing that same motion over a long enough period makes it become automatic. This learning process could take months, even years, to perfect, depending on the individual's dedication to practice, and their unique biochemical neuromuscular learning system to retain that practice. In detail, inside the brain are neurons that produce impulses, which carry tiny electrical currents. These currents cross the synapses between neurons with chemical transporters called neurotransmitters to carry the communication. Neurotransmitters are the body’s communicative mechanisms and one of their many functions is to travel through the central nervous system and carry the signal from visual cue to the muscle for the contraction. Although there are many types of neurotransmitters, the communicative ones primarily used in muscle memory are acetylcholine and serotonin. Acetylcholine is the major neurotransmitter used in memory, focus, concentration, and muscle memory. It is the substance that transports messages from one nerve cell to another. Acetylcholine is critical to the process of creating and remembering the muscle contraction. It achieves this through motor neurons. Serotonin is imperative in the muscle memory process. Serotonin has multiple physiological actions at neuromuscular junctions where communication crosses over. This includes facilitation of transmitter release from nerve terminals and an increase in the communication to muscle fibers. When a motor neuron depolarizes, an electrical current is passed down the nerve fiber and the impulse causes the neurotransmitter acetylcholine to be released to the muscle cell. Acetylcholine then binds with receptors on the muscle membrane to create the contraction. Over time, with acetylcholine the brain-muscle learns the chosen motion and induces its own form of memory. This process is also called neuromuscular facilitation. Once muscle memory is created and retained, there is no longer need to actively think about the movement and this frees up capacity for other activities.	Muscle memory Muscle memory is a common term for neuromuscular facilitation, which is the process of the neuromuscular system memorizing motor skills. # Overview When an active person repeatedly trains movement, often of the same activity, in an effort to stimulate the mind’s adaptation process, the outcome is to induce physiological changes which attain increased levels of accuracy through repetition. Even though the process is really brain-muscle memory or motor memory, the colloquial expression "muscle memory" is commonly used. Individuals rely upon the mind’s ability to assimilate a given activity and adapt to the training. As the brain and muscle adapts to training, the subsequent changes are a form or representation of its muscle memory. There are two types of motor skills involved in muscle memory: fine and gross. Fine motor skills are very minute and small skills we perform with our hands such as brushing teeth, combing hair, using a pencil or pen to write, touch typing or even playing video games. Gross motor skills are those actions that require large body parts and large body movements as in the throwing sports such as bowling, American football, and baseball, sports such as archery, basketball, golfing, judo, swimming, and tennis, and activities such as driving a car (especially one with a manual transmission), playing a musical instrument, and marksmanship.[citation needed] Muscle memory is fashioned over time through repetition of a given suite of motor skills and the ability through brain activity to inculcate and instill it such it they become automatic. Activities such as brushing the teeth, combing the hair, or even driving a vehicle are not as easy as they look to the beginner. As one reinforces those movements through repetition, the neural system learns those fine and gross motor skills to the degree that one no longer needs to think about them, but merely to react and perform appropriately. In this sense the muscle memory process is an example of automating an OODA Loop insofar as one learns to Observe, Orient, Decide, and Act. When one picks up a hair brush, one automatically has a certain motion, style, number of strokes, and amount of pressure as the hair is brushed without requiring conscious thought about each movement. Other forms of rather elaborate motions that have become automatic include speech. As one speaks, one usually does not consciously think about the complex tongue movements, synchronisation with vocal cords and various lip movements that are required to produce phonemes, because of muscle memory. In speaking a language that is not one's native language, one typically speaks with an accent, because one's muscle memory is tuned to forming the phonemes of one's native language, rather than those of the language one is speaking. An accent can be eliminated only by carefully retraining the muscle memory.[citation needed] # Physiology Muscle memory starts with a visual cue. A classic example are chords while playing instruments such as the piano or guitar. The beginner must think and interpret these chords, but after repetition, the letters and symbols on the page become cues to the muscle movements. As the brain processes the information about the desired activity and motion such as a golf swing, one then commits to that motion thought as correct. Over time, the accuracy and skills in performing the swing or movement improve. Muscle memory is the control center of the movement. In maximizing muscle memory to learn a new motion, practicing that same motion over a long enough period makes it become automatic. This learning process could take months, even years, to perfect, depending on the individual's dedication to practice, and their unique biochemical neuromuscular learning system to retain that practice. In detail, inside the brain are neurons that produce impulses, which carry tiny electrical currents. These currents cross the synapses between neurons with chemical transporters called neurotransmitters to carry the communication. Neurotransmitters are the body’s communicative mechanisms and one of their many functions is to travel through the central nervous system and carry the signal from visual cue to the muscle for the contraction. Although there are many types of neurotransmitters, the communicative ones primarily used in muscle memory are acetylcholine and serotonin. Acetylcholine is the major neurotransmitter used in memory, focus, concentration, and muscle memory. It is the substance that transports messages from one nerve cell to another. Acetylcholine is critical to the process of creating and remembering the muscle contraction. It achieves this through motor neurons. Serotonin is imperative in the muscle memory process. Serotonin has multiple physiological actions at neuromuscular junctions where communication crosses over. This includes facilitation of transmitter release from nerve terminals and an increase in the communication to muscle fibers. When a motor neuron depolarizes, an electrical current is passed down the nerve fiber and the impulse causes the neurotransmitter acetylcholine to be released to the muscle cell. Acetylcholine then binds with receptors on the muscle membrane to create the contraction. Over time, with acetylcholine the brain-muscle learns the chosen motion and induces its own form of memory. This process is also called neuromuscular facilitation. Once muscle memory is created and retained, there is no longer need to actively think about the movement and this frees up capacity for other activities. Template:Muscular system Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Muscle_memory
7011bcc965bc79cb8c4c8ea1660ca0d67b235709	wikidoc	Mustard plant	Mustard plant Mustards are several plant species in the genera Brassica and Sinapis whose small mustard seeds are used as a spice and, by grinding and mixing them with water, vinegar or other liquids, are turned into a condiment also known as mustard. The seeds are also pressed to make mustard oil, and the edible leaves can be eaten as mustard greens. Mild white mustard (Sinapis hirta) grows wild in North Africa, the Middle East and Mediterranean Europe and has spread farther by long cultivation; brown or Indian mustard (B. juncea), originally from the foothills of the Himalaya, is grown commercially in the UK, Canada and the US; black mustard (B. nigra) in Argentina, Chile, the US and some European countries. Canada grows 90% of all the mustard seed for the international market. In addition to the mustards, the genus Brassica also includes cabbages, cauliflower, rapeseed and turnips. Although the varieties of mustard are well-established crops in Hellenistic and Roman times, which leads to the assumption that it was brought into cultivation at an earlier time, Zohary and Hopf note that "there are almost no archeological records available for any of these crops." Wild forms of mustard and its relatives the radish and turnip can be found over west Asia and Europe, suggesting that their domestication took place somewhere in that area. However Zohary and Hopf conclude, "Suggestions as to the origins of these plants are necessarily based on linguistic considerations." There has been recent research into varieties of mustards that have a high oil content for use in the production of biodiesel, a renewable liquid fuel similar to diesel fuel. The biodiesel made from mustard oil has good cold flow properties and cetane ratings. The leftover meal after pressing out the oil has also been found to be an effective pesticide. An interesting genetic relationship between many species of mustard has been observed, and is described as the Triangle of U. ## Diseases # Notes - ↑ Daniel Zohary and Maria Hopf, Domestication of plants in the Old World, third edition (Oxford: University Press, 2000), p. 139 ca:Mostassa it:Senape he:חרדל id:Sesawi	Mustard plant Mustards are several plant species in the genera Brassica and Sinapis whose small mustard seeds are used as a spice and, by grinding and mixing them with water, vinegar or other liquids, are turned into a condiment also known as mustard. The seeds are also pressed to make mustard oil, and the edible leaves can be eaten as mustard greens. Mild white mustard (Sinapis hirta) grows wild in North Africa, the Middle East and Mediterranean Europe and has spread farther by long cultivation; brown or Indian mustard (B. juncea), originally from the foothills of the Himalaya, is grown commercially in the UK, Canada and the US; black mustard (B. nigra) in Argentina, Chile, the US and some European countries. Canada grows 90% of all the mustard seed for the international market. In addition to the mustards, the genus Brassica also includes cabbages, cauliflower, rapeseed and turnips. Although the varieties of mustard are well-established crops in Hellenistic and Roman times, which leads to the assumption that it was brought into cultivation at an earlier time, Zohary and Hopf note that "there are almost no archeological records available for any of these crops." Wild forms of mustard and its relatives the radish and turnip can be found over west Asia and Europe, suggesting that their domestication took place somewhere in that area. However Zohary and Hopf conclude, "Suggestions as to the origins of these plants are necessarily based on linguistic considerations."[1] There has been recent research into varieties of mustards that have a high oil content for use in the production of biodiesel, a renewable liquid fuel similar to diesel fuel. The biodiesel made from mustard oil has good cold flow properties and cetane ratings. The leftover meal after pressing out the oil has also been found to be an effective pesticide. [1] An interesting genetic relationship between many species of mustard has been observed, and is described as the Triangle of U. ## Diseases # Notes - ↑ Daniel Zohary and Maria Hopf, Domestication of plants in the Old World, third edition (Oxford: University Press, 2000), p. 139 ca:Mostassa it:Senape he:חרדל id:Sesawi Template:Brassicales-stub	https://www.wikidoc.org/index.php/Mustard_plant
74dada2605fc010bfec0b18c2dba4d60f60f1eb5	wikidoc	Mutation rate	Mutation rate In genetics, the mutation rate is the chance of a mutation occurring in an organism or gene in each generation (or, in the case of multicellular organisms, cell division). See Luria-Delbrück experiment. The mutation frequency is the number of individuals in a population with a particular mutation, and tends to be reported more often as it is easier to measure (for instance, there is no need to restrict the population to experiencing only one generation, as needed to measure mutation rate). This is important in fields such as evolutionary biology and oncology. In evolutionary biology, mutations can have a neutral, favorable or unfavorable effect on the organism, with respect to the present environment. The effect of a low mutation rate on a population is that few variations are available to respond to sudden environmental change. This means the species is slower to adapt. A higher mutation rate damages more individuals, but by increasing variation in the population could increase the speed at which the population can adapt to changing circumstances. The majority of mutations in a multi-cellular organism's genome are neutral and do not harm the organism. Occasional mutations are unfavorable, and rarely a mutation will be favorable. As a result of natural selection, unfavorable mutations will typically be eliminated from a population while favorable and neutral changes accumulate (genetic drift). The rate of elimination or accumulation depends on how unfavorable or favorable the mutation is. There appear to be limits on how advantageous a high mutation rate can be, and there is evidence that mutation rates (as determined by polymerase fidelity) are under selection to be neither too high, nor too low. An exciting extension of the idea that mutation rates can be too high is that drugs can be used to increase the mutation rates of pathogens to intolerable levels. Studies have shown that treating RNA viruses such as poliovirus with ribavirin produce results consistent with the idea that the viruses mutated too frequently to maintain the integrity of the information in their genomes. Mutation rates differ between species and even between different regions of the genome of a single species. This should not be confused with the idea that mutations accumulate at different rates over longer periods of time than a generation. These different rates of nucleotide substitution are measured in substitutions (fixed mutations) per base pair per year. For example, mutations in so-called Junk DNA which do not affect organism function tend to accumulate mutations at a faster rate than DNA which is actively in use by in the organism (gene expression), and this is due not necessarily to higher mutation rate, but lower levels of purifying selection. A region which mutates at predictable rate is a candidate for use as a molecular clock. If the mutation rate of a gene is assumed to be constant (clock-like) the degree of difference between the same gene in two different species can be used to estimate how long ago two species diverged (see molecular clock). In fact, the mutation rate of an organism may change in response to environmental stress. For example UV light damages DNA, which may result in error prone attempts by the cell to perform DNA repair. An extreme example of this is the increased mutation rate of organisms living near Chernobyl since the nuclear accident. The human mutation rate is higher in the male germ line (sperm) than the female (egg cells), but estimates of the exact rate have varied by an order of magnitude or more.. More generally, the mutation rate in eukaryotes is in generally 10-4 to 10-6 mutations per base pair per generation, and for bacteria the rate is around 10-8 per base pair per generation. The highest mutation rates are found in viruses, which can have either RNA or DNA genomes. DNA viruses have mutation rates between 10-6 to 10-8 mutations per base per generation, and RNA viruses have mutation rates between 10-3 to 10-5 per base per generation.	Mutation rate In genetics, the mutation rate is the chance of a mutation occurring in an organism or gene in each generation (or, in the case of multicellular organisms, cell division). See Luria-Delbrück experiment. The mutation frequency is the number of individuals in a population with a particular mutation, and tends to be reported more often as it is easier to measure (for instance, there is no need to restrict the population to experiencing only one generation, as needed to measure mutation rate). This is important in fields such as evolutionary biology and oncology. In evolutionary biology, mutations can have a neutral, favorable or unfavorable effect on the organism, with respect to the present environment. The effect of a low mutation rate on a population is that few variations are available to respond to sudden environmental change. This means the species is slower to adapt. A higher mutation rate damages more individuals, but by increasing variation in the population could increase the speed at which the population can adapt to changing circumstances. The majority of mutations in a multi-cellular organism's genome are neutral and do not harm the organism[1]. Occasional mutations are unfavorable, and rarely a mutation will be favorable. As a result of natural selection, unfavorable mutations will typically be eliminated from a population while favorable and neutral changes accumulate (genetic drift). The rate of elimination or accumulation depends on how unfavorable or favorable the mutation is. There appear to be limits on how advantageous a high mutation rate can be, and there is evidence that mutation rates (as determined by polymerase fidelity) are under selection to be neither too high, nor too low. An exciting extension of the idea that mutation rates can be too high is that drugs can be used to increase the mutation rates of pathogens to intolerable levels. Studies have shown that treating RNA viruses such as poliovirus with ribavirin produce results consistent with the idea that the viruses mutated too frequently to maintain the integrity of the information in their genomes[2]. Mutation rates differ between species and even between different regions of the genome of a single species. This should not be confused with the idea that mutations accumulate at different rates over longer periods of time than a generation. These different rates of nucleotide substitution are measured in substitutions (fixed mutations) per base pair per year. For example, mutations in so-called Junk DNA which do not affect organism function tend to accumulate mutations at a faster rate than DNA which is actively in use by in the organism (gene expression), and this is due not necessarily to higher mutation rate, but lower levels of purifying selection. A region which mutates at predictable rate is a candidate for use as a molecular clock. If the mutation rate of a gene is assumed to be constant (clock-like) the degree of difference between the same gene in two different species can be used to estimate how long ago two species diverged (see molecular clock). In fact, the mutation rate of an organism may change in response to environmental stress. For example UV light damages DNA, which may result in error prone attempts by the cell to perform DNA repair. An extreme example of this is the increased mutation rate of organisms living near Chernobyl since the nuclear accident[3]. The human mutation rate is higher in the male germ line (sperm) than the female (egg cells), but estimates of the exact rate have varied by an order of magnitude or more.[4].[5] More generally, the mutation rate in eukaryotes is in generally 10-4 to 10-6 mutations per base pair per generation[6], and for bacteria the rate is around 10-8 per base pair per generation[7]. The highest mutation rates are found in viruses, which can have either RNA or DNA genomes. DNA viruses have mutation rates between 10-6 to 10-8 mutations per base per generation, and RNA viruses have mutation rates between 10-3 to 10-5 per base per generation[8].	https://www.wikidoc.org/index.php/Mutation_rate
662771824621d3c59d591a67f6788ffd9a842516	wikidoc	Mycophenolate	Mycophenolate # 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 Mycophenolate is an antibiotic, anti-neoplastic agent that is FDA approved for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, leukopenia, sepsis, vomiting, opportunistic infections. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Mycophenolate mofetil is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids. - Mycophenolate mofetil intravenous is an alternative dosage form to mycophenolate mofetil capsules, tablets and oral suspension. Mycophenolate mofetil intravenous should be administered within 24 hours following transplantation. Mycophenolate mofetil intravenous can be administered for up to 14 days; patients should be switched to oral mycophenolate mofetil as soon as they can tolerate oral medication. - Dosing Information: - Renal Transplantation - Adults - A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of mycophenolate mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. - Cardiac Transplantation - Adults - A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients. - Hepatic Transplantation - Adults - A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients. - Mycophenolate Mofetil Capsules, Tablets, and Oral Suspension - The initial oral dose of mycophenolate mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that mycophenolate mofetil be administered on an empty stomach. However, in stable renal transplant patients, mycophenolate mofetil may be administered with food if necessary. - Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take mycophenolate mofetil at the usual times. - Note - If required, mycophenolate mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter). - Patients With Hepatic Impairment - No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies. - No data are available for cardiac transplant patients with severe hepatic parenchymal disease. - Geriatrics - The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients. - Dosage Adjustments - In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of mycophenolate mofetil greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively. - No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks. - If neutropenia develops (ANC <1.3× 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see WARNINGS: Neutropenia, ADVERSE REACTIONS, and PRECAUTIONS: Laboratory Tests). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Mycophenolate in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Mycophenolate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Renal Transplantation - Pediatrics (3 months to 18 years of age) - The recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be dosed with mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Mycophenolate in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Mycophenolate in pediatric patients. # Contraindications - Allergic reactions to mycophenolate mofetil have been observed; therefore, mycophenolate mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product. Mycophenolate mofetil intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN). # Warnings Embryofetal Toxicity - Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant female. Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. Pregnancy Exposure Prevention and Planning - Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning. For recommended pregnancy testing and contraception methods. Lymphoma and Malignancy - Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolate mofetil, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see ADVERSE REACTIONS). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. - Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients (see ADVERSE REACTIONS). - In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed (see ADVERSE REACTIONS). Combination with Other Immunosuppressive Agents - Mycophenolate mofetil has been administered in combination with the following agents in clinical trials: antithymocyte globulin (ATGAM®), OKT3 (Orthoclone OKT® 3), cyclosporine (Sandimmune®, Neoral®) and corticosteroids. The efficacy and safety of the use of mycophenolate mofetil in combination with other immunosuppressive agents have not been determined. Serious Infections - Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections. These infections may lead to serious, including fatal outcomes. Because of the danger of over suppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution (see ADVERSE REACTIONS). New or Reactivated Viral Infections - Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including mycophenolate mofetil. Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft. - PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss. Patient monitoring may help detect patients at risk for PVAN. - PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function (see ADVERSE REACTIONS: Postmarketing Experience). In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. - The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. - Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended. Neutropenia - Severe neutropenia developed in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see ADVERSE REACTIONS). Patients receiving mycophenolate mofetil should be monitored for neutropenia. The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes. If neutropenia develops (ANC <1.3 × 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately. Neutropenia has been observed most frequently in the period from 31 to 180 days posttransplant in patients treated for prevention of renal, cardiac, and hepatic rejection. - Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Pure Red Cell Aplasia (PRCA) - Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. The mechanism for mycophenolate mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown. In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk. - CAUTION: MYCOPHENOLATE MOFETIL INTRAVENOUS SOLUTION SHOULD NEVER BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION. ### PRECAUTIONS Pregnancy Exposure Prevention and Planning - Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning. - Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient’s healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical from a bilateral oophorectomy. Pregnancy Testing - To prevent unplanned exposure during pregnancy, females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting mycophenolate mofetil. Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. - In the event of a positive pregnancy test, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. Contraception - Females of reproductive potential taking mycophenolate mofetil must receive contraceptive counseling and use acceptable contraception (see Table 8 for acceptable contraception methods). - Patients must use acceptable birth control during entire mycophenolate mofetil therapy, and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely). - Patients should be aware that mycophenolate mofetil reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness. Pregnancy Planning - For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolate mofetil should be discussed with the patient. Gastrointestinal Disorders - Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with mycophenolate mofetil 3 g daily. In pediatric renal transplant patients, 5/148 cases of gastrointestinal bleeding (requiring hospitalization) were observed. - Gastrointestinal perforations have rarely been observed. Most patients receiving mycophenolate mofetil were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with mycophenolate mofetil. Because mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation, mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease. Patients with Renal Impairment - Subjects with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) who have received single doses of mycophenolate mofetil showed higher plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG. Doses of mycophenolate mofetil greater than 1 g administered twice a day to renal transplant patients should be avoided and they should be carefully observed. - No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks. - In patients with delayed renal graft function posttransplant, mean MPA AUC(0–12h) was comparable, but MPAG AUC(0–12h) was 2-fold to 3-fold higher, compared to that seen in posttransplant patients without delayed renal graft function. In the three controlled studies of prevention of renal rejection, there were 298 of 1483 patients (20%) with delayed graft function. Although patients with delayed graft function have a higher incidence of certain adverse events (anemia, thrombocytopenia, hyperkalemia) than patients without delayed graft function, these events were not more frequent in patients receiving mycophenolate mofetil than azathioprine or placebo. No dose adjustment is recommended for these patients; however, they should be carefully observed. Infections in Cardiac Transplant Patients - In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with mycophenolate mofetil than in those receiving azathioprine therapy, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil (see ADVERSE REACTIONS). - There were more herpes virus (H. simplex, H. zoster, and cytomegalovirus) infections in cardiac transplant patients treated with mycophenolate mofetil compared to those treated with azathioprine (see ADVERSE REACTIONS). Concomitant Medications - It is recommended that mycophenolate mofetil not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied clinically. - In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of mycophenolate mofetil with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of mycophenolate mofetil. Patients with HGPRT Deficiency - On theoretical grounds, because mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome. Immunizations - During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Phenylketonurics - Mycophenolate mofetil oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Therefore, care should be taken if mycophenolate mofetil oral suspension is administered to patients with phenylketonuria. Laboratory Tests - Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year (see WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). # Adverse Reactions ## Clinical Trials Experience - The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections eg, opportunistic infection. The adverse event profile associated with the administration of mycophenolate mofetil intravenous has been shown to be similar to that observed after administration of oral dosage forms of mycophenolate mofetil. Mycophenolate Mofetil Oral - The incidence of adverse events for mycophenolate mofetil was determined in randomized, comparative, double-blind trials in prevention of rejection in renal (2 active, 1 placebo-controlled trials), cardiac (1 active-controlled trial), and hepatic (1 active-controlled trial) transplant patients. Geriatrics - Elderly patients (≥65 years), particularly those who are receiving mycophenolate mofetil as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals (see PRECAUTIONS). - Safety data are summarized below for all active-controlled trials in renal (2 trials), cardiac (1 trial), and hepatic (1 trial) transplant patients. Approximately 53% of the renal patients, 65% of the cardiac patients, and 48% of the hepatic patients have been treated for more than 1 year. Adverse events reported in ≥20% of patients in the mycophenolate mofetil treatment groups are presented below. - The placebo-controlled renal transplant study generally showed fewer adverse events occurring in ≥20% of patients. In addition, those that occurred were not only qualitatively similar to the azathioprine-controlled renal transplant studies, but also occurred at lower rates, particularly for infection, leukopenia, hypertension, diarrhea and respiratory infection. - The above data demonstrate that in three controlled trials for prevention of renal rejection, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. - The above data demonstrate that the types of adverse events observed in multicenter controlled trials in renal, cardiac, and hepatic transplant patients are qualitatively similar except for those that are unique to the specific organ involved. - Sepsis, which was generally CMV viremia, was slightly more common in renal transplant patients treated with mycophenolate mofetil compared to patients treated with azathioprine. The incidence of sepsis was comparable in mycophenolate mofetil and in azathioprine-treated patients in cardiac and hepatic studies. - In the digestive system, diarrhea was increased in renal and cardiac transplant patients receiving mycophenolate mofetil compared to patients receiving azathioprine, but was comparable in hepatic transplant patients treated with mycophenolate mofetil or azathioprine. - Patients receiving mycophenolate mofetil alone or as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The incidence of malignancies among the 1483 patients treated in controlled trials for the prevention of renal allograft rejection who were followed for ≥1 year was similar to the incidence reported in the literature for renal allograft recipients. - Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients followed for at least 1 year (see WARNINGS: Lymphoma and Malignancy). Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. - In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed. - Severe neutropenia (ANC <0.5 × 103/µL) developed in up to 2.0% of renal transplant patients, up to 2.8% of cardiac transplant patients and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily. - All transplant patients are at increased risk of opportunistic infections. The risk increases with total immunosuppressive load (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections). Table 10 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials: - The following other opportunistic infections occurred with an incidence of less than 4% in mycophenolate mofetil patients in the above azathioprine-controlled studies: Herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis carinii. - In the placebo-controlled renal transplant study, the same pattern of opportunistic infection was observed compared to the azathioprine-controlled renal studies, with a notably lower incidence of the following: Herpes simplex and CMV tissue-invasive disease. - In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients. - In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with mycophenolate mofetil than in those receiving azathioprine, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil. - The following adverse events were reported with 3% to<20% incidence in renal, cardiac, and hepatic transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids. Pediatrics - The type and frequency of adverse events in a clinical study in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil oral suspension 600 mg/m2 bid (up to 1 g bid) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 g bid with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric patients. Mycophenolate Mofetil Intravenous - The adverse event profile of mycophenolate mofetil intravenous was determined from a single, double-blind, controlled comparative study of the safety of 2 g/day of intravenous and oral mycophenolate mofetil in renal transplant patients in the immediate posttransplant period (administered for the first 5 days). The potential venous irritation of mycophenolate mofetil intravenous was evaluated by comparing the adverse events attributable to peripheral venous infusion of mycophenolate mofetil intravenous with those observed in the intravenous placebo group; patients in this group received active medication by the oral route. - Adverse events attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with mycophenolate mofetil intravenous. - In the active controlled study in hepatic transplant patients, 2 g/day of mycophenolate mofetil intravenous were administered in the immediate posttransplant period (up to 14 days). The safety profile of intravenous mycophenolate mofetil was similar to that of intravenous azathioprine. ## Postmarketing Experience Congenital Disorders : Embryofetal Toxicity: - Congenital malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to mycophenolate mofetil during pregnancy (see PRECAUTIONS: Pregnancy). Digestive - Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy. Hematologic and Lymphatic: - Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. - Infections: - Serious life-threatening infections such as meningitis and infectious endocarditis have been reported occasionally - There is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infection. - Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune function. - Polyomavirus associated neuropathy (PVAN), especially due to BK virus infection, has been observed in patients receiving immunosuppressants, including mycophenolate mofetil. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss. - Viral reactivation has been reported in patients infected with HBV or HCV. Respiratory - Interstitial lung disorders, including fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in posttransplant patients receiving mycophenolate mofetil. # Drug Interactions - Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. Mycophenolate mofetil has not been administered concomitantly with azathioprine. Acyclovir - Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (eg, valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs. Antacids With Magnesium and Aluminum Hydroxides - Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when administered to ten rheumatoid arthritis patients also taking Maalox® TC (10 mL qid). The Cmax and AUC(0–24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. Mycophenolate mofetil may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that mycophenolate mofetil and the antacid not be administered simultaneously. Proton Pump Inhibitors (PPIs) - Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to mycophenolic acid (MPA). An approximate reduction of 30 to 70% in the Cmax and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and mycophenolate mofetil. Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with mycophenolate mofetil. Cholestyramine - Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine. Some degree of enterohepatic recirculation is also anticipated following intravenous administration of mycophenolate mofetil. Therefore, mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation. Cyclosporine - Cyclosporine (Sandimmune®) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in 10 stable renal transplant patients. The mean (±SD) AUC(0–12h) and Cmax of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (±822) ng∙h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng∙h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of mycophenolate mofetil. - In renal transplant patients, mean MPA exposure (AUC0-12h) was approximately 30 to 50% greater when mycophenolate mofetil is administered without cyclosporine compared with when mycophenolate mofetil is coadministered with cyclosporine. This interaction is due to cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA. This information should be taken into consideration when MMF is used without cyclosporine. Ganciclovir - Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) were 54.3 (±19.0) µg∙h/mL and 11.5 (±1.8) µg/mL, respectively, after coadministration of the two drugs, compared to 51.0 (±17.0) µg∙h/mL and 10.6 (±2.0) µg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (±SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (±21.6) µg∙h/mL and 27.8 (±13.9) µg/mL, respectively, compared to values of 80.3 (±16.4) µg∙h/mL and 30.9 (±11.2) µg/mL, respectively, after administration of mycophenolate mofetil alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (eg, valganciclovir) are coadministered, patients should be monitored carefully. Oral Contraceptives - A study of coadministration of mycophenolate mofetil (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over 3 consecutive menstrual cycles. Mean AUC(0–24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC(0–24h) significantly decreased by about 15%. There was large inter-patient variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol. Mean serum levels of LH, FSH and progesterone were not significantly affected. Mycophenolate mofetil may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. It is recommended to coadminister mycophenolate mofetil with hormonal contraceptives (eg, birth control pill, transdermal patch, vaginal ring, injection, and implant) with caution and additional barrier contraceptive methods must be used. Sevelamer - Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA Cmax and AUC0-12h by 36% and 26% respectively. This data suggest that sevelamer and other calcium free phosphate binders should not be administered simultaneously with mycophenolate mofetil. Alternatively, it is recommended that sevelamer and other calcium free phosphate binders preferentially could be given 2 hours after mycophenolate mofetil intake to minimize the impact on the absorption of MPA. Trimethoprim/sulfamethoxazole - Following single-dose administration of mycophenolate mofetil (1.5 g) to 12 healthy male volunteers on day 8 of a 10 day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered bid, no effect on the bioavailability of MPA was observed. The mean (±SD) AUC and Cmax of MPA after concomitant administration were 75.2 (±19.8) µg∙h/mL and 34.0 (±6.6) µg/mL, respectively, compared to 79.2 (±27.9) µg∙h/mL and 34.2 (±10.7) µg/mL, respectively, after administration of mycophenolate mofetil alone. Norfloxacin and Metronidazole - Following single-dose administration of mycophenolate mofetil (1 g) to 11 healthy volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean MPA AUC0-48h was significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p<0.05). Therefore, mycophenolate mofetil is not recommended to be given with the combination of norfloxacin and metronidazole. There was no significant effect on mean MPA AUC0-48h when mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately. The mean (±SD) MPA AUC0-48h after coadministration of mycophenolate mofetil with norfloxacin or metronidazole separately was 48.3 (±24) µgh/mL and 42.7 (±23) µgh/mL, respectively, compared with 56.2 (±24) µgh/mL after administration of mycophenolate mofetil alone. Ciprofloxacin and Amoxicillin plus Clavulanic Acid - A total of 64 mycophenolate mofetil-treated renal transplant recipients received either oral ciprofloxacin 500 mg bid or amoxicillin plus clavulanic acid 375 mg tid for 7 or at least 14 days. Approximately 50% reductions in median trough MPA concentrations (predose) from baseline (mycophenolate mofetil alone) were observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA concentrations tended to diminish within 14 days of antibiotic therapy and ceased within 3 days after discontinuation of antibiotics. The postulated mechanism for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading to a decrease in enterohepatic recirculation of MPA. The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear. Rifampin - In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC0-12h) has been observed with concomitant administration of mycophenolate mofetil and rifampin. Therefore, mycophenolate mofetil is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk. Other Interactions - The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in plasma MPA AUC. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion. - Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. Live Vaccines - During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - See WARNINGS section. - Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. In animal studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic acid at dose multiples similar to and less than clinical doses. 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 hazard to the fetus. - Risks and benefits of mycophenolate mofetil should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryofetal toxicity. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. For those females using mycophenolate mofetil at any time during pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy, the healthcare practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry (1-800-617-8191). The healthcare practitioner should strongly encourage the patient to enroll in the pregnancy registry. The information provided to the registry will help the healthcare community better understand the effects of mycophenolate in pregnancy. - In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing data (collected 1995 to 2007) on 77 females exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities. Because these postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4 to 5% among babies born to organ transplant patients using other immunosuppressive drugs. - In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Female rats and rabbits received mycophenolate mofetil (MMF) doses equivalent to 0.02 to 0.9 times the recommended human dose for renal and cardiac transplant patients, based on body surface area conversions. In rat offspring, malformations included anophthalmia, agnathia, and hydrocephaly. In rabbit offspring, malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mycophenolate in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Mycophenolate during labor and delivery. ### Nursing Mothers - Studies in rats treated with mycophenolate mofetil have shown mycophenolic acid to be excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mycophenolate mofetil, 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 - Based on pharmacokinetic and safety data in pediatric patients after renal transplantation, the recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 bid (up to a maximum of 1 g bid). Also see CLINICAL PHARMACOLOGY, CLINICAL STUDIES, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION. - Safety and effectiveness in pediatric patients receiving allogeneic cardiac or hepatic transplants have not been established. ### Geriatic Use - Clinical studies of mycophenolate mofetil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant or other drug therapy. Elderly patients may be at an increased risk of adverse reactions compared with younger individuals (see ADVERSE REACTIONS). ### Gender - There is no FDA guidance on the use of Mycophenolate with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Mycophenolate with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Mycophenolate in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Mycophenolate in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Mycophenolate in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Mycophenolate in patients who are immunocompromised. # Administration and Monitoring ### Administration Renal Transplantation Adults - A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of mycophenolate mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. Pediatrics (3 months to 18 years of age) - The recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be dosed with mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). Cardiac Transplantation Adults - A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients. - Hepatic Transplantation Adults - A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients. - Mycophenolate Mofetil Capsules, Tablets, and Oral Suspension - The initial oral dose of mycophenolate mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that mycophenolate mofetil be administered on an empty stomach. However, in stable renal transplant patients, mycophenolate mofetil may be administered with food if necessary. - Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take mycophenolate mofetil at the usual times. Note - If required, mycophenolate mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter). Patients With Hepatic Impairment - No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies. - No data are available for cardiac transplant patients with severe hepatic parenchymal disease. Geriatrics - The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients. Dosage Adjustments - In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of mycophenolate mofetil greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively. - No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks. - If neutropenia develops (ANC <1.3× 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately. ### Monitoring - There is limited information regarding Monitoring of Mycophenolate in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Mycophenolate in the drug label. # Overdosage - The experience with overdose of mycophenolate mofetil in humans is very limited. The events received from reports of overdose fall within the known safety profile of the drug. The highest dose administered to renal transplant patients in clinical trials has been 4 g/day. In limited experience with cardiac and hepatic transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologic abnormalities, principally neutropenia, leading to a need to reduce or discontinue dosing. - In acute oral toxicity studies, no deaths occurred in adult mice at doses up to 4000 mg/kg or in adult monkeys at doses up to 1000 mg/kg; these were the highest doses of mycophenolate mofetil tested in these species. These doses represent 11 times the recommended clinical dose in renal transplant patients and approximately 7 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In adult rats, deaths occurred after single-oral doses of 500 mg/kg of mycophenolate mofetil. The dose represents approximately 3 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. - MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 µg/mL), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine (see CLINICAL PHARMACOLOGY: Pharmacokinetics). # Pharmacology ## Mechanism of Action - Mycophenolate mofetil has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow). - Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. Mycophenolate mofetil also inhibited proliferative arteriopathy in experimental models of aortic and cardiac allografts in rats, as well as in primate cardiac xenografts. Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies. Mycophenolate mofetil has been demonstrated to inhibit immunologically mediated inflammatory responses in animal models and to inhibit tumor development and prolong survival in murine tumor transplant models. - Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed to form MPA, which is the active metabolite. MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection. Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation. ## Structure - Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor. - The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C23H31NO7, a molecular weight of 433.50, and the following structural formula: - Mycophenolate mofetil is a white to off-white crystalline powder. It is slightly soluble in water (43 µg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group. - Mycophenolate mofetil is available for oral administration as capsules containing 250 mg of mycophenolate mofetil and tablets containing 500 mg of mycophenolate mofetil. - Inactive ingredients in mycophenolate mofetil 250 mg capsules include croscarmellose sodium, magnesium stearate, povidone (K-90), microcrystalline cellulose, hydroxy propyl cellulose and talc. - The capsule shells contain FD&C blue #2, gelatin, red iron oxide,sodium lauryl sulfate, titanium dioxide, and yellow iron oxide. The imprinting ink contains shellac, iron oxide black and potassium hydroxide. - Inactive ingredients in mycophenolate mofetil tablets 500 mg include iron oxide black , croscarmellose sodium, FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-90), iron oxide red, talc, and titanium dioxide ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Mycophenolate in the drug label. ## Pharmacokinetics - Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 µg/mL). Absorption - In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of mycophenolate mofetil up to a daily dose of 3 g (see Table 1). - Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g bid to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food (see DOSAGE AND ADMINISTRATION). Distribution - The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations (observed in patients with renal impairment or delayed renal graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood. - In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with HSA) and MPAG (at ≥460 µg/mL with plasma proteins) increased the free fraction of MPA. At concentrations that exceeded what is encountered clinically, cyclosporine, digoxin, naproxen, prednisone, propranolol, tacrolimus, theophylline, tolbutamide, and warfarin did not increase the free fraction of MPA. MPA at concentrations as high as 100 µg/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%. Metabolism - Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine. - Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in approximately a 40% decrease in the MPA AUC (largely as a consequence of lower concentrations in the terminal portion of the profile). These observations suggest that enterohepatic recirculation contributes to MPA plasma concentrations. - Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency. Excretion - Negligible amount of drug is excreted as MPA (100 µg/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the drug (see OVERDOSAGE). - Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and 177 (±31) mL/min following intravenous administration, respectively. - Pharmacokinetics in Healthy Volunteers, Renal, Cardiac, and Hepatic Transplant Patients Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the administration of mycophenolate mofetil given as single doses to healthy volunteers and multiple doses to renal, cardiac, and hepatic transplant patients. In the early posttransplant period (<40 days posttransplant), renal, cardiac, and hepatic transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean Cmax approximately 32% to 44% lower compared to the late transplant period (3 to 6 months posttransplant). - Mean MPA AUC values following administration of 1 g bid intravenous mycophenolate mofetil over 2 hours to renal transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate posttransplant phase. In hepatic transplant patients, administration of 1 g bid intravenous mycophenolate mofetil followed by 1.5 g bid oral mycophenolate mofetil resulted in mean MPA AUC values similar to those found in renal transplant patients administered 1 g mycophenolate mofetil bid. - Two 500 mg tablets have been shown to be bioequivalent to four 250 mg capsules. Five mL of the 200 mg/mL constituted oral suspension have been shown to be bioequivalent to four 250 mg capsules. Special Populations - Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal or hepatic impairment. Renal Insufficiency - In a single-dose study, MMF was administered as capsule or intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment [glomerular filtration rate (GFR) 80 mL/min/1.73 m2). In addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG. - Plasma MPA AUC observed after single-dose (1 g) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR<25 mL/min/1.73 m2) was 62.4 µg∙h/mL (±19.3). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. - In patients with delayed renal graft function posttransplant, mean MPA AUC(0–12h) was comparable to that seen in posttransplant patients without delayed renal graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. However, dose adjustment does not appear to be necessary in patients with delayed renal graft function. Mean plasma MPAG AUC(0–12h) was 2-fold to 3-fold higher than in posttransplant patients without delayed renal graft function. - In 8 patients with primary graft non-function following renal transplantation, plasma concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28 days. Accumulation of MPA was about 1-fold to 2-fold. - The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (>100 µg/mL), hemodialysis removes only small amounts of MPAG. Hepatic Insufficiency - In a single-dose (1 g oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies, such as primary biliary cirrhosis, may show a different effect. In a single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, MMF was rapidly converted to MPA. MPA AUC was 44.1 µg∙h/mL (±15.5). Pediatrics - The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric patients (ranging from 1 year to 18 years of age) receiving mycophenolate mofetil oral suspension at a dose of 600 mg/m2 bid (up to a maximum of 1 g bid) after allogeneic renal transplantation. The pharmacokinetic data for MPA is provided in Table 3. - The mycophenolate mofetil oral suspension dose of 600 mg/m2 bid (up to a maximum of 1 g bid) achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal transplant patients receiving mycophenolate mofetil capsules at a dose of 1 g bid in the early posttransplant period. There was wide variability in the data. As observed in adults, early posttransplant MPA AUC values were approximately 45% to 53% lower than those observed in the later posttransplant period (>3 months). MPA AUC values were similar in the early and late posttransplant period across the 1 year to 18 year age range. Gender - Data obtained from several studies were pooled to look at any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (±SD) MPA AUC(0–12h) for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) µg∙h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64)µg/mL in the females. These differences are not of clinical significance. Geriatrics - Pharmacokinetics in the elderly have not been studied. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.5 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.3 times the recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.08 times the recommended clinical dose in renal transplant patients and 0.05 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. While these animal doses were lower than those given to patients, they were maximal in those species and were considered adequate to evaluate the potential for human risk (see WARNINGS). - The genotoxic potential of mycophenolate mofetil was determined in five assays. Mycophenolate mofetil was genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivo mouse micronucleus assay. Mycophenolate mofetil was not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay. - Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal transplant patients and 0.07 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and eyes) in the first generation offspring in the absence of maternal toxicity. This dose was 0.02 times the recommended clinical dose in renal transplant patients and 0.01 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation. # Clinical Studies Adults - The safety and efficacy of mycophenolate mofetil in combination with corticosteroids and cyclosporine for the prevention of organ rejection were assessed in randomized, double-blind, multicenter trials in renal (3 trials), in cardiac (1 trial), and in hepatic (1 trial) adult transplant patients. Renal Transplant Adults - The three renal studies compared two dose levels of oral mycophenolate mofetil (1 g bid and 1.5 g bid) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine (Sandimmune®) and corticosteroids to prevent acute rejection episodes. One study also included antithymocyte globulin (ATGAM®) induction therapy. These studies are described by geographic location of the investigational sites. One study was conducted in the USA at 14 sites, one study was conducted in Europe at 20 sites, and one study was conducted in Europe, Canada, and Australia at a total of 21 sites. - The primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation (defined as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or early termination from the study for any reason without prior biopsy-proven rejection). Mycophenolate mofetil, when administered with antithymocyte globulin (ATGAM®) induction (one study) and with cyclosporine and corticosteroids (all three studies), was compared to the following three therapeutic regimens: (1) antithymocyte globulin (ATGAM®) induction/azathioprine/cyclosporine/corticosteroids, (2) azathioprine/cyclosporine/corticosteroids, and (3) cyclosporine/corticosteroids. - Mycophenolate mofetil, in combination with corticosteroids and cyclosporine reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first 6 months following transplantation. Table 4 and Table 5 summarize the results of these studies. These tables show (1) the proportion of patients experiencing treatment failure, (2) the proportion of patients who experienced biopsy-proven acute rejection on treatment, and (3) early termination, for any reason other than graft loss or death, without a prior biopsy-proven acute rejection episode. Patients who prematurely discontinued treatment were followed for the occurrence of death or graft loss, and the cumulative incidence of graft loss and patient death are summarized separately. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination. More patients receiving mycophenolate mofetil discontinued without prior biopsy-proven rejection, death or graft loss than discontinued in the control groups, with the highest rate in the mycophenolate mofetil 3 g/day group. Therefore, the acute rejection rates may be underestimates, particularly in the mycophenolate mofetil 3 g/day group. - The cumulative incidence of 12-month graft loss or patient death is presented below. No advantage of mycophenolate mofetil with respect to graft loss or patient death was established. Numerically, patients receiving mycophenolate mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving mycophenolate mofetil 2 g/day experienced a better outcome than mycophenolate mofetil 3 g/day in two of the three studies. Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss or patient death at 1 year. Pediatrics - One open-label, safety and pharmacokinetic study of mycophenolate mofetil oral suspension 600 mg/m2 bid (up to 1 g bid) in combination with cyclosporine and corticosteroids was performed at centers in the US (9), Europe (5) and Australia (1) in 100 pediatric patients (3 months to 18 years of age) for the prevention of renal allograft rejection. Mycophenolate mofetil was well tolerated in pediatric patients (see ADVERSE REACTIONS), and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g bid mycophenolate mofetil capsules. The rate of biopsy-proven rejection was similar across the age groups (3 months to <6 years, 6 years to <12 years, 12 years to 18 years). The overall biopsy-proven rejection rate at 6 months was comparable to adults. The combined incidence of graft loss (5%) and patient death (2%) at 12 months posttransplant was similar to that observed in adult renal transplant patients. Cardiac Transplant - A double-blind, randomized, comparative, parallel-group, multicenter study in primary cardiac transplant recipients was performed at 20 centers in the United States, 1 in Canada, 5 in Europe and 2 in Australia. The total number of patients enrolled was 650; 72 never received study drug and 578 received study drug. Patients received mycophenolate mofetil 1.5 g bid (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The two primary efficacy endpoints were: (1) the proportion of patients who, after transplantation, had at least one endomyocardial biopsy-proven rejection with hemodynamic compromise, or were retransplanted or died, within the first 6 months, and (2) the proportion of patients who died or were retransplanted during the first 12 months following transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for 1 year. - Rejection: No difference was established between mycophenolate mofetil and azathioprine (AZA) with respect to biopsy-proven rejection with hemodynamic compromise. - Survival: Mycophenolate mofetil was shown to be at least as effective as AZA in preventing death or retransplantation at 1 year (see Table 6). Hepatic Transplant - A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at 16 centers in the United States, 2 in Canada, 4 in Europe and 1 in Australia. The total number of patients enrolled was 565. Per protocol, patients received mycophenolate mofetil 1 g bid intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g bid orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The actual median oral dose of azathioprine on study was 1.5 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) initially and 1.26 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) at 12 months. The two primary endpoints were: (1) the proportion of patients who experienced, in the first 6 months posttransplantation, one or more episodes of biopsy-proven and treated rejection or death or retransplantation, and (2) the proportion of patients who experienced graft loss (death or retransplantation) during the first 12 months posttransplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or retransplantation) for 1 year. Results - In combination with corticosteroids and cyclosporine, mycophenolate mofetil obtained a lower rate of acute rejection at 6 months and a similar rate of death or retransplantation at 1 year compared to azathioprine. # How Supplied Mycophenolate Mofetil Capsules USP 250 mg - Light blue/peach, size ‘1’ hard gelatin capsules, printed in black with ‘GC1’ on body containing white to off white powder. - NDC Number Size - NDC 16729-094-01- Bottle of 100 - NDC 16729-094-29- Bottle of 120 - NDC 16729-094-16- Bottle of 500 - Mycophenolate Mofetil Tablets USP 500 mg - Purple coloured, capsule shaped,biconvex film-coated tablets debossed ‘AHI ’ on one side and ‘500 ’ on other side. - NDC Number Size - NDC 16729-019-01- Bottle of 100 - NDC 16729-019-16- Bottle of 500 ## Storage Mycophenolate Mofetil Capsules USP 250 mg - Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Mycophenolate Mofetil Tablets USP 500 mg - Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense in light-resistant containers, such as the manufacturer's original containers. ### =HANDLING AND DISPOSAL - Mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits (see Pregnancy and WARNINGS: Embryofetal Toxicity). Mycophenolate mofetil tablets should not be crushed and mycophenolate mofetil capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in mycophenolate mofetil capsules and mycophenolate mofetil oral suspension (before or after constitution). If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. Should a spill occur, wipe up using paper towels wetted with water to remove spilled powder or suspension. Caution should be exercised in the handling and preparation of solutions of mycophenolate mofetil intravenous.Avoid direct contact of the prepared solution of mycophenolate mofetil intravenous with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - See Medication Guide - Inform females of reproductive potential that use of mycophenolate mofetil during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, and advise them as to the appropriate steps to manage these risks, including that they must use acceptable contraception (see WARNINGS: Embryofetal Toxicity, PRECAUTIONS: Pregnancy Exposure Prevention and Planning). - Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential. In the event of a positive pregnancy test, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. - Females of reproductive potential must use acceptable birth control during entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses to avoid heterosexual intercourse completely (abstinence) (seePRECAUTIONS: Pregnancy Exposure Prevention and Planning, Table 8). - For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolate mofetil should be discussed with the patient. - Give patients complete dosage instructions and inform them about the increased risk of lymphoproliferative disease and certain other malignancies. - Inform patients that they need repeated appropriate laboratory tests while they are taking mycophenolate mofetil. - Advise patients that they should not breastfeed during mycophenolate mofetil therapy. # Precautions with Alcohol - Alcohol-Mycophenolate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Mycophenolate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [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. # Black Box Warning # Overview Mycophenolate is an antibiotic, anti-neoplastic agent that is FDA approved for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, leukopenia, sepsis, vomiting, opportunistic infections. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Mycophenolate mofetil is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids. - Mycophenolate mofetil intravenous is an alternative dosage form to mycophenolate mofetil capsules, tablets and oral suspension. Mycophenolate mofetil intravenous should be administered within 24 hours following transplantation. Mycophenolate mofetil intravenous can be administered for up to 14 days; patients should be switched to oral mycophenolate mofetil as soon as they can tolerate oral medication. - Dosing Information: - Renal Transplantation - Adults - A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of mycophenolate mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. - Cardiac Transplantation - Adults - A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients. - Hepatic Transplantation - Adults - A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients. - Mycophenolate Mofetil Capsules, Tablets, and Oral Suspension - The initial oral dose of mycophenolate mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that mycophenolate mofetil be administered on an empty stomach. However, in stable renal transplant patients, mycophenolate mofetil may be administered with food if necessary. - Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take mycophenolate mofetil at the usual times. - Note - If required, mycophenolate mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter). - Patients With Hepatic Impairment - No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies. - No data are available for cardiac transplant patients with severe hepatic parenchymal disease. - Geriatrics - The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients. - Dosage Adjustments - In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of mycophenolate mofetil greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively. - No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks. - If neutropenia develops (ANC <1.3× 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see WARNINGS: Neutropenia, ADVERSE REACTIONS, and PRECAUTIONS: Laboratory Tests). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Mycophenolate in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Mycophenolate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Renal Transplantation - Pediatrics (3 months to 18 years of age) - The recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be dosed with mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Mycophenolate in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Mycophenolate in pediatric patients. # Contraindications - Allergic reactions to mycophenolate mofetil have been observed; therefore, mycophenolate mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product. Mycophenolate mofetil intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN). # Warnings Embryofetal Toxicity - Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant female. Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. Pregnancy Exposure Prevention and Planning - Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning. For recommended pregnancy testing and contraception methods. Lymphoma and Malignancy - Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolate mofetil, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see ADVERSE REACTIONS). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. - Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients (see ADVERSE REACTIONS). - In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed (see ADVERSE REACTIONS). Combination with Other Immunosuppressive Agents - Mycophenolate mofetil has been administered in combination with the following agents in clinical trials: antithymocyte globulin (ATGAM®), OKT3 (Orthoclone OKT® 3), cyclosporine (Sandimmune®, Neoral®) and corticosteroids. The efficacy and safety of the use of mycophenolate mofetil in combination with other immunosuppressive agents have not been determined. Serious Infections - Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections. These infections may lead to serious, including fatal outcomes. Because of the danger of over suppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution (see ADVERSE REACTIONS). New or Reactivated Viral Infections - Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including mycophenolate mofetil. Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft. - PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss. Patient monitoring may help detect patients at risk for PVAN. - PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function (see ADVERSE REACTIONS: Postmarketing Experience). In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. - The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. - Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended. Neutropenia - Severe neutropenia [absolute neutrophil count (ANC)<0.5× 103/µL] developed in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see ADVERSE REACTIONS). Patients receiving mycophenolate mofetil should be monitored for neutropenia. The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes. If neutropenia develops (ANC <1.3 × 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately. Neutropenia has been observed most frequently in the period from 31 to 180 days posttransplant in patients treated for prevention of renal, cardiac, and hepatic rejection. - Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Pure Red Cell Aplasia (PRCA) - Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. The mechanism for mycophenolate mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown. In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk. - CAUTION: MYCOPHENOLATE MOFETIL INTRAVENOUS SOLUTION SHOULD NEVER BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION. ### PRECAUTIONS Pregnancy Exposure Prevention and Planning - Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning. - Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient’s healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical from a bilateral oophorectomy. Pregnancy Testing - To prevent unplanned exposure during pregnancy, females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting mycophenolate mofetil. Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. - In the event of a positive pregnancy test, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. Contraception - Females of reproductive potential taking mycophenolate mofetil must receive contraceptive counseling and use acceptable contraception (see Table 8 for acceptable contraception methods). - Patients must use acceptable birth control during entire mycophenolate mofetil therapy, and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely). - Patients should be aware that mycophenolate mofetil reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness. Pregnancy Planning - For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolate mofetil should be discussed with the patient. Gastrointestinal Disorders - Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with mycophenolate mofetil 3 g daily. In pediatric renal transplant patients, 5/148 cases of gastrointestinal bleeding (requiring hospitalization) were observed. - Gastrointestinal perforations have rarely been observed. Most patients receiving mycophenolate mofetil were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with mycophenolate mofetil. Because mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation, mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease. Patients with Renal Impairment - Subjects with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) who have received single doses of mycophenolate mofetil showed higher plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG. Doses of mycophenolate mofetil greater than 1 g administered twice a day to renal transplant patients should be avoided and they should be carefully observed. - No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks. - In patients with delayed renal graft function posttransplant, mean MPA AUC(0–12h) was comparable, but MPAG AUC(0–12h) was 2-fold to 3-fold higher, compared to that seen in posttransplant patients without delayed renal graft function. In the three controlled studies of prevention of renal rejection, there were 298 of 1483 patients (20%) with delayed graft function. Although patients with delayed graft function have a higher incidence of certain adverse events (anemia, thrombocytopenia, hyperkalemia) than patients without delayed graft function, these events were not more frequent in patients receiving mycophenolate mofetil than azathioprine or placebo. No dose adjustment is recommended for these patients; however, they should be carefully observed. Infections in Cardiac Transplant Patients - In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with mycophenolate mofetil than in those receiving azathioprine therapy, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil (see ADVERSE REACTIONS). - There were more herpes virus (H. simplex, H. zoster, and cytomegalovirus) infections in cardiac transplant patients treated with mycophenolate mofetil compared to those treated with azathioprine (see ADVERSE REACTIONS). Concomitant Medications - It is recommended that mycophenolate mofetil not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied clinically. - In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of mycophenolate mofetil with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of mycophenolate mofetil. Patients with HGPRT Deficiency - On theoretical grounds, because mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome. Immunizations - During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Phenylketonurics - Mycophenolate mofetil oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Therefore, care should be taken if mycophenolate mofetil oral suspension is administered to patients with phenylketonuria. Laboratory Tests - Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year (see WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). # Adverse Reactions ## Clinical Trials Experience - The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections eg, opportunistic infection. The adverse event profile associated with the administration of mycophenolate mofetil intravenous has been shown to be similar to that observed after administration of oral dosage forms of mycophenolate mofetil. Mycophenolate Mofetil Oral - The incidence of adverse events for mycophenolate mofetil was determined in randomized, comparative, double-blind trials in prevention of rejection in renal (2 active, 1 placebo-controlled trials), cardiac (1 active-controlled trial), and hepatic (1 active-controlled trial) transplant patients. Geriatrics - Elderly patients (≥65 years), particularly those who are receiving mycophenolate mofetil as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals (see PRECAUTIONS). - Safety data are summarized below for all active-controlled trials in renal (2 trials), cardiac (1 trial), and hepatic (1 trial) transplant patients. Approximately 53% of the renal patients, 65% of the cardiac patients, and 48% of the hepatic patients have been treated for more than 1 year. Adverse events reported in ≥20% of patients in the mycophenolate mofetil treatment groups are presented below. - The placebo-controlled renal transplant study generally showed fewer adverse events occurring in ≥20% of patients. In addition, those that occurred were not only qualitatively similar to the azathioprine-controlled renal transplant studies, but also occurred at lower rates, particularly for infection, leukopenia, hypertension, diarrhea and respiratory infection. - The above data demonstrate that in three controlled trials for prevention of renal rejection, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. - The above data demonstrate that the types of adverse events observed in multicenter controlled trials in renal, cardiac, and hepatic transplant patients are qualitatively similar except for those that are unique to the specific organ involved. - Sepsis, which was generally CMV viremia, was slightly more common in renal transplant patients treated with mycophenolate mofetil compared to patients treated with azathioprine. The incidence of sepsis was comparable in mycophenolate mofetil and in azathioprine-treated patients in cardiac and hepatic studies. - In the digestive system, diarrhea was increased in renal and cardiac transplant patients receiving mycophenolate mofetil compared to patients receiving azathioprine, but was comparable in hepatic transplant patients treated with mycophenolate mofetil or azathioprine. - Patients receiving mycophenolate mofetil alone or as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The incidence of malignancies among the 1483 patients treated in controlled trials for the prevention of renal allograft rejection who were followed for ≥1 year was similar to the incidence reported in the literature for renal allograft recipients. - Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients followed for at least 1 year (see WARNINGS: Lymphoma and Malignancy). Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. - In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed. - Severe neutropenia (ANC <0.5 × 103/µL) developed in up to 2.0% of renal transplant patients, up to 2.8% of cardiac transplant patients and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily. - All transplant patients are at increased risk of opportunistic infections. The risk increases with total immunosuppressive load (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections). Table 10 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials: - The following other opportunistic infections occurred with an incidence of less than 4% in mycophenolate mofetil patients in the above azathioprine-controlled studies: Herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis carinii. - In the placebo-controlled renal transplant study, the same pattern of opportunistic infection was observed compared to the azathioprine-controlled renal studies, with a notably lower incidence of the following: Herpes simplex and CMV tissue-invasive disease. - In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients. - In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with mycophenolate mofetil than in those receiving azathioprine, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil. - The following adverse events were reported with 3% to<20% incidence in renal, cardiac, and hepatic transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids. Pediatrics - The type and frequency of adverse events in a clinical study in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil oral suspension 600 mg/m2 bid (up to 1 g bid) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 g bid with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric patients. Mycophenolate Mofetil Intravenous - The adverse event profile of mycophenolate mofetil intravenous was determined from a single, double-blind, controlled comparative study of the safety of 2 g/day of intravenous and oral mycophenolate mofetil in renal transplant patients in the immediate posttransplant period (administered for the first 5 days). The potential venous irritation of mycophenolate mofetil intravenous was evaluated by comparing the adverse events attributable to peripheral venous infusion of mycophenolate mofetil intravenous with those observed in the intravenous placebo group; patients in this group received active medication by the oral route. - Adverse events attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with mycophenolate mofetil intravenous. - In the active controlled study in hepatic transplant patients, 2 g/day of mycophenolate mofetil intravenous were administered in the immediate posttransplant period (up to 14 days). The safety profile of intravenous mycophenolate mofetil was similar to that of intravenous azathioprine. ## Postmarketing Experience Congenital Disorders : Embryofetal Toxicity: - Congenital malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to mycophenolate mofetil during pregnancy (see PRECAUTIONS: Pregnancy). Digestive - Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy. Hematologic and Lymphatic: - Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. - Infections: - Serious life-threatening infections such as meningitis and infectious endocarditis have been reported occasionally - There is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infection. - Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune function. - Polyomavirus associated neuropathy (PVAN), especially due to BK virus infection, has been observed in patients receiving immunosuppressants, including mycophenolate mofetil. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss. - Viral reactivation has been reported in patients infected with HBV or HCV. Respiratory - Interstitial lung disorders, including fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in posttransplant patients receiving mycophenolate mofetil. # Drug Interactions - Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. Mycophenolate mofetil has not been administered concomitantly with azathioprine. Acyclovir - Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (eg, valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs. Antacids With Magnesium and Aluminum Hydroxides - Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when administered to ten rheumatoid arthritis patients also taking Maalox® TC (10 mL qid). The Cmax and AUC(0–24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. Mycophenolate mofetil may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that mycophenolate mofetil and the antacid not be administered simultaneously. Proton Pump Inhibitors (PPIs) - Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to mycophenolic acid (MPA). An approximate reduction of 30 to 70% in the Cmax and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and mycophenolate mofetil. Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with mycophenolate mofetil. Cholestyramine - Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine. Some degree of enterohepatic recirculation is also anticipated following intravenous administration of mycophenolate mofetil. Therefore, mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation. Cyclosporine - Cyclosporine (Sandimmune®) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in 10 stable renal transplant patients. The mean (±SD) AUC(0–12h) and Cmax of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (±822) ng∙h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng∙h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of mycophenolate mofetil. - In renal transplant patients, mean MPA exposure (AUC0-12h) was approximately 30 to 50% greater when mycophenolate mofetil is administered without cyclosporine compared with when mycophenolate mofetil is coadministered with cyclosporine. This interaction is due to cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA. This information should be taken into consideration when MMF is used without cyclosporine. Ganciclovir - Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) were 54.3 (±19.0) µg∙h/mL and 11.5 (±1.8) µg/mL, respectively, after coadministration of the two drugs, compared to 51.0 (±17.0) µg∙h/mL and 10.6 (±2.0) µg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (±SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (±21.6) µg∙h/mL and 27.8 (±13.9) µg/mL, respectively, compared to values of 80.3 (±16.4) µg∙h/mL and 30.9 (±11.2) µg/mL, respectively, after administration of mycophenolate mofetil alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (eg, valganciclovir) are coadministered, patients should be monitored carefully. Oral Contraceptives - A study of coadministration of mycophenolate mofetil (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over 3 consecutive menstrual cycles. Mean AUC(0–24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC(0–24h) significantly decreased by about 15%. There was large inter-patient variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol. Mean serum levels of LH, FSH and progesterone were not significantly affected. Mycophenolate mofetil may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. It is recommended to coadminister mycophenolate mofetil with hormonal contraceptives (eg, birth control pill, transdermal patch, vaginal ring, injection, and implant) with caution and additional barrier contraceptive methods must be used. Sevelamer - Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA Cmax and AUC0-12h by 36% and 26% respectively. This data suggest that sevelamer and other calcium free phosphate binders should not be administered simultaneously with mycophenolate mofetil. Alternatively, it is recommended that sevelamer and other calcium free phosphate binders preferentially could be given 2 hours after mycophenolate mofetil intake to minimize the impact on the absorption of MPA. Trimethoprim/sulfamethoxazole - Following single-dose administration of mycophenolate mofetil (1.5 g) to 12 healthy male volunteers on day 8 of a 10 day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered bid, no effect on the bioavailability of MPA was observed. The mean (±SD) AUC and Cmax of MPA after concomitant administration were 75.2 (±19.8) µg∙h/mL and 34.0 (±6.6) µg/mL, respectively, compared to 79.2 (±27.9) µg∙h/mL and 34.2 (±10.7) µg/mL, respectively, after administration of mycophenolate mofetil alone. Norfloxacin and Metronidazole - Following single-dose administration of mycophenolate mofetil (1 g) to 11 healthy volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean MPA AUC0-48h was significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p<0.05). Therefore, mycophenolate mofetil is not recommended to be given with the combination of norfloxacin and metronidazole. There was no significant effect on mean MPA AUC0-48h when mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately. The mean (±SD) MPA AUC0-48h after coadministration of mycophenolate mofetil with norfloxacin or metronidazole separately was 48.3 (±24) µg•h/mL and 42.7 (±23) µg•h/mL, respectively, compared with 56.2 (±24) µg•h/mL after administration of mycophenolate mofetil alone. Ciprofloxacin and Amoxicillin plus Clavulanic Acid - A total of 64 mycophenolate mofetil-treated renal transplant recipients received either oral ciprofloxacin 500 mg bid or amoxicillin plus clavulanic acid 375 mg tid for 7 or at least 14 days. Approximately 50% reductions in median trough MPA concentrations (predose) from baseline (mycophenolate mofetil alone) were observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA concentrations tended to diminish within 14 days of antibiotic therapy and ceased within 3 days after discontinuation of antibiotics. The postulated mechanism for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading to a decrease in enterohepatic recirculation of MPA. The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear. Rifampin - In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC0-12h) has been observed with concomitant administration of mycophenolate mofetil and rifampin. Therefore, mycophenolate mofetil is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk. Other Interactions - The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in plasma MPA AUC. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion. - Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. Live Vaccines - During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - See WARNINGS section. - Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. In animal studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic acid at dose multiples similar to and less than clinical doses. 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 hazard to the fetus. - Risks and benefits of mycophenolate mofetil should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryofetal toxicity. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. For those females using mycophenolate mofetil at any time during pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy, the healthcare practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry (1-800-617-8191). The healthcare practitioner should strongly encourage the patient to enroll in the pregnancy registry. The information provided to the registry will help the healthcare community better understand the effects of mycophenolate in pregnancy. - In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing data (collected 1995 to 2007) on 77 females exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities. Because these postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4 to 5% among babies born to organ transplant patients using other immunosuppressive drugs. - In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Female rats and rabbits received mycophenolate mofetil (MMF) doses equivalent to 0.02 to 0.9 times the recommended human dose for renal and cardiac transplant patients, based on body surface area conversions. In rat offspring, malformations included anophthalmia, agnathia, and hydrocephaly. In rabbit offspring, malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mycophenolate in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Mycophenolate during labor and delivery. ### Nursing Mothers - Studies in rats treated with mycophenolate mofetil have shown mycophenolic acid to be excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mycophenolate mofetil, 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 - Based on pharmacokinetic and safety data in pediatric patients after renal transplantation, the recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 bid (up to a maximum of 1 g bid). Also see CLINICAL PHARMACOLOGY, CLINICAL STUDIES, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION. - Safety and effectiveness in pediatric patients receiving allogeneic cardiac or hepatic transplants have not been established. ### Geriatic Use - Clinical studies of mycophenolate mofetil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant or other drug therapy. Elderly patients may be at an increased risk of adverse reactions compared with younger individuals (see ADVERSE REACTIONS). ### Gender - There is no FDA guidance on the use of Mycophenolate with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Mycophenolate with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Mycophenolate in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Mycophenolate in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Mycophenolate in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Mycophenolate in patients who are immunocompromised. # Administration and Monitoring ### Administration Renal Transplantation Adults - A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of mycophenolate mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. Pediatrics (3 months to 18 years of age) - The recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be dosed with mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). Cardiac Transplantation Adults - A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients. - Hepatic Transplantation Adults - A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients. - Mycophenolate Mofetil Capsules, Tablets, and Oral Suspension - The initial oral dose of mycophenolate mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that mycophenolate mofetil be administered on an empty stomach. However, in stable renal transplant patients, mycophenolate mofetil may be administered with food if necessary. - Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take mycophenolate mofetil at the usual times. Note - If required, mycophenolate mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter). Patients With Hepatic Impairment - No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies. - No data are available for cardiac transplant patients with severe hepatic parenchymal disease. Geriatrics - The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients. Dosage Adjustments - In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of mycophenolate mofetil greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively. - No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks. - If neutropenia develops (ANC <1.3× 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately. ### Monitoring - There is limited information regarding Monitoring of Mycophenolate in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Mycophenolate in the drug label. # Overdosage - The experience with overdose of mycophenolate mofetil in humans is very limited. The events received from reports of overdose fall within the known safety profile of the drug. The highest dose administered to renal transplant patients in clinical trials has been 4 g/day. In limited experience with cardiac and hepatic transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologic abnormalities, principally neutropenia, leading to a need to reduce or discontinue dosing. - In acute oral toxicity studies, no deaths occurred in adult mice at doses up to 4000 mg/kg or in adult monkeys at doses up to 1000 mg/kg; these were the highest doses of mycophenolate mofetil tested in these species. These doses represent 11 times the recommended clinical dose in renal transplant patients and approximately 7 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In adult rats, deaths occurred after single-oral doses of 500 mg/kg of mycophenolate mofetil. The dose represents approximately 3 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. - MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 µg/mL), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine (see CLINICAL PHARMACOLOGY: Pharmacokinetics). # Pharmacology ## Mechanism of Action - Mycophenolate mofetil has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow). - Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. Mycophenolate mofetil also inhibited proliferative arteriopathy in experimental models of aortic and cardiac allografts in rats, as well as in primate cardiac xenografts. Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies. Mycophenolate mofetil has been demonstrated to inhibit immunologically mediated inflammatory responses in animal models and to inhibit tumor development and prolong survival in murine tumor transplant models. - Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed to form MPA, which is the active metabolite. MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection. Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation. ## Structure - Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor. - The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C23H31NO7, a molecular weight of 433.50, and the following structural formula: - Mycophenolate mofetil is a white to off-white crystalline powder. It is slightly soluble in water (43 µg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group. - Mycophenolate mofetil is available for oral administration as capsules containing 250 mg of mycophenolate mofetil and tablets containing 500 mg of mycophenolate mofetil. - Inactive ingredients in mycophenolate mofetil 250 mg capsules include croscarmellose sodium, magnesium stearate, povidone (K-90), microcrystalline cellulose, hydroxy propyl cellulose and talc. - The capsule shells contain FD&C blue #2, gelatin, red iron oxide,sodium lauryl sulfate, titanium dioxide, and yellow iron oxide. The imprinting ink contains shellac, iron oxide black and potassium hydroxide. - Inactive ingredients in mycophenolate mofetil tablets 500 mg include iron oxide black , croscarmellose sodium, FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-90), iron oxide red, talc, and titanium dioxide ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Mycophenolate in the drug label. ## Pharmacokinetics - Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 µg/mL). Absorption - In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of mycophenolate mofetil up to a daily dose of 3 g (see Table 1). - Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g bid to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food (see DOSAGE AND ADMINISTRATION). Distribution - The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations (observed in patients with renal impairment or delayed renal graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood. - In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with HSA) and MPAG (at ≥460 µg/mL with plasma proteins) increased the free fraction of MPA. At concentrations that exceeded what is encountered clinically, cyclosporine, digoxin, naproxen, prednisone, propranolol, tacrolimus, theophylline, tolbutamide, and warfarin did not increase the free fraction of MPA. MPA at concentrations as high as 100 µg/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%. Metabolism - Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine. - Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in approximately a 40% decrease in the MPA AUC (largely as a consequence of lower concentrations in the terminal portion of the profile). These observations suggest that enterohepatic recirculation contributes to MPA plasma concentrations. - Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency. Excretion - Negligible amount of drug is excreted as MPA (<1% of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil resulted in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 µg/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the drug (see OVERDOSAGE). - Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and 177 (±31) mL/min following intravenous administration, respectively. - Pharmacokinetics in Healthy Volunteers, Renal, Cardiac, and Hepatic Transplant Patients Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the administration of mycophenolate mofetil given as single doses to healthy volunteers and multiple doses to renal, cardiac, and hepatic transplant patients. In the early posttransplant period (<40 days posttransplant), renal, cardiac, and hepatic transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean Cmax approximately 32% to 44% lower compared to the late transplant period (3 to 6 months posttransplant). - Mean MPA AUC values following administration of 1 g bid intravenous mycophenolate mofetil over 2 hours to renal transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate posttransplant phase. In hepatic transplant patients, administration of 1 g bid intravenous mycophenolate mofetil followed by 1.5 g bid oral mycophenolate mofetil resulted in mean MPA AUC values similar to those found in renal transplant patients administered 1 g mycophenolate mofetil bid. - Two 500 mg tablets have been shown to be bioequivalent to four 250 mg capsules. Five mL of the 200 mg/mL constituted oral suspension have been shown to be bioequivalent to four 250 mg capsules. Special Populations - Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal or hepatic impairment. Renal Insufficiency - In a single-dose study, MMF was administered as capsule or intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment [glomerular filtration rate (GFR) <25 mL/min/1.73 m2] was about 75% higher relative to that observed in healthy volunteers (GFR >80 mL/min/1.73 m2). In addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG. - Plasma MPA AUC observed after single-dose (1 g) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR<25 mL/min/1.73 m2) was 62.4 µg∙h/mL (±19.3). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. - In patients with delayed renal graft function posttransplant, mean MPA AUC(0–12h) was comparable to that seen in posttransplant patients without delayed renal graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. However, dose adjustment does not appear to be necessary in patients with delayed renal graft function. Mean plasma MPAG AUC(0–12h) was 2-fold to 3-fold higher than in posttransplant patients without delayed renal graft function. - In 8 patients with primary graft non-function following renal transplantation, plasma concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28 days. Accumulation of MPA was about 1-fold to 2-fold. - The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (>100 µg/mL), hemodialysis removes only small amounts of MPAG. Hepatic Insufficiency - In a single-dose (1 g oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies, such as primary biliary cirrhosis, may show a different effect. In a single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, MMF was rapidly converted to MPA. MPA AUC was 44.1 µg∙h/mL (±15.5). Pediatrics - The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric patients (ranging from 1 year to 18 years of age) receiving mycophenolate mofetil oral suspension at a dose of 600 mg/m2 bid (up to a maximum of 1 g bid) after allogeneic renal transplantation. The pharmacokinetic data for MPA is provided in Table 3. - The mycophenolate mofetil oral suspension dose of 600 mg/m2 bid (up to a maximum of 1 g bid) achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal transplant patients receiving mycophenolate mofetil capsules at a dose of 1 g bid in the early posttransplant period. There was wide variability in the data. As observed in adults, early posttransplant MPA AUC values were approximately 45% to 53% lower than those observed in the later posttransplant period (>3 months). MPA AUC values were similar in the early and late posttransplant period across the 1 year to 18 year age range. Gender - Data obtained from several studies were pooled to look at any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (±SD) MPA AUC(0–12h) for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) µg∙h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64)µg/mL in the females. These differences are not of clinical significance. Geriatrics - Pharmacokinetics in the elderly have not been studied. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.5 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.3 times the recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.08 times the recommended clinical dose in renal transplant patients and 0.05 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. While these animal doses were lower than those given to patients, they were maximal in those species and were considered adequate to evaluate the potential for human risk (see WARNINGS). - The genotoxic potential of mycophenolate mofetil was determined in five assays. Mycophenolate mofetil was genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivo mouse micronucleus assay. Mycophenolate mofetil was not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay. - Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal transplant patients and 0.07 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and eyes) in the first generation offspring in the absence of maternal toxicity. This dose was 0.02 times the recommended clinical dose in renal transplant patients and 0.01 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation. # Clinical Studies Adults - The safety and efficacy of mycophenolate mofetil in combination with corticosteroids and cyclosporine for the prevention of organ rejection were assessed in randomized, double-blind, multicenter trials in renal (3 trials), in cardiac (1 trial), and in hepatic (1 trial) adult transplant patients. Renal Transplant Adults - The three renal studies compared two dose levels of oral mycophenolate mofetil (1 g bid and 1.5 g bid) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine (Sandimmune®) and corticosteroids to prevent acute rejection episodes. One study also included antithymocyte globulin (ATGAM®) induction therapy. These studies are described by geographic location of the investigational sites. One study was conducted in the USA at 14 sites, one study was conducted in Europe at 20 sites, and one study was conducted in Europe, Canada, and Australia at a total of 21 sites. - The primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation (defined as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or early termination from the study for any reason without prior biopsy-proven rejection). Mycophenolate mofetil, when administered with antithymocyte globulin (ATGAM®) induction (one study) and with cyclosporine and corticosteroids (all three studies), was compared to the following three therapeutic regimens: (1) antithymocyte globulin (ATGAM®) induction/azathioprine/cyclosporine/corticosteroids, (2) azathioprine/cyclosporine/corticosteroids, and (3) cyclosporine/corticosteroids. - Mycophenolate mofetil, in combination with corticosteroids and cyclosporine reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first 6 months following transplantation. Table 4 and Table 5 summarize the results of these studies. These tables show (1) the proportion of patients experiencing treatment failure, (2) the proportion of patients who experienced biopsy-proven acute rejection on treatment, and (3) early termination, for any reason other than graft loss or death, without a prior biopsy-proven acute rejection episode. Patients who prematurely discontinued treatment were followed for the occurrence of death or graft loss, and the cumulative incidence of graft loss and patient death are summarized separately. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination. More patients receiving mycophenolate mofetil discontinued without prior biopsy-proven rejection, death or graft loss than discontinued in the control groups, with the highest rate in the mycophenolate mofetil 3 g/day group. Therefore, the acute rejection rates may be underestimates, particularly in the mycophenolate mofetil 3 g/day group. - The cumulative incidence of 12-month graft loss or patient death is presented below. No advantage of mycophenolate mofetil with respect to graft loss or patient death was established. Numerically, patients receiving mycophenolate mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving mycophenolate mofetil 2 g/day experienced a better outcome than mycophenolate mofetil 3 g/day in two of the three studies. Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss or patient death at 1 year. Pediatrics - One open-label, safety and pharmacokinetic study of mycophenolate mofetil oral suspension 600 mg/m2 bid (up to 1 g bid) in combination with cyclosporine and corticosteroids was performed at centers in the US (9), Europe (5) and Australia (1) in 100 pediatric patients (3 months to 18 years of age) for the prevention of renal allograft rejection. Mycophenolate mofetil was well tolerated in pediatric patients (see ADVERSE REACTIONS), and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g bid mycophenolate mofetil capsules. The rate of biopsy-proven rejection was similar across the age groups (3 months to <6 years, 6 years to <12 years, 12 years to 18 years). The overall biopsy-proven rejection rate at 6 months was comparable to adults. The combined incidence of graft loss (5%) and patient death (2%) at 12 months posttransplant was similar to that observed in adult renal transplant patients. Cardiac Transplant - A double-blind, randomized, comparative, parallel-group, multicenter study in primary cardiac transplant recipients was performed at 20 centers in the United States, 1 in Canada, 5 in Europe and 2 in Australia. The total number of patients enrolled was 650; 72 never received study drug and 578 received study drug. Patients received mycophenolate mofetil 1.5 g bid (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The two primary efficacy endpoints were: (1) the proportion of patients who, after transplantation, had at least one endomyocardial biopsy-proven rejection with hemodynamic compromise, or were retransplanted or died, within the first 6 months, and (2) the proportion of patients who died or were retransplanted during the first 12 months following transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for 1 year. - Rejection: No difference was established between mycophenolate mofetil and azathioprine (AZA) with respect to biopsy-proven rejection with hemodynamic compromise. - Survival: Mycophenolate mofetil was shown to be at least as effective as AZA in preventing death or retransplantation at 1 year (see Table 6). Hepatic Transplant - A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at 16 centers in the United States, 2 in Canada, 4 in Europe and 1 in Australia. The total number of patients enrolled was 565. Per protocol, patients received mycophenolate mofetil 1 g bid intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g bid orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The actual median oral dose of azathioprine on study was 1.5 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) initially and 1.26 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) at 12 months. The two primary endpoints were: (1) the proportion of patients who experienced, in the first 6 months posttransplantation, one or more episodes of biopsy-proven and treated rejection or death or retransplantation, and (2) the proportion of patients who experienced graft loss (death or retransplantation) during the first 12 months posttransplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or retransplantation) for 1 year. Results - In combination with corticosteroids and cyclosporine, mycophenolate mofetil obtained a lower rate of acute rejection at 6 months and a similar rate of death or retransplantation at 1 year compared to azathioprine. # How Supplied Mycophenolate Mofetil Capsules USP 250 mg - Light blue/peach, size ‘1’ hard gelatin capsules, printed in black with ‘GC1’ on body containing white to off white powder. - NDC Number Size - NDC 16729-094-01- Bottle of 100 - NDC 16729-094-29- Bottle of 120 - NDC 16729-094-16- Bottle of 500 - Mycophenolate Mofetil Tablets USP 500 mg - Purple coloured, capsule shaped,biconvex film-coated tablets debossed ‘AHI ’ on one side and ‘500 ’ on other side. - NDC Number Size - NDC 16729-019-01- Bottle of 100 - NDC 16729-019-16- Bottle of 500 ## Storage Mycophenolate Mofetil Capsules USP 250 mg - Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Mycophenolate Mofetil Tablets USP 500 mg - Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense in light-resistant containers, such as the manufacturer's original containers. ### =HANDLING AND DISPOSAL - Mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits (see Pregnancy and WARNINGS: Embryofetal Toxicity). Mycophenolate mofetil tablets should not be crushed and mycophenolate mofetil capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in mycophenolate mofetil capsules and mycophenolate mofetil oral suspension (before or after constitution). If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. Should a spill occur, wipe up using paper towels wetted with water to remove spilled powder or suspension. Caution should be exercised in the handling and preparation of solutions of mycophenolate mofetil intravenous.Avoid direct contact of the prepared solution of mycophenolate mofetil intravenous with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - See Medication Guide - Inform females of reproductive potential that use of mycophenolate mofetil during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, and advise them as to the appropriate steps to manage these risks, including that they must use acceptable contraception (see WARNINGS: Embryofetal Toxicity, PRECAUTIONS: Pregnancy Exposure Prevention and Planning). - Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential. In the event of a positive pregnancy test, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. - Females of reproductive potential must use acceptable birth control during entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses to avoid heterosexual intercourse completely (abstinence) (seePRECAUTIONS: Pregnancy Exposure Prevention and Planning, Table 8). - For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolate mofetil should be discussed with the patient. - Give patients complete dosage instructions and inform them about the increased risk of lymphoproliferative disease and certain other malignancies. - Inform patients that they need repeated appropriate laboratory tests while they are taking mycophenolate mofetil. - Advise patients that they should not breastfeed during mycophenolate mofetil therapy. # Precautions with Alcohol - Alcohol-Mycophenolate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ®[1] # Look-Alike Drug Names - A® — B®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Mycophenolate
5ec42d38cd1a1bbd831163d802a39d1fd7e9b5dc	wikidoc	Myelophthisis	Myelophthisis Synonyms and keywords: Myelophthisic anemia # Overview Myelophthisis refers to the displacement of hemopoietic bone-marrow tissue into the peripheral blood, either by fibrosis (myelofibrosis), tumors, or granulomas. A myelophthisic blood smear is one which contains nucleated red blood cells, granulocyte precursors, and teardrop-shaped erythrocytes. This condition is also known as Myelophthisic anemia. Myelophthisis can be observed in cancers that that involve the bone marrow such as leukemia, lymphoma, and myeloma or metastatic carcinoma. The commonest cause is metastatic cancer, most often carcinomas arising in breast, lung and prostate.However any infiltrative process (e.g.,granulomatous disease) involving the marrow can produce identical findings.It should be remembered that it is also a feature of spent phase of myeloproliferative disorders.They cause marrow distortion and fibrosis which act to displace normal marrow elements and disturb mechanisms that regulate the egress of red cells and granulocytes from the marrow. # Historical Perspective # Classification # Pathophysiology Myelophthisis is thought to be caused by damage to the normal hematopoietic stem cells, which leads to the release of cytokines, growth factors and other substance. Immature cells, stem cells and progenitor cells are thus released and relocate in the spleen and the liver . # Causes - Fibrosis (myelofibrosis) - Metastatic carcinoma - Lymphoma - Granuloma - Tuberculosis - Gaucher disease # Differentiating Myelophthisis from Other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications, and Prognosis ## Natural History ## Complications The complications are related to pancytopenia including anemia and its complications , infections and the bleeding tendency in addition to the hypersplenism which leads to refractory thrombocytopenia and portal hypertension. ## Prognosis The prognosis of Myelophthisis depends on treating the etiology # Diagnosis ## Diagnostic Criteria ## History and Symptoms patients usually complain of symptoms of palpitations , fatigue , dyspnea and weakness . ## Physical Examination ## Laboratory Findings Peripheral blood picture will show : - normocytic normochromic anemia . - Increased RBCs count. - leukoerthroblasts - Abnormally shaped RBCs. - Bone marrow is often confirmatory ; will likely show dry tap due to the replacement of normal cells by fibrosis and abnormal cells which will aid in the diagnosis of the underlying etiology . ## Imaging Findings ## Other Diagnostic Studies # Treatment Treatment of Myelophthisis depends on treating the underlying cause. ## Medical Therapy ## Surgery ## Prevention	Myelophthisis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Soumya Sachdeva Synonyms and keywords: Myelophthisic anemia # Overview Myelophthisis refers to the displacement of hemopoietic bone-marrow tissue into the peripheral blood, either by fibrosis (myelofibrosis), tumors, or granulomas. A myelophthisic blood smear is one which contains nucleated red blood cells, granulocyte precursors, and teardrop-shaped erythrocytes. This condition is also known as Myelophthisic anemia. Myelophthisis can be observed in cancers that that involve the bone marrow such as leukemia, lymphoma, and myeloma or metastatic carcinoma. The commonest cause is metastatic cancer, most often carcinomas arising in breast, lung and prostate.However any infiltrative process (e.g.,granulomatous disease) involving the marrow can produce identical findings.It should be remembered that it is also a feature of spent phase of myeloproliferative disorders.They cause marrow distortion and fibrosis which act to displace normal marrow elements and disturb mechanisms that regulate the egress of red cells and granulocytes from the marrow. # Historical Perspective # Classification # Pathophysiology Myelophthisis is thought to be caused by damage to the normal hematopoietic stem cells, which leads to the release of cytokines, growth factors and other substance. Immature cells, stem cells and progenitor cells are thus released and relocate in the spleen and the liver . # Causes - Fibrosis (myelofibrosis) - Metastatic carcinoma - Lymphoma - Granuloma - Tuberculosis - Gaucher disease # Differentiating Myelophthisis from Other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications, and Prognosis ## Natural History ## Complications [1] The complications are related to pancytopenia including anemia and its complications , infections and the bleeding tendency in addition to the hypersplenism which leads to refractory thrombocytopenia and portal hypertension. ## Prognosis The prognosis of Myelophthisis depends on treating the etiology # Diagnosis ## Diagnostic Criteria ## History and Symptoms patients usually complain of symptoms of palpitations , fatigue , dyspnea and weakness . ## Physical Examination ## Laboratory Findings Peripheral blood picture will show : - normocytic normochromic anemia . - Increased RBCs count. - leukoerthroblasts - Abnormally shaped RBCs. - Bone marrow is often confirmatory ; will likely show dry tap due to the replacement of normal cells by fibrosis and abnormal cells which will aid in the diagnosis of the underlying etiology . ## Imaging Findings ## Other Diagnostic Studies # Treatment Treatment of Myelophthisis depends on treating the underlying cause. ## Medical Therapy ## Surgery ## Prevention	https://www.wikidoc.org/index.php/Myelophthisic_anemia
d8f9c24fb11153059eac65772d9baddc85f7ffa7	wikidoc	Myotendinosis	Myotendinosis Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Related Key Words and Synonyms: # Overview # Epidemiology and Demographics # Risk Factors # Screening # Pathophysiology & Etiology # Molecular Biology # Genetics # Natural History and Complications # Diagnosis ## Common Causes ## Complete Differential Diagnosis of the Causes of ... (In alphabetical order) - a... - z... Make sure that each diagnosis is linked to a page. ## Complete Differential Diagnosis of the Causes of ... (By organ system) ## History and Symptoms ## Physical Examination ### Appearance of the Patient ### Vital Signs ### Skin ### Eyes ### Ear Nose and Throat ### Heart ### Lungs ### Abdomen ### Extremities ### Neurologic ### Other ## Laboratory Findings ### Electrolyte and Biomarker Studies ### Electrocardiogram ### Chest X Ray ### MRI and CT ### Echocardiography or Ultrasound ### Other Imaging Findings ## Pathology ### Gross Pathology ### Microscopic Pathology ## Other Diagnostic Studies # Risk Stratification and Prognosis # Treatment ## Pharmacotherapy ### Acute Pharmacotherapies ### Chronic Pharmacotherapies ## Surgery and Device Based Therapy ### Indications for Surgery ### Pre-Operative Assessment ### Post-Operative Management ### Transplantation ## Primary Prevention ## Secondary Prevention ## Cost-Effectiveness of Therapy ## Future or Investigational Therapies # "The Way I Like To Do It ..." Tips and Tricks From Clinicians Around The World ## Suggested Revisions to the Current Guidelines	Myotendinosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Related Key Words and Synonyms: # Overview # Epidemiology and Demographics # Risk Factors # Screening # Pathophysiology & Etiology # Molecular Biology # Genetics # Natural History and Complications # Diagnosis ## Common Causes ## Complete Differential Diagnosis of the Causes of ... (In alphabetical order) - a... - z... Make sure that each diagnosis is linked to a page. ## Complete Differential Diagnosis of the Causes of ... (By organ system) ## History and Symptoms ## Physical Examination ### Appearance of the Patient ### Vital Signs ### Skin ### Eyes ### Ear Nose and Throat ### Heart ### Lungs ### Abdomen ### Extremities ### Neurologic ### Other ## Laboratory Findings ### Electrolyte and Biomarker Studies ### Electrocardiogram ### Chest X Ray ### MRI and CT ### Echocardiography or Ultrasound ### Other Imaging Findings ## Pathology ### Gross Pathology ### Microscopic Pathology ## Other Diagnostic Studies # Risk Stratification and Prognosis # Treatment ## Pharmacotherapy ### Acute Pharmacotherapies ### Chronic Pharmacotherapies ## Surgery and Device Based Therapy ### Indications for Surgery ### Pre-Operative Assessment ### Post-Operative Management ### Transplantation ## Primary Prevention ## Secondary Prevention ## Cost-Effectiveness of Therapy ## Future or Investigational Therapies # "The Way I Like To Do It ..." Tips and Tricks From Clinicians Around The World ## Suggested Revisions to the Current Guidelines	https://www.wikidoc.org/index.php/Myotendinosis
c32aacaa2a0b96b1f3c63bf3381e12035d244767	wikidoc	NMDA receptor	NMDA receptor # Overview The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl d-aspartate) is a name of its selective specific agonist). Activation of NMDA receptors results in the opening of an ion channel which is nonselective to cations. This allows flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell. Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in that it is both ligand-gated and voltage-dependent. # Structure The NMDA receptor forms a heterodimer between NR1 and NR2 subunits, which explains why NMDA receptors contain two obligatory NR1 subunits and two regionally localized NR2 subunits. A related gene family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor isoforms with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits. Each receptor subunit has modular design and each structural module also represents a functional unit: - The extracellular domain contains two globular structures: a modulatory domain and a ligand binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate. - The agonist-binding module links to a membrane domain which consists of three trans-membrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels. - The membrane domain contributes residues to the channel pore and is responsible for the receptor's high unitary conductance, high calcium permeability, and voltage-dependent magnesium block. - Lastly, each subunit has an extensive cytoplasmic domain which contain residues that can be directly modified by a series of protein kinases and protein phosphatases as well as residues which interact with a large number of structural, adaptor and scaffolding proteins. The glycine-binding module of the NR1 subunit and the glutamate-binding module of the NR2A subunit have been expressed as a soluble proteins and their three-dimensional structure has been solved at atomic resolution by x-ray crystallography. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors. # Variants ## NR1 There are eight variants of NR1 subunit produced by alternative splicing of GRIN1: - NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form. - NR1-2a, NR1-2b; - NR1-3a, NR1-3b; - NR1-4a, NR1-4b; ## NR2 Various isoforms of NR2 subunits exist, and are referred to with the nomenclature NR2A through D (GRIN2A, GRIN2B, GRIN2C, GRIN2D). They contain the binding-site for the neurotransmitter glutamate. Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding-site for the selective inhibitor ifenprodil. While NR2B is predominant in the early postnatal brain, the number of NR2A subunits grows, and eventually NR2A subunits outnumber NR2B. This is called NR2B-NR2A developmental switch, and is notable because of the different kinetics each NR2 subunit lends to the receptor. There are three hypothetic models to describe this switch mechanism: - Dramatic increase in synaptic NR2A along with decrease in NR2B, or - Extrasynaptic displacement of NR2B away from the synapse with increase in NR2A, or - Increase of NR2A diluting the number of NR2B without the decrease of the former. The NR2B and NR2A subunits also have differential roles in mediating excitotoxic neuronal death. The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity. Disruption of the gene for NR2B in mice causes perinatal lethality, while the disruption of NR2A gene produces viable mice, although with impaired hippocampal plasticity. # Agonists Activation of NMDA receptors requires binding of glutamate or aspartate (aspartate does not stimulate the receptors as strongly.) In addition, NMDARs also require the binding of the co-agonist glycine for the efficient opening of the ion channel which is a part of this receptor. D-serine has also been found to co-agonize the NMDA receptor with even greater potency than glycine. D-serine is produced by serine racemase in astrocyte cells and is enriched in the same areas as NMDA receptors. Removal of D-serine can block NMDA mediated excitatory neurotransmission in many areas. Recently, it has been shown that D-serine is also synthesized in neurons, indicating a role for neuron-derived D-serine in NMDA receptor regulation. In addition, a third requirement is membrane depolarization. A positive change in transmembrane potential will make it more likely that the ion channel in the NMDA receptor will open by expelling the Mg2+ ion that blocks the channel from the outside. This property is fundamental to the role of the NMDA receptor in memory and learning, and it has been suggested that this channel is a biochemical substrate of Hebbian learning, where it can act as a coincidence detector for membrane depolarization and synaptic transmission. # Antagonists NMDA Receptor Antagonists are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs because of their hallucinogenic properties. When NMDA Receptor Antagonists are given to rodents in large doses, they can cause a form of brain damage called Olney's Lesions. However, there are fundamental differences between human and rodent brains. For now there is not enough research to show that large doses of NMDA antagonists cause Olney's Lesions in humans or monkeys. Common NMDA Receptor Antagonists include: - Memantine - Amantadine - Dextromethorphan - Dextrorphan - Ibogaine - Ketamine - Nitrous oxide - Phencyclidine - Tramadol # Modulators The NMDA receptor is modulated by a number of endogenous and exogenous compounds: - Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. Magnesium treatment has been used to produce rapid recovery from depression. - Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. - Zn2+ blocks the NMDA current in a noncompetitive and a voltage-independent manner. - It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses. - Aminoglycosides have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect. - The activity of NMDA receptors is also strikingly sensitive to the changes in H+ concentration, and partially inhibited by the ambient concentration of H+ under physiological conditions. The level of inhibition by H+ is greaty reduced in receptors containing the NR1a subtype, which contains the positively charged insert Exon 5. The effect of this insert may be mimicked by positively charged polyamines and aminoglycosides, explaining their mode of action. - NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site." Through this site, reductants dramatically enhance NMDA channel activity while oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid and the essential nutrient pyrroloquinoline quinone. # Role This channel complex contributes to excitatory synaptic transmission at sites throughout the brain and the spinal cord, and is modulated by a number of endogenous and exogenous compounds. NMDA receptors play a key role in a wide range of physiologic and pathologic processes.	NMDA receptor # Overview The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl d-aspartate) is a name of its selective specific agonist). Activation of NMDA receptors results in the opening of an ion channel which is nonselective to cations. This allows flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell. Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in that it is both ligand-gated and voltage-dependent. # Structure The NMDA receptor forms a heterodimer between NR1 and NR2 subunits, which explains why NMDA receptors contain two obligatory NR1 subunits and two regionally localized NR2 subunits.[1] A related gene family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor isoforms with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits. Each receptor subunit has modular design and each structural module also represents a functional unit: - The extracellular domain contains two globular structures: a modulatory domain and a ligand binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate. - The agonist-binding module links to a membrane domain which consists of three trans-membrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels. - The membrane domain contributes residues to the channel pore and is responsible for the receptor's high unitary conductance, high calcium permeability, and voltage-dependent magnesium block. - Lastly, each subunit has an extensive cytoplasmic domain which contain residues that can be directly modified by a series of protein kinases and protein phosphatases as well as residues which interact with a large number of structural, adaptor and scaffolding proteins. The glycine-binding module of the NR1 subunit and the glutamate-binding module of the NR2A subunit have been expressed as a soluble proteins and their three-dimensional structure has been solved at atomic resolution by x-ray crystallography. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors. # Variants ## NR1 There are eight variants of NR1 subunit produced by alternative splicing of GRIN1:[2] - NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form. - NR1-2a, NR1-2b; - NR1-3a, NR1-3b; - NR1-4a, NR1-4b; ## NR2 Various isoforms of NR2 subunits exist, and are referred to with the nomenclature NR2A through D (GRIN2A, GRIN2B, GRIN2C, GRIN2D). They contain the binding-site for the neurotransmitter glutamate. Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding-site for the selective inhibitor ifenprodil. While NR2B is predominant in the early postnatal brain, the number of NR2A subunits grows, and eventually NR2A subunits outnumber NR2B. This is called NR2B-NR2A developmental switch, and is notable because of the different kinetics each NR2 subunit lends to the receptor.[3] There are three hypothetic models to describe this switch mechanism: - Dramatic increase in synaptic NR2A along with decrease in NR2B, or - Extrasynaptic displacement of NR2B away from the synapse with increase in NR2A, or - Increase of NR2A diluting the number of NR2B without the decrease of the former. The NR2B and NR2A subunits also have differential roles in mediating excitotoxic neuronal death.[4] The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.[5] Disruption of the gene for NR2B in mice causes perinatal lethality, while the disruption of NR2A gene produces viable mice, although with impaired hippocampal plasticity. # Agonists Activation of NMDA receptors requires binding of glutamate or aspartate (aspartate does not stimulate the receptors as strongly.[6]) In addition, NMDARs also require the binding of the co-agonist glycine for the efficient opening of the ion channel which is a part of this receptor. D-serine has also been found to co-agonize the NMDA receptor with even greater potency than glycine. D-serine is produced by serine racemase in astrocyte cells and is enriched in the same areas as NMDA receptors. Removal of D-serine can block NMDA mediated excitatory neurotransmission in many areas. Recently, it has been shown that D-serine is also synthesized in neurons, indicating a role for neuron-derived D-serine in NMDA receptor regulation. In addition, a third requirement is membrane depolarization. A positive change in transmembrane potential will make it more likely that the ion channel in the NMDA receptor will open by expelling the Mg2+ ion that blocks the channel from the outside. This property is fundamental to the role of the NMDA receptor in memory and learning, and it has been suggested that this channel is a biochemical substrate of Hebbian learning, where it can act as a coincidence detector for membrane depolarization and synaptic transmission. # Antagonists NMDA Receptor Antagonists are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs because of their hallucinogenic properties. When NMDA Receptor Antagonists are given to rodents in large doses, they can cause a form of brain damage called Olney's Lesions. However, there are fundamental differences between human and rodent brains. For now there is not enough research to show that large doses of NMDA antagonists cause Olney's Lesions in humans or monkeys.[7] Common NMDA Receptor Antagonists include: - Memantine - Amantadine[8] - Dextromethorphan - Dextrorphan - Ibogaine[9] - Ketamine - Nitrous oxide - Phencyclidine - Tramadol # Modulators The NMDA receptor is modulated by a number of endogenous and exogenous compounds: - Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. Magnesium treatment has been used to produce rapid recovery from depression.[10] - Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. - Zn2+ blocks the NMDA current in a noncompetitive and a voltage-independent manner. - It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses. - Aminoglycosides have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect. - The activity of NMDA receptors is also strikingly sensitive to the changes in H+ concentration, and partially inhibited by the ambient concentration of H+ under physiological conditions. The level of inhibition by H+ is greaty reduced in receptors containing the NR1a subtype, which contains the positively charged insert Exon 5. The effect of this insert may be mimicked by positively charged polyamines and aminoglycosides, explaining their mode of action. - NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site." Through this site, reductants dramatically enhance NMDA channel activity while oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid and the essential nutrient pyrroloquinoline quinone.[11] # Role This channel complex contributes to excitatory synaptic transmission at sites throughout the brain and the spinal cord, and is modulated by a number of endogenous and exogenous compounds. NMDA receptors play a key role in a wide range of physiologic and pathologic processes.	https://www.wikidoc.org/index.php/N-methyl-D-aspartate_receptor
fbae2ac8e87efeb070f12c7ffe3fa4b08916ae9a	wikidoc	Na+/K+-ATPase	Na+/K+-ATPase Na+/K+-ATPase (also known as the Na+/K+ pump, sodium-potassium pump, or simply NAKA, for short) is an enzyme (EC 3.6.3.9) located in the plasma membrane (specifically an electrogenic transmembrane ATPase). It is found in the human cell and is found in all metazoa (animals). # Sodium-Potassium Pumps Active transport is responsible for the well-established observation that cells contain relatively high concentrations of potassium ions but low concentrations of sodium ions. The mechanism responsible for this is the sodium-potassium pump which moves these two ions in opposite directions across the plasma membrane. Is this two-way movement of potassium and sodium ions performed by the same carrier or by two different ones? This was investigated by following the passage of radioactively labelled ions across the plasma membrane of certain ones. It was found that the concentrations of sodium and potassium ions on the two other sides of the membrane are interdependent, suggesting that the same carrier transports both ions. It is now known that the carrier is an ATPhase and that it pumps three sodium ions out of the cell for every two potassium ions pumped in. The sodium-potassium pump was discovered in the 1950’s by a Danish scientist, Jens Skou, who was awarded a Nobel Prize in 1997. It marked an important step forward in our understanding of how ions get into and out of cells, and it has a particular significance for excitable cells such as nervous cells, which depend on it for responding to stimuli and transmitting impulses. (Advanced Biology - Michael Roberts, Michael Reiss, Grace Monger. 2000) # Function The Na+/K+-ATPase helps maintain resting potential, avail transport and regulate cellular volume. ## Resting potential In order to maintain the cell potential, cells must keep a low concentration of sodium ions and high levels of potassium ions within the cell (intracellular). Outside of the cells (extracellular), there are high concentrations of sodium and low concentrations of potassium, so diffusion occurs through ion channels in the plasma membrane. In order to keep the appropriate concentrations, the sodium-potassium pump pumps sodium out and potassium in through active transport. As the plasma membrane is far less permeable to sodium than it is to potassium ions, an electric potential (negative intracellularly) is the eventual result. The resting potential avails action potentials of nerves and muscles. ## Transport Export of sodium from the cell provides the driving force for several facilitated membrane transport proteins, which import glucose, amino acids and other nutrients into the cell. Translocation of sodium from one side of a cell membrane to the other side creates an osmotic gradient that drives the absorption of water. Another important task of the Na+-K+ pump is to provide an Na+ gradient that is used by certain carrier processes. In the gut, for example, sodium is transported out of the resorbing cell on the blood side via the Na+-K+ pump, whereas, on the resorbing side, the Na+-Glucose symporter uses the created Na+ gradient as a source of energy to import both Na+ and Glucose, which is far more efficient than simple diffusion. Similar processes are located in the renal tubular system. # Mechanism - The pump, with bound ATP, binds 3 intracellular Na+ ions. - ATP is hydrolyzed, leading to phosphorylation of the pump at a highly conserved aspartate residue and subsequent release of ADP. - A conformational change in the pump exposes the Na+ ions to the outside. The phosphorylated form of the pump has a low affinity for Na+ ions, so they are released. - The pump binds 2 extracellular K+ ions. This causes the dephosphorylation of the pump, reverting it to its previous conformational state, transporting the K+ ions into the cell. - The unphosphorylated form of the pump has a higher affinity for Na+ ions than K+ ions, so the two bound K+ ions are released. ATP binds, and the process starts again. # Regulation ## Endogenous The Na+/K+-ATPase is thought to be downregulated by cAMP. Thus, substances causing an increase in cAMP downregulates Na+/K+-ATPase. These include the ligands of the Gs-coupled GPCRs. In contrast, substances causing a decrease in cAMP upregulates Na+/K+-ATPase. These include the ligands of the Gi-coupled GPCRs. It should be noted that cAMP also acts as a second messenger causing an increase in protein abundance of Na-K-ATPase. ## Exogenous The Na+-K+-ATPase can be pharmacologically modified by administrating drugs exogenously. For instance, Na+-K+-ATPase found in the membrane of heart cells is an important target of cardiac glycosides (for example digoxin and ouabain), inotropic drugs used to improve heart performance by increasing its force of contraction. Contraction of any muscle is dependent on a 100- to 10,000-times higher-than-resting intracellular Ca2+ concentration, which, as soon as it is put back again on its normal level by a carrier enzyme in the plasma membrane, and a calcium pump in sarcoplasmic reticulum, muscle relaxes. Since this carrier enzyme (Na+-Ca2+ translocator) uses the Na gradient generated by the Na+-K+ pump to remove Ca2+ from the intracellular space, slowing down the Na+-K+ pump results in a permanently-higher Ca2+ level in the muscle, which will eventually lead to stronger contractions. # Discovery Na+/K+-ATPase was discovered by Jens Christian Skou in 1957 while working as assistant professor at the Department of Physiology, University of Aarhus, Denmark. He published his work in 1957. In 1997, he received one-half of the Nobel Prize in Chemistry "for the first discovery of an ion-transporting enzyme, Na+, K+ -ATPase." # Genes - Alpha: ATP1A1Template:Gene2, ATP1A2Template:Gene2, ATP1A3Template:Gene2, ATP1A4Template:Gene2. #1 predominates in kidney. #2 is also known as "alpha(+)" - Beta: ATP1B1Template:Gene2, ATP1B2, ATP1B3Template:Gene2, ATP1B4	Na+/K+-ATPase Template:Downsize Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Na+/K+-ATPase (also known as the Na+/K+ pump, sodium-potassium pump, or simply NAKA, for short) is an enzyme (EC 3.6.3.9) located in the plasma membrane (specifically an electrogenic transmembrane ATPase). It is found in the human cell and is found in all metazoa (animals). # Sodium-Potassium Pumps Active transport is responsible for the well-established observation that cells contain relatively high concentrations of potassium ions but low concentrations of sodium ions. The mechanism responsible for this is the sodium-potassium pump which moves these two ions in opposite directions across the plasma membrane. Is this two-way movement of potassium and sodium ions performed by the same carrier or by two different ones? This was investigated by following the passage of radioactively labelled ions across the plasma membrane of certain ones. It was found that the concentrations of sodium and potassium ions on the two other sides of the membrane are interdependent, suggesting that the same carrier transports both ions. It is now known that the carrier is an ATPhase and that it pumps three sodium ions out of the cell for every two potassium ions pumped in. The sodium-potassium pump was discovered in the 1950’s by a Danish scientist, Jens Skou, who was awarded a Nobel Prize in 1997. It marked an important step forward in our understanding of how ions get into and out of cells, and it has a particular significance for excitable cells such as nervous cells, which depend on it for responding to stimuli and transmitting impulses. (Advanced Biology - Michael Roberts, Michael Reiss, Grace Monger. 2000) # Function The Na+/K+-ATPase helps maintain resting potential, avail transport and regulate cellular volume. ## Resting potential Template:Seealso In order to maintain the cell potential, cells must keep a low concentration of sodium ions and high levels of potassium ions within the cell (intracellular). Outside of the cells (extracellular), there are high concentrations of sodium and low concentrations of potassium, so diffusion occurs through ion channels in the plasma membrane. In order to keep the appropriate concentrations, the sodium-potassium pump pumps sodium out and potassium in through active transport. As the plasma membrane is far less permeable to sodium than it is to potassium ions, an electric potential (negative intracellularly) is the eventual result. The resting potential avails action potentials of nerves and muscles. ## Transport Export of sodium from the cell provides the driving force for several facilitated membrane transport proteins, which import glucose, amino acids and other nutrients into the cell. Translocation of sodium from one side of a cell membrane to the other side creates an osmotic gradient that drives the absorption of water. Another important task of the Na+-K+ pump is to provide an Na+ gradient that is used by certain carrier processes. In the gut, for example, sodium is transported out of the resorbing cell on the blood side via the Na+-K+ pump, whereas, on the resorbing side, the Na+-Glucose symporter uses the created Na+ gradient as a source of energy to import both Na+ and Glucose, which is far more efficient than simple diffusion. Similar processes are located in the renal tubular system. # Mechanism - The pump, with bound ATP, binds 3 intracellular Na+ ions. - ATP is hydrolyzed, leading to phosphorylation of the pump at a highly conserved aspartate residue and subsequent release of ADP. - A conformational change in the pump exposes the Na+ ions to the outside. The phosphorylated form of the pump has a low affinity for Na+ ions, so they are released. - The pump binds 2 extracellular K+ ions. This causes the dephosphorylation of the pump, reverting it to its previous conformational state, transporting the K+ ions into the cell. - The unphosphorylated form of the pump has a higher affinity for Na+ ions than K+ ions, so the two bound K+ ions are released. ATP binds, and the process starts again. # Regulation ## Endogenous The Na+/K+-ATPase is thought to be downregulated by cAMP.[1] Thus, substances causing an increase in cAMP downregulates Na+/K+-ATPase. These include the ligands of the Gs-coupled GPCRs. In contrast, substances causing a decrease in cAMP upregulates Na+/K+-ATPase. These include the ligands of the Gi-coupled GPCRs. It should be noted that cAMP also acts as a second messenger causing an increase in protein abundance of Na-K-ATPase. ## Exogenous The Na+-K+-ATPase can be pharmacologically modified by administrating drugs exogenously. For instance, Na+-K+-ATPase found in the membrane of heart cells is an important target of cardiac glycosides (for example digoxin and ouabain), inotropic drugs used to improve heart performance by increasing its force of contraction. Contraction of any muscle is dependent on a 100- to 10,000-times higher-than-resting intracellular Ca2+ concentration, which, as soon as it is put back again on its normal level by a carrier enzyme in the plasma membrane, and a calcium pump in sarcoplasmic reticulum, muscle relaxes. Since this carrier enzyme (Na+-Ca2+ translocator) uses the Na gradient generated by the Na+-K+ pump to remove Ca2+ from the intracellular space, slowing down the Na+-K+ pump results in a permanently-higher Ca2+ level in the muscle, which will eventually lead to stronger contractions. # Discovery Na+/K+-ATPase was discovered by Jens Christian Skou in 1957 while working as assistant professor at the Department of Physiology, University of Aarhus, Denmark. He published his work in 1957.[2] In 1997, he received one-half of the Nobel Prize in Chemistry "for the first discovery of an ion-transporting enzyme, Na+, K+ -ATPase."[3] # Genes - Alpha: ATP1A1Template:Gene2, ATP1A2Template:Gene2, ATP1A3Template:Gene2, ATP1A4Template:Gene2. #1 predominates in kidney. #2 is also known as "alpha(+)" - Beta: ATP1B1Template:Gene2, ATP1B2, ATP1B3Template:Gene2, ATP1B4	https://www.wikidoc.org/index.php/Na%2B/K%2B-ATPase
e7b31846b1c7b87861e4d5b3c9b97c82e4144124	wikidoc	Naftidrofuryl	Naftidrofuryl # Overview Naftidrofuryl (INN, also known as nafronyl or as the oxalate salt naftidrofuryl oxalate or nafronyl oxalate) is a drug used in the management of peripheral and cerebral vascular disorders. It is claimed to enhance cellular oxidative capacity and to be a spasmolytic. It may also be a 5-HT2 receptor antagonist. It is also licenced for the treatment of intermittent claudication due to peripheral arterial disease. It is sold under the brand name Dusodril (Merck) and cerebromap for multiapex in middle east. It is also sold as Praxilene in the United Kingdom. Historically, it has been used to treat sudden idiopathic hearing loss and acute tinnitus. Naftidrofuryl may be effective for relieving the pain of muscle cramps.	Naftidrofuryl Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Naftidrofuryl (INN, also known as nafronyl or as the oxalate salt naftidrofuryl oxalate or nafronyl oxalate) is a drug used in the management of peripheral and cerebral vascular disorders. It is claimed to enhance cellular oxidative capacity and to be a spasmolytic.[1] It may also be a 5-HT2 receptor antagonist. It is also licenced for the treatment of intermittent claudication due to peripheral arterial disease. It is sold under the brand name Dusodril (Merck) and cerebromap for multiapex in middle east. It is also sold as Praxilene in the United Kingdom.[2] Historically, it has been used to treat sudden idiopathic hearing loss and acute tinnitus.[3] Naftidrofuryl may be effective for relieving the pain of muscle cramps.[4]	https://www.wikidoc.org/index.php/Naftidrofuryl
ceed4d732c202e8bdaf162c96ccb3d8f1daa445a	wikidoc	Native copper	Native copper Copper, as native copper, is one of the few metallic elements to occur in uncombined form as a natural mineral, although most commonly occurs in oxidized states and mixed with other elements. Native copper was an important ore of copper in historic times and was used by pre-historic peoples. Native copper occurs as rarely isometric cubic and octahedral crystals, but more typically as irregular masses and fracture fillings. It is a copper-red color on fresh surfaces, but typically is weathered and coated with a green tarnish of copper(II) carbonate. Its specific gravity is 8.9 and the hardness is 2.5. The mines of the Keweenaw native copper deposits of Upper Michigan were major copper producers in the 19th and early 20th centuries, and are the largest deposits of native copper in the world. Native Americans mined copper on a small scale, and evidence exists of copper trading routes throughout North America among native peoples, proven by isotopic analysis. The first commercial mines in the Keweenaw Peninsula (which is nicknamed the "Copper Country") opened in the 1840s. Isle Royale in western Lake Superior, was also a site of many tons of native copper. Some of it was extracted by native peoples, but only one of several commercial attempts at mining turned a profit there. Another major native copper deposit is in Corocoro, Bolivia. The name copper comes from the Greek kyprios, of Cyprus, the location of copper mines since pre-historic times.	Native copper Copper, as native copper, is one of the few metallic elements to occur in uncombined form as a natural mineral, although most commonly occurs in oxidized states and mixed with other elements. Native copper was an important ore of copper in historic times and was used by pre-historic peoples. Native copper occurs as rarely isometric cubic and octahedral crystals, but more typically as irregular masses and fracture fillings. It is a copper-red color on fresh surfaces, but typically is weathered and coated with a green tarnish of copper(II) carbonate. Its specific gravity is 8.9 and the hardness is 2.5.[1] The mines of the Keweenaw native copper deposits of Upper Michigan were major copper producers in the 19th and early 20th centuries, and are the largest deposits of native copper in the world.[2] Native Americans mined copper on a small scale, and evidence exists of copper trading routes throughout North America among native peoples, proven by isotopic analysis. The first commercial mines in the Keweenaw Peninsula (which is nicknamed the "Copper Country") opened in the 1840s. Isle Royale in western Lake Superior, was also a site of many tons of native copper. Some of it was extracted by native peoples, but only one of several commercial attempts at mining turned a profit there.[2] Another major native copper deposit is in Corocoro, Bolivia. The name copper comes from the Greek kyprios, of Cyprus, the location of copper mines since pre-historic times.[3]	https://www.wikidoc.org/index.php/Native_Copper
fe4e77392f7792882e176294795b7cbe9c33775c	wikidoc	Naxos disease	Naxos disease # Overview Naxos disease is an autosomal recessive variant of ARVD, described initially on the Greek island of Naxos. There, the penetrance is >90%. It involves the gene that codes for plakoglobin (a protein that is involved in cellular adhesion), on chromosome 17p. Naxos disease is described as a triad of ARVD, palmoplantar keratosis, and wooly hair. The signs of Naxos disease are more severe than with autosomal dominant ARVD.	Naxos disease Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Naxos disease is an autosomal recessive variant of ARVD, described initially on the Greek island of Naxos. There, the penetrance is >90%. It involves the gene that codes for plakoglobin (a protein that is involved in cellular adhesion), on chromosome 17p. Naxos disease is described as a triad of ARVD, palmoplantar keratosis, and wooly hair. The signs of Naxos disease are more severe than with autosomal dominant ARVD.	https://www.wikidoc.org/index.php/Naxos_disease
7d93bfc17f67918884fda453f7369842b45fd8f5	wikidoc	Pentobarbital	Pentobarbital # 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 Pentobarbital is a sedative hypnotic and anticonvulsant that is FDA approved for the treatment of insomnia and acute convulsive episodes. Common adverse reactions include confusion, dizziness, somnolence, and agitation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Sedatives - Hypnotics, for the short-term treatment of insomnia, since they appear to lose their effectiveness for sleep induction and sleep maintenance after 2 weeks. - Preanesthetics - Anticonvulsant, in anesthetic doses, in the emergency control of certain acute convulsive episodes, e.g., those associated with status epilepticus, cholera, eclampsia, meningitis, tetanus, and toxic reactions to strychnine or local anesthetics. - Dosages of barbiturates must be individualized with full knowledge of their particular characteristics and recommended rate of administration. Factors of consideration are the patient's age, weight, and condition. Parenteral routes should be used only when oral administration is impossible or impractical. - Intramuscular Administration: IM injection of the sodium salts of barbiturates should be made deeply into a large muscle, and a volume of 5 mL should not be exceeded at any one site because of possible tissue irritation. After IM injection of a hypnotic dose, the patient's vital signs should be monitored. The usual adult dosage of NEMBUTAL Sodium Solution is 150 to 200 mg as a single IM injection; the recommended pediatric dosage ranges from 2 to 6 mg/kg as a single IM injection not to exceed 100 mg. - Intravenous Administration: NEMBUTAL Sodium Solution should not be admixed with any other medication or solution. IV injection is restricted to conditions in which other routes are not feasible, either because the patient is unconscious (as in cerebral hemorrhage, eclampsia, or status epilepticus), or because the patient resists (as in delirium), or because prompt action is imperative. Slow IV injection is essential, and patients should be carefully observed during administration. This requires that blood pressure, respiration, and cardiac function be maintained, vital signs be recorded, and equipment for resuscitation and artificial ventilation be available. The rate of IV injection should not exceed 50 mg/min for pentobarbital sodium. - There is no average intravenous dose of NEMBUTAL Sodium Solution (pentobarbital sodium injection) that can be relied on to produce similar effects in different patients. The possibility of overdose and respiratory depression is remote when the drug is injected slowly in fractional doses. - A commonly used initial dose for the 70 kg adult is 100 mg. Proportional reduction in dosage should be made for pediatric or debilitated patients. At least one minute is necessary to determine the full effect of intravenous pentobarbital. If necessary, additional small increments of the drug may be given up to a total of from 200 to 500 mg for normal adults. - Anticonvulsant use: In convulsive states, dosage of NEMBUTAL Sodium Solution should be kept to a minimum to avoid compounding the depression which may follow convulsions. The injection must be made slowly with due regard to the time required for the drug to penetrate the blood-brain barrier. - Special patient population: Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease. - Inspection: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution containers permit. Solutions for injection showing evidence of precipitation should not be used. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pentobarbital in adult patients. ### Non–Guideline-Supported Use - Dosing Information - A loading dose of 10 milligrams/kilogram (mg/kg) over 30 minutes then 5 mg/kg every hour times 3 doses followed by a maintenance infusion of 1 mg/kg/hour has been recommended. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) No adequate well-controlled studies have been conducted in pediatric patients; however, safety and effectiveness of pentobarbital in pediatric patients is supported by numerous studies and case reports cited in the literature. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pentobarbital in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentobarbital in pediatric patients. # Contraindications Barbiturates are contraindicated in patients with known barbiturate sensitivity. Barbiturates are also contraindicated in patients with a history of manifest or latent porphyria. # Warnings - Barbiturates may be habit forming. Tolerance, psychological and physical dependence may occur with continued use. Patients who have psychological dependence on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. To minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in the dependent person may result in withdrawal symptoms, including delirium, convulsions, and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive dosage over long periods of time. - Too rapid administration may cause respiratory depression, apnea, laryngospasm, or vasodilation with fall in blood pressure. - Caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. However, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established. - Barbiturates can cause fetal damage when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Following oral or parenteral administration, barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver, and brain. Fetal blood levels approach maternal blood levels following parenteral administration. - Withdrawal symptoms occur in infants born to mothers who receive barbiturates throughout the last trimester of pregnancy. 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 hazard to the fetus. The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects. # Adverse Reactions ## Clinical Trials Experience - Somnolence - Agitation - Confusion - Hyperkinesia - Ataxia - CNS depression - Nightmares - Nervousness - Psychiatric disturbance - Hallucinations - Insomnia - Anxiety - Dizziness - Thinking abnormality - Bradycardia - Hypotension - Syncope - Hypoventilation - Apnea - Nausea - Vomiting - Constipation - Headache - Injection site reactions - Hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic phenobarbital use ## Postmarketing Experience There is limited information regarding postmarketing experience of Pentobarbital in the drug label. # Drug Interactions - Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital. However, the application of these data to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies. - Anticoagulants: Phenobarbital lowers the plasma levels of dicumarol (name previously used: bishydroxycoumarin) and causes a decrease in anticoagulant activity as measured by the prothrombin time. Barbiturates can induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response of oral anticoagulants (e.g., warfarin, acenocoumarol, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. - Corticosteroids: Barbiturates appear to enhance the metabolism of exogenous corticosteroids probably through the induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. - Griseofulvin: Phenobarbital appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. The effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. However, it would be preferable to avoid concomitant administration of these drugs. - Doxycycline: Phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. This mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. If phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. - Phenytoin, sodium valproate, valproic acid: The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, while others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. - Central nervous system depressants: The concomitant use of other central nervous system depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects. - Monoamine oxidase inhibitors (MAOI): MAOI prolong the effects of barbiturates probably because metabolism of the barbiturate is inhibited. - Estradiol, estrone, progesterone and other steroidal hormones: Pretreatment with or concurrent administration of phenobarbital may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who became pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking phenobarbital. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Barbiturates can cause fetal damage when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Following oral or parenteral administration, barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver, and brain. Fetal blood levels approach maternal blood levels following parenteral administration. - Withdrawal symptoms occur in infants born to mothers who receive barbiturates throughout the last trimester of pregnancy. 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 hazard to the fetus. - Reports of infants suffering from long-term barbiturate exposure in utero included the acute withdrawal syndrome of seizures and hyperirritability from birth to a delayed onset of up to 14 days. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentobarbital in women who are pregnant. ### Labor and Delivery - Hypnotic doses of these barbiturates do not appear to significantly impair uterine activity during labor. Full anesthetic doses of barbiturates decrease the force and frequency of uterine contractions. Administration of sedative-hypnotic barbiturates to the mother during labor may result in respiratory depression in the newborn. Premature infants are particularly susceptible to the depressant effects of barbiturates. If barbiturates are used during labor and delivery, resuscitation equipment should be available. - Data are currently not available to evaluate the effect of these barbiturates when forceps delivery or other intervention is necessary. Also, data are not available to determine the effect of these barbiturates on the later growth, development, and functional maturation of the child. ### Nursing Mothers - Caution should be exercised when a barbiturate is administered to a nursing woman since small amounts of barbiturates are excreted in the milk. ### Pediatric Use - No adequate well-controlled studies have been conducted in pediatric patients; however, safety and effectiveness of pentobarbital in pediatric patients is supported by numerous studies and case reports cited in the literature. ### Geriatic Use - Clinical studies of Nembutal have not included sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - Elderly patients may react to barbiturates with marked excitement, depression, and confusion. In some persons, barbiturates repeatedly produce excitement rather than depression. Dosage should be reduced in the elderly because these patients may be more sensitive to barbiturates. ### Gender There is no FDA guidance on the use of Pentobarbital with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pentobarbital with respect to specific race populations. ### Renal Impairment There is no FDA guidance on the use of Pentobarbital with respect to specific renal impairment populations. ### Hepatic Impairment There is no FDA guidance on the use of Pentobarbital with respect to specific hepatic impairment populations. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pentobarbital in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pentobarbital in patients who are immunocompromised. ### Others # Administration and Monitoring ### Administration - Intravenous - Intramuscular ### Monitoring - If phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. - The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, while others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. - After IM injection of a hypnotic dose, the patient's vital signs should be monitored. # IV Compatibility There is limited information regarding IV Compatibility of Pentobarbital in the drug label. # Overdosage - The toxic dose of barbiturates varies considerably. In general, an oral dose of 1 gram of most barbiturates produces serious poisoning in an adult. Death commonly occurs after 2 to 10 grams of ingested barbiturate. Barbiturate intoxication may be confused with alcoholism, bromide intoxication, and with various neurological disorders. - Acute overdosage with barbiturates is manifested by CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may show paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur. In extreme overdose, all electrical activity in the brain may cease, in which case a “flat” EEG normally equated with clinical death cannot be accepted. This effect is fully reversible unless hypoxic damage occurs. Consideration should be given to the possibility of barbiturate intoxication even in situations that appear to involve trauma. - Complications such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur. Uremia may increase CNS sensitivity to barbiturates. Differential diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents, convulsive states, and diabetic coma. Blood levels from acute overdosage for some barbiturates are listed in Table 1. - Under the influence and appreciably impaired for purposes of driving a motor vehicle or performing tasks requiring alertness and unimpaired judgment and reaction time. - Sedated, therapeutic range, calm, relaxed, and easily aroused. - Comatose, difficult to arouse, significant depression of respiration. - Compatible with death in aged or ill persons or in presence of obstructed airway, other toxic agents, or exposure to cold. - Usual lethal level, the upper end of the range includes those who received some supportive treatment. - Treatment of overdosage is mainly supportive and consists of the following: - Maintenance of an adequate airway, with assisted respiration and oxygen administration as necessary. - Monitoring of vital signs and fluid balance. - Fluid therapy and other standard treatment for shock, if needed. - If renal function is normal, forced diuresis may aid in the elimination of the barbiturate. Alkalinization of the urine increases renal excretion of some barbiturates, especially phenobarbital, also aprobarbital and mephobarbital (which is metabolized to phenobarbital). - Although not recommended as a routine procedure, hemodialysis may be used in severe barbiturate intoxications or if the patient is anuric or in shock. - Patient should be rolled from side to side every 30 minutes. - Antibiotics should be given if pneumonia is suspected. - Appropriate nursing care to prevent hypostatic pneumonia, decubiti, aspiration, and other complications of patients with altered states of consciousness. # Pharmacology ## Mechanism of Action - Barbiturates are capable of producing all levels of CNS mood alteration from excitation to mild sedation, to hypnosis, and deep coma. Overdosage can produce death. In high enough therapeutic doses, barbiturates induce anesthesia. - Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. - Barbiturate-induced sleep differs from physiological sleep. Sleep laboratory studies have demonstrated that barbiturates reduce the amount of time spent in the rapid eye movement (REM) phase of sleep or dreaming stage. Also, Stages III and IV sleep are decreased. Following abrupt cessation of barbiturates used regularly, patients may experience markedly increased dreaming, nightmares, and/or insomnia. Therefore, withdrawal of a single therapeutic dose over 5 or 6 days has been recommended to lessen the REM rebound and disturbed sleep which contribute to drug withdrawal syndrome (for example, decrease the dose from 3 to 2 doses a day for 1 week). - In studies, secobarbital sodium and pentobarbital sodium have been found to lose most of their effectiveness for both inducing and maintaining sleep by the end of 2 weeks of continued drug administration at fixed doses. The short-, intermediate-, and, to a lesser degree, long-acting barbiturates have been widely prescribed for treating insomnia. Although the clinical literature abounds with claims that the short-acting barbiturates are superior for producing sleep while the intermediate-acting compounds are more effective in maintaining sleep, controlled studies have failed to demonstrate these differential effects. Therefore, as sleep medications, the barbiturates are of limited value beyond short-term use. - Barbiturates have little analgesic action at subanesthetic doses. Rather, in subanesthetic doses these drugs may increase the reaction to painful stimuli. All barbiturates exhibit anticonvulsant activity in anesthetic doses. However, of the drugs in this class, only phenobarbital, mephobarbital, and metharbital have been clinically demonstrated to be effective as oral anticonvulsants in subhypnotic doses. - Barbiturates are respiratory depressants. The degree of respiratory depression is dependent upon dose. With hypnotic doses, respiratory depression produced by barbiturates is similar to that which occurs during physiologic sleep with slight decrease in blood pressure and heart rate. - Studies in laboratory animals have shown that barbiturates cause reduction in the tone and contractility of the uterus, ureters, and urinary bladder. However, concentrations of the drugs required to produce this effect in humans are not reached with sedative-hypnotic doses. - Barbiturates do not impair normal hepatic function, but have been shown to induce liver microsomal enzymes, thus increasing and/or altering the metabolism of barbiturates and other drugs. ## Structure - The barbiturates are nonselective central nervous system depressants which are primarily used as sedative hypnotics and also anticonvulsants in subhypnotic doses. The barbiturates and their sodium salts are subject to control under the Federal Controlled Substances Act. The sodium salts of amobarbital, pentobarbital, phenobarbital, and secobarbital are available as sterile parenteral solutions. - Barbiturates are substituted pyrimidine derivatives in which the basic structure common to these drugs is barbituric acid, a substance which has no central nervous system (CNS) activity. CNS activity is obtained by substituting alkyl, alkenyl, or aryl groups on the pyrimidine ring. - NEMBUTAL Sodium Solution (pentobarbital sodium injection) is a sterile solution for intravenous or intramuscular injection. Each mL contains pentobarbital sodium 50 mg, in a vehicle of propylene glycol, 40%, alcohol, 10% and water for injection, to volume. The pH is adjusted to approximately 9.5 with hydrochloric acid and/or sodium hydroxide. - NEMBUTAL Sodium is a short-acting barbiturate, chemically designated as sodium 5-ethyl-5-(1-methylbutyl) barbiturate. The structural formula for pentobarbital sodium is: - The sodium salt occurs as a white, slightly bitter powder which is freely soluble in water and alcohol but practically insoluble in benzene and ether. ## Pharmacodynamics There is limited information regarding pharmacodynamics of Pentobarbital in the drug label. ## Pharmacokinetics - Barbiturates are absorbed in varying degrees following oral, rectal, or parenteral administration. The salts are more rapidly absorbed than are the acids. - The onset of action for oral or rectal administration varies from 20 to 60 minutes. For IM administration, the onset of action is slightly faster. Following IV administration, the onset of action ranges from almost immediately for pentobarbital sodium to 5 minutes for phenobarbital sodium. Maximal CNS depression may not occur until 15 minutes or more after IV administration for phenobarbital sodium. - Duration of action, which is related to the rate at which the barbiturates are redistributed throughout the body, varies among persons and in the same person from time to time. - No studies have demonstrated that the different routes of administration are equivalent with respect to bioavailability. - Barbiturates are weak acids that are absorbed and rapidly distributed to all tissues and fluids with high concentrations in the brain, liver, and kidneys. Lipid solubility of the barbiturates is the dominant factor in their distribution within the body. The more lipid soluble the barbiturate, the more rapidly it penetrates all tissues of the body. Barbiturates are bound to plasma and tissue proteins to a varying degree with the degree of binding increasing directly as a function of lipid solubility. - Phenobarbital has the lowest lipid solubility, lowest plasma binding, lowest brain protein binding, the longest delay in onset of activity, and the longest duration of action. At the opposite extreme is secobarbital which has the highest lipid solubility, plasma protein binding, brain protein binding, the shortest delay in onset of activity, and the shortest duration of action. Butabarbital is classified as an intermediate barbiturate. - The plasma half-life for pentobarbital in adults is 15 to 50 hours and appears to be dose dependent. - Barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine, and less commonly, in the feces. Approximately 25 to 50 percent of a dose of aprobarbital or phenobarbital is eliminated unchanged in the urine, whereas the amount of other barbiturates excreted unchanged in the urine is negligible. The excretion of unmetabolized barbiturate is one feature that distinguishes the long-acting category from those belonging to other categories which are almost entirely metabolized. The inactive metabolites of the barbiturates are excreted as conjugates of glucuronic acid. ## Nonclinical Toxicology There is limited information regarding nonclinical toxicology of Pentobarbital in the drug label. # Clinical Studies There is limited information regarding clinical studies of Pentobarbital in the drug label. # How Supplied - NEMBUTAL Sodium Solution (pentobarbital sodium injection, USP) is available in the following sizes: 20-mL multiple-dose vial, 1 g per vial (NDC 76478-501-20); and 50-mL multiple-dose vial, 2.5 g per vial (NDC 76478-501-50). - Each mL contains: - Vial stoppers are latex free. ## Storage - Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at 20°-25°C (68°-77°F), however, brief excursions are permitted between 15°-30°C (59°-86°F). See USP controlled room temperature. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Pentobarbital in the drug label. # Precautions with Alcohol The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects. # Brand Names - Nembutal # Look-Alike Drug Names - PENTobarbital - PHENobarbital sodium # Drug Shortage Status # Price	Pentobarbital 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 Pentobarbital is a sedative hypnotic and anticonvulsant that is FDA approved for the treatment of insomnia and acute convulsive episodes. Common adverse reactions include confusion, dizziness, somnolence, and agitation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Sedatives - Hypnotics, for the short-term treatment of insomnia, since they appear to lose their effectiveness for sleep induction and sleep maintenance after 2 weeks. - Preanesthetics - Anticonvulsant, in anesthetic doses, in the emergency control of certain acute convulsive episodes, e.g., those associated with status epilepticus, cholera, eclampsia, meningitis, tetanus, and toxic reactions to strychnine or local anesthetics. - Dosages of barbiturates must be individualized with full knowledge of their particular characteristics and recommended rate of administration. Factors of consideration are the patient's age, weight, and condition. Parenteral routes should be used only when oral administration is impossible or impractical. - Intramuscular Administration: IM injection of the sodium salts of barbiturates should be made deeply into a large muscle, and a volume of 5 mL should not be exceeded at any one site because of possible tissue irritation. After IM injection of a hypnotic dose, the patient's vital signs should be monitored. The usual adult dosage of NEMBUTAL Sodium Solution is 150 to 200 mg as a single IM injection; the recommended pediatric dosage ranges from 2 to 6 mg/kg as a single IM injection not to exceed 100 mg. - Intravenous Administration: NEMBUTAL Sodium Solution should not be admixed with any other medication or solution. IV injection is restricted to conditions in which other routes are not feasible, either because the patient is unconscious (as in cerebral hemorrhage, eclampsia, or status epilepticus), or because the patient resists (as in delirium), or because prompt action is imperative. Slow IV injection is essential, and patients should be carefully observed during administration. This requires that blood pressure, respiration, and cardiac function be maintained, vital signs be recorded, and equipment for resuscitation and artificial ventilation be available. The rate of IV injection should not exceed 50 mg/min for pentobarbital sodium. - There is no average intravenous dose of NEMBUTAL Sodium Solution (pentobarbital sodium injection) that can be relied on to produce similar effects in different patients. The possibility of overdose and respiratory depression is remote when the drug is injected slowly in fractional doses. - A commonly used initial dose for the 70 kg adult is 100 mg. Proportional reduction in dosage should be made for pediatric or debilitated patients. At least one minute is necessary to determine the full effect of intravenous pentobarbital. If necessary, additional small increments of the drug may be given up to a total of from 200 to 500 mg for normal adults. - Anticonvulsant use: In convulsive states, dosage of NEMBUTAL Sodium Solution should be kept to a minimum to avoid compounding the depression which may follow convulsions. The injection must be made slowly with due regard to the time required for the drug to penetrate the blood-brain barrier. - Special patient population: Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease. - Inspection: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution containers permit. Solutions for injection showing evidence of precipitation should not be used. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pentobarbital in adult patients. ### Non–Guideline-Supported Use - Dosing Information - A loading dose of 10 milligrams/kilogram (mg/kg) over 30 minutes then 5 mg/kg every hour times 3 doses followed by a maintenance infusion of 1 mg/kg/hour has been recommended.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) No adequate well-controlled studies have been conducted in pediatric patients; however, safety and effectiveness of pentobarbital in pediatric patients is supported by numerous studies and case reports cited in the literature. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pentobarbital in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentobarbital in pediatric patients. # Contraindications Barbiturates are contraindicated in patients with known barbiturate sensitivity. Barbiturates are also contraindicated in patients with a history of manifest or latent porphyria. # Warnings - Barbiturates may be habit forming. Tolerance, psychological and physical dependence may occur with continued use. Patients who have psychological dependence on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. To minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in the dependent person may result in withdrawal symptoms, including delirium, convulsions, and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive dosage over long periods of time. - Too rapid administration may cause respiratory depression, apnea, laryngospasm, or vasodilation with fall in blood pressure. - Caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. However, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established. - Barbiturates can cause fetal damage when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Following oral or parenteral administration, barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver, and brain. Fetal blood levels approach maternal blood levels following parenteral administration. - Withdrawal symptoms occur in infants born to mothers who receive barbiturates throughout the last trimester of pregnancy. 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 hazard to the fetus. The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects. # Adverse Reactions ## Clinical Trials Experience - Somnolence - Agitation - Confusion - Hyperkinesia - Ataxia - CNS depression - Nightmares - Nervousness - Psychiatric disturbance - Hallucinations - Insomnia - Anxiety - Dizziness - Thinking abnormality - Bradycardia - Hypotension - Syncope - Hypoventilation - Apnea - Nausea - Vomiting - Constipation - Headache - Injection site reactions - Hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic phenobarbital use ## Postmarketing Experience There is limited information regarding postmarketing experience of Pentobarbital in the drug label. # Drug Interactions - Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital. However, the application of these data to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies. - Anticoagulants: Phenobarbital lowers the plasma levels of dicumarol (name previously used: bishydroxycoumarin) and causes a decrease in anticoagulant activity as measured by the prothrombin time. Barbiturates can induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response of oral anticoagulants (e.g., warfarin, acenocoumarol, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. - Corticosteroids: Barbiturates appear to enhance the metabolism of exogenous corticosteroids probably through the induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. - Griseofulvin: Phenobarbital appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. The effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. However, it would be preferable to avoid concomitant administration of these drugs. - Doxycycline: Phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. This mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. If phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. - Phenytoin, sodium valproate, valproic acid: The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, while others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. - Central nervous system depressants: The concomitant use of other central nervous system depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects. - Monoamine oxidase inhibitors (MAOI): MAOI prolong the effects of barbiturates probably because metabolism of the barbiturate is inhibited. - Estradiol, estrone, progesterone and other steroidal hormones: Pretreatment with or concurrent administration of phenobarbital may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who became pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking phenobarbital. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Barbiturates can cause fetal damage when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Following oral or parenteral administration, barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver, and brain. Fetal blood levels approach maternal blood levels following parenteral administration. - Withdrawal symptoms occur in infants born to mothers who receive barbiturates throughout the last trimester of pregnancy. 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 hazard to the fetus. - Reports of infants suffering from long-term barbiturate exposure in utero included the acute withdrawal syndrome of seizures and hyperirritability from birth to a delayed onset of up to 14 days. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentobarbital in women who are pregnant. ### Labor and Delivery - Hypnotic doses of these barbiturates do not appear to significantly impair uterine activity during labor. Full anesthetic doses of barbiturates decrease the force and frequency of uterine contractions. Administration of sedative-hypnotic barbiturates to the mother during labor may result in respiratory depression in the newborn. Premature infants are particularly susceptible to the depressant effects of barbiturates. If barbiturates are used during labor and delivery, resuscitation equipment should be available. - Data are currently not available to evaluate the effect of these barbiturates when forceps delivery or other intervention is necessary. Also, data are not available to determine the effect of these barbiturates on the later growth, development, and functional maturation of the child. ### Nursing Mothers - Caution should be exercised when a barbiturate is administered to a nursing woman since small amounts of barbiturates are excreted in the milk. ### Pediatric Use - No adequate well-controlled studies have been conducted in pediatric patients; however, safety and effectiveness of pentobarbital in pediatric patients is supported by numerous studies and case reports cited in the literature. ### Geriatic Use - Clinical studies of Nembutal have not included sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - Elderly patients may react to barbiturates with marked excitement, depression, and confusion. In some persons, barbiturates repeatedly produce excitement rather than depression. Dosage should be reduced in the elderly because these patients may be more sensitive to barbiturates. ### Gender There is no FDA guidance on the use of Pentobarbital with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pentobarbital with respect to specific race populations. ### Renal Impairment There is no FDA guidance on the use of Pentobarbital with respect to specific renal impairment populations. ### Hepatic Impairment There is no FDA guidance on the use of Pentobarbital with respect to specific hepatic impairment populations. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pentobarbital in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pentobarbital in patients who are immunocompromised. ### Others # Administration and Monitoring ### Administration - Intravenous - Intramuscular ### Monitoring - If phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. - The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, while others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. - After IM injection of a hypnotic dose, the patient's vital signs should be monitored. # IV Compatibility There is limited information regarding IV Compatibility of Pentobarbital in the drug label. # Overdosage - The toxic dose of barbiturates varies considerably. In general, an oral dose of 1 gram of most barbiturates produces serious poisoning in an adult. Death commonly occurs after 2 to 10 grams of ingested barbiturate. Barbiturate intoxication may be confused with alcoholism, bromide intoxication, and with various neurological disorders. - Acute overdosage with barbiturates is manifested by CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may show paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur. In extreme overdose, all electrical activity in the brain may cease, in which case a “flat” EEG normally equated with clinical death cannot be accepted. This effect is fully reversible unless hypoxic damage occurs. Consideration should be given to the possibility of barbiturate intoxication even in situations that appear to involve trauma. - Complications such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur. Uremia may increase CNS sensitivity to barbiturates. Differential diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents, convulsive states, and diabetic coma. Blood levels from acute overdosage for some barbiturates are listed in Table 1. - Under the influence and appreciably impaired for purposes of driving a motor vehicle or performing tasks requiring alertness and unimpaired judgment and reaction time. - Sedated, therapeutic range, calm, relaxed, and easily aroused. - Comatose, difficult to arouse, significant depression of respiration. - Compatible with death in aged or ill persons or in presence of obstructed airway, other toxic agents, or exposure to cold. - Usual lethal level, the upper end of the range includes those who received some supportive treatment. - Treatment of overdosage is mainly supportive and consists of the following: - Maintenance of an adequate airway, with assisted respiration and oxygen administration as necessary. - Monitoring of vital signs and fluid balance. - Fluid therapy and other standard treatment for shock, if needed. - If renal function is normal, forced diuresis may aid in the elimination of the barbiturate. Alkalinization of the urine increases renal excretion of some barbiturates, especially phenobarbital, also aprobarbital and mephobarbital (which is metabolized to phenobarbital). - Although not recommended as a routine procedure, hemodialysis may be used in severe barbiturate intoxications or if the patient is anuric or in shock. - Patient should be rolled from side to side every 30 minutes. - Antibiotics should be given if pneumonia is suspected. - Appropriate nursing care to prevent hypostatic pneumonia, decubiti, aspiration, and other complications of patients with altered states of consciousness. # Pharmacology ## Mechanism of Action - Barbiturates are capable of producing all levels of CNS mood alteration from excitation to mild sedation, to hypnosis, and deep coma. Overdosage can produce death. In high enough therapeutic doses, barbiturates induce anesthesia. - Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. - Barbiturate-induced sleep differs from physiological sleep. Sleep laboratory studies have demonstrated that barbiturates reduce the amount of time spent in the rapid eye movement (REM) phase of sleep or dreaming stage. Also, Stages III and IV sleep are decreased. Following abrupt cessation of barbiturates used regularly, patients may experience markedly increased dreaming, nightmares, and/or insomnia. Therefore, withdrawal of a single therapeutic dose over 5 or 6 days has been recommended to lessen the REM rebound and disturbed sleep which contribute to drug withdrawal syndrome (for example, decrease the dose from 3 to 2 doses a day for 1 week). - In studies, secobarbital sodium and pentobarbital sodium have been found to lose most of their effectiveness for both inducing and maintaining sleep by the end of 2 weeks of continued drug administration at fixed doses. The short-, intermediate-, and, to a lesser degree, long-acting barbiturates have been widely prescribed for treating insomnia. Although the clinical literature abounds with claims that the short-acting barbiturates are superior for producing sleep while the intermediate-acting compounds are more effective in maintaining sleep, controlled studies have failed to demonstrate these differential effects. Therefore, as sleep medications, the barbiturates are of limited value beyond short-term use. - Barbiturates have little analgesic action at subanesthetic doses. Rather, in subanesthetic doses these drugs may increase the reaction to painful stimuli. All barbiturates exhibit anticonvulsant activity in anesthetic doses. However, of the drugs in this class, only phenobarbital, mephobarbital, and metharbital have been clinically demonstrated to be effective as oral anticonvulsants in subhypnotic doses. - Barbiturates are respiratory depressants. The degree of respiratory depression is dependent upon dose. With hypnotic doses, respiratory depression produced by barbiturates is similar to that which occurs during physiologic sleep with slight decrease in blood pressure and heart rate. - Studies in laboratory animals have shown that barbiturates cause reduction in the tone and contractility of the uterus, ureters, and urinary bladder. However, concentrations of the drugs required to produce this effect in humans are not reached with sedative-hypnotic doses. - Barbiturates do not impair normal hepatic function, but have been shown to induce liver microsomal enzymes, thus increasing and/or altering the metabolism of barbiturates and other drugs. ## Structure - The barbiturates are nonselective central nervous system depressants which are primarily used as sedative hypnotics and also anticonvulsants in subhypnotic doses. The barbiturates and their sodium salts are subject to control under the Federal Controlled Substances Act. The sodium salts of amobarbital, pentobarbital, phenobarbital, and secobarbital are available as sterile parenteral solutions. - Barbiturates are substituted pyrimidine derivatives in which the basic structure common to these drugs is barbituric acid, a substance which has no central nervous system (CNS) activity. CNS activity is obtained by substituting alkyl, alkenyl, or aryl groups on the pyrimidine ring. - NEMBUTAL Sodium Solution (pentobarbital sodium injection) is a sterile solution for intravenous or intramuscular injection. Each mL contains pentobarbital sodium 50 mg, in a vehicle of propylene glycol, 40%, alcohol, 10% and water for injection, to volume. The pH is adjusted to approximately 9.5 with hydrochloric acid and/or sodium hydroxide. - NEMBUTAL Sodium is a short-acting barbiturate, chemically designated as sodium 5-ethyl-5-(1-methylbutyl) barbiturate. The structural formula for pentobarbital sodium is: - The sodium salt occurs as a white, slightly bitter powder which is freely soluble in water and alcohol but practically insoluble in benzene and ether. ## Pharmacodynamics There is limited information regarding pharmacodynamics of Pentobarbital in the drug label. ## Pharmacokinetics - Barbiturates are absorbed in varying degrees following oral, rectal, or parenteral administration. The salts are more rapidly absorbed than are the acids. - The onset of action for oral or rectal administration varies from 20 to 60 minutes. For IM administration, the onset of action is slightly faster. Following IV administration, the onset of action ranges from almost immediately for pentobarbital sodium to 5 minutes for phenobarbital sodium. Maximal CNS depression may not occur until 15 minutes or more after IV administration for phenobarbital sodium. - Duration of action, which is related to the rate at which the barbiturates are redistributed throughout the body, varies among persons and in the same person from time to time. - No studies have demonstrated that the different routes of administration are equivalent with respect to bioavailability. - Barbiturates are weak acids that are absorbed and rapidly distributed to all tissues and fluids with high concentrations in the brain, liver, and kidneys. Lipid solubility of the barbiturates is the dominant factor in their distribution within the body. The more lipid soluble the barbiturate, the more rapidly it penetrates all tissues of the body. Barbiturates are bound to plasma and tissue proteins to a varying degree with the degree of binding increasing directly as a function of lipid solubility. - Phenobarbital has the lowest lipid solubility, lowest plasma binding, lowest brain protein binding, the longest delay in onset of activity, and the longest duration of action. At the opposite extreme is secobarbital which has the highest lipid solubility, plasma protein binding, brain protein binding, the shortest delay in onset of activity, and the shortest duration of action. Butabarbital is classified as an intermediate barbiturate. - The plasma half-life for pentobarbital in adults is 15 to 50 hours and appears to be dose dependent. - Barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine, and less commonly, in the feces. Approximately 25 to 50 percent of a dose of aprobarbital or phenobarbital is eliminated unchanged in the urine, whereas the amount of other barbiturates excreted unchanged in the urine is negligible. The excretion of unmetabolized barbiturate is one feature that distinguishes the long-acting category from those belonging to other categories which are almost entirely metabolized. The inactive metabolites of the barbiturates are excreted as conjugates of glucuronic acid. ## Nonclinical Toxicology There is limited information regarding nonclinical toxicology of Pentobarbital in the drug label. # Clinical Studies There is limited information regarding clinical studies of Pentobarbital in the drug label. # How Supplied - NEMBUTAL Sodium Solution (pentobarbital sodium injection, USP) is available in the following sizes: 20-mL multiple-dose vial, 1 g per vial (NDC 76478-501-20); and 50-mL multiple-dose vial, 2.5 g per vial (NDC 76478-501-50). - Each mL contains: - Vial stoppers are latex free. ## Storage - Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at 20°-25°C (68°-77°F), however, brief excursions are permitted between 15°-30°C (59°-86°F). See USP controlled room temperature. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Pentobarbital in the drug label. # Precautions with Alcohol The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects. # Brand Names - Nembutal # Look-Alike Drug Names - PENTobarbital - PHENobarbital sodium # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Nembutal
5c3d20fe20050d1b91d254c89733b26a5814ced9	wikidoc	Nepetalactone	Nepetalactone Nepetalactone is a lactone chemical compound first isolated in the plant catnip, Nepeta cataria (apparently named after the Italian town of Nepete). It was first isolated in 1941 using steam distillation. Nepetalactone's structure is two rings – a cyclopentane and a cyclic ester, making a terpenoid. Its empirical formula is C10H14O2. The structure and the effect of the compound is similar to valepotriates. There are a number of isomers of nepetalactone. As 4aα,7α,7aα-nepetalactone it is the active chemical in Nepeta cataria that causes its characteristic effect on cats. Around 75% of cats are affected; susceptibility is gene-linked. The chemical interacts as a vapour at the olfactory epithelium. In humans, the compound has a number of very mild effects; it is a weak sedative, antispasmodic, febrifuge and antibacterial. In high doses it also has an emetic effect. It also has an effect on some insects, repelling the cockroach and mosquito, poisonous to some common flies, but a sex pheromone to aphids.	Nepetalactone Template:Chembox new Nepetalactone is a lactone chemical compound first isolated in the plant catnip, Nepeta cataria (apparently named after the Italian town of Nepete). It was first isolated in 1941 using steam distillation.[1] Nepetalactone's structure is two rings – a cyclopentane and a cyclic ester, making a terpenoid. Its empirical formula is C10H14O2. The structure and the effect of the compound is similar to valepotriates. There are a number of isomers of nepetalactone. As 4aα,7α,7aα-nepetalactone it is the active chemical in Nepeta cataria that causes its characteristic effect on cats. Around 75% of cats are affected; susceptibility is gene-linked. The chemical interacts as a vapour at the olfactory epithelium. In humans, the compound has a number of very mild effects; it is a weak sedative, antispasmodic, febrifuge and antibacterial. In high doses it also has an emetic effect. It also has an effect on some insects, repelling the cockroach and mosquito, poisonous to some common flies, but a sex pheromone to aphids.	https://www.wikidoc.org/index.php/Nepetalactone
4a3c01b3c50f88ecce85d1b493151b2f7a6eaac3	wikidoc	S-100 protein	S-100 protein S-100 protein is a type of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix ("EF-hand type") conformation. There are at least 21 different types of S100 proteins. The name is derived from the fact that the protein is 100% Soluble in ammonium sulfate at neutral pH. # Structure Most S100 proteins are homodimeric, consisting of two identical polypeptides held together by non-covalent bonds. Although S100 proteins are structurally similar to calmodulin, they differ in that they are cell-specific, expressed in particular cells at different levels depending on environmental factors. To contrast, calmodulin is a ubiquitous and universal intracellular Ca++ receptor widely expressed in many cells. # Normal function S-100 is normally present in cells derived from the neural crest (Schwann cells, melanocytes, and glial cells), chondrocytes, adipocytes, myoepithelial cells, macrophages, Langerhans cells, dendritic cells, and keratinocytes. It may be present in some breast epithelial cells. S100 proteins have been implicated in a variety of intracellular and extracellular functions. S100 proteins are involved in regulation of protein phosphorylation, transcription factors, Ca++ homeostasis, the dynamics of cytoskeleton constituents, enzyme activities, cell growth and differentiation, and the inflammatory response. # Pathology Several members of the S-100 protein family are useful as markers for certain tumors and epidermal differentiation. It can be found in melanomas, 50% of malignant peripheral nerve sheath tumors, and clear cell sarcomas. S100 proteins have been used in the lab as cell markers for anatomic pathology.	S-100 protein S-100 protein is a type of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix ("EF-hand type") conformation. There are at least 21 different types of S100 proteins. The name is derived from the fact that the protein is 100% Soluble in ammonium sulfate at neutral pH. # Structure Most S100 proteins are homodimeric, consisting of two identical polypeptides held together by non-covalent bonds. Although S100 proteins are structurally similar to calmodulin, they differ in that they are cell-specific, expressed in particular cells at different levels depending on environmental factors. To contrast, calmodulin is a ubiquitous and universal intracellular Ca++ receptor widely expressed in many cells. # Normal function S-100 is normally present in cells derived from the neural crest (Schwann cells, melanocytes, and glial cells), chondrocytes, adipocytes, myoepithelial cells, macrophages, Langerhans cells, dendritic cells, and keratinocytes. It may be present in some breast epithelial cells. S100 proteins have been implicated in a variety of intracellular and extracellular functions. S100 proteins are involved in regulation of protein phosphorylation, transcription factors, Ca++ homeostasis, the dynamics of cytoskeleton constituents, enzyme activities, cell growth and differentiation, and the inflammatory response. # Pathology Several members of the S-100 protein family are useful as markers for certain tumors and epidermal differentiation. It can be found in melanomas, 50% of malignant peripheral nerve sheath tumors, and clear cell sarcomas. S100 proteins have been used in the lab as cell markers for anatomic pathology.	https://www.wikidoc.org/index.php/Nerve_tissue_protein_S_100
2b6c11890d29055bd07392ada0938ac2388f152c	wikidoc	Neurofilament	Neurofilament Neurofilaments (NF) are intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring approximately 10 nm in diameter and many micrometers in length. Together with microtubules and microfilaments, they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into 6 classes based on their gene organization and protein structure. Class I and II are the keratins which are expressed in epithelia. Class III contains the proteins vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP). Note that the neuronal intermediate filament protein peripherin, which was named by Portier and colleagues in 1983, should not be confused with another protein of the same name (also known as peripherin-2 or peripherin-2/rds) that is expressed in the retina. Class IV consists of the neurofilament proteins L, M, H and internexin. Class V consists of the nuclear lamins, and Class VI consists of the protein nestin. The class IV intermediate filament genes all share two unique introns not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive class IV gene. The term neurofibril is an antiquated term that refers to the fibrous appearance of bundles of neurofilaments in nerve cells when observed in histologically stained tissue sections. # Neurofilament proteins The protein composition of neurofilaments varies widely across different animal phyla. Most is known about mammalian neurofilaments. Historically, mammalian neurofilaments were originally thought to be composed of just three proteins called neurofilament protein L (low molecular weight; NFL), M (medium molecular weight; NFM) and H (high molecular weight; NFH). These proteins were discovered from studies of axonal transport and are often referred to as the "neurofilament triplet". However, it is now clear that neurofilaments in the mammalian nervous system also contain the protein internexin and that neurofilaments in the peripheral nervous system can also contain the protein peripherin. Thus mammalian neurofilaments are heteropolymers of up to five different proteins: NFL, NFM, NFH, internexin and peripherin and it is incorrect to consider neurofilaments as being composed of just the neurofilament triplet proteins. Moreover, it is clear that the five neurofilament proteins can coassemble in different combinations and with variable stoichiometry in different nerve cell types and at different stages of development. The precise composition of neurofilaments in any given nerve cell depends on the relative expression levels of the neurofilament proteins in that cell at that time. For example, NFH expression is low in developing neurons and increases postnatally in neurons that are myelinated. In the adult nervous system neurofilaments in small unmyelinated axons contain more peripherin and less NFH whereas neurofilaments in large myelinated axons contain more NFH and less peripherin. The Class III intermediate filament subunit, vimentin, is expressed in developing neurons and a few very unusual neurons in the adult in association with Class IV proteins, such as the horizontal neurons of the retina. The triplet proteins are named based upon their relative size (low, medium, high). The apparent molecular mass of each protein determined by SDS-PAGE is greater than the mass predicted from the amino sequence. This is due to the anomalous electrophoretic migration of these proteins and is particularly extreme for neurofilament proteins M and H due to their high content of charged amino acids and extensive phosphorylation. All three neurofilament triplet proteins contain long stretches of polypeptide sequence rich in glutamic acid and lysine residues, and NF-M and especially NF-H also contain multiple tandemly repeated serine phosphorylation sites. These sites almost all contain the peptide lysine-serine-proline (KSP), and phosphorylation is normally found on axonal and not dendritic neurofilaments. Human NF-M has 13 of these KSP sites, while human NF-H is expressed from two alleles one of which produces 44 and the other 45 KSP repeats. # Neurofilament assembly and structure Like other intermediate filament proteins, the neurofilament proteins all share a common central alpha helical region, known as the rod domain because of its rod-like tertiary structure, flanked by amino terminal and carboxy terminal domains that are largely unstructured. The rod domains of two neurofilament proteins dimerize to form an alpha-helical coiled coil. Two dimers associate in a staggered antiparallel manner to form a tetramer. This tetramer is believed to be the basic subunit (i.e. building block) of the neurofilament. Tetramer subunits associate side-to-side to form unit-length filaments, which then anneal end-to-end to form the mature neurofilament polymer, but the precise organization of these subunits within the polymer is not known, largely because of the heterogeneous protein composition and the inability to crystallize neurofilaments or neurofilament proteins. Structural models generally assume eight tetramers (32 neurofilament polypeptides) in a filament cross-section, but measurements of linear mass density suggest that this can vary. The amino terminal domains of the neurofilament proteins contain numerous phosphorylation sites and appear to be important for subunit interactions during filament assembly. The carboxy terminal domains appear to be intrinsically disordered domains that lack alpha helix or beta sheet. The different sizes of the neurofilament proteins are largely due to differences in the length of the carboxy terminal domains. These domains are rich in acidic and basic amino acid residues. The carboxy terminal domains of NFM and NFH are the longest and are modified extensively by post-translational modifications such as phosphorylation and glycosylation in vivo. They project radially from the filament backbone to form a dense brush border of highly charged and unstructured domains analogous to the bristles on a bottle brush. These entropically flailing domains have been proposed to define a zone of exclusion around each filament, effectively spacing the filaments apart from their neighbors. In this way, the carboxy terminal projections maximize the space-filling properties of the neurofilament polymers. By electron microscopy, these domains appear as projections called sidearms that appear to contact neighboring filaments. # Neurofilament function Neurofilaments are found in vertebrate neurons in especially high concentrations in axons, where they are all aligned in parallel along the long axis of the axon forming a continuously overlapping array. They have been proposed to function as space-filling structures that increase axonal diameter. Their contribution to axon diameter is determined by the number of neurofilaments in the axon and their packing density. The number of neurofilaments in the axon is thought to be determined by neurofilament gene expression and axonal transport. The packing density of the filaments is determined by their side-arms which define the spacing between neighboring filaments. Phosphorylation of the sidearms is thought to increase their extensibility, increasing the spacing between neighboring filaments by the binding of divalent cations between the sidearms of adjacent filaments Early in development, axons are narrow processes that contain relatively few neurofilaments. Those axons that become myelinated accumulate more neurofilaments, which drives the expansion of their caliber. After an axon has grown and connected with its target cell, the diameter of the axon may increase as much as fivefold. This is caused by an increase in the number of neurofilaments exported from the nerve cell body as well as a slowing of their rate of transport. In mature myelinated axons, neurofilaments can be the single most abundant cytoplasmic structure and can occupy most of the axonal cross-sectional area. For example, a large myelinated axon may contain thousands of neurofilaments in one cross-section. Mutant mice with neurofilament abnormalities have phenotypes resembling amyotrophic lateral sclerosis. # Neurofilament transport In addition to their structural role in axons, neurofilaments are also cargoes of axonal transport. Most of the neurofilament proteins in axons are synthesized in the nerve cell body, where they rapidly assemble into neurofilament polymers within about 30 minutes. These assembled neurofilament polymers are transported along the axon on microtubule tracks powered by microtubule motor proteins. The filaments move bidirectionally, i.e. both towards the axon tip (anterograde) and towards the cell body (retrograde), but the net direction is anterograde. The filaments move at velocities of up to 8 µm/s on short time scales (seconds or minutes), with average velocities of approximately 1 µm/s. However, the average velocity on longer time scales (hours or days) is slow because the movements are very infrequent, consisting of brief sprints interrupted by long pauses. Thus on long time scales neurofilaments move in the slow component of axonal transport. # Clinical and research applications Numerous specific antibodies to neurofilament proteins have been developed and are commercially available. These antibodies can be used to detect neurofilament proteins in cells and tissues using immunofluorescence microscopy or immunohistochemistry. Such antibodies are widely used to identify neurons and their processes in histological sections and in tissue culture. The Class VI intermediate filament protein nestin is expressed in developing neurons and glia. Nestin is considered a marker of neuronal stem cells, and the presence of this protein is widely used to define neurogenesis. This protein is lost as development proceeds. Neurofilament antibodies are also commonly used in diagnostic neuropathology. Staining with these antibodies can distinguish neurons (positive for neurofilament proteins) from glia (negative for neurofilament proteins). There is also considerable clinical interest in the use of neurofilament proteins as biomarkers of axonal damage in neurodegenerative diseases. When neurons or axons degenerate, neurofilament proteins are released into the blood or cerebrospinal fluid. Immunoassays of neurofilament proteins in cerebrospinal fluid and plasma can thus serve as indicators of axonal damage in neurological disorders. NFL is a useful marker for disease monitoring in Amyotrophic Lateral Sclerosis, multiple sclerosis and more recently Huntington's disease.	Neurofilament Neurofilaments (NF) are intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring approximately 10 nm in diameter and many micrometers in length. Together with microtubules and microfilaments, they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into 6 classes based on their gene organization and protein structure. Class I and II are the keratins which are expressed in epithelia. Class III contains the proteins vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP). Note that the neuronal intermediate filament protein peripherin, which was named by Portier and colleagues in 1983,[1] should not be confused with another protein of the same name (also known as peripherin-2 or peripherin-2/rds) that is expressed in the retina. Class IV consists of the neurofilament proteins L, M, H and internexin. Class V consists of the nuclear lamins, and Class VI consists of the protein nestin. The class IV intermediate filament genes all share two unique introns not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive class IV gene. The term neurofibril is an antiquated term that refers to the fibrous appearance of bundles of neurofilaments in nerve cells when observed in histologically stained tissue sections.[2] # Neurofilament proteins The protein composition of neurofilaments varies widely across different animal phyla. Most is known about mammalian neurofilaments. Historically, mammalian neurofilaments were originally thought to be composed of just three proteins called neurofilament protein L (low molecular weight; NFL), M (medium molecular weight; NFM) and H (high molecular weight; NFH). These proteins were discovered from studies of axonal transport and are often referred to as the "neurofilament triplet".[3] However, it is now clear that neurofilaments in the mammalian nervous system also contain the protein internexin[4] and that neurofilaments in the peripheral nervous system can also contain the protein peripherin.[5] Thus mammalian neurofilaments are heteropolymers of up to five different proteins: NFL, NFM, NFH, internexin and peripherin and it is incorrect to consider neurofilaments as being composed of just the neurofilament triplet proteins. Moreover, it is clear that the five neurofilament proteins can coassemble in different combinations and with variable stoichiometry in different nerve cell types and at different stages of development. The precise composition of neurofilaments in any given nerve cell depends on the relative expression levels of the neurofilament proteins in that cell at that time. For example, NFH expression is low in developing neurons and increases postnatally in neurons that are myelinated.[6] In the adult nervous system neurofilaments in small unmyelinated axons contain more peripherin and less NFH whereas neurofilaments in large myelinated axons contain more NFH and less peripherin. The Class III intermediate filament subunit, vimentin, is expressed in developing neurons and a few very unusual neurons in the adult in association with Class IV proteins, such as the horizontal neurons of the retina. The triplet proteins are named based upon their relative size (low, medium, high). The apparent molecular mass of each protein determined by SDS-PAGE is greater than the mass predicted from the amino sequence. This is due to the anomalous electrophoretic migration of these proteins and is particularly extreme for neurofilament proteins M and H due to their high content of charged amino acids and extensive phosphorylation. All three neurofilament triplet proteins contain long stretches of polypeptide sequence rich in glutamic acid and lysine residues, and NF-M and especially NF-H also contain multiple tandemly repeated serine phosphorylation sites. These sites almost all contain the peptide lysine-serine-proline (KSP), and phosphorylation is normally found on axonal and not dendritic neurofilaments. Human NF-M has 13 of these KSP sites, while human NF-H is expressed from two alleles one of which produces 44 and the other 45 KSP repeats. # Neurofilament assembly and structure Like other intermediate filament proteins, the neurofilament proteins all share a common central alpha helical region, known as the rod domain because of its rod-like tertiary structure, flanked by amino terminal and carboxy terminal domains that are largely unstructured. The rod domains of two neurofilament proteins dimerize to form an alpha-helical coiled coil. Two dimers associate in a staggered antiparallel manner to form a tetramer. This tetramer is believed to be the basic subunit (i.e. building block) of the neurofilament. Tetramer subunits associate side-to-side to form unit-length filaments, which then anneal end-to-end to form the mature neurofilament polymer, but the precise organization of these subunits within the polymer is not known, largely because of the heterogeneous protein composition and the inability to crystallize neurofilaments or neurofilament proteins. Structural models generally assume eight tetramers (32 neurofilament polypeptides) in a filament cross-section, but measurements of linear mass density suggest that this can vary. The amino terminal domains of the neurofilament proteins contain numerous phosphorylation sites and appear to be important for subunit interactions during filament assembly. The carboxy terminal domains appear to be intrinsically disordered domains that lack alpha helix or beta sheet. The different sizes of the neurofilament proteins are largely due to differences in the length of the carboxy terminal domains. These domains are rich in acidic and basic amino acid residues. The carboxy terminal domains of NFM and NFH are the longest and are modified extensively by post-translational modifications such as phosphorylation and glycosylation in vivo. They project radially from the filament backbone to form a dense brush border of highly charged and unstructured domains analogous to the bristles on a bottle brush. These entropically flailing domains have been proposed to define a zone of exclusion around each filament, effectively spacing the filaments apart from their neighbors. In this way, the carboxy terminal projections maximize the space-filling properties of the neurofilament polymers. By electron microscopy, these domains appear as projections called sidearms that appear to contact neighboring filaments. # Neurofilament function Neurofilaments are found in vertebrate neurons in especially high concentrations in axons, where they are all aligned in parallel along the long axis of the axon forming a continuously overlapping array. They have been proposed to function as space-filling structures that increase axonal diameter. Their contribution to axon diameter is determined by the number of neurofilaments in the axon and their packing density. The number of neurofilaments in the axon is thought to be determined by neurofilament gene expression [7] and axonal transport. The packing density of the filaments is determined by their side-arms which define the spacing between neighboring filaments. Phosphorylation of the sidearms is thought to increase their extensibility, increasing the spacing between neighboring filaments [8] by the binding of divalent cations between the sidearms of adjacent filaments [9][10] Early in development, axons are narrow processes that contain relatively few neurofilaments. Those axons that become myelinated accumulate more neurofilaments, which drives the expansion of their caliber. After an axon has grown and connected with its target cell, the diameter of the axon may increase as much as fivefold[citation needed]. This is caused by an increase in the number of neurofilaments exported from the nerve cell body as well as a slowing of their rate of transport. In mature myelinated axons, neurofilaments can be the single most abundant cytoplasmic structure and can occupy most of the axonal cross-sectional area. For example, a large myelinated axon may contain thousands of neurofilaments in one cross-section. Mutant mice with neurofilament abnormalities have phenotypes resembling amyotrophic lateral sclerosis.[11] # Neurofilament transport In addition to their structural role in axons, neurofilaments are also cargoes of axonal transport.[3] Most of the neurofilament proteins in axons are synthesized in the nerve cell body, where they rapidly assemble into neurofilament polymers within about 30 minutes.[12] These assembled neurofilament polymers are transported along the axon on microtubule tracks powered by microtubule motor proteins.[13] The filaments move bidirectionally, i.e. both towards the axon tip (anterograde) and towards the cell body (retrograde), but the net direction is anterograde. The filaments move at velocities of up to 8 µm/s on short time scales (seconds or minutes), with average velocities of approximately 1 µm/s.[14] However, the average velocity on longer time scales (hours or days) is slow because the movements are very infrequent, consisting of brief sprints interrupted by long pauses.[15][16] Thus on long time scales neurofilaments move in the slow component of axonal transport. # Clinical and research applications Numerous specific antibodies to neurofilament proteins have been developed and are commercially available. These antibodies can be used to detect neurofilament proteins in cells and tissues using immunofluorescence microscopy or immunohistochemistry. Such antibodies are widely used to identify neurons and their processes in histological sections and in tissue culture. The Class VI intermediate filament protein nestin is expressed in developing neurons and glia. Nestin is considered a marker of neuronal stem cells, and the presence of this protein is widely used to define neurogenesis. This protein is lost as development proceeds. Neurofilament antibodies are also commonly used in diagnostic neuropathology. Staining with these antibodies can distinguish neurons (positive for neurofilament proteins) from glia (negative for neurofilament proteins). There is also considerable clinical interest in the use of neurofilament proteins as biomarkers of axonal damage in neurodegenerative diseases. When neurons or axons degenerate, neurofilament proteins are released into the blood or cerebrospinal fluid. Immunoassays of neurofilament proteins in cerebrospinal fluid and plasma can thus serve as indicators of axonal damage in neurological disorders.[17] NFL is a useful marker for disease monitoring in Amyotrophic Lateral Sclerosis,[18] multiple sclerosis[19] and more recently Huntington's disease.[20]	https://www.wikidoc.org/index.php/Neurofilament
19140a1f2400d96ef21d174430b81a12ed45f192	wikidoc	Neurotoxicity	Neurotoxicity # Overview Neurotoxicity occurs when the exposure to natural or manmade toxic substances, which are called neurotoxins, alters the normal activity of the nervous system. This can eventually disrupt or even kill neurons, key cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies and organ transplants, as well as exposure to heavy metals such as lead and mercury, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, headache, cognitive and behavioral problems and sexual dysfunction. Individuals with certain disorders may be especially vulnerable to neurotoxins. The name implies the role of a neurotoxin although the term 'neurotoxic' may be used more loosely to describe states that are known to cause physical brain damage but where no obvious neurotoxin has been identified. The term neurotoxic is used to describe a substance, condition or state that damages the nervous system and/or brain, usually by killing neurons. The term is generally used to describe a condition or substance that has been shown to result in observable physical damage. The presence of neurocognitive deficits alone is not usually considered sufficient evidence of neurotoxicity, as many substances exist which may impair neurocognitive performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is metabolised from the body. In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods. ## Causes ## Drug Causes - Amikacin sulfate - Fludarabine - Fluorouracil - Cladribine - Cytarabine - Cytarabine liposome - Isoniazid - Nelarabine - Procarbazine - Sodium phenylbutyrate # Prognosis The prognosis depends upon the length and degree of exposure and the severity of neurological injury. In some instances, exposure to neurotoxins can be fatal. In others, patients may survive but not fully recover. In other situations, many individuals recover completely after treatment.	Neurotoxicity # Overview Neurotoxicity occurs when the exposure to natural or manmade toxic substances, which are called neurotoxins, alters the normal activity of the nervous system. This can eventually disrupt or even kill neurons, key cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies and organ transplants, as well as exposure to heavy metals such as lead and mercury, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, headache, cognitive and behavioral problems and sexual dysfunction. Individuals with certain disorders may be especially vulnerable to neurotoxins. The name implies the role of a neurotoxin although the term 'neurotoxic' may be used more loosely to describe states that are known to cause physical brain damage but where no obvious neurotoxin has been identified. The term neurotoxic is used to describe a substance, condition or state that damages the nervous system and/or brain, usually by killing neurons. The term is generally used to describe a condition or substance that has been shown to result in observable physical damage. The presence of neurocognitive deficits alone is not usually considered sufficient evidence of neurotoxicity, as many substances exist which may impair neurocognitive performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is metabolised from the body. In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods. ## Causes ## Drug Causes - Amikacin sulfate - Fludarabine - Fluorouracil - Cladribine - Cytarabine - Cytarabine liposome - Isoniazid - Nelarabine - Procarbazine - Sodium phenylbutyrate # Prognosis The prognosis depends upon the length and degree of exposure and the severity of neurological injury. In some instances, exposure to neurotoxins can be fatal. In others, patients may survive but not fully recover. In other situations, many individuals recover completely after treatment.	https://www.wikidoc.org/index.php/Neurologic_toxicity
ac7f2596c8929170685910ea16aeb0894fda5b32	wikidoc	Neuromyotonia	Neuromyotonia Synonyms and keywords: # Overview Neuromyotonia, also known as Isaacs' Syndrome, is spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin. # Historical Perspective - was first discovered by , a , in during/following . - In , mutations were first identified in the pathogenesis of . - In , the first was developed by to treat/diagnose . # Classification - may be classified according to into subtypes/groups: - Other variants of include , , and . # Pathophysiology - The pathogenesis of is characterized by , , and . - The gene/Mutation in has been associated with the development of , involving the pathway. - On gross pathology, , , and are characteristic findings of . - On microscopic histopathological analysis, , , and are characteristic findings of . # Causes It develops as a result of both acquired or hereditary diseases. Acquired form is more frequent and is usually caused by antibodies against neuromuscular junction. Autoreactive antibodies can be detected in a variety of peripheral (e.g. myasthenia gravis, Lambert-Eaton myasthenic syndrome) and central nervous system (e.g. paraneoplastic cerebellar degeneration, paraneoplastic limbic encephalitis) disorders. Their causative role has been established in some of these diseases but not all. Neuromyotonia is considered to be one of these with accumulating evidence for autoimmune origin over the last few years. Some neuromyotonia cases do not only improve after plasma exchange but they may also have antibodies in their serum samples against voltage-gated potassium channels. Moreover, these antibodies have been demonstrated to reduce potassium channel function in neuronal cell lines. # Differentiating from other Diseases - must be differentiated from other diseases that cause , , and , such as: # Epidemiology and Demographics - The prevalence of is approximately per 100,000 individuals worldwide. - In , the incidence of was estimated to be cases per 100,000 individuals in . ## Age - Patients of all age groups may develop . - is more commonly observed among patients aged years old. - is more commonly observed among . ## Gender - affects men and women equally. - are more commonly affected with than . - The to ratio is approximately to 1. ## Race - There is no racial predilection for . - usually affects individuals of the race. - individuals are less likely to develop . # Risk Factors - Common risk factors in the development of are , , , and . # Natural History, Complications and Prognosis - The majority of patients with remain asymptomatic for . - Early clinical features include , , and . - If left untreated, of patients with may progress to develop , , and . - Common complications of include , , and . - Prognosis is generally , and the of patients with is approximately . # Diagnosis As a result of muscular hyperactivity patients may present with muscle cramps, myotonia-like symptoms, excessive sweating, myokymia and fasciculations. A very small proportion of cases with neuromyotonia may develop central nervous system findings in their clinical course, causing a disorder called Morvan's syndrome and they may also have antibodies against potassium channels in their serum samples. Sleep disorder is only one of a variety of clinical conditions observed in Morvan's syndrome cases ranging from confusion and memory loss to hallucinations and delusions. # Diagnosis ## Diagnostic Criteria - The diagnosis of is made when at least of the following diagnostic criteria are met: ## Symptoms - is usually asymptomatic. - Symptoms of may include the following: ## Physical Examination - Patients with usually appear . - Physical examination may be remarkable for: ## Laboratory Findings - There are no specific laboratory findings associated with . - A is diagnostic of . - An concentration of is diagnostic of . - Other laboratory findings consistent with the diagnosis of include , , and . ## Imaging Findings - There are no findings associated with . - is the imaging modality of choice for . - On , is characterized by , , and . - may demonstrate , , and . ## Other Diagnostic Studies - may also be diagnosed using . - Findings on include , , and . # Treatment There is no known cure for neuromyotonia. The long-term prognosis for individuals with the disorder is uncertain. Anticonvulsants, including phenytoin and carbamazepine, usually provide significant relief from the stiffness, muscle spasms, and pain associated with neuromyotonia. Plasma exchange may provide short-term relief for patients with some forms of the acquired disorder. ## Medical Therapy - There is no treatment for ; the mainstay of therapy is supportive care. - The mainstay of therapy for is and . - acts by . - Response to can be monitored with every . ## Surgery - Surgery is the mainstay of therapy for . - in conjunction with is the most common approach to the treatment of . - can only be performed for patients with . ## Prevention - There are no primary preventive measures available for . - Effective measures for the primary prevention of include , , and . - Once diagnosed and successfully treated, patients with are followed-up every . Follow-up testing includes , , and .	Neuromyotonia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: # Overview Neuromyotonia, also known as Isaacs' Syndrome, is spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin. # Historical Perspective - [Disease name] was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event]. - In [year], [gene] mutations were first identified in the pathogenesis of [disease name]. - In [year], the first [discovery] was developed by [scientist] to treat/diagnose [disease name]. # Classification - [Disease name] may be classified according to [classification method] into [number] subtypes/groups: - [group1] - [group2] - [group3] - Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3]. # Pathophysiology - The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3]. - The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway. - On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. - On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. # Causes It develops as a result of both acquired or hereditary diseases. Acquired form is more frequent and is usually caused by antibodies against neuromuscular junction. Autoreactive antibodies can be detected in a variety of peripheral (e.g. myasthenia gravis, Lambert-Eaton myasthenic syndrome) and central nervous system (e.g. paraneoplastic cerebellar degeneration, paraneoplastic limbic encephalitis) disorders. Their causative role has been established in some of these diseases but not all. Neuromyotonia is considered to be one of these with accumulating evidence for autoimmune origin over the last few years. Some neuromyotonia cases do not only improve after plasma exchange but they may also have antibodies in their serum samples against voltage-gated potassium channels.[1] Moreover, these antibodies have been demonstrated to reduce potassium channel function in neuronal cell lines. # Differentiating [disease name] from other Diseases - [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as: - [Differential dx1] - [Differential dx2] - [Differential dx3] # Epidemiology and Demographics - The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide. - In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location]. ## Age - Patients of all age groups may develop [disease name]. - [Disease name] is more commonly observed among patients aged [age range] years old. - [Disease name] is more commonly observed among [elderly patients/young patients/children]. ## Gender - [Disease name] affects men and women equally. - [Gender 1] are more commonly affected with [disease name] than [gender 2]. - The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1. ## Race - There is no racial predilection for [disease name]. - [Disease name] usually affects individuals of the [race 1] race. - [Race 2] individuals are less likely to develop [disease name]. # Risk Factors - Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4]. # Natural History, Complications and Prognosis - The majority of patients with [disease name] remain asymptomatic for [duration/years]. - Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3]. - If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3]. - Common complications of [disease name] include [complication 1], [complication 2], and [complication 3]. - Prognosis is generally [excellent/good/poor], and the [1/5/10year mortality/survival rate] of patients with [disease name] is approximately [#%]. # Diagnosis As a result of muscular hyperactivity patients may present with muscle cramps, myotonia-like symptoms, excessive sweating, myokymia and fasciculations. A very small proportion of cases with neuromyotonia may develop central nervous system findings in their clinical course, causing a disorder called Morvan's syndrome and they may also have antibodies against potassium channels in their serum samples. Sleep disorder is only one of a variety of clinical conditions observed in Morvan's syndrome cases ranging from confusion and memory loss to hallucinations and delusions. # Diagnosis ## Diagnostic Criteria - The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: - [criterion 1] - [criterion 2] - [criterion 3] - [criterion 4] ## Symptoms - [Disease name] is usually asymptomatic. - Symptoms of [disease name] may include the following: - [symptom 1] - [symptom 2] - [symptom 3] - [symptom 4] - [symptom 5] - [symptom 6] ## Physical Examination - Patients with [disease name] usually appear [general appearance]. - Physical examination may be remarkable for: - [finding 1] - [finding 2] - [finding 3] - [finding 4] - [finding 5] - [finding 6] ## Laboratory Findings - There are no specific laboratory findings associated with [disease name]. - A [positive/negative] [test name] is diagnostic of [disease name]. - An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name]. - Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3]. ## Imaging Findings - There are no [imaging study] findings associated with [disease name]. - [Imaging study 1] is the imaging modality of choice for [disease name]. - On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3]. - [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3]. ## Other Diagnostic Studies - [Disease name] may also be diagnosed using [diagnostic study name]. - Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3]. # Treatment There is no known cure for neuromyotonia. The long-term prognosis for individuals with the disorder is uncertain. Anticonvulsants, including phenytoin and carbamazepine, usually provide significant relief from the stiffness, muscle spasms, and pain associated with neuromyotonia. Plasma exchange may provide short-term relief for patients with some forms of the acquired disorder. ## Medical Therapy - There is no treatment for [disease name]; the mainstay of therapy is supportive care. - The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2]. - [Medical therapy 1] acts by [mechanism of action 1]. - Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration]. ## Surgery - Surgery is the mainstay of therapy for [disease name]. - [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name]. - [Surgical procedure] can only be performed for patients with [disease stage] [disease name]. ## Prevention - There are no primary preventive measures available for [disease name]. - Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3]. - Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].	https://www.wikidoc.org/index.php/Neuromyotonia
3f738841d380b94c89565bf0130ce057b65afe69	wikidoc	Neutral spine	Neutral spine A Neutral Spine or "good posture" refers to the "three natural curves are present in a healthy spine." # Posture The word "posture" comes from the Latin verb "ponere" which is defined as "to put or place." The general concept of human posture refers to "the carriage of the body as a whole, the attitude of the body, or the position of the limbs (the arms and legs)." Good posture is the stance which is attained, "when the joints are not bent and the spine is aligned and not twisted."In this position, a person is thus able to completely and optimally attain balance and proportion of the body mass and framework. Good posture optimizes breathing and affects the circulation of bodily fluids. Padmasana or the Lotus Position is a central stance in yoga which is used to enhance breathing through good posture. The word padmasana is a combination of the sanskrit words padma (lotus) and asana (posture). # Neutral spine In medicine and occupations concerned with physical fitness, the concept of good posture is referred to as "Neutral Spine." In this context, proper posture or "Neutral Spine," In contrast, a non-neutral spine leads to "improper posture, especially when walking, puts increased stress on your back and causes discomfort and damage." A non-neutral spine develops as the result of a person's lifestyle. People who sit for long hours on the job are susceptible to a number of misalignments." "Neutral Spine" is ideally maintained while sitting, standing, and sleeping.	Neutral spine A Neutral Spine or "good posture" refers to the "three natural curves [that] are present in a healthy spine."[1] # Posture The word "posture" comes from the Latin verb "ponere" which is defined as "to put or place." The general concept of human posture refers to "the carriage of the body as a whole, the attitude of the body, or the position of the limbs (the arms and legs)." [2] Good posture is the stance which is attained, "when the joints are not bent and the spine is aligned and not twisted."[3]In this position, a person is thus able to completely and optimally attain balance and proportion of the body mass and framework. Good posture optimizes breathing and affects the circulation of bodily fluids. Padmasana or the Lotus Position is a central stance in yoga which is used to enhance breathing through good posture. The word padmasana is a combination of the sanskrit words padma (lotus) and asana (posture). [4] # Neutral spine In medicine and occupations concerned with physical fitness, the concept of good posture is referred to as "Neutral Spine." [5] In this context, proper posture or "Neutral Spine," In contrast, a non-neutral spine leads to "improper posture, [that] especially when walking, puts increased stress on your back and causes discomfort and damage." [6]A non-neutral spine develops as the result of a person's lifestyle. People who sit for long hours on the job are susceptible to a number of misalignments."[7] "Neutral Spine" is ideally maintained while sitting, standing, and sleeping.[8]	https://www.wikidoc.org/index.php/Neutral_spine
8d64262d1ea03043b1b69fa03d0287e112c56560	wikidoc	Nitrenium ion	Nitrenium ion A nitrenium ion (also called: aminylium ion) in organic chemistry is a reactive intermediate based on nitrogen with both an electron lone pair and a positive charge and with two substituents (R2N+) . The compound can have both a singlet and a triplet state. Aryl nitrenium ions are currently investigated because of their involvement in certain DNA damaging processes. These intermediates can have microsecond or longer lifetimes in water . Nitrenium ions are also intermediates in organic reactions for instance the Bamberger rearrangement. They can also act as electrophiles in electrophilic aromatic substitution . The term imidonium ion with the same meaning is now obsolete.	Nitrenium ion A nitrenium ion (also called: aminylium ion) in organic chemistry is a reactive intermediate based on nitrogen with both an electron lone pair and a positive charge and with two substituents (R2N+) [1]. The compound can have both a singlet and a triplet state. Aryl nitrenium ions are currently investigated because of their involvement in certain DNA damaging processes. These intermediates can have microsecond or longer lifetimes in water [2]. Nitrenium ions are also intermediates in organic reactions for instance the Bamberger rearrangement. They can also act as electrophiles in electrophilic aromatic substitution [3]. The term imidonium ion with the same meaning is now obsolete.	https://www.wikidoc.org/index.php/Nitrenium_ion
e8a504f7f5aaa93d9904fcf9e00b0bebd93c82d9	wikidoc	Nitrification	Nitrification Nitrification is the biological oxidation of ammonia with oxygen into nitrite followed by the oxidation of these nitrites into nitrates. Nitrification is an important step in the nitrogen cycle in soil. This process was discovered by the Russian microbiologist, Sergei Winogradsky. The oxidation of ammonia into nitrite, and the subsequent oxidation to nitrate is performed by two different bacteria (nitrifying bacteria). The first step is done by bacteria of (amongst others) the genus Nitrosomonas and Nitrosococcus. The second step (oxidation of nitrite into nitrate) is (mainly) done by bacteria of the genus Nitrobacter, with both steps producing energy to be coupled to ATP synthesis. Nitrifying organisms are chemoautotrophs, and use carbon dioxide as their carbon source for growth. Nitrification also plays an important role in the removal of nitrogen from municipal wastewater. The conventional removal is nitrification, followed by denitrification. The cost of this process resides mainly in aeration (bringing oxygen in the reactor) and the addition of an external carbon source (e.g. methanol) for the denitrification. In most environments both organisms are found together, yielding nitrate as the final product. It is possible however to design systems in which selectively nitrite is formed (the Sharon process). Together with ammonification, nitrification forms a mineralization process which refers to the complete decomposition of organic material, with the release of available nitrogen compounds. This replenishes the nitrogen cycle. # Chemistry Nitrification is a process of nitrogen compound oxidation (effectively, loss of electrons from the nitrogen atom to the oxygen atoms) : - NH3 + O2 → NO2− + 3H+ + 2e− - NO2− + H2O → NO3− + 2H+ + 2e−	Nitrification Nitrification is the biological oxidation of ammonia with oxygen into nitrite followed by the oxidation of these nitrites into nitrates. Nitrification is an important step in the nitrogen cycle in soil. This process was discovered by the Russian microbiologist, Sergei Winogradsky. The oxidation of ammonia into nitrite, and the subsequent oxidation to nitrate is performed by two different bacteria (nitrifying bacteria). The first step is done by bacteria of (amongst others) the genus Nitrosomonas and Nitrosococcus. The second step (oxidation of nitrite into nitrate) is (mainly) done by bacteria of the genus Nitrobacter, with both steps producing energy to be coupled to ATP synthesis. Nitrifying organisms are chemoautotrophs, and use carbon dioxide as their carbon source for growth. Nitrification also plays an important role in the removal of nitrogen from municipal wastewater. The conventional removal is nitrification, followed by denitrification. The cost of this process resides mainly in aeration (bringing oxygen in the reactor) and the addition of an external carbon source (e.g. methanol) for the denitrification. In most environments both organisms are found together, yielding nitrate as the final product. It is possible however to design systems in which selectively nitrite is formed (the Sharon process). Together with ammonification, nitrification forms a mineralization process which refers to the complete decomposition of organic material, with the release of available nitrogen compounds. This replenishes the nitrogen cycle. # Chemistry Nitrification is a process of nitrogen compound oxidation (effectively, loss of electrons from the nitrogen atom to the oxygen atoms) : - NH3 + O2 → NO2− + 3H+ + 2e− - NO2− + H2O → NO3− + 2H+ + 2e−	https://www.wikidoc.org/index.php/Nitrification
c08b83d693edf78591d4c30f197b822aa01a703d	wikidoc	Nitroprusside	Nitroprusside # 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 Nitroprusside is a vasodilator that is FDA approved for the treatment of hypertensive crisis and acute congestive heart failure. It is also indicated for producing controlled hypotension in order to reduce bleeding during surgery.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include excessive hypotension and cyanide toxicity. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion Avoidance of excessive hypotension - While the average effective rate in adult and pediatric patients is about 3 μg/kg/min, some patients will become dangerously hypotensive when they receive Nitropress at this rate. Infusion of sodium nitroprusside should therefore be started at a very low rate (0.3 μg/kg/min), with upward titration every few minutes until the desired effect is achieved or the maximum recommended infusion rate (10 μg/kg/min) has been reached. - Because sodium nitroprusside's hypotensive effect is very rapid in onset and in dissipation, small variations in infusion rate can lead to wide, undesirable variations in blood pressure. Since there is inherent variation in blood pressure measurement, confirm the drug effect at any infusion rate after an additional 5 minutes before titrating to a higher dose to achieve the desired blood pressure. Sodium nitroprusside should not be infused through ordinary I.V. apparatus, regulated only by gravity and mechanical clamps. Only an infusion pump, preferably a volumetric pump, should be used. - Because sodium nitroprusside can induce essentially unlimited blood pressure reduction, the blood pressure of a patient receiving this drug must be continuously monitored, using either a continually reinflated sphygmomanometer or (preferably) an intra-arterial pressure sensor. Special caution should be used in elderly patients, since they may be more sensitive to the hypotensive effects of the drug. - When sodium nitroprusside is used in the treatment of acute congestive heart failure, titration of the infusion rate must be guided by the results of invasive hemodynamic monitoring with simultaneous monitoring of urine output. Sodium nitroprusside can be titrated by increasing the infusion rate until: measured cardiac output is no longer increasing, systemic blood pressure cannot be further reduced without compromising the perfusion of vital organs, or the maximum recommended infusion rate has been reached, whichever comes earliest. Specific hemodynamic goals must be tailored to the clinical situation, but improvements in cardiac output and left ventricular filling pressure must not be purchased at the price of undue hypotension and consequent hypoperfusion. - Table 2 below shows the infusion rates corresponding to the recommended initial and maximal doses (0.3 μg/kg/min and 10 μg/kg/min, respectively) for both adult and pediatric patients of various weights. This infusion rate may be lower than indicated in the table for patients less than 10 kg. Note that when the concentration used in a given patient is changed, the tubing is still filled with a solution at the previous concentration. Avoidance of cyanide toxicity - When more than 500 μg/kg of sodium nitroprusside is administered faster than 2 μg/kg/min, cyanide is generated faster than the unaided patient can eliminate it. Administration of sodium thiosulfate has been shown to increase the rate of cyanide processing, reducing the hazard of cyanide toxicity. Although toxic reactions to sodium thiosulfate have not been reported, the co-infusion regimen has not been extensively studied, and it cannot be recommended without reservation. In one study, sodium thiosulfate appeared to potentiate the hypotensive effects of sodium nitroprusside. - Co-infusions of sodium thiosulfate have been administered at rates of 5-10 times that of sodium nitroprusside. Care must be taken to avoid the indiscriminate use of prolonged or high doses of sodium nitroprusside with sodium thiosulfate as this may result in thiocyanate toxicity and hypovolemia. Incautious administration of sodium nitroprusside must still be avoided, and all of the precautions concerning sodium nitroprusside administration must still be observed. Consideration of methemoglobinemia and thiocyanate toxicity - Rare patients receiving more than 10 mg/kg of sodium nitroprusside will develop methemoglobinemia; other patients, especially those with impaired renal function, will predictably develop thiocyanate toxicity after prolonged, rapid infusions. Patients with suggestive findings should be tested for these toxicities. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nitroprusside in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 1–3 μg/kg/min IV infusion - 1–2 μg/kg/min IV infusion - Dosing Information - 10–33 μg/kg/min IV infusion, initially within 24 hours of onset of symptoms # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion Avoidance of excessive hypotension - While the average effective rate in adult and pediatric patients is about 3 μg/kg/min, some patients will become dangerously hypotensive when they receive Nitropress at this rate. Infusion of sodium nitroprusside should therefore be started at a very low rate (0.3 μg/kg/min), with upward titration every few minutes until the desired effect is achieved or the maximum recommended infusion rate (10 μg/kg/min) has been reached. - Because sodium nitroprusside's hypotensive effect is very rapid in onset and in dissipation, small variations in infusion rate can lead to wide, undesirable variations in blood pressure. Since there is inherent variation in blood pressure measurement, confirm the drug effect at any infusion rate after an additional 5 minutes before titrating to a higher dose to achieve the desired blood pressure. Sodium nitroprusside should not be infused through ordinary I.V. apparatus, regulated only by gravity and mechanical clamps. Only an infusion pump, preferably a volumetric pump, should be used. - Because sodium nitroprusside can induce essentially unlimited blood pressure reduction, the blood pressure of a patient receiving this drug must be continuously monitored, using either a continually reinflated sphygmomanometer or (preferably) an intra-arterial pressure sensor. Special caution should be used in elderly patients, since they may be more sensitive to the hypotensive effects of the drug. - When sodium nitroprusside is used in the treatment of acute congestive heart failure, titration of the infusion rate must be guided by the results of invasive hemodynamic monitoring with simultaneous monitoring of urine output. Sodium nitroprusside can be titrated by increasing the infusion rate until: measured cardiac output is no longer increasing, systemic blood pressure cannot be further reduced without compromising the perfusion of vital organs, or the maximum recommended infusion rate has been reached, whichever comes earliest. Specific hemodynamic goals must be tailored to the clinical situation, but improvements in cardiac output and left ventricular filling pressure must not be purchased at the price of undue hypotension and consequent hypoperfusion. - Table 2 below shows the infusion rates corresponding to the recommended initial and maximal doses (0.3 μg/kg/min and 10 μg/kg/min, respectively) for both adult and pediatric patients of various weights. This infusion rate may be lower than indicated in the table for patients less than 10 kg. Note that when the concentration used in a given patient is changed, the tubing is still filled with a solution at the previous concentration. Avoidance of cyanide toxicity - When more than 500 μg/kg of sodium nitroprusside is administered faster than 2 μg/kg/min, cyanide is generated faster than the unaided patient can eliminate it. Administration of sodium thiosulfate has been shown to increase the rate of cyanide processing, reducing the hazard of cyanide toxicity. Although toxic reactions to sodium thiosulfate have not been reported, the co-infusion regimen has not been extensively studied, and it cannot be recommended without reservation. In one study, sodium thiosulfate appeared to potentiate the hypotensive effects of sodium nitroprusside. - Co-infusions of sodium thiosulfate have been administered at rates of 5-10 times that of sodium nitroprusside. Care must be taken to avoid the indiscriminate use of prolonged or high doses of sodium nitroprusside with sodium thiosulfate as this may result in thiocyanate toxicity and hypovolemia. Incautious administration of sodium nitroprusside must still be avoided, and all of the precautions concerning sodium nitroprusside administration must still be observed. Consideration of methemoglobinemia and thiocyanate toxicity - Rare patients receiving more than 10 mg/kg of sodium nitroprusside will develop methemoglobinemia; other patients, especially those with impaired renal function, will predictably develop thiocyanate toxicity after prolonged, rapid infusions. Patients with suggestive findings should be tested for these toxicities. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nitroprusside in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - 1–5 μg/kg/min IV infusion for 2–8 days - Dosing Information - 15–20 mg/day inhalation - 0.2–6.0 μg/kg/min IV infusion # Contraindications - Compensatory hypertension in aortic coarctation or arteriovenous shunts - Sodium nitroprusside should not be used in the treatment of compensatory hypertension, where the primary hemodynamic lesion is aortic coarctation or arteriovenous shunts. - Inadequate cerebral circulation or moribund patients - Sodium nitroprusside should not be used to produce hypotension during surgery in patients with known inadequate cerebral circulation, or in moribund patients (A.S.A. Class 5E) coming to emergency surgery. - High cyanide/thiocyanate ratios - Patients with congenital (Leber’s) optic atrophy or with tobacco amblyopia have unusually high cyanide/thiocyanate ratios. These rare conditions are probably associated with defective or absent rhodanase, and sodium nitroprusside should be avoided in these patients. - Acute congestive heart failure associated with reduced peripheral vascular resistance - Sodium nitroprusside should not be used for the treatment of acute congestive heart failure associated with reduced peripheral vascular resistance such as high-output heart failure that may be seen in endotoxic sepsis. # Warnings - The principal hazards of Nitropress administration are excessive hypotension and excessive accumulation of cyanide. - Excessive Hypotension - Small transient excesses in the infusion rate of sodium nitroprusside can result in excessive hypotension, sometimes to levels so low as to compromise the perfusion of vital organs. These hemodynamic changes may lead to a variety of associated symptoms. Nitroprusside-induced hypotension will be self-limited within 1-10 minutes after discontinuation of the nitroprusside infusion; during these few minutes, it may be helpful to put the patient into a head-down (Trendelenburg) position to maximize venous return. If hypotension persists more than a few minutes after discontinuation of the infusion of Nitropress, Nitropress is not the cause, and the true cause must be sought. - Cyanide Toxicity - Sodium nitroprusside infusions at rates above 2 μg/kg/min generate cyanide ion (CN¯) faster than the body can normally dispose of it. (When sodium thiosulfate is given, the body’s capacity for CN¯ elimination is greatly increased.) Methemoglobin normally present in the body can buffer a certain amount of CN¯, but the capacity of this system is exhausted by the CN¯ produced from about 500 μg/kg of sodium nitroprusside. This amount of sodium nitroprusside is administered in less than an hour when the drug is administered at 10 μg/kg/min (the maximum recommended rate). Thereafter, the toxic effects of CN¯ may be rapid, serious, and even lethal. - The true rates of clinically important cyanide toxicity cannot be assessed from spontaneous reports or published data. Most patients reported to have experienced such toxicity have received relatively prolonged infusions, and the only patients whose deaths have been unequivocally attributed to nitroprusside-induced cyanide toxicity have been patients who had received nitroprusside infusions at rates (30-120 μg/kg/min) much greater than those now recommended. Elevated cyanide levels, metabolic acidosis, and marked clinical deterioration, however, have occasionally been reported in patients who received infusions at recommended rates for only a few hours and even, in one case, for only 35 minutes. In some of these cases, infusion of sodium thiosulfate caused dramatic clinical improvement, supporting the diagnosis of cyanide toxicity. - Cyanide toxicity may manifest itself as venous hyperoxemia with bright red venous blood, as cells become unable to extract the oxygen delivered to them; metabolic acidosis (lactic acidosis); air hunger; confusion; and death. Cyanide toxicity due to causes other than nitroprusside has been associated with angina pectoris and myocardial infarction; ataxia, seizures, and stroke; and other diffuse ischemic damage. - Hypertensive patients, and patients concomitantly receiving other antihypertensive medications, may be more sensitive to the effects of sodium nitroprusside than normal subjects. ### Precautions - General - Like other vasodilators, sodium nitroprusside can cause increases in intracranial pressure. In patients whose intracranial pressure is already elevated, sodium nitroprusside should be used only with extreme caution. - Hepatic - Use caution when administering nitroprusside to patients with hepatic insufficiency. - Use in Anesthesia - When sodium nitroprusside (or any other vasodilator) is used for controlled hypotension during anesthesia, the patient’s capacity to compensate for anemia and hypovolemia may be diminished. If possible, pre-existing anemia and hypovolemia should be corrected prior to administration of Nitropress. Hypotensive anesthetic techniques may also cause abnormalities of the pulmonary ventilation/perfusion ratio. Patients intolerant of these abnormalities may require a higher fraction of inspired oxygen. Extreme caution should be exercised in patients who are especially poor surgical risks (A.S.A. Class 4 and 4E). - Laboratory Tests - The cyanide level assay is technically difficult, and cyanide levels in body fluids other than packed red blood cells are difficult to interpret. Cyanide toxicity will lead to lactic acidosis and venous hyperoxemia, but these findings may not be present until an hour or more after the cyanide capacity of the body’s red-cell mass has been exhausted. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Nitroprusside in the drug label. ## Postmarketing Experience - The most important adverse reactions to sodium nitroprusside are the avoidable ones of excessive hypotension and cyanide toxicity. The adverse reactions described in this section develop less rapidly and, as it happens, less commonly. - Methemoglobinemia - Sodium nitroprusside infusions can cause sequestration of hemoglobin as methemoglobin. The back-conversion process is normally rapid, and clinically significant methemoglobinemia (>10%) is seen only rarely in patients receiving Nitropress. Even patients congenitally incapable of back-converting methemoglobin should demonstrate 10% methemoglobinemia only after they have received about 10 mg/kg of sodium nitroprusside, and a patient receiving sodium nitroprusside at the maximum recommended rate (10 μg/kg/min) would take over 16 hours to reach this total accumulated dose. - Methemoglobin levels can be measured by most clinical laboratories. The diagnosis should be suspected in patients who have received >10 mg/kg of sodium nitroprusside and who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. - When methemoglobinemia is diagnosed, the treatment of choice is 1-2 mg/kg of methylene blue, administered intravenously over several minutes. In patients likely to have substantial amounts of cyanide bound to methemoglobin as cyanmethemoglobin, treatment of methemoglobinemia with methylene blue must be undertaken with extreme caution. - Thiocyanate Toxicity - Most of the cyanide produced during metabolism of sodium nitroprusside is eliminated in the form of thiocyanate. When cyanide elimination is accelerated by the co-infusion of thiosulfate, thiocyanate production is increased. - Thiocyanate is mildly neurotoxic (tinnitus, miosis, hyperreflexia) at serum levels of 1 mmol/L (60 mg/L). Thiocyanate toxicity is life-threatening when levels are 3 or 4 times higher (200 mg/L). - The steady-state thiocyanate level after prolonged infusions of sodium nitroprusside is increased with increased infusion rate, and the half-time of accumulation is 3-4 days. To keep the steady-state thiocyanate level below 1 mmol/L, a prolonged infusion of sodium nitroprusside should not be more rapid than 3 μg/kg/min; in anuric patients, the corresponding limit is just 1 μg/kg/min. When prolonged infusions are more rapid than these, thiocyanate levels should be measured daily. - Physiologic maneuvers (e.g., those that alter the pH of the urine) are not known to increase the elimination of thiocyanate. Thiocyanate clearance rates during dialysis, on the other hand, can approach the blood flow rate of the dialyzer. - Thiocyanate interferes with iodine uptake by the thyroid. - Abdominal pain, apprehension, diaphoresis, dizziness, headache, muscle twitching, nausea, palpitations, restlessness, retching, and retrosternal discomfort have been noted when the blood pressure was too rapidly reduced. These symptoms quickly disappeared when the infusion was slowed or discontinued, and they did not reappear with a continued (or resumed) slower infusion. - Other adverse reactions reported are: Increased intracranial pressure. Bradycardia, electrocardiographic changes, tachycardia. Ileus. Decreased platelet aggregation. Rash. Hypothyroidism. Flushing, venous streaking, irritation at the infusion site. # Drug Interactions - Antihypertensive agents - The hypotensive effect of sodium nitroprusside is augmented by that of most other hypotensive drugs, including ganglionic blocking agents, negative inotropic agents, and inhaled anesthetics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic effects - There are no adequate, well-controlled studies of Nitropress in either laboratory animals or pregnant women. It is not known whether Nitropress can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Nitropress should be given to a pregnant woman only if clearly needed. - Nonteratogenic effects - In three studies in pregnant ewes, nitroprusside was shown to cross the placental barrier. Fetal cyanide levels were shown to be dose-related to maternal levels of nitroprusside. The metabolic transformation of sodium nitroprusside given to pregnant ewes led to fatal levels of cyanide in the fetuses. The infusion of 25 μg/kg/min of sodium nitroprusside for one hour in pregnant ewes resulted in the death of all fetuses. Pregnant ewes infused with 1 μg/kg/min of sodium nitroprusside for one hour delivered normal lambs. - According to one investigator, a pregnant woman at 24 weeks gestation was given sodium nitroprusside to control gestational hypertension secondary to mitral valve disease. Sodium nitroprusside was infused at 3.9 μg/kg/min for a total of 3.5 mg/kg over 15 hours prior to delivery of a 478 gram stillborn infant without any obvious anomalies. Cyanide levels in the fetal liver were less than 10 μg/mL. Toxic levels have been reported to be more than 30-40 μg/mL. The mother demonstrated no cyanide toxicity. - The effects of administering sodium thiosulfate in pregnancy, either by itself or as a co-infusion with sodium nitroprusside, are completely unknown. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitroprusside in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nitroprusside during labor and delivery. ### Nursing Mothers - It is not known whether sodium nitroprusside and its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from sodium nitroprusside, 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 - Efficacy in the pediatric population was established based on adult trials and supported by the dose-ranging trial (Study 1) and an open label trial of at least 12 hour infusion at a rate that achieved adequate MAP control (Study 2) with pediatric patients on sodium nitroprusside. No novel safety issues were seen in these studies in pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Nitroprusside with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Nitroprusside with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nitroprusside with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nitroprusside in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nitroprusside in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nitroprusside in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nitroprusside in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Dilution to proper strength for infusion - Depending on the desired concentration, the solution containing 50 mg of Nitropress must be further diluted in 250-1000 mL of sterile 5% dextrose injection. The diluted solution should be protected from light, using the supplied opaque sleeve, aluminum foil, or other opaque material. It is not necessary to cover the infusion drip chamber or the tubing. - Verification of the chemical integrity of the product - Sodium nitroprusside solution can be inactivated by reactions with trace contaminants. The products of these reactions are often blue, green, or red, much brighter than the faint brownish color of unreacted Nitropress. Discolored solutions, or solutions in which particulate matter is visible, should not be used. If properly protected from light, the freshly diluted solution is stable for 24 hours. - No other drugs should be administered in the same solution with sodium nitroprusside. ### Monitoring - Because sodium nitroprusside can induce essentially unlimited blood pressure reduction, the blood pressure of a patient receiving this drug must be continuously monitored, using either a continually reinflated sphygmomanometer or (preferably) an intra-arterial pressure sensor. Special caution should be used in elderly patients, since they may be more sensitive to the hypotensive effects of the drug. - When sodium nitroprusside is used in the treatment of acute congestive heart failure, titration of the infusion rate must be guided by the results of invasive hemodynamic monitoring with simultaneous monitoring of urine output. # IV Compatibility There is limited information regarding the compatibility of Nitroprusside and IV administrations. # Overdosage ## Acute Overdose ### Signs and Symptoms - Overdosage of nitroprusside can be manifested as excessive hypotension or cyanide toxicity or as thiocyanate toxicity. - The acute intravenous mean lethal doses (LD50) of nitroprusside in rabbits, dogs, mice, and rats are 2.8, 5.0, 8.4, and 11.2 mg/kg, respectively. ### Management - Treatment of cyanide toxicity - Cyanide levels can be measured by many laboratories, and blood-gas studies that can detect venous hyperoxemia or acidosis are widely available. Acidosis may not appear until more than an hour after the appearance of dangerous cyanide levels, and laboratory tests should not be awaited. Reasonable suspicion of cyanide toxicity is adequate grounds for initiation of treatment. - Treatment of cyanide toxicity consists of: - Discontinuing the administration of sodium nitroprusside - Providing a buffer for cyanide by using sodium nitrite to convert as much hemoglobin into methemoglobin as the patient can safely tolerate - Infusing sodium thiosulfate in sufficient quantity to convert the cyanide into thiocyanate - The necessary medications for this treatment are contained in commercially available Cyanide Antidote Kits. Alternatively, discrete stocks of medications can be used. - Hemodialysis is ineffective in removal of cyanide, but it will eliminate most thiocyanate. - Cyanide Antidote Kits contain both amyl nitrite and sodium nitrite for induction of methemoglobinemia. The amyl nitrite is supplied in the form of inhalant ampoules, for administration in environments where intravenous administration of sodium nitrite may be delayed. In a patient who already has a patent intravenous line, use of amyl nitrite confers no benefit that is not provided by infusion of sodium nitrite. - Sodium nitrite is available in a 3% solution, and 4-6 mg/kg (about 0.2 mL/kg) should be injected over 2-4 minutes. This dose can be expected to convert about 10% of the patient’s hemoglobin into methemoglobin; this level of methemoglobinemia is not associated with any important hazard of its own. The nitrite infusion may cause transient vasodilatation and hypotension, and this hypotension must, if it occurs, be routinely managed. - Immediately after infusion of the sodium nitrite, sodium thiosulfate should be infused. This agent is available in 10% and 25% solutions, and the recommended dose is 150-200 mg/kg; a typical adult dose is 50 mL of the 25% solution. Thiosulfate treatment of an acutely cyanide-toxic patient will raise thiocyanate levels, but not to a dangerous degree. - The nitrite/thiosulfate regimen may be repeated, at half the original doses, after two hours. ## Chronic Overdose There is limited information regarding Chronic Overdose of Nitroprusside in the drug label. # Pharmacology ## Mechanism of Action - The principal pharmacological action of sodium nitroprusside is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins. Other smooth muscle (e.g., uterus, duodenum) is not affected. Sodium nitroprusside is more active on veins than on arteries, but this selectivity is much less marked than that of nitroglycerin. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. ## Structure - Sodium nitroprusside is disodium pentacyanonitrosylferrate(2-) dihydrate, a hypotensive agent whose structural formula is: - The molecular formula is Na2 - 2H2O, and the molecular weight is 297.95. Dry sodium nitroprusside is a reddish-brown powder, soluble in water. In an aqueous solution infused intravenously, sodium nitroprusside is a rapid-acting vasodilator, active on both arteries and veins. - Sodium nitroprusside solution is rapidly degraded by trace contaminants, often with resulting color changes. The solution is also sensitive to certain wavelengths of light, and it must be protected from light in clinical use. ## Pharmacodynamics - In association with the decrease in blood pressure, sodium nitroprusside administered intravenously to hypertensive and normotensive patients produces slight increases in heart rate and a variable effect on cardiac output. In hypertensive patients, moderate doses induce renal vasodilatation roughly proportional to the decrease in systemic blood pressure, so there is no appreciable change in renal blood flow or glomerular filtration rate. - In normotensive subjects, acute reduction of mean arterial pressure to 60-75 mm Hg by infusion of sodium nitroprusside caused a significant increase in renin activity. In the same study, ten renovascular-hypertensive patients given sodium nitroprusside had significant increases in renin release from the involved kidney at mean arterial pressures of 90-137 mm Hg. - The hypotensive effect of sodium nitroprusside is seen within a minute or two after the start of an adequate infusion, and it dissipates almost as rapidly after an infusion is discontinued. The effect is augmented by ganglionic blocking agents and inhaled anesthetics. ## Pharmacokinetics - Infused sodium nitroprusside is rapidly distributed to a volume that is approximately coextensive with the extracellular space. The drug is cleared from this volume by intraerythrocytic reaction with hemoglobin (Hgb), and sodium nitroprusside’s resulting circulatory half-life is about 2 minutes. - The products of the nitroprusside/hemoglobin reaction are cyanmethemoglobin (cyanmetHgb) and cyanide ion (CN¯). Safe use of sodium nitroprusside injection must be guided by knowledge of the further metabolism of these products. - As shown in the diagram below, the essential features of nitroprusside metabolism are: - One molecule of sodium nitroprusside is metabolized by combination with hemoglobin to produce one molecule of cyanmethemoglobin and four CN¯ ions - Methemoglobin, obtained from hemoglobin, can sequester cyanide as cyanmethemoglobin - Thiosulfate reacts with cyanide to produce thiocyanate - Thiocyanate is eliminated in the urine - Cyanide not otherwise removed binds to cytochromes - Cyanide is much more toxic than methemoglobin or thiocyanate - Cyanide ion is normally found in serum; it is derived from dietary substrates and from tobacco smoke. Cyanide binds avidly (but reversibly) to ferric ion (Fe+++), most body stores of which are found in erythrocyte methemoglobin (metHgb) and in mitochondrial cytochromes. When CN¯ is infused or generated within the bloodstream, essentially all of it is bound to methemoglobin until intraerythrocytic methemoglobin has been saturated. - When the Fe+++ of cytochromes is bound to cyanide, the cytochromes are unable to participate in oxidative metabolism. In this situation, cells may be able to provide for their energy needs by utilizing anaerobic pathways, but they thereby generate an increasing body burden of lactic acid. Other cells may be unable to utilize these alternative pathways, and they may die hypoxic deaths. - CN¯ levels in packed erythrocytes are typically less than 1 µmol/L (less than 25 mcg/L); levels are roughly doubled in heavy smokers. - At healthy steady state, most people have less than 1% of their hemoglobin in the form of methemoglobin. Nitroprusside metabolism can lead to methemoglobin formation (a) through dissociation of cyanmethemoglobin formed in the original reaction of sodium nitroprusside with Hgb and (b) by direct oxidation of Hgb by the released nitroso group. Relatively large quantities of sodium nitroprusside, however, are required to produce significant methemoglobinemia. - At physiologic methemoglobin levels, the CN¯ binding capacity of packed red cells is a little less than 200 µmol/L (5 mg/L). Cytochrome toxicity is seen at levels only slightly higher, and death has been reported at levels from 300 to 3000 µmol/L (8–80 mg/L). Put another way, a patient with a normal red-cell mass (35 mL/kg) and normal methemoglobin levels can buffer about 175 mcg/kg of CN¯, corresponding to a little less than 500 mcg/kg of infused sodium nitroprusside. - Some cyanide is eliminated from the body as expired hydrogen cyanide, but most is enzymatically converted to thiocyanate (SCN¯) by thiosulfate-cyanide sulfur transferase (rhodanase, EC 2.8.1.1), a mitochondrial enzyme. The enzyme is normally present in great excess, so the reaction is rate-limited by the availability of sulfur donors, especially thiosulfate, cystine, and cysteine. - Thiosulfate is a normal constituent of serum, produced from cysteine by way of β-mercaptopyruvate. Physiological levels of thiosulfate are typically about 0.1 mmol/L (11 mg/L), but they are approximately twice this level in pediatric and adult patients who are not eating. Infused thiosulfate is cleared from the body (primarily by the kidneys) with a half-life of about 20 minutes. - When thiosulfate is being supplied only by normal physiologic mechanisms, conversion of CN¯ to SCN¯ generally proceeds at about 1 mcg/kg/min. This rate of CN¯ clearance corresponds to steady-state processing of a sodium nitroprusside infusion of slightly more than 2 mcg/kg/min. CN¯ begins to accumulate when sodium nitroprusside infusions exceed this rate. - Thiocyanate (SCN¯) is also a normal physiological constituent of serum, with normal levels typically in the range of 50-250 µmol/L (3-15 mg/L). Clearance of SCN¯ is primarily renal, with a half-life of about 3 days. In renal failure, the half-life can be doubled or tripled. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, and Impairment of Fertility - Animal studies assessing sodium nitroprusside’s carcinogenicity and mutagenicity have not been conducted. Similarly, sodium nitroprusside has not been tested for effects on fertility. # Clinical Studies - Baseline-controlled clinical trials have uniformly shown that sodium nitroprusside has a prompt hypotensive effect, at least initially, in all populations. With increasing rates of infusion, sodium nitroprusside has been able to lower blood pressure without an observed limit of effect. - Clinical trials have also shown that the hypotensive effect of sodium nitroprusside is associated with reduced blood loss in a variety of major surgical procedures. - In patients with acute congestive heart failure and increased peripheral vascular resistance, administration of sodium nitroprusside causes reductions in peripheral resistance, increases in cardiac output, and reductions in left ventricular filling pressure. - Many trials have verified the clinical significance of the metabolic pathways described above. In patients receiving unopposed infusions of sodium nitroprusside, cyanide and thiocyanate levels have increased with increasing rates of sodium nitroprusside infusion. Mild to moderate metabolic acidosis has usually accompanied higher cyanide levels, but peak base deficits have lagged behind the peak cyanide levels by an hour or more. - Progressive tachyphylaxis to the hypotensive effects of sodium nitroprusside has been reported in several trials and numerous case reports. This tachyphylaxis has frequently been attributed to concomitant cyanide toxicity, but the only evidence adduced for this assertion has been the observation that in patients treated with sodium nitroprusside and found to be resistant to its hypotensive effects, cyanide levels are often found to be elevated. In the only reported comparisons of cyanide levels in resistant and nonresistant patients, cyanide levels did not correlate with tachyphylaxis. The mechanism of tachyphylaxis to sodium nitroprusside remains unknown. - The effects of sodium nitroprusside to induce hypotension were evaluated in two trials in pediatric patients less than 17 years of age. In both trials, at least 50% of the patients were pre-pubertal, and about 50% of these pre-pubertal patients were less than 2 years of age, including 4 neonates. The primary efficacy variable was the mean arterial pressure (MAP). - There were 203 pediatric patients in a parallel, dose-ranging study (Study 1). During the 30 minute blinded phase, patients were randomized 1:1:1:1 to receive sodium nitroprusside 0.3, 1, 2, or 3 μg/kg/min. The infusion rate was increased step-wise to the target dose rate (i.e., 1/3 of the full rate for the first 5 minutes, 2/3 of the full rate for the next 5 minutes, and the full dose rate for the last 20 minutes). If the investigator believed that an increase to the next higher dose rate would be unsafe, the infusion remained at the current rate for the remainder of the blinded infusion. Since there was no placebo group, the change from baseline likely overestimates the true magnitude of blood pressure effect. Nevertheless, MAP decreased 11 to 20 mmHg from baseline across the four doses (Table 1). - There were 63 pediatric patients in a long-term infusion trial (Study 2). During an open-label phase (12 to 24 hours), sodium nitroprusside was started at ≤0.3 μg/kg/min and titrated according to the BP response. - Patients were then randomized to placebo or to continuing the same dose of sodium nitroprusside. The average MAP was greater in the control group than in the sodium nitroprusside group for every time point during the blinded withdrawal phase, demonstrating that sodium nitroprusside is effective for at least 12 hours. - In both studies, similar effects on MAP were seen in all age groups. # How Supplied - Nitropress (sodium nitroprusside injection) is supplied in amber-colored, single-dose 50 mg/2 mL Fliptop Vials (NDC 0409-3024-01). - Store at 20 to 25°C (68 to 77°F). - To protect Nitropress from light, it should be stored in its carton until it is used. ## Storage There is limited information regarding Nitroprusside Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Nitroprusside in the drug label. # Precautions with Alcohol - Alcohol-Nitroprusside interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names File:Nitroprusside11.png # Look-Alike Drug Names - N/A # Drug Shortage Status # Price	Nitroprusside Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; # 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 Nitroprusside is a vasodilator that is FDA approved for the treatment of hypertensive crisis and acute congestive heart failure. It is also indicated for producing controlled hypotension in order to reduce bleeding during surgery.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include excessive hypotension and cyanide toxicity. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion Avoidance of excessive hypotension - While the average effective rate in adult and pediatric patients is about 3 μg/kg/min, some patients will become dangerously hypotensive when they receive Nitropress at this rate. Infusion of sodium nitroprusside should therefore be started at a very low rate (0.3 μg/kg/min), with upward titration every few minutes until the desired effect is achieved or the maximum recommended infusion rate (10 μg/kg/min) has been reached. - Because sodium nitroprusside's hypotensive effect is very rapid in onset and in dissipation, small variations in infusion rate can lead to wide, undesirable variations in blood pressure. Since there is inherent variation in blood pressure measurement, confirm the drug effect at any infusion rate after an additional 5 minutes before titrating to a higher dose to achieve the desired blood pressure. Sodium nitroprusside should not be infused through ordinary I.V. apparatus, regulated only by gravity and mechanical clamps. Only an infusion pump, preferably a volumetric pump, should be used. - Because sodium nitroprusside can induce essentially unlimited blood pressure reduction, the blood pressure of a patient receiving this drug must be continuously monitored, using either a continually reinflated sphygmomanometer or (preferably) an intra-arterial pressure sensor. Special caution should be used in elderly patients, since they may be more sensitive to the hypotensive effects of the drug. - When sodium nitroprusside is used in the treatment of acute congestive heart failure, titration of the infusion rate must be guided by the results of invasive hemodynamic monitoring with simultaneous monitoring of urine output. Sodium nitroprusside can be titrated by increasing the infusion rate until: measured cardiac output is no longer increasing, systemic blood pressure cannot be further reduced without compromising the perfusion of vital organs, or the maximum recommended infusion rate has been reached, whichever comes earliest. Specific hemodynamic goals must be tailored to the clinical situation, but improvements in cardiac output and left ventricular filling pressure must not be purchased at the price of undue hypotension and consequent hypoperfusion. - Table 2 below shows the infusion rates corresponding to the recommended initial and maximal doses (0.3 μg/kg/min and 10 μg/kg/min, respectively) for both adult and pediatric patients of various weights. This infusion rate may be lower than indicated in the table for patients less than 10 kg. Note that when the concentration used in a given patient is changed, the tubing is still filled with a solution at the previous concentration. Avoidance of cyanide toxicity - When more than 500 μg/kg of sodium nitroprusside is administered faster than 2 μg/kg/min, cyanide is generated faster than the unaided patient can eliminate it. Administration of sodium thiosulfate has been shown to increase the rate of cyanide processing, reducing the hazard of cyanide toxicity. Although toxic reactions to sodium thiosulfate have not been reported, the co-infusion regimen has not been extensively studied, and it cannot be recommended without reservation. In one study, sodium thiosulfate appeared to potentiate the hypotensive effects of sodium nitroprusside. - Co-infusions of sodium thiosulfate have been administered at rates of 5-10 times that of sodium nitroprusside. Care must be taken to avoid the indiscriminate use of prolonged or high doses of sodium nitroprusside with sodium thiosulfate as this may result in thiocyanate toxicity and hypovolemia. Incautious administration of sodium nitroprusside must still be avoided, and all of the precautions concerning sodium nitroprusside administration must still be observed. Consideration of methemoglobinemia and thiocyanate toxicity - Rare patients receiving more than 10 mg/kg of sodium nitroprusside will develop methemoglobinemia; other patients, especially those with impaired renal function, will predictably develop thiocyanate toxicity after prolonged, rapid infusions. Patients with suggestive findings should be tested for these toxicities. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nitroprusside in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 1–3 μg/kg/min IV infusion[1] - 1–2 μg/kg/min IV infusion[2] - Dosing Information - 10–33 μg/kg/min IV infusion, initially within 24 hours of onset of symptoms[3] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion - Dosing Information - Initial dose: 0.3 μg/kg/min IV infusion, titrate every few min to desired effect. - Average dose: 3 μg/kg/min IV infusion - Maximum dose: 10 μg/kg/min IV infusion Avoidance of excessive hypotension - While the average effective rate in adult and pediatric patients is about 3 μg/kg/min, some patients will become dangerously hypotensive when they receive Nitropress at this rate. Infusion of sodium nitroprusside should therefore be started at a very low rate (0.3 μg/kg/min), with upward titration every few minutes until the desired effect is achieved or the maximum recommended infusion rate (10 μg/kg/min) has been reached. - Because sodium nitroprusside's hypotensive effect is very rapid in onset and in dissipation, small variations in infusion rate can lead to wide, undesirable variations in blood pressure. Since there is inherent variation in blood pressure measurement, confirm the drug effect at any infusion rate after an additional 5 minutes before titrating to a higher dose to achieve the desired blood pressure. Sodium nitroprusside should not be infused through ordinary I.V. apparatus, regulated only by gravity and mechanical clamps. Only an infusion pump, preferably a volumetric pump, should be used. - Because sodium nitroprusside can induce essentially unlimited blood pressure reduction, the blood pressure of a patient receiving this drug must be continuously monitored, using either a continually reinflated sphygmomanometer or (preferably) an intra-arterial pressure sensor. Special caution should be used in elderly patients, since they may be more sensitive to the hypotensive effects of the drug. - When sodium nitroprusside is used in the treatment of acute congestive heart failure, titration of the infusion rate must be guided by the results of invasive hemodynamic monitoring with simultaneous monitoring of urine output. Sodium nitroprusside can be titrated by increasing the infusion rate until: measured cardiac output is no longer increasing, systemic blood pressure cannot be further reduced without compromising the perfusion of vital organs, or the maximum recommended infusion rate has been reached, whichever comes earliest. Specific hemodynamic goals must be tailored to the clinical situation, but improvements in cardiac output and left ventricular filling pressure must not be purchased at the price of undue hypotension and consequent hypoperfusion. - Table 2 below shows the infusion rates corresponding to the recommended initial and maximal doses (0.3 μg/kg/min and 10 μg/kg/min, respectively) for both adult and pediatric patients of various weights. This infusion rate may be lower than indicated in the table for patients less than 10 kg. Note that when the concentration used in a given patient is changed, the tubing is still filled with a solution at the previous concentration. Avoidance of cyanide toxicity - When more than 500 μg/kg of sodium nitroprusside is administered faster than 2 μg/kg/min, cyanide is generated faster than the unaided patient can eliminate it. Administration of sodium thiosulfate has been shown to increase the rate of cyanide processing, reducing the hazard of cyanide toxicity. Although toxic reactions to sodium thiosulfate have not been reported, the co-infusion regimen has not been extensively studied, and it cannot be recommended without reservation. In one study, sodium thiosulfate appeared to potentiate the hypotensive effects of sodium nitroprusside. - Co-infusions of sodium thiosulfate have been administered at rates of 5-10 times that of sodium nitroprusside. Care must be taken to avoid the indiscriminate use of prolonged or high doses of sodium nitroprusside with sodium thiosulfate as this may result in thiocyanate toxicity and hypovolemia. Incautious administration of sodium nitroprusside must still be avoided, and all of the precautions concerning sodium nitroprusside administration must still be observed. Consideration of methemoglobinemia and thiocyanate toxicity - Rare patients receiving more than 10 mg/kg of sodium nitroprusside will develop methemoglobinemia; other patients, especially those with impaired renal function, will predictably develop thiocyanate toxicity after prolonged, rapid infusions. Patients with suggestive findings should be tested for these toxicities. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nitroprusside in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - 1–5 μg/kg/min IV infusion for 2–8 days[4] - Dosing Information - 15–20 mg/day inhalation[5] - 0.2–6.0 μg/kg/min IV infusion[6] # Contraindications - Compensatory hypertension in aortic coarctation or arteriovenous shunts - Sodium nitroprusside should not be used in the treatment of compensatory hypertension, where the primary hemodynamic lesion is aortic coarctation or arteriovenous shunts. - Inadequate cerebral circulation or moribund patients - Sodium nitroprusside should not be used to produce hypotension during surgery in patients with known inadequate cerebral circulation, or in moribund patients (A.S.A. Class 5E) coming to emergency surgery. - High cyanide/thiocyanate ratios - Patients with congenital (Leber’s) optic atrophy or with tobacco amblyopia have unusually high cyanide/thiocyanate ratios. These rare conditions are probably associated with defective or absent rhodanase, and sodium nitroprusside should be avoided in these patients. - Acute congestive heart failure associated with reduced peripheral vascular resistance - Sodium nitroprusside should not be used for the treatment of acute congestive heart failure associated with reduced peripheral vascular resistance such as high-output heart failure that may be seen in endotoxic sepsis. # Warnings - The principal hazards of Nitropress administration are excessive hypotension and excessive accumulation of cyanide. - Excessive Hypotension - Small transient excesses in the infusion rate of sodium nitroprusside can result in excessive hypotension, sometimes to levels so low as to compromise the perfusion of vital organs. These hemodynamic changes may lead to a variety of associated symptoms. Nitroprusside-induced hypotension will be self-limited within 1-10 minutes after discontinuation of the nitroprusside infusion; during these few minutes, it may be helpful to put the patient into a head-down (Trendelenburg) position to maximize venous return. If hypotension persists more than a few minutes after discontinuation of the infusion of Nitropress, Nitropress is not the cause, and the true cause must be sought. - Cyanide Toxicity - Sodium nitroprusside infusions at rates above 2 μg/kg/min generate cyanide ion (CN¯) faster than the body can normally dispose of it. (When sodium thiosulfate is given, the body’s capacity for CN¯ elimination is greatly increased.) Methemoglobin normally present in the body can buffer a certain amount of CN¯, but the capacity of this system is exhausted by the CN¯ produced from about 500 μg/kg of sodium nitroprusside. This amount of sodium nitroprusside is administered in less than an hour when the drug is administered at 10 μg/kg/min (the maximum recommended rate). Thereafter, the toxic effects of CN¯ may be rapid, serious, and even lethal. - The true rates of clinically important cyanide toxicity cannot be assessed from spontaneous reports or published data. Most patients reported to have experienced such toxicity have received relatively prolonged infusions, and the only patients whose deaths have been unequivocally attributed to nitroprusside-induced cyanide toxicity have been patients who had received nitroprusside infusions at rates (30-120 μg/kg/min) much greater than those now recommended. Elevated cyanide levels, metabolic acidosis, and marked clinical deterioration, however, have occasionally been reported in patients who received infusions at recommended rates for only a few hours and even, in one case, for only 35 minutes. In some of these cases, infusion of sodium thiosulfate caused dramatic clinical improvement, supporting the diagnosis of cyanide toxicity. - Cyanide toxicity may manifest itself as venous hyperoxemia with bright red venous blood, as cells become unable to extract the oxygen delivered to them; metabolic acidosis (lactic acidosis); air hunger; confusion; and death. Cyanide toxicity due to causes other than nitroprusside has been associated with angina pectoris and myocardial infarction; ataxia, seizures, and stroke; and other diffuse ischemic damage. - Hypertensive patients, and patients concomitantly receiving other antihypertensive medications, may be more sensitive to the effects of sodium nitroprusside than normal subjects. ### Precautions - General - Like other vasodilators, sodium nitroprusside can cause increases in intracranial pressure. In patients whose intracranial pressure is already elevated, sodium nitroprusside should be used only with extreme caution. - Hepatic - Use caution when administering nitroprusside to patients with hepatic insufficiency. - Use in Anesthesia - When sodium nitroprusside (or any other vasodilator) is used for controlled hypotension during anesthesia, the patient’s capacity to compensate for anemia and hypovolemia may be diminished. If possible, pre-existing anemia and hypovolemia should be corrected prior to administration of Nitropress. Hypotensive anesthetic techniques may also cause abnormalities of the pulmonary ventilation/perfusion ratio. Patients intolerant of these abnormalities may require a higher fraction of inspired oxygen. Extreme caution should be exercised in patients who are especially poor surgical risks (A.S.A. Class 4 and 4E). - Laboratory Tests - The cyanide level assay is technically difficult, and cyanide levels in body fluids other than packed red blood cells are difficult to interpret. Cyanide toxicity will lead to lactic acidosis and venous hyperoxemia, but these findings may not be present until an hour or more after the cyanide capacity of the body’s red-cell mass has been exhausted. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Nitroprusside in the drug label. ## Postmarketing Experience - The most important adverse reactions to sodium nitroprusside are the avoidable ones of excessive hypotension and cyanide toxicity. The adverse reactions described in this section develop less rapidly and, as it happens, less commonly. - Methemoglobinemia - Sodium nitroprusside infusions can cause sequestration of hemoglobin as methemoglobin. The back-conversion process is normally rapid, and clinically significant methemoglobinemia (>10%) is seen only rarely in patients receiving Nitropress. Even patients congenitally incapable of back-converting methemoglobin should demonstrate 10% methemoglobinemia only after they have received about 10 mg/kg of sodium nitroprusside, and a patient receiving sodium nitroprusside at the maximum recommended rate (10 μg/kg/min) would take over 16 hours to reach this total accumulated dose. - Methemoglobin levels can be measured by most clinical laboratories. The diagnosis should be suspected in patients who have received >10 mg/kg of sodium nitroprusside and who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. - When methemoglobinemia is diagnosed, the treatment of choice is 1-2 mg/kg of methylene blue, administered intravenously over several minutes. In patients likely to have substantial amounts of cyanide bound to methemoglobin as cyanmethemoglobin, treatment of methemoglobinemia with methylene blue must be undertaken with extreme caution. - Thiocyanate Toxicity - Most of the cyanide produced during metabolism of sodium nitroprusside is eliminated in the form of thiocyanate. When cyanide elimination is accelerated by the co-infusion of thiosulfate, thiocyanate production is increased. - Thiocyanate is mildly neurotoxic (tinnitus, miosis, hyperreflexia) at serum levels of 1 mmol/L (60 mg/L). Thiocyanate toxicity is life-threatening when levels are 3 or 4 times higher (200 mg/L). - The steady-state thiocyanate level after prolonged infusions of sodium nitroprusside is increased with increased infusion rate, and the half-time of accumulation is 3-4 days. To keep the steady-state thiocyanate level below 1 mmol/L, a prolonged infusion of sodium nitroprusside should not be more rapid than 3 μg/kg/min; in anuric patients, the corresponding limit is just 1 μg/kg/min. When prolonged infusions are more rapid than these, thiocyanate levels should be measured daily. - Physiologic maneuvers (e.g., those that alter the pH of the urine) are not known to increase the elimination of thiocyanate. Thiocyanate clearance rates during dialysis, on the other hand, can approach the blood flow rate of the dialyzer. - Thiocyanate interferes with iodine uptake by the thyroid. - Abdominal pain, apprehension, diaphoresis, dizziness, headache, muscle twitching, nausea, palpitations, restlessness, retching, and retrosternal discomfort have been noted when the blood pressure was too rapidly reduced. These symptoms quickly disappeared when the infusion was slowed or discontinued, and they did not reappear with a continued (or resumed) slower infusion. - Other adverse reactions reported are: Increased intracranial pressure. Bradycardia, electrocardiographic changes, tachycardia. Ileus. Decreased platelet aggregation. Rash. Hypothyroidism. Flushing, venous streaking, irritation at the infusion site. # Drug Interactions - Antihypertensive agents - The hypotensive effect of sodium nitroprusside is augmented by that of most other hypotensive drugs, including ganglionic blocking agents, negative inotropic agents, and inhaled anesthetics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic effects - There are no adequate, well-controlled studies of Nitropress in either laboratory animals or pregnant women. It is not known whether Nitropress can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Nitropress should be given to a pregnant woman only if clearly needed. - Nonteratogenic effects - In three studies in pregnant ewes, nitroprusside was shown to cross the placental barrier. Fetal cyanide levels were shown to be dose-related to maternal levels of nitroprusside. The metabolic transformation of sodium nitroprusside given to pregnant ewes led to fatal levels of cyanide in the fetuses. The infusion of 25 μg/kg/min of sodium nitroprusside for one hour in pregnant ewes resulted in the death of all fetuses. Pregnant ewes infused with 1 μg/kg/min of sodium nitroprusside for one hour delivered normal lambs. - According to one investigator, a pregnant woman at 24 weeks gestation was given sodium nitroprusside to control gestational hypertension secondary to mitral valve disease. Sodium nitroprusside was infused at 3.9 μg/kg/min for a total of 3.5 mg/kg over 15 hours prior to delivery of a 478 gram stillborn infant without any obvious anomalies. Cyanide levels in the fetal liver were less than 10 μg/mL. Toxic levels have been reported to be more than 30-40 μg/mL. The mother demonstrated no cyanide toxicity. - The effects of administering sodium thiosulfate in pregnancy, either by itself or as a co-infusion with sodium nitroprusside, are completely unknown. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitroprusside in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nitroprusside during labor and delivery. ### Nursing Mothers - It is not known whether sodium nitroprusside and its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from sodium nitroprusside, 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 - Efficacy in the pediatric population was established based on adult trials and supported by the dose-ranging trial (Study 1) and an open label trial of at least 12 hour infusion at a rate that achieved adequate MAP control (Study 2) with pediatric patients on sodium nitroprusside. No novel safety issues were seen in these studies in pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Nitroprusside with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Nitroprusside with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nitroprusside with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nitroprusside in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nitroprusside in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nitroprusside in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nitroprusside in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Dilution to proper strength for infusion - Depending on the desired concentration, the solution containing 50 mg of Nitropress must be further diluted in 250-1000 mL of sterile 5% dextrose injection. The diluted solution should be protected from light, using the supplied opaque sleeve, aluminum foil, or other opaque material. It is not necessary to cover the infusion drip chamber or the tubing. - Verification of the chemical integrity of the product - Sodium nitroprusside solution can be inactivated by reactions with trace contaminants. The products of these reactions are often blue, green, or red, much brighter than the faint brownish color of unreacted Nitropress. Discolored solutions, or solutions in which particulate matter is visible, should not be used. If properly protected from light, the freshly diluted solution is stable for 24 hours. - No other drugs should be administered in the same solution with sodium nitroprusside. ### Monitoring - Because sodium nitroprusside can induce essentially unlimited blood pressure reduction, the blood pressure of a patient receiving this drug must be continuously monitored, using either a continually reinflated sphygmomanometer or (preferably) an intra-arterial pressure sensor. Special caution should be used in elderly patients, since they may be more sensitive to the hypotensive effects of the drug. - When sodium nitroprusside is used in the treatment of acute congestive heart failure, titration of the infusion rate must be guided by the results of invasive hemodynamic monitoring with simultaneous monitoring of urine output. # IV Compatibility There is limited information regarding the compatibility of Nitroprusside and IV administrations. # Overdosage ## Acute Overdose ### Signs and Symptoms - Overdosage of nitroprusside can be manifested as excessive hypotension or cyanide toxicity or as thiocyanate toxicity. - The acute intravenous mean lethal doses (LD50) of nitroprusside in rabbits, dogs, mice, and rats are 2.8, 5.0, 8.4, and 11.2 mg/kg, respectively. ### Management - Treatment of cyanide toxicity - Cyanide levels can be measured by many laboratories, and blood-gas studies that can detect venous hyperoxemia or acidosis are widely available. Acidosis may not appear until more than an hour after the appearance of dangerous cyanide levels, and laboratory tests should not be awaited. Reasonable suspicion of cyanide toxicity is adequate grounds for initiation of treatment. - Treatment of cyanide toxicity consists of: - Discontinuing the administration of sodium nitroprusside - Providing a buffer for cyanide by using sodium nitrite to convert as much hemoglobin into methemoglobin as the patient can safely tolerate - Infusing sodium thiosulfate in sufficient quantity to convert the cyanide into thiocyanate - The necessary medications for this treatment are contained in commercially available Cyanide Antidote Kits. Alternatively, discrete stocks of medications can be used. - Hemodialysis is ineffective in removal of cyanide, but it will eliminate most thiocyanate. - Cyanide Antidote Kits contain both amyl nitrite and sodium nitrite for induction of methemoglobinemia. The amyl nitrite is supplied in the form of inhalant ampoules, for administration in environments where intravenous administration of sodium nitrite may be delayed. In a patient who already has a patent intravenous line, use of amyl nitrite confers no benefit that is not provided by infusion of sodium nitrite. - Sodium nitrite is available in a 3% solution, and 4-6 mg/kg (about 0.2 mL/kg) should be injected over 2-4 minutes. This dose can be expected to convert about 10% of the patient’s hemoglobin into methemoglobin; this level of methemoglobinemia is not associated with any important hazard of its own. The nitrite infusion may cause transient vasodilatation and hypotension, and this hypotension must, if it occurs, be routinely managed. - Immediately after infusion of the sodium nitrite, sodium thiosulfate should be infused. This agent is available in 10% and 25% solutions, and the recommended dose is 150-200 mg/kg; a typical adult dose is 50 mL of the 25% solution. Thiosulfate treatment of an acutely cyanide-toxic patient will raise thiocyanate levels, but not to a dangerous degree. - The nitrite/thiosulfate regimen may be repeated, at half the original doses, after two hours. ## Chronic Overdose There is limited information regarding Chronic Overdose of Nitroprusside in the drug label. # Pharmacology ## Mechanism of Action - The principal pharmacological action of sodium nitroprusside is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins. Other smooth muscle (e.g., uterus, duodenum) is not affected. Sodium nitroprusside is more active on veins than on arteries, but this selectivity is much less marked than that of nitroglycerin. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. ## Structure - Sodium nitroprusside is disodium pentacyanonitrosylferrate(2-) dihydrate, a hypotensive agent whose structural formula is: - The molecular formula is Na2[Fe(CN)5NO] • 2H2O, and the molecular weight is 297.95. Dry sodium nitroprusside is a reddish-brown powder, soluble in water. In an aqueous solution infused intravenously, sodium nitroprusside is a rapid-acting vasodilator, active on both arteries and veins. - Sodium nitroprusside solution is rapidly degraded by trace contaminants, often with resulting color changes. The solution is also sensitive to certain wavelengths of light, and it must be protected from light in clinical use. ## Pharmacodynamics - In association with the decrease in blood pressure, sodium nitroprusside administered intravenously to hypertensive and normotensive patients produces slight increases in heart rate and a variable effect on cardiac output. In hypertensive patients, moderate doses induce renal vasodilatation roughly proportional to the decrease in systemic blood pressure, so there is no appreciable change in renal blood flow or glomerular filtration rate. - In normotensive subjects, acute reduction of mean arterial pressure to 60-75 mm Hg by infusion of sodium nitroprusside caused a significant increase in renin activity. In the same study, ten renovascular-hypertensive patients given sodium nitroprusside had significant increases in renin release from the involved kidney at mean arterial pressures of 90-137 mm Hg. - The hypotensive effect of sodium nitroprusside is seen within a minute or two after the start of an adequate infusion, and it dissipates almost as rapidly after an infusion is discontinued. The effect is augmented by ganglionic blocking agents and inhaled anesthetics. ## Pharmacokinetics - Infused sodium nitroprusside is rapidly distributed to a volume that is approximately coextensive with the extracellular space. The drug is cleared from this volume by intraerythrocytic reaction with hemoglobin (Hgb), and sodium nitroprusside’s resulting circulatory half-life is about 2 minutes. - The products of the nitroprusside/hemoglobin reaction are cyanmethemoglobin (cyanmetHgb) and cyanide ion (CN¯). Safe use of sodium nitroprusside injection must be guided by knowledge of the further metabolism of these products. - As shown in the diagram below, the essential features of nitroprusside metabolism are: - One molecule of sodium nitroprusside is metabolized by combination with hemoglobin to produce one molecule of cyanmethemoglobin and four CN¯ ions - Methemoglobin, obtained from hemoglobin, can sequester cyanide as cyanmethemoglobin - Thiosulfate reacts with cyanide to produce thiocyanate - Thiocyanate is eliminated in the urine - Cyanide not otherwise removed binds to cytochromes - Cyanide is much more toxic than methemoglobin or thiocyanate - Cyanide ion is normally found in serum; it is derived from dietary substrates and from tobacco smoke. Cyanide binds avidly (but reversibly) to ferric ion (Fe+++), most body stores of which are found in erythrocyte methemoglobin (metHgb) and in mitochondrial cytochromes. When CN¯ is infused or generated within the bloodstream, essentially all of it is bound to methemoglobin until intraerythrocytic methemoglobin has been saturated. - When the Fe+++ of cytochromes is bound to cyanide, the cytochromes are unable to participate in oxidative metabolism. In this situation, cells may be able to provide for their energy needs by utilizing anaerobic pathways, but they thereby generate an increasing body burden of lactic acid. Other cells may be unable to utilize these alternative pathways, and they may die hypoxic deaths. - CN¯ levels in packed erythrocytes are typically less than 1 µmol/L (less than 25 mcg/L); levels are roughly doubled in heavy smokers. - At healthy steady state, most people have less than 1% of their hemoglobin in the form of methemoglobin. Nitroprusside metabolism can lead to methemoglobin formation (a) through dissociation of cyanmethemoglobin formed in the original reaction of sodium nitroprusside with Hgb and (b) by direct oxidation of Hgb by the released nitroso group. Relatively large quantities of sodium nitroprusside, however, are required to produce significant methemoglobinemia. - At physiologic methemoglobin levels, the CN¯ binding capacity of packed red cells is a little less than 200 µmol/L (5 mg/L). Cytochrome toxicity is seen at levels only slightly higher, and death has been reported at levels from 300 to 3000 µmol/L (8–80 mg/L). Put another way, a patient with a normal red-cell mass (35 mL/kg) and normal methemoglobin levels can buffer about 175 mcg/kg of CN¯, corresponding to a little less than 500 mcg/kg of infused sodium nitroprusside. - Some cyanide is eliminated from the body as expired hydrogen cyanide, but most is enzymatically converted to thiocyanate (SCN¯) by thiosulfate-cyanide sulfur transferase (rhodanase, EC 2.8.1.1), a mitochondrial enzyme. The enzyme is normally present in great excess, so the reaction is rate-limited by the availability of sulfur donors, especially thiosulfate, cystine, and cysteine. - Thiosulfate is a normal constituent of serum, produced from cysteine by way of β-mercaptopyruvate. Physiological levels of thiosulfate are typically about 0.1 mmol/L (11 mg/L), but they are approximately twice this level in pediatric and adult patients who are not eating. Infused thiosulfate is cleared from the body (primarily by the kidneys) with a half-life of about 20 minutes. - When thiosulfate is being supplied only by normal physiologic mechanisms, conversion of CN¯ to SCN¯ generally proceeds at about 1 mcg/kg/min. This rate of CN¯ clearance corresponds to steady-state processing of a sodium nitroprusside infusion of slightly more than 2 mcg/kg/min. CN¯ begins to accumulate when sodium nitroprusside infusions exceed this rate. - Thiocyanate (SCN¯) is also a normal physiological constituent of serum, with normal levels typically in the range of 50-250 µmol/L (3-15 mg/L). Clearance of SCN¯ is primarily renal, with a half-life of about 3 days. In renal failure, the half-life can be doubled or tripled. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, and Impairment of Fertility - Animal studies assessing sodium nitroprusside’s carcinogenicity and mutagenicity have not been conducted. Similarly, sodium nitroprusside has not been tested for effects on fertility. # Clinical Studies - Baseline-controlled clinical trials have uniformly shown that sodium nitroprusside has a prompt hypotensive effect, at least initially, in all populations. With increasing rates of infusion, sodium nitroprusside has been able to lower blood pressure without an observed limit of effect. - Clinical trials have also shown that the hypotensive effect of sodium nitroprusside is associated with reduced blood loss in a variety of major surgical procedures. - In patients with acute congestive heart failure and increased peripheral vascular resistance, administration of sodium nitroprusside causes reductions in peripheral resistance, increases in cardiac output, and reductions in left ventricular filling pressure. - Many trials have verified the clinical significance of the metabolic pathways described above. In patients receiving unopposed infusions of sodium nitroprusside, cyanide and thiocyanate levels have increased with increasing rates of sodium nitroprusside infusion. Mild to moderate metabolic acidosis has usually accompanied higher cyanide levels, but peak base deficits have lagged behind the peak cyanide levels by an hour or more. - Progressive tachyphylaxis to the hypotensive effects of sodium nitroprusside has been reported in several trials and numerous case reports. This tachyphylaxis has frequently been attributed to concomitant cyanide toxicity, but the only evidence adduced for this assertion has been the observation that in patients treated with sodium nitroprusside and found to be resistant to its hypotensive effects, cyanide levels are often found to be elevated. In the only reported comparisons of cyanide levels in resistant and nonresistant patients, cyanide levels did not correlate with tachyphylaxis. The mechanism of tachyphylaxis to sodium nitroprusside remains unknown. - The effects of sodium nitroprusside to induce hypotension were evaluated in two trials in pediatric patients less than 17 years of age. In both trials, at least 50% of the patients were pre-pubertal, and about 50% of these pre-pubertal patients were less than 2 years of age, including 4 neonates. The primary efficacy variable was the mean arterial pressure (MAP). - There were 203 pediatric patients in a parallel, dose-ranging study (Study 1). During the 30 minute blinded phase, patients were randomized 1:1:1:1 to receive sodium nitroprusside 0.3, 1, 2, or 3 μg/kg/min. The infusion rate was increased step-wise to the target dose rate (i.e., 1/3 of the full rate for the first 5 minutes, 2/3 of the full rate for the next 5 minutes, and the full dose rate for the last 20 minutes). If the investigator believed that an increase to the next higher dose rate would be unsafe, the infusion remained at the current rate for the remainder of the blinded infusion. Since there was no placebo group, the change from baseline likely overestimates the true magnitude of blood pressure effect. Nevertheless, MAP decreased 11 to 20 mmHg from baseline across the four doses (Table 1). - There were 63 pediatric patients in a long-term infusion trial (Study 2). During an open-label phase (12 to 24 hours), sodium nitroprusside was started at ≤0.3 μg/kg/min and titrated according to the BP response. - Patients were then randomized to placebo or to continuing the same dose of sodium nitroprusside. The average MAP was greater in the control group than in the sodium nitroprusside group for every time point during the blinded withdrawal phase, demonstrating that sodium nitroprusside is effective for at least 12 hours. - In both studies, similar effects on MAP were seen in all age groups. # How Supplied - Nitropress (sodium nitroprusside injection) is supplied in amber-colored, single-dose 50 mg/2 mL Fliptop Vials (NDC 0409-3024-01). - Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] - To protect Nitropress from light, it should be stored in its carton until it is used. ## Storage There is limited information regarding Nitroprusside Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Nitroprusside in the drug label. # Precautions with Alcohol - Alcohol-Nitroprusside interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names File:Nitroprusside11.png # Look-Alike Drug Names - N/A[7] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Nitropress
b9166b965e0898450ef296350ea87a0273338235	wikidoc	Nitrosylation	Nitrosylation Nitrosylation is a protein modification, in which a nitrosyl group is post-translationally added to a protein. There are a range of enzymes that produce nitric oxide, and the frequent consequence of this production is nitrosylation. S-nitrosylation is a biologically important reaction of nitric oxide; it refers to the conversion of thiol groups, including cysteine residues in proteins, to form S-nitrosothiols (RSNOs). S-Nitrosylation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.	Nitrosylation Nitrosylation is a protein modification, in which a nitrosyl group is post-translationally added to a protein. There are a range of enzymes that produce nitric oxide, and the frequent consequence of this production is nitrosylation. S-nitrosylation is a biologically important reaction of nitric oxide; it refers to the conversion of thiol groups, including cysteine residues in proteins, to form S-nitrosothiols (RSNOs). S-Nitrosylation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein. Template:WH Template:WS	https://www.wikidoc.org/index.php/Nitrosylation
aa93bd6c5adcd3cc0a6c162ebae2fad9cbdb3c35	wikidoc	Norethindrone	Norethindrone # 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 Norethindrone is an oral contraceptive that is FDA approved for the prevention of of pregnancy. Common adverse reactions include nausea, headache, abnormal menstrual cycle, breast tenderness, irregular periods. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - To achieve maximum contraceptive effectiveness, norethindrone tablets must be taken exactly as directed. One tablet is taken every day, at the same time. Administration is continuous, with no interruption between pill packs. - Efficacy - If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. Table 1 lists the pregnancy rates for users of all major methods of contraception. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Norethindrone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Norethindrone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Norethindrone in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Norethindrone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Norethindrone in pediatric patients. # Contraindications - Known or suspected pregnancy - Known or suspected carcinoma of the breast - Undiagnosed abnormal genital bleeding - Hypersensitivity to any component of this product - Benign or malignant liver tumors - Acute liver disease # Warnings - Cigarette smoking increases the risk of serious cardiovascular disease. Women who use oral contraceptives should be strongly advised not to smoke. - Norethindrone tablets do not contain estrogen and, therefore, this insert does not discuss the serious health risks that have been associated with the estrogen component of combined oral contraceptives (COCs). The healthcare professional is referred to the prescribing information of combined oral contraceptives for a discussion of those risks. The relationship between progestin-only oral contraceptives and these risks is not fully defined. The healthcare professional should remain alert to the earliest manifestation of symptoms of any serious disease and discontinue oral contraceptive therapy when appropriate. - Ectopic Pregnancy - The incidence of ectopic pregnancies for progestin-only oral contraceptive users is 5 per 1000 woman-years. Up to 10% of pregnancies reported in clinical studies of progestin-only oral contraceptive users are extrauterine. Although symptoms of ectopic pregnancy should be watched for, a history of ectopic pregnancy need not be considered a contraindication to use of this contraceptive method. Healthcare professionals should be alert to the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while on progestin-only oral contraceptives. - Delayed Follicular Atresia/Ovarian Cysts - If follicular development occurs, atresia of the follicle is sometimes delayed and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally these enlarged follicles disappear spontaneously. Often they are asymptomatic; in some cases they are associated with mild abdominal pain. Rarely they may twist or rupture, requiring surgical intervention. - Irregular Genital Bleeding - Irregular menstrual patterns are common among women using progestin-only oral contraceptives. If genital bleeding is suggestive of infection, malignancy or other abnormal conditions, such nonpharmacologic causes should be ruled out. If prolonged amenorrhea occurs, the possibility of pregnancy should be evaluated. - Carcinoma of the Breast and Reproductive Organs - Some epidemiological studies of oral contraceptive users have reported an increased relative risk of developing breast cancer, particularly at a younger age and apparently related to duration of use. These studies have predominantly involved combined oral contraceptives and there is insufficient data to determine whether the use of POPs similarly increases the risk. - A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. - This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use. - Women with breast cancer should not use oral contraceptives because the role of female hormones in breast cancer has not been fully determined. - Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. There is insufficient data to determine whether the use of POPs increases the risk of developing cervical intraepithelial neoplasia. - Hepatic Neoplasia - Benign hepatic adenomas are associated with combined oral contraceptive use, although the incidence of benign tumors is rare in the United States. Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. - Studies have shown an increased risk of developing hepatocellular carcinoma in combined oral contraceptive users. However, these cancers are rare in the U.S. There is insufficient data to determine whether POPs increase the risk of developing hepatic neoplasia. ### Precautions - General - Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. - Physical Examination and Follow-up - It is considered good medical practice for sexually active women using oral contraceptives to have annual history and physical examinations. The physical examination may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the healthcare professional. - Carbohydrate and Lipid Metabolism - Some users may experience slight deterioration in glucose tolerance, with increases in plasma insulin but women with diabetes mellitus who use progestin-only oral contraceptives do not generally experience changes in their insulin requirements. Nonetheless, prediabetic and diabetic women in particular should be carefully monitored while taking POPs. - Lipid metabolism is occasionally affected in that HDL, HDL2, and apolipoprotein A-I and A-II may be decreased; hepatic lipase may be increased. There is usually no effect on total cholesterol, HDL3, LDL, or VLDL. - Headache - The onset or exacerbation of migraine or development of severe headache with focal neurological symptoms which is recurrent or persistent requires discontinuation of progestin-only contraceptives and evaluation of the cause. # Adverse Reactions ## Clinical Trials Experience - Adverse reactions reported with the use of POPs include: - Menstrual irregularity is the most frequently reported side effect. - Frequent and irregular bleeding are common, while long duration of bleeding episodes and amenorrhea are less likely. - Headache, breast tenderness, nausea, and dizziness are increased among progestin-only oral contraceptive users in some studies. - Androgenic side effects such as acne, hirsutism, and weight gain occur rarely. - The following adverse reactions were also reported in clinical trials : fatigue, edema vomiting, abdominal pain, hepatitis, jaundice cholestatic pain in extremity depression, nervousness anaphylactic/anaphylactoid reaction, hypersensitivity, alopecia, rash, rash pruritic. genital discharge; breast pain, menstruation delayed, suppressed lactation, vaginal hemorrhage, menorrhagia, withdrawal bleed when product is stopped ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Norethindrone in the drug label. # Drug Interactions - The effectiveness of progestin-only pills is reduced by hepatic enzyme-inducing drugs such as the anticonvulsants phenytoin, carbamazepine, and barbiturates, and the antituberculosis drug rifampin. No significant interaction has been found with broad-spectrum antibiotics. - Herbal products containing St. John’s Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. - Concurrent use of bosentan and norethindrone containing products may result in decreased concentrations of these contraceptive hormones thereby increasing the risk of unintended pregnancy and unscheduled bleeding. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category - Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted have not demonstrated significant adverse effects. It is nonetheless prudent to rule out suspected pregnancy before initiating any hormonal contraceptive use. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Norethindrone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Norethindrone during labor and delivery. ### Nursing Mothers - In general, no adverse effects have been found on breastfeeding performance or on the health, growth, or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers, resulting in detectable steroid levels in infant plasma. ### Pediatric Use - Safety and efficacy of norethindronetablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. ### Geriatic Use There is no FDA guidance on the use of Norethindrone with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Norethindrone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Norethindrone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Norethindrone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Norethindrone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Norethindrone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Norethindrone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Norethindrone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Norethindrone in the drug label. # Overdosage ## Acute Overdose - There have been no reports of serious ill effects from overdosage, including ingestion by children. ## Chronic Overdose There is limited information regarding Chronic Overdose of Norethindrone in the drug label. # Pharmacology ## Mechanism of Action - Errin® progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the midcycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium. ## Structure - Norethindrone, USP is a white to creamy white, odorless, crystalline powder. It is stable in air. Practically insoluble in water; soluble in chloroform and in dioxane; sparingly soluble in alcohol; slightly soluble in ether. The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one. The structural formula is as follows: - Each yellow tablet contains 0.35 mg norethindrone, USP and has the following inactive ingredients: anhydrous lactose, corn starch, D&C yellow no. 10 aluminum lake, ethylcellulose aqueous dispersion, lactose monohydrate, magnesium stearate, microcrystalline cellulose and povidone. - Meets USP Dissolution Test 2. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Norethindrone in the drug label. ## Pharmacokinetics - Serum progestin levels peak about two hours after oral administration, followed by rapid distribution and elimination. By 24 hours after drug ingestion, serum levels are near baseline, making efficacy dependent upon rigid adherence to the dosing schedule. There are large variations in serum levels among individual users. Progestin-only administration results in lower steady-state serum progestin levels and a shorter elimination half-life than concomitant administration with estrogens. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Norethindrone in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Norethindrone in the drug label. # How Supplied - Errin® (norethindrone tablets, USP 0.35 mg) are packaged in cartons of six blister cards each containing 28 tablets. Each yellow, round, flat-faced, beveled-edge, unscored tablet is debossed with stylized b on one side and 344 on the other side. - Store at 20° to 25°C (68° to 77°F). - KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. ## Storage There is limited information regarding Norethindrone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Counseling Issues - The following points should be discussed with prospective users before prescribing progestin-only oral contraceptives: - The necessity of taking pills at the same time every day, including throughout all bleeding episodes. - The need to use a backup method such as a condom and spermicide for the next 48 hours whenever a progestin-only oral contraceptive is taken 3 or more hours late. - The potential side effects of progestin-only oral contraceptives, particularly menstrual irregularities. - The need to inform the healthcare professional of prolonged episodes of bleeding, amenorrhea or severe abdominal pain. - The importance of using a barrier method in addition to progestin-only oral contraceptives if a woman is at risk of contracting or transmitting STDs/HIV. # Precautions with Alcohol - Alcohol-Norethindrone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ERRIN® # Look-Alike Drug Names There is limited information regarding Norethindrone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Norethindrone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, 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 Norethindrone is an oral contraceptive that is FDA approved for the prevention of of pregnancy. Common adverse reactions include nausea, headache, abnormal menstrual cycle, breast tenderness, irregular periods. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - To achieve maximum contraceptive effectiveness, norethindrone tablets must be taken exactly as directed. One tablet is taken every day, at the same time. Administration is continuous, with no interruption between pill packs. - Efficacy - If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. Table 1 lists the pregnancy rates for users of all major methods of contraception. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Norethindrone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Norethindrone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Norethindrone in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Norethindrone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Norethindrone in pediatric patients. # Contraindications - Known or suspected pregnancy - Known or suspected carcinoma of the breast - Undiagnosed abnormal genital bleeding - Hypersensitivity to any component of this product - Benign or malignant liver tumors - Acute liver disease # Warnings - Cigarette smoking increases the risk of serious cardiovascular disease. Women who use oral contraceptives should be strongly advised not to smoke. - Norethindrone tablets do not contain estrogen and, therefore, this insert does not discuss the serious health risks that have been associated with the estrogen component of combined oral contraceptives (COCs). The healthcare professional is referred to the prescribing information of combined oral contraceptives for a discussion of those risks. The relationship between progestin-only oral contraceptives and these risks is not fully defined. The healthcare professional should remain alert to the earliest manifestation of symptoms of any serious disease and discontinue oral contraceptive therapy when appropriate. - Ectopic Pregnancy - The incidence of ectopic pregnancies for progestin-only oral contraceptive users is 5 per 1000 woman-years. Up to 10% of pregnancies reported in clinical studies of progestin-only oral contraceptive users are extrauterine. Although symptoms of ectopic pregnancy should be watched for, a history of ectopic pregnancy need not be considered a contraindication to use of this contraceptive method. Healthcare professionals should be alert to the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while on progestin-only oral contraceptives. - Delayed Follicular Atresia/Ovarian Cysts - If follicular development occurs, atresia of the follicle is sometimes delayed and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally these enlarged follicles disappear spontaneously. Often they are asymptomatic; in some cases they are associated with mild abdominal pain. Rarely they may twist or rupture, requiring surgical intervention. - Irregular Genital Bleeding - Irregular menstrual patterns are common among women using progestin-only oral contraceptives. If genital bleeding is suggestive of infection, malignancy or other abnormal conditions, such nonpharmacologic causes should be ruled out. If prolonged amenorrhea occurs, the possibility of pregnancy should be evaluated. - Carcinoma of the Breast and Reproductive Organs - Some epidemiological studies of oral contraceptive users have reported an increased relative risk of developing breast cancer, particularly at a younger age and apparently related to duration of use. These studies have predominantly involved combined oral contraceptives and there is insufficient data to determine whether the use of POPs similarly increases the risk. - A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. - This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use. - Women with breast cancer should not use oral contraceptives because the role of female hormones in breast cancer has not been fully determined. - Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. There is insufficient data to determine whether the use of POPs increases the risk of developing cervical intraepithelial neoplasia. - Hepatic Neoplasia - Benign hepatic adenomas are associated with combined oral contraceptive use, although the incidence of benign tumors is rare in the United States. Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. - Studies have shown an increased risk of developing hepatocellular carcinoma in combined oral contraceptive users. However, these cancers are rare in the U.S. There is insufficient data to determine whether POPs increase the risk of developing hepatic neoplasia. ### Precautions - General - Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. - Physical Examination and Follow-up - It is considered good medical practice for sexually active women using oral contraceptives to have annual history and physical examinations. The physical examination may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the healthcare professional. - Carbohydrate and Lipid Metabolism - Some users may experience slight deterioration in glucose tolerance, with increases in plasma insulin but women with diabetes mellitus who use progestin-only oral contraceptives do not generally experience changes in their insulin requirements. Nonetheless, prediabetic and diabetic women in particular should be carefully monitored while taking POPs. - Lipid metabolism is occasionally affected in that HDL, HDL2, and apolipoprotein A-I and A-II may be decreased; hepatic lipase may be increased. There is usually no effect on total cholesterol, HDL3, LDL, or VLDL. - Headache - The onset or exacerbation of migraine or development of severe headache with focal neurological symptoms which is recurrent or persistent requires discontinuation of progestin-only contraceptives and evaluation of the cause. # Adverse Reactions ## Clinical Trials Experience - Adverse reactions reported with the use of POPs include: - Menstrual irregularity is the most frequently reported side effect. - Frequent and irregular bleeding are common, while long duration of bleeding episodes and amenorrhea are less likely. - Headache, breast tenderness, nausea, and dizziness are increased among progestin-only oral contraceptive users in some studies. - Androgenic side effects such as acne, hirsutism, and weight gain occur rarely. - The following adverse reactions were also reported in clinical trials : fatigue, edema vomiting, abdominal pain, hepatitis, jaundice cholestatic pain in extremity depression, nervousness anaphylactic/anaphylactoid reaction, hypersensitivity, alopecia, rash, rash pruritic. genital discharge; breast pain, menstruation delayed, suppressed lactation, vaginal hemorrhage, menorrhagia, withdrawal bleed when product is stopped ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Norethindrone in the drug label. # Drug Interactions - The effectiveness of progestin-only pills is reduced by hepatic enzyme-inducing drugs such as the anticonvulsants phenytoin, carbamazepine, and barbiturates, and the antituberculosis drug rifampin. No significant interaction has been found with broad-spectrum antibiotics. - Herbal products containing St. John’s Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. - Concurrent use of bosentan and norethindrone containing products may result in decreased concentrations of these contraceptive hormones thereby increasing the risk of unintended pregnancy and unscheduled bleeding. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category - Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted have not demonstrated significant adverse effects. It is nonetheless prudent to rule out suspected pregnancy before initiating any hormonal contraceptive use. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Norethindrone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Norethindrone during labor and delivery. ### Nursing Mothers - In general, no adverse effects have been found on breastfeeding performance or on the health, growth, or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers, resulting in detectable steroid levels in infant plasma. ### Pediatric Use - Safety and efficacy of norethindronetablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. ### Geriatic Use There is no FDA guidance on the use of Norethindrone with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Norethindrone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Norethindrone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Norethindrone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Norethindrone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Norethindrone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Norethindrone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Norethindrone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Norethindrone in the drug label. # Overdosage ## Acute Overdose - There have been no reports of serious ill effects from overdosage, including ingestion by children. ## Chronic Overdose There is limited information regarding Chronic Overdose of Norethindrone in the drug label. # Pharmacology ## Mechanism of Action - Errin® progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the midcycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium. ## Structure - Norethindrone, USP is a white to creamy white, odorless, crystalline powder. It is stable in air. Practically insoluble in water; soluble in chloroform and in dioxane; sparingly soluble in alcohol; slightly soluble in ether. The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one. The structural formula is as follows: - Each yellow tablet contains 0.35 mg norethindrone, USP and has the following inactive ingredients: anhydrous lactose, corn starch, D&C yellow no. 10 aluminum lake, ethylcellulose aqueous dispersion, lactose monohydrate, magnesium stearate, microcrystalline cellulose and povidone. - Meets USP Dissolution Test 2. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Norethindrone in the drug label. ## Pharmacokinetics - Serum progestin levels peak about two hours after oral administration, followed by rapid distribution and elimination. By 24 hours after drug ingestion, serum levels are near baseline, making efficacy dependent upon rigid adherence to the dosing schedule. There are large variations in serum levels among individual users. Progestin-only administration results in lower steady-state serum progestin levels and a shorter elimination half-life than concomitant administration with estrogens. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Norethindrone in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Norethindrone in the drug label. # How Supplied - Errin® (norethindrone tablets, USP 0.35 mg) are packaged in cartons of six blister cards each containing 28 tablets. Each yellow, round, flat-faced, beveled-edge, unscored tablet is debossed with stylized b on one side and 344 on the other side. - Store at 20° to 25°C (68° to 77°F). - KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. ## Storage There is limited information regarding Norethindrone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Counseling Issues - The following points should be discussed with prospective users before prescribing progestin-only oral contraceptives: - The necessity of taking pills at the same time every day, including throughout all bleeding episodes. - The need to use a backup method such as a condom and spermicide for the next 48 hours whenever a progestin-only oral contraceptive is taken 3 or more hours late. - The potential side effects of progestin-only oral contraceptives, particularly menstrual irregularities. - The need to inform the healthcare professional of prolonged episodes of bleeding, amenorrhea or severe abdominal pain. - The importance of using a barrier method in addition to progestin-only oral contraceptives if a woman is at risk of contracting or transmitting STDs/HIV. # Precautions with Alcohol - Alcohol-Norethindrone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ERRIN®[1] # Look-Alike Drug Names There is limited information regarding Norethindrone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Norethindrone
e032628068f573384d625db8fd6df75375a0c58d	wikidoc	Norfluoxetine	Norfluoxetine Lua error in Module:Redirect at line 65: could not parse redirect on page "Prozac". # Overview Fluoxetine hydrochloride (Prozac) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine is approved for the treatment of clinical depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder. Despite the availability of newer agents, it remains extremely popular. Over 22.2 million prescriptions for generic formulations of fluoxetine were filled in the United States in 2007, making it the third most prescribed antidepressant. # History According to David Wong, the work which eventually led to the discovery of fluoxetine began at Eli Lilly in 1970 as a collaboration between Bryan Molloy and Robert Rathburn. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized dozens of its derivatives. Testing the physiological effects of these compounds in mice resulted in nisoxetine, a selective norepinephrine reuptake inhibitor currently widely used in biochemical experiments. Later, hoping to find a derivative inhibiting only serotonin reuptake, Wong proposed to re-test the series for the in-vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972, showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series. A controversy ensued after Lilly researchers published a paper entitled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug" implicitly claiming fluoxetine to be the first selective serotonin reuptake inhibitor (SSRI). Two years later they had to issue a correction, admitting that the first SSRI was zimelidine developed by Arvid Carlsson and colleagues. Fluoxetine made its appearance on the Belgian market in 1986 and was approved for use by the FDA in the United States in December 1987. Fluoxetine was the fourth SSRI to make it to market, after zimelidine, indalpine and fluvoxamine. However, the first two were withdrawn due to the side effects, and a vigorous marketing campaign by Eli Lilly made sure that in the popular culture fluoxetine has been perceived as a scientific breakthrough and associated with the title of the first SSRI. Eli Lilly's patent on Prozac (fluoxetine) expired in August, 2001, prompting an influx of generic drugs onto the market. # Indications Fluoxetine has been approved by the FDA for the treatment of clinical depression, obsessive compulsive disorder, bulimia nervosa and panic disorder. Fluoxetine was shown to be effective for depression in 6-week long double-blind controlled trials where it also alleviated anxiety and improved sleep. Fluoxetine was better than placebo for the prevention of depression recurrence when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric as well as pediatric depression was also demonstrated in placebo-controlled trials. The peculiar pharmacokinetics of fluoxetine with its brain levels rising extremely slowly over at least first 5 weeks of treatment (see Fluoxetine#Pharmacokinetics) makes it unclear whether the 20-mg/day optimal dose established in the short term (6-8 weeks) trials is applicable for the longer term supportive treatment. One 60-mg dose of fluoxetine per week was found to be equivalent to 20 mg/day for the continuation treatment of responders to 20 mg/day of fluoxetine. Furthermore, 5 mg/day fluoxetine was shown to be better than placebo and similar to 20 mg/day, and one weekly dose of 80 mg fluoxetine was equivalent to 60 mg/day fluoxetine or 150 mg/day amitriptyline. On the other hand, increase of the dose to 60 mg/day in non-responders from 20 mg/day brought no additional benefits as compared to continuing the 20 mg/day treatment. The recent research suggests that a significant part of the resistance to the SSRIs paroxetine (Paxil) and citalopram (Celexa) can be explained by the genetic variation of Pgp transporter. Paroxetine and citalopram, which are Pgp substrates, are actively transported from the brain by this protein. Fluoxetine is not a substrate of Pgp, and thus a switch from paroxetine or citalopram to fluoxetine may be beneficial to the non-responders. OCD was successfully treated by fluoxetine in two adult and one pediatric placebo-controlled 13-week trials. The higher doses of fluoxetine appeared to result in better response, while the reverse relationship was observed in the treatment of depression. Fluoxetine dramatically, by 40-50%, decreased the frequency of panic attacks in two controlled trials of panic disorder patients. In three double-blind trials fluoxetine significantly decreased the number of binge-eating and purging episodes of bulimia nervosa. Continued year-long treatment of the patients, who originally responded to fluoxetine, was more effective than placebo for the prevention of bulimia nervosa episodes. # Adverse effects According to the manufacturer of Prozac brand of fluoxetine Eli Lilly, fluoxetine is contraindicated in individuals taking monoamine oxidase inhibitors, pimozide (Orap) or thioridazine (Mellaril). The prescribing information recommends that the treatment of the patients with liver impairment "must be approached with caution". The elimination of fluoxetine and its metabolite norfluoxetine is about twice slower in these patients, resulting in the proportionate increase of exposure to the drug. Among the common adverse effects associated with fluoxetine and listed in the prescribing information, the effects with the greatest difference from placebo are nausea (22% vs 9% for placebo), insomnia (19% vs 10% for placebo), somnolence (12% vs 5% for placebo), anorexia (10% vs 3% for placebo), anxiety (12% vs 6% for placebo), nervousness (13% vs 8% for placebo), asthenia (11% vs 6% for placebo) and tremor (9% vs 2% for placebo). Those that most often resulted in interruption of the treatment were anxiety, insomnia, and nervousness (1-2% each), and in pediatric trials—mania (2%). In addition, rash or urticaria, sometimes serious, was observed in 7% patients in clinical trials; one-third of these cases resulted in discontinuation of the treatment. Postmarketing reports note several cases of complications developed in patients with rash. The symptoms included vasculitis and lupus-like syndrome. Death has been reported to occur in association with these systemic events. Akathisia, that is inner tension, restlessness, and the inability to stay still, often accompanied by "constant pacing, purposeless movements of the feet and legs, and marked anxiety," is a common side effect of fluoxetine. Akathisia usually begins after the initiation of the treatment or increase of the dose and disappears after fluoxetine is stopped or its dose is decreased, or after treatment with propranolol. There are case reports directly linking akathisia with suicidal attempts, with patients feeling better after the withdrawal of fluoxetine, and again developing severe akathisia on repeated exposure to fluoxetine. These patients described "that the development of the akathisia made them feel suicidal and that it had precipitated their prior suicide attempts." The experts note that because of the link of akathisia with suicide and the distress it causes to the patient, "it is of vital importance to increase awareness amongst staff and patients of the symptoms of this relatively common condition". More rarely, fluoxetine has been associated with related movement disorders acute dystonia and tardive dyskinesia. Other side effects may occur, including sexual dysfunction. Possible sexual side effects can include anorgasmia, reduced libido and impotence. Fluoxetine taken during pregnancy also increases rate of poor neonatal adaptation. Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. The American Association of Pediatrics classifies fluoxetine as a drug for which the effect on the nursing infant is unknown but may be of concern. ## Discontinuation syndrome Several case reports in the literature describe severe withdrawal or discontinuation symptoms following an abrupt interruption of fluoxetine treatment. Considering the number of fluoxetine prescriptions dispensed over the years, this is exceedingly rare. It is generally believed that the side effects of the fluoxetine discontinuation are mild, and one of the recommended strategies for the management of discontinuation syndrome with other SSRIs is to substitute fluoxetine for the original agent. The double-blind controlled studies support this opinion. No increase in side effects was observed in several studies when the treatment with fluoxetine was blindly interrupted for a short time (4-8 days) and then re-instated, this result being consistent with its slow elimination from the body. More side effects occurred during the interruption of sertraline in these studies, and significantly more—during the interruption of paroxetine. In a longer, 6 week-long, blind discontinuation study, insignificantly higher (32% vs 27%) overall rate of new or worsened side effects was observed in the group that discontinued fluoxetine than in the group that continued treatment. However, significantly higher 4% rate of somnolence at week 2 and 5-7% rate of dizziness at weeks 4-6 were reported by the patients in the discontinuation group. This prolonged course of the discontinuation symptoms, with dizziness persisting to the end of the study, is also consistent with the long half-life of fluoxetine in the body. ## Suicidality in antidepressant trials The FDA requires all antidepressants, including fluoxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group. This analysis was criticized by Donald Klein who noted that suicidality, that is suicidal ideation and behavior, is not necessarily a good surrogate marker for completed suicide, and it is still possible that antidepressants may prevent actual suicide while increasing suicidality. This opinion goes against the general consensus that "suicidal ideation has been associated with suicide attempt in retrospective studies and with suicide in prospective studies." ## Suicidality and fluoxetine Suicidal ideation and behavior in clinical trials are rare. For the above analysis the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50% (not statistically significant), and in adults decreased the odds of suicidality by approximately 30% (statistically significant). Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%. # Pharmacokinetics The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6 to 8 hours. It is highly bound to plasma proteins, mostly albumin. Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. Only one metabolite of fluoxetine, norfluoxetine (demethylated fluoxetine), is biologically active. The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine elimination half-life changes from 1 to 3 days, after a single dose—to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use. Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks. Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment. That means that the full benefits of the current dose a patient receives are not realized for at least a month since its initiation. For example, in one 6-week study, the median time to achieving consistent response was 29 days. Likewise, complete excretion of the drug may take several weeks. During the first week after the treatment discontinuation, the brain concentration of fluoxetine decreases only by 50%, The blood level of norfluoxetine 4 weeks after the treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and 7 weeks after the discontinuation norfluoxetine is still detectable in the blood. A PET study compared the action of a single dose of fluoxetine on exclusively heterosexual and exclusively homosexual men who attested that their past and present sexual behavior, desires, and fantasies were directed entirely toward women or men, respectively. The study found that in some areas of the brain the metabolic response in these two groups was different. "Both groups, however, did exhibit similar widespread lateralized metabolic responses to fluoxetine (relative to placebo), with most areas of the brain responding in the same direction." They "did not differ on behavioral measures or blood levels of fluoxetine". # Interactions The simultaneous use of fluoxetine with triptans, tramadol or other serotonergic agents can result in a rare, but potentially life-threatening adverse drug reaction called serotonin syndrome. # Controversy "In 1989, Joseph Wesbecker shot dead eight people and injured 12 others before killing himself at his place of work in Kentucky. Wesbecker had been taking the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine for four weeks before these homicides, and this led to a legal action against the makers of fluoxetine, Eli Lilly. The case was tried and settled in 1994, and as part of the settlement a number of pharmaceutical company documents about drug-induced activation were released into the public domain. Subsequent legal cases...have further raised the possibility of a link between antidepressant use and violence." A meta-analysis published in February 2008 combined 35 clinical trials of four newer antidepressants (fluoxetine, paroxetine (Paxil), nefazodone (Serzone) and venlafaxine (Effexor)). These antidepressants belonging to three different pharmacological groups were considered together, and the authors did not analyze them separately. The authors concluded that "although the difference easily attained statistical significance", it did not meet the criterion for clinical significance, as used by National Institute for Health and Clinical Excellence (UK), "for any but the most severely depressed patients." Some articles in the press using the titles "The creation of the Prozac myth" and "Prozac does not work in majority of depressed patients" presented these general findings about the relative efficacy of antidepressants and placebo as the findings about ineffectiveness of fluoxetine.	Norfluoxetine Lua error in Module:Redirect at line 65: could not parse redirect on page "Prozac". # Overview Fluoxetine hydrochloride (Prozac) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine is approved for the treatment of clinical depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder.[1] Despite the availability of newer agents, it remains extremely popular. Over 22.2 million prescriptions for generic formulations of fluoxetine were filled in the United States in 2007, making it the third most prescribed antidepressant.[2] # History According to David Wong,[3] the work which eventually led to the discovery of fluoxetine began at Eli Lilly in 1970 as a collaboration between Bryan Molloy and Robert Rathburn. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized dozens of its derivatives. Testing the physiological effects of these compounds in mice resulted in nisoxetine, a selective norepinephrine reuptake inhibitor currently widely used in biochemical experiments.[3] Later, hoping to find a derivative inhibiting only serotonin reuptake, Wong proposed to re-test the series for the in-vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972,[3] showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.[4] A controversy ensued after Lilly researchers published a paper entitled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug"[3] implicitly claiming fluoxetine to be the first selective serotonin reuptake inhibitor (SSRI). Two years later they had to issue a correction, admitting that the first SSRI was zimelidine developed by Arvid Carlsson and colleagues.[5] Fluoxetine made its appearance on the Belgian market in 1986[6] and was approved for use by the FDA in the United States in December 1987.[7] Fluoxetine was the fourth SSRI to make it to market, after zimelidine, indalpine and fluvoxamine. However, the first two were withdrawn due to the side effects, and a vigorous marketing campaign by Eli Lilly made sure that in the popular culture fluoxetine has been perceived as a scientific breakthrough and associated with the title of the first SSRI. Eli Lilly's patent on Prozac (fluoxetine) expired in August, 2001,[8] prompting an influx of generic drugs onto the market. # Indications Fluoxetine has been approved by the FDA for the treatment of clinical depression, obsessive compulsive disorder, bulimia nervosa and panic disorder.[9] Fluoxetine was shown to be effective for depression in 6-week long double-blind controlled trials where it also alleviated anxiety and improved sleep. Fluoxetine was better than placebo for the prevention of depression recurrence when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric as well as pediatric depression was also demonstrated in placebo-controlled trials.[9] The peculiar pharmacokinetics of fluoxetine with its brain levels rising extremely slowly over at least first 5 weeks of treatment (see Fluoxetine#Pharmacokinetics) makes it unclear whether the 20-mg/day optimal dose established in the short term (6-8 weeks) trials is applicable for the longer term supportive treatment. One 60-mg dose of fluoxetine per week was found to be equivalent to 20 mg/day for the continuation treatment of responders to 20 mg/day of fluoxetine.[10][11] Furthermore, 5 mg/day fluoxetine was shown to be better than placebo and similar to 20 mg/day,[12] and one weekly dose of 80 mg fluoxetine was equivalent to 60 mg/day fluoxetine or 150 mg/day amitriptyline.[11] On the other hand, increase of the dose to 60 mg/day in non-responders from 20 mg/day brought no additional benefits as compared to continuing the 20 mg/day treatment.[12] The recent research suggests that a significant part of the resistance to the SSRIs paroxetine (Paxil) and citalopram (Celexa) can be explained by the genetic variation of Pgp transporter. Paroxetine and citalopram, which are Pgp substrates, are actively transported from the brain by this protein. Fluoxetine is not a substrate of Pgp, and thus a switch from paroxetine or citalopram to fluoxetine may be beneficial to the non-responders.[13][14] OCD was successfully treated by fluoxetine in two adult and one pediatric placebo-controlled 13-week trials. The higher doses of fluoxetine appeared to result in better response, while the reverse relationship was observed in the treatment of depression.[9] Fluoxetine dramatically, by 40-50%, decreased the frequency of panic attacks in two controlled trials of panic disorder patients. In three double-blind trials fluoxetine significantly decreased the number of binge-eating and purging episodes of bulimia nervosa. Continued year-long treatment of the patients, who originally responded to fluoxetine, was more effective than placebo for the prevention of bulimia nervosa episodes.[9] # Adverse effects According to the manufacturer of Prozac brand of fluoxetine Eli Lilly, fluoxetine is contraindicated in individuals taking monoamine oxidase inhibitors, pimozide (Orap) or thioridazine (Mellaril).[9] The prescribing information recommends that the treatment of the patients with liver impairment "must be approached with caution". The elimination of fluoxetine and its metabolite norfluoxetine is about twice slower in these patients, resulting in the proportionate increase of exposure to the drug.[9] Among the common adverse effects associated with fluoxetine and listed in the prescribing information, the effects with the greatest difference from placebo are nausea (22% vs 9% for placebo), insomnia (19% vs 10% for placebo), somnolence (12% vs 5% for placebo), anorexia (10% vs 3% for placebo), anxiety (12% vs 6% for placebo), nervousness (13% vs 8% for placebo), asthenia (11% vs 6% for placebo) and tremor (9% vs 2% for placebo). Those that most often resulted in interruption of the treatment were anxiety, insomnia, and nervousness (1-2% each), and in pediatric trials—mania (2%).[9] In addition, rash or urticaria, sometimes serious, was observed in 7% patients in clinical trials; one-third of these cases resulted in discontinuation of the treatment. Postmarketing reports note several cases of complications developed in patients with rash. The symptoms included vasculitis and lupus-like syndrome. Death has been reported to occur in association with these systemic events.[9] Akathisia, that is inner tension, restlessness, and the inability to stay still, often accompanied by "constant pacing, purposeless movements of the feet and legs, and marked anxiety," is a common side effect of fluoxetine.[15][16] Akathisia usually begins after the initiation of the treatment or increase of the dose and disappears after fluoxetine is stopped or its dose is decreased, or after treatment with propranolol.[17][18][15] There are case reports directly linking akathisia with suicidal attempts, with patients feeling better after the withdrawal of fluoxetine, and again developing severe akathisia on repeated exposure to fluoxetine. These patients described "that the development of the akathisia made them feel suicidal and that it had precipitated their prior suicide attempts."[18] The experts note that because of the link of akathisia with suicide and the distress it causes to the patient, "it is of vital importance to increase awareness amongst staff and patients of the symptoms of this relatively common condition".[19][20] More rarely, fluoxetine has been associated with related movement disorders acute dystonia and tardive dyskinesia.[16][21][22] Other side effects may occur, including sexual dysfunction. Possible sexual side effects can include anorgasmia, reduced libido and impotence.[23] Fluoxetine taken during pregnancy also increases rate of poor neonatal adaptation.[23] Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.[24] The American Association of Pediatrics classifies fluoxetine as a drug for which the effect on the nursing infant is unknown but may be of concern.[25] ## Discontinuation syndrome Several case reports in the literature describe severe withdrawal or discontinuation symptoms following an abrupt interruption of fluoxetine treatment.[26] Considering the number of fluoxetine prescriptions dispensed over the years, this is exceedingly rare. It is generally believed that the side effects of the fluoxetine discontinuation are mild,[26] and one of the recommended strategies for the management of discontinuation syndrome with other SSRIs is to substitute fluoxetine for the original agent.[27][28] The double-blind controlled studies support this opinion. No increase in side effects was observed in several studies when the treatment with fluoxetine was blindly interrupted for a short time (4-8 days) and then re-instated, this result being consistent with its slow elimination from the body. More side effects occurred during the interruption of sertraline in these studies, and significantly more—during the interruption of paroxetine.[29] In a longer, 6 week-long, blind discontinuation study, insignificantly higher (32% vs 27%) overall rate of new or worsened side effects was observed in the group that discontinued fluoxetine than in the group that continued treatment. However, significantly higher 4% rate of somnolence at week 2 and 5-7% rate of dizziness at weeks 4-6 were reported by the patients in the discontinuation group. This prolonged course of the discontinuation symptoms, with dizziness persisting to the end of the study, is also consistent with the long half-life of fluoxetine in the body.[30] ## Suicidality in antidepressant trials The FDA requires all antidepressants, including fluoxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group.[31][32][33] This analysis was criticized by Donald Klein who noted that suicidality, that is suicidal ideation and behavior, is not necessarily a good surrogate marker for completed suicide, and it is still possible that antidepressants may prevent actual suicide while increasing suicidality.[34] This opinion goes against the general consensus that "suicidal ideation has been associated with suicide attempt in retrospective studies and with suicide in prospective studies."[35] ## Suicidality and fluoxetine Suicidal ideation and behavior in clinical trials are rare. For the above analysis the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50% (not statistically significant),[36] and in adults decreased the odds of suicidality by approximately 30% (statistically significant).[32][33] Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.[37][38] # Pharmacokinetics The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6 to 8 hours. It is highly bound to plasma proteins, mostly albumin. Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6.[1] The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. Only one metabolite of fluoxetine, norfluoxetine (demethylated fluoxetine), is biologically active. The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine elimination half-life changes from 1 to 3 days, after a single dose—to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use.[1][39][11] Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks.[40][41] Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment.[42] That means that the full benefits of the current dose a patient receives are not realized for at least a month since its initiation. For example, in one 6-week study, the median time to achieving consistent response was 29 days.[40] Likewise, complete excretion of the drug may take several weeks. During the first week after the treatment discontinuation, the brain concentration of fluoxetine decreases only by 50%,[42] The blood level of norfluoxetine 4 weeks after the treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and 7 weeks after the discontinuation norfluoxetine is still detectable in the blood.[11] A PET study compared the action of a single dose of fluoxetine on exclusively heterosexual and exclusively homosexual men who attested that their past and present sexual behavior, desires, and fantasies were directed entirely toward women or men, respectively. The study found that in some areas of the brain the metabolic response in these two groups was different. "Both groups, however, did exhibit similar widespread lateralized metabolic responses to fluoxetine (relative to placebo), with most areas of the brain responding in the same direction." They "did not differ on behavioral measures or blood levels of fluoxetine".[43] # Interactions The simultaneous use of fluoxetine with triptans, tramadol or other serotonergic agents can result in a rare, but potentially life-threatening adverse drug reaction called serotonin syndrome. # Controversy "In 1989, Joseph Wesbecker shot dead eight people and injured 12 others before killing himself at his place of work in Kentucky. Wesbecker had been taking the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine for four weeks before these homicides, and this led to a legal action against the makers of fluoxetine, Eli Lilly.[44] The case was tried and settled in 1994, and as part of the settlement a number of pharmaceutical company documents about drug-induced activation were released into the public domain. Subsequent legal cases...have further raised the possibility of a link between antidepressant use and violence."[45] A meta-analysis published in February 2008 combined 35 clinical trials of four newer antidepressants (fluoxetine, paroxetine (Paxil), nefazodone (Serzone) and venlafaxine (Effexor)). These antidepressants belonging to three different pharmacological groups were considered together, and the authors did not analyze them separately. The authors concluded that "although the difference [between the placebo and antidepressants] easily attained statistical significance", it did not meet the criterion for clinical significance, as used by National Institute for Health and Clinical Excellence (UK), "for any but the most severely depressed patients."[46] Some articles in the press using the titles "The creation of the Prozac myth"[47] and "Prozac does not work in majority of depressed patients"[48][49] presented these general findings about the relative efficacy of antidepressants and placebo as the findings about ineffectiveness of fluoxetine.	https://www.wikidoc.org/index.php/Norfluoxetine
cd1989b93a053ff8c8cd1abcccdb7451a24da379	wikidoc	Norman Holter	Norman Holter Holter graduated from the University of California at Los Angeles in 1937. He then earned Master's degrees in chemistry and physics, and continued his education by completing postgraduate work at the University of Heidelberg (Germany), the University -f Chicago, the Oak Ridge Institute of Nuclear Studies, and the University of Oregon Medical School. During World War II, Holter served as senior physicist in the U.S. Navy, studying the characteristics of waves. In 1946, he headed a government research team involved in the atomic-bomb testing at Bikini Atoll. After the war, he continued work with the United States Atomic Energy Commission, and served as president of the Society of Nuclear Medicine from 1955-1956. In 1964, he became a full professor at the University of California in San Diego, coordinating activities at the Institute of Geophysics and Planetary Physics. In 1979, the Association for the Advancement of Medical Instrumentation (AAMI) awarded Holter with the AAMI Foundation Laufman-Greatbatch Prize for his contributions to medical technology. Holter was the son and grandson, respectively, of Montana pioneers Norman B. Holter and Anton M. Holter. Numerous landmarks in and around Helena, Montana bear his family's name. de:Norman J. Holter	Norman Holter Holter graduated from the University of California at Los Angeles in 1937. He then earned Master's degrees in chemistry and physics, and continued his education by completing postgraduate work at the University of Heidelberg (Germany), the University of Chicago, the Oak Ridge Institute of Nuclear Studies, and the University of Oregon Medical School. During World War II, Holter served as senior physicist in the U.S. Navy, studying the characteristics of waves. In 1946, he headed a government research team involved in the atomic-bomb testing at Bikini Atoll. After the war, he continued work with the United States Atomic Energy Commission, and served as president of the Society of Nuclear Medicine from 1955-1956. In 1964, he became a full professor at the University of California in San Diego, coordinating activities at the Institute of Geophysics and Planetary Physics. In 1979, the Association for the Advancement of Medical Instrumentation (AAMI) awarded Holter with the AAMI Foundation Laufman-Greatbatch Prize for his contributions to medical technology. Holter was the son and grandson, respectively, of Montana pioneers Norman B. Holter and Anton M. Holter. Numerous landmarks in and around Helena, Montana bear his family's name. --- de:Norman J. Holter Template:WH Template:WS	https://www.wikidoc.org/index.php/Norman_Holter
33e6a1c566402143d608eb2ad06065b5e0092373	wikidoc	Northern blot	Northern blot The northern blot is a technique used in molecular biology research to study gene expression. It takes its name from the similarity of the procedure to the Southern blot procedure, named for biologist Edwin Southern, used to study DNA, with the key difference that, in the northern blot, RNA, rather than DNA, is the substance being analyzed by electrophoresis and detection with a hybridization probe. This technique was developed in 1977 by James Alwine, David Kemp, and George Stark at Stanford University. The gels may be run on either agarose or denaturing polyacrylamide gels depending on the size of the RNA to be detected. A notable difference in the procedure in case of agarose gels, (as compared with the Southern blot) is the addition of formaldehyde which acts as a denaturant. For smaller fragments denaturing polyacrylamide urea gels are employed. As in the Southern blot, the hybridization probe may be made from DNA or RNA. A variant of the procedure known as the reverse northern blot was occasionally (although, infrequently) used. In this procedure, the substrate nucleic acid (that is affixed to the membrane) is a collection of isolated DNA fragments, and the probe is RNA extracted from a tissue and radioactively labelled. The use of DNA microarrays that have come into widespread use in the late 1990s and early 2000s is more akin to the reverse procedure, in that they involve the use of isolated DNA fragments affixed to a substrate, and hybridization with a probe made from cellular RNA. Thus the reverse procedure, though originally uncommon, enabled the one-at-a-time study of gene expression using northern analysis to evolve into gene expression profiling, in which many (possibly all) of the genes in an organism may have their expression monitored.	Northern blot The northern blot is a technique used in molecular biology research to study gene expression. It takes its name from the similarity of the procedure to the Southern blot procedure, named for biologist Edwin Southern, used to study DNA, with the key difference that, in the northern blot, RNA, rather than DNA, is the substance being analyzed by electrophoresis and detection with a hybridization probe. This technique was developed in 1977 by James Alwine, David Kemp, and George Stark at Stanford University.[1] The gels may be run on either agarose or denaturing polyacrylamide gels depending on the size of the RNA to be detected. A notable difference in the procedure in case of agarose gels, (as compared with the Southern blot) is the addition of formaldehyde which acts as a denaturant. For smaller fragments denaturing polyacrylamide urea gels are employed. As in the Southern blot, the hybridization probe may be made from DNA or RNA. A variant of the procedure known as the reverse northern blot was occasionally (although, infrequently) used. In this procedure, the substrate nucleic acid (that is affixed to the membrane) is a collection of isolated DNA fragments, and the probe is RNA extracted from a tissue and radioactively labelled. The use of DNA microarrays that have come into widespread use in the late 1990s and early 2000s is more akin to the reverse procedure, in that they involve the use of isolated DNA fragments affixed to a substrate, and hybridization with a probe made from cellular RNA. Thus the reverse procedure, though originally uncommon, enabled the one-at-a-time study of gene expression using northern analysis to evolve into gene expression profiling, in which many (possibly all) of the genes in an organism may have their expression monitored.	https://www.wikidoc.org/index.php/Northern_Blot
5c62d19107373c81c294c23ed5a45cedf22f405b	wikidoc	Nortriptyline	Nortriptyline # 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 Nortriptyline is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Depression - 25 mg ORALLY 3 to 4 times daily; alternatively, administer as a single daily dose; MAX 150 mg/day ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Nortriptyline in adult patients. ### Non–Guideline-Supported Use Attention deficit hyperactivity disorder Neurogenic bladder Nicotine dependence Nocturnal enuresis Postherpetic neuralgia # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Depression - Adolescents may receive 30 to 50 mg/day ORALLY (in divided doses or single daily dose) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Nortriptyline in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Nortriptyline in pediatric patients. # Contraindications - MAOIs - The use of MAOIs intended to treat psychiatric disorders with nortriptyline hydrochloride or within 14 days of stopping treatment with nortriptyline hydrochloride is contraindicated because of an increased risk of serotonin syndrome. The use of nortriptyline hydrochloride within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. Starting nortriptyline hydrochloride in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. - Hypersensitivity to Tricyclic Antidepressants - Cross-sensitivity between nortriptyline hydrochloride and other dibenzazepines is a possibility. - Myocardial Infarction - Nortriptyline hydrochloride is contraindicated during the acute recovery period after myocardial infarction. # Warnings Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including nortriptyline hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of nortriptyline hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated. Nortriptyline hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking nortriptyline hydrochloride. Nortriptyline hydrochloride should be discontinued before initiating treatment with the MAOI. - If concomitant use of nortriptyline hydrochloride with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with nortriptyline hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for nortriptyline hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that nortriptyline hydrochloride is not approved for use in treating bipolar depression. - Patients with cardiovascular disease should be given nortriptyline hydrochloride only under close supervision because of the tendency of the drug to produce sinus tachycardia and to prolong the conduction time. Myocardial infarction, arrhythmia, and strokes have occurred. The antihypertensive action of guanethidine and similar agents may be blocked. Because of its anticholinergic activity, nortriptyline hydrochloride should be used with great caution in patients who have glaucoma or a history of urinary retention. Patients with a history of seizures should be followed closely when nortriptyline hydrochloride is administered, inasmuch as this drug is known to lower the convulsive threshold. Great care is required if nortriptyline hydrochloride is given to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop. Nortriptyline hydrochloride may impair the mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a car; therefore, the patient should be warned accordingly. - Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation. The concomitant administration of quinidine and nortriptyline may result in a significantly longer plasma half-life, higher AUC, and lower clearance of nortriptyline. # Adverse Reactions ## Clinical Trials Experience Note: Included in the following list are a few adverse reactions that have not been reported with this specific drug. However, the pharmacologic similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when nortriptyline is administered. Central Nervous System Cardiovascular Gastrointestinal Hypersensitive Reactions Psychiatric Anticholinergic Hematologic Endocrine Miscellaneous Withdrawal Symptoms ## Postmarketing Experience There is limited information regarding Nortriptyline Postmarketing Experience in the drug label. # Drug Interactions Administration of reserpine during therapy with a tricyclic antidepressant has been shown to produce a "stimulating" effect in some depressed patients. Close supervision and careful adjustment of the dosage are required when nortriptyline hydrochloride is used with other anticholinergic drugs and sympathomimetic drugs. Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressant. The patient should be informed that the response to alcohol may be exaggerated. A case of significant hypoglycemia has been reported in a type II diabetic patient maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline (125 mg/day). - Monoamine Oxidase Inhibitors (MAOIs) - Serotonergic Drugs - Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Safe use of nortriptyline hydrochloride during pregnancy and lactation has not been established; therefore, when the drug is administered to pregnant patients, nursing mothers, or women of childbearing potential, the potential benefits must be weighed against the possible hazards. Animal reproduction studies have yielded inconclusive results. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nortriptyline in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nortriptyline during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Nortriptyline in women who are nursing. ### Pediatric Use Safety and effectiveness in the pediatric population have not been established. Anyone considering the use of nortriptyline hydrochloride in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use Clinical studies of nortriptyline hydrochloride did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience indicates that, as with other tricyclic antidepressants, hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes) are observed very rarely in geriatric patients and deaths associated with cholestatic liver damage have been reported in isolated instances. Cardiovascular function, particularly arrhythmias and fluctuations in blood pressure, should be monitored. There have also been reports of confusional states following tricyclic antidepressant administration in the elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10-hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic antidepressants, dose selection for an elderly patient should usually be limited to the smallest effective total daily dose ### Gender There is no FDA guidance on the use of Nortriptyline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nortriptyline with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nortriptyline in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nortriptyline in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nortriptyline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nortriptyline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Nortriptyline hydrochloride is not recommended for children. - Nortriptyline hydrochloride is administered orally in the form of capsules or liquid. Lower than usual dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients than for hospitalized patients who will be under close supervision. The physician should initiate dosage at a low level and increase it gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission. If a patient develops minor side effects, the dosage should be reduced. The drug should be discontinued promptly if adverse effects of a serious nature or allergic manifestations occur. - Usual Adult Dose - 25 mg three or four times daily; dosage should begin at a low level and be increased as required. As an alternate regimen, the total daily dosage may be given once a day. When doses above 100 mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150 ng/mL. Doses above 150 mg/day are not recommended. Elderly and Adolescent Patients - 30 to 50 mg/day in divided doses, or the total daily dosage may be given once a day. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with nortriptyline hydrochloride. Conversely, at least 14 days should be allowed after stopping nortriptyline hydrochloride before starting an MAOI intended to treat psychiatric disorders. - Use of Nortriptyline Hydrochloride With Other MAOIs, Such as Linezolid or Methylene Blue Do not start nortriptyline hydrochloride in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. - In some cases, a patient already receiving nortriptyline hydrochloride therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, nortriptyline hydrochloride should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with nortriptyline hydrochloride may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue . The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with nortriptyline hydrochloride is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use . ### Monitoring There is limited information regarding Nortriptyline Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Nortriptyline and IV administrations. # Overdosage Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. - Manifestations - Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. - Other signs of overdose may include: confusion, restlessness, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the acute symptoms listed under ADVERSE REACTIONS. There have been reports of patients recovering from nortriptyline overdoses of up to 525 mg. - Management - General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. EMESIS IS CONTRAINDICATED. - Cardiovascular: A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (eg, quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. - CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (eg, phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. - Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. - Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. # Pharmacology ## Mechanism of Action The mechanism of mood elevation by tricyclic antidepressants is at present unknown. Nortriptyline hydrochloride is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. Studies suggest that nortriptyline hydrochloride interferes with the transport, release, and storage of catecholamines. Operant conditioning techniques in rats and pigeons suggest that nortriptyline hydrochloride has a combination of stimulant and depressant properties. ## Structure Nortriptyline Hydrochloride, USP is 1-Propanamine, 3-(10, 11-dihydro-5H-dibenzo cyclohepten-5-ylidene)-N-methyl, hydrochloride. Its molecular weight is 299.8, and its molecular formula is C19H21NHCl. The structural formula is as follows: Chemical Structure Each capsule, for oral administration, contains nortriptyline hydrochloride equivalent to 10 mg, 25 mg, 50 mg or 75 mg of nortriptyline. In addition, each capsule contains the following inactive ingredients: black iron oxide, colloidal silicon dioxide, D&C Yellow #10 (aluminum lake), D&C Yellow #10, FD&C Blue #1 (aluminum lake), FD&C Blue #2 (aluminum lake), FD&C Green #3 (10, 50 and 75 mg only), FD&C Red #40 (aluminum lake), gelatin, I.M.S. 74 OP, magnesium stearate, pregelatinized corn starch, shellac, sodium lauryl sulfate and titanium dioxide. ## Pharmacodynamics There is limited information regarding Nortriptyline Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Nortriptyline Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Nortriptyline Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Nortriptyline Clinical Studies in the drug label. # How Supplied Nortriptyline Hydrochloride Capsules USP, equivalent to 10 mg, 25 mg, 50 mg, and 75 mg base, are available in: 10 mg: Opaque light green cap and body, imprinted "TARO" on the cap and "NTP 10" on the body. Bottles of 30 NDC 51672-4001-6 Bottles of 90 NDC 51672-4001-5 Bottles of 500 NDC 51672-4001-2 25 mg: Opaque ivory cap and body, imprinted "TARO" on the cap and "NTP 25" on the body. Bottles of 30 NDC 51672-4002-6 Bottles of 60 NDC 51672-4002-4 Bottles of 90 NDC 51672-4002-5 Bottles of 500 NDC 51672-4002-2 50 mg: Opaque dark green cap with an opaque white body, imprinted "TARO" on the cap and "NTP 50" on the body. Bottles of 30 NDC 51672-4003-6 Bottles of 90 NDC 51672-4003-5 Bottles of 500 NDC 51672-4003-2 75 mg: Opaque dark green cap and body, imprinted "TARO" on the cap and "NTP 75" on the body. Bottles of 30 NDC 51672-4004-6 Bottles of 90 NDC 51672-4004-5 Bottles of 500 NDC 51672-4004-2 ## Storage Store at 20°-25°C (68°-77°F) . Dispense in tight container (USP) with a child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with nortriptyline hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for nortriptyline hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking nortriptyline hydrochloride. Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. - The use of nortriptyline hydrochloride in schizophrenic patients may result in exacerbation of the psychosis or may activate latent schizophrenic symptoms. If the drug is given to overactive or agitated patients, increased anxiety and agitation may occur. In manic-depressive patients, nortriptyline hydrochloride may cause symptoms of the manic phase to emerge. - Troublesome patient hostility may be aroused by the use of nortriptyline hydrochloride. Epileptiform seizures may accompany its administration, as is true of other drugs of its class. When it is essential, the drug may be administered with electroconvulsive therapy, although the hazards may be increased. Discontinue the drug for several days, if possible, prior to elective surgery. - The possibility of a suicidal attempt by a depressed patient remains after the initiation of treatment; in this regard, it is important that the least possible quantity of drug be dispensed at any given time. - Both elevation and lowering of blood sugar levels have been reported. # Precautions with Alcohol Alcohol-Nortriptyline 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 Nortriptyline Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Nortriptyline Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Nortriptyline Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [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. # Black Box Warning # Overview Nortriptyline is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Depression - 25 mg ORALLY 3 to 4 times daily; alternatively, administer as a single daily dose; MAX 150 mg/day ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Nortriptyline in adult patients. ### Non–Guideline-Supported Use Attention deficit hyperactivity disorder Neurogenic bladder Nicotine dependence Nocturnal enuresis Postherpetic neuralgia # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Depression - Adolescents may receive 30 to 50 mg/day ORALLY (in divided doses or single daily dose) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Nortriptyline in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Nortriptyline in pediatric patients. # Contraindications - MAOIs - The use of MAOIs intended to treat psychiatric disorders with nortriptyline hydrochloride or within 14 days of stopping treatment with nortriptyline hydrochloride is contraindicated because of an increased risk of serotonin syndrome. The use of nortriptyline hydrochloride within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. Starting nortriptyline hydrochloride in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. - Hypersensitivity to Tricyclic Antidepressants - Cross-sensitivity between nortriptyline hydrochloride and other dibenzazepines is a possibility. - Myocardial Infarction - Nortriptyline hydrochloride is contraindicated during the acute recovery period after myocardial infarction. # Warnings Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including nortriptyline hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of nortriptyline hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated. Nortriptyline hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking nortriptyline hydrochloride. Nortriptyline hydrochloride should be discontinued before initiating treatment with the MAOI. - If concomitant use of nortriptyline hydrochloride with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with nortriptyline hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for nortriptyline hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that nortriptyline hydrochloride is not approved for use in treating bipolar depression. - Patients with cardiovascular disease should be given nortriptyline hydrochloride only under close supervision because of the tendency of the drug to produce sinus tachycardia and to prolong the conduction time. Myocardial infarction, arrhythmia, and strokes have occurred. The antihypertensive action of guanethidine and similar agents may be blocked. Because of its anticholinergic activity, nortriptyline hydrochloride should be used with great caution in patients who have glaucoma or a history of urinary retention. Patients with a history of seizures should be followed closely when nortriptyline hydrochloride is administered, inasmuch as this drug is known to lower the convulsive threshold. Great care is required if nortriptyline hydrochloride is given to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop. Nortriptyline hydrochloride may impair the mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a car; therefore, the patient should be warned accordingly. - Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation. The concomitant administration of quinidine and nortriptyline may result in a significantly longer plasma half-life, higher AUC, and lower clearance of nortriptyline. # Adverse Reactions ## Clinical Trials Experience Note: Included in the following list are a few adverse reactions that have not been reported with this specific drug. However, the pharmacologic similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when nortriptyline is administered. Central Nervous System Cardiovascular Gastrointestinal Hypersensitive Reactions Psychiatric Anticholinergic Hematologic Endocrine Miscellaneous Withdrawal Symptoms ## Postmarketing Experience There is limited information regarding Nortriptyline Postmarketing Experience in the drug label. # Drug Interactions Administration of reserpine during therapy with a tricyclic antidepressant has been shown to produce a "stimulating" effect in some depressed patients. Close supervision and careful adjustment of the dosage are required when nortriptyline hydrochloride is used with other anticholinergic drugs and sympathomimetic drugs. Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressant. The patient should be informed that the response to alcohol may be exaggerated. A case of significant hypoglycemia has been reported in a type II diabetic patient maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline (125 mg/day). - Monoamine Oxidase Inhibitors (MAOIs) - Serotonergic Drugs - Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Safe use of nortriptyline hydrochloride during pregnancy and lactation has not been established; therefore, when the drug is administered to pregnant patients, nursing mothers, or women of childbearing potential, the potential benefits must be weighed against the possible hazards. Animal reproduction studies have yielded inconclusive results. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nortriptyline in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nortriptyline during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Nortriptyline in women who are nursing. ### Pediatric Use Safety and effectiveness in the pediatric population have not been established. Anyone considering the use of nortriptyline hydrochloride in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use Clinical studies of nortriptyline hydrochloride did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience indicates that, as with other tricyclic antidepressants, hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes) are observed very rarely in geriatric patients and deaths associated with cholestatic liver damage have been reported in isolated instances. Cardiovascular function, particularly arrhythmias and fluctuations in blood pressure, should be monitored. There have also been reports of confusional states following tricyclic antidepressant administration in the elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10-hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic antidepressants, dose selection for an elderly patient should usually be limited to the smallest effective total daily dose ### Gender There is no FDA guidance on the use of Nortriptyline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nortriptyline with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nortriptyline in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nortriptyline in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nortriptyline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nortriptyline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Nortriptyline hydrochloride is not recommended for children. - Nortriptyline hydrochloride is administered orally in the form of capsules or liquid. Lower than usual dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients than for hospitalized patients who will be under close supervision. The physician should initiate dosage at a low level and increase it gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission. If a patient develops minor side effects, the dosage should be reduced. The drug should be discontinued promptly if adverse effects of a serious nature or allergic manifestations occur. - Usual Adult Dose - 25 mg three or four times daily; dosage should begin at a low level and be increased as required. As an alternate regimen, the total daily dosage may be given once a day. When doses above 100 mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150 ng/mL. Doses above 150 mg/day are not recommended. Elderly and Adolescent Patients - 30 to 50 mg/day in divided doses, or the total daily dosage may be given once a day. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with nortriptyline hydrochloride. Conversely, at least 14 days should be allowed after stopping nortriptyline hydrochloride before starting an MAOI intended to treat psychiatric disorders. - Use of Nortriptyline Hydrochloride With Other MAOIs, Such as Linezolid or Methylene Blue Do not start nortriptyline hydrochloride in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. - In some cases, a patient already receiving nortriptyline hydrochloride therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, nortriptyline hydrochloride should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with nortriptyline hydrochloride may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue . The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with nortriptyline hydrochloride is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use . ### Monitoring There is limited information regarding Nortriptyline Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Nortriptyline and IV administrations. # Overdosage Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. - Manifestations - Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. - Other signs of overdose may include: confusion, restlessness, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the acute symptoms listed under ADVERSE REACTIONS. There have been reports of patients recovering from nortriptyline overdoses of up to 525 mg. - Management - General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. EMESIS IS CONTRAINDICATED. - Cardiovascular: A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (eg, quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. - CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (eg, phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. - Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. - Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. # Pharmacology ## Mechanism of Action The mechanism of mood elevation by tricyclic antidepressants is at present unknown. Nortriptyline hydrochloride is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. Studies suggest that nortriptyline hydrochloride interferes with the transport, release, and storage of catecholamines. Operant conditioning techniques in rats and pigeons suggest that nortriptyline hydrochloride has a combination of stimulant and depressant properties. ## Structure Nortriptyline Hydrochloride, USP is 1-Propanamine, 3-(10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5-ylidene)-N-methyl, hydrochloride. Its molecular weight is 299.8, and its molecular formula is C19H21N•HCl. The structural formula is as follows: Chemical Structure Each capsule, for oral administration, contains nortriptyline hydrochloride equivalent to 10 mg, 25 mg, 50 mg or 75 mg of nortriptyline. In addition, each capsule contains the following inactive ingredients: black iron oxide, colloidal silicon dioxide, D&C Yellow #10 (aluminum lake), D&C Yellow #10, FD&C Blue #1 (aluminum lake), FD&C Blue #2 (aluminum lake), FD&C Green #3 (10, 50 and 75 mg only), FD&C Red #40 (aluminum lake), gelatin, I.M.S. 74 OP, magnesium stearate, pregelatinized corn starch, shellac, sodium lauryl sulfate and titanium dioxide. ## Pharmacodynamics There is limited information regarding Nortriptyline Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Nortriptyline Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Nortriptyline Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Nortriptyline Clinical Studies in the drug label. # How Supplied Nortriptyline Hydrochloride Capsules USP, equivalent to 10 mg, 25 mg, 50 mg, and 75 mg base, are available in: 10 mg: Opaque light green cap and body, imprinted "TARO" on the cap and "NTP 10" on the body. Bottles of 30 NDC 51672-4001-6 Bottles of 90 NDC 51672-4001-5 Bottles of 500 NDC 51672-4001-2 25 mg: Opaque ivory cap and body, imprinted "TARO" on the cap and "NTP 25" on the body. Bottles of 30 NDC 51672-4002-6 Bottles of 60 NDC 51672-4002-4 Bottles of 90 NDC 51672-4002-5 Bottles of 500 NDC 51672-4002-2 50 mg: Opaque dark green cap with an opaque white body, imprinted "TARO" on the cap and "NTP 50" on the body. Bottles of 30 NDC 51672-4003-6 Bottles of 90 NDC 51672-4003-5 Bottles of 500 NDC 51672-4003-2 75 mg: Opaque dark green cap and body, imprinted "TARO" on the cap and "NTP 75" on the body. Bottles of 30 NDC 51672-4004-6 Bottles of 90 NDC 51672-4004-5 Bottles of 500 NDC 51672-4004-2 ## Storage Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP) with a child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with nortriptyline hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for nortriptyline hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking nortriptyline hydrochloride. Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. - The use of nortriptyline hydrochloride in schizophrenic patients may result in exacerbation of the psychosis or may activate latent schizophrenic symptoms. If the drug is given to overactive or agitated patients, increased anxiety and agitation may occur. In manic-depressive patients, nortriptyline hydrochloride may cause symptoms of the manic phase to emerge. - Troublesome patient hostility may be aroused by the use of nortriptyline hydrochloride. Epileptiform seizures may accompany its administration, as is true of other drugs of its class. When it is essential, the drug may be administered with electroconvulsive therapy, although the hazards may be increased. Discontinue the drug for several days, if possible, prior to elective surgery. - The possibility of a suicidal attempt by a depressed patient remains after the initiation of treatment; in this regard, it is important that the least possible quantity of drug be dispensed at any given time. - Both elevation and lowering of blood sugar levels have been reported. # Precautions with Alcohol Alcohol-Nortriptyline 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 Nortriptyline Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Nortriptyline Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Nortriptyline
605fa5e23674bd76c520cadca35cb858d3ece688	wikidoc	Nutrification	Nutrification Enriching or fortifying foods with nutrients is called nutrification. Food enrichment is the restoration of the natural nutritive value of a food before it was processed, while fortification is the adding of vitamins or minerals to a food at levels higher than it originally possessed, though "fortification" is commonly used to refer to both processes. Functional foods, designer foods, and techno-foods, are foods that are manufactured by food companies in collaboration with sellers of dietary supplements, in order to produce products that they can promote as healthy. Techno-foods “refer to foods and beverages that have been fortified in some way to confer health benefits beyond the original nutritional value of the foods themselves.” Initially, fortification was used as a public health strategy in the United States to eradicate vitamin and mineral deficiencies. For example, through the addition of iodine to table salt, goiter, a thyroid gland dysfunction, is now very uncommon. Other examples include the addition of vitamin D to milk and fluoride to tap water. As a public health measure, fortification has been very successful, though there are concerns that the “consumer must consciously desire and be involved in nutritional change” With fortification came the interweaving of science and commercial issues.. As with drugs, the benefits of nutrients are dose dependent, and eating too much of them can cause adverse effects . Yet, fortification is used regularly as a marketing strategy, so that now most processed foods are fortified in some way. Continued proliferation of this practice raises the concern that fortification will become too much of a good thing, where nutrient content in food in general may eventually increase to levels detrimental to the population. Economic issues pertaining to food fortification have also emerged. The wealthy, who may already eat enough nutrients, may be consuming more than they need when they purchase fortified products, while those in most need of the added nutrients may not be able to afford to buy enough fortified foods.	Nutrification Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Enriching or fortifying foods with nutrients is called nutrification. Food enrichment is the restoration of the natural nutritive value of a food before it was processed, while fortification is the adding of vitamins or minerals to a food at levels higher than it originally possessed, though "fortification" is commonly used to refer to both processes. Functional foods, designer foods, and techno-foods, are foods that are manufactured by food companies in collaboration with sellers of dietary supplements, in order to produce products that they can promote as healthy. Techno-foods “refer to foods and beverages that have been fortified in some way to confer health benefits beyond the original nutritional value of the foods themselves.”[1] Initially, fortification was used as a public health strategy in the United States to eradicate vitamin and mineral deficiencies. For example, through the addition of iodine to table salt, goiter, a thyroid gland dysfunction, is now very uncommon. Other examples include the addition of vitamin D to milk and fluoride to tap water. As a public health measure, fortification has been very successful, though there are concerns that the “consumer must consciously desire and be involved in nutritional change”[2] With fortification came the interweaving of science and commercial issues.[3]. As with drugs, the benefits of nutrients are dose dependent, and eating too much of them can cause adverse effects [REFERENCE NEEDED]. Yet, fortification is used regularly as a marketing strategy, so that now most processed foods are fortified in some way. Continued proliferation of this practice raises the concern that fortification will become too much of a good thing, where nutrient content in food in general may eventually increase to levels detrimental to the population. Economic issues pertaining to food fortification have also emerged. The wealthy, who may already eat enough nutrients, may be consuming more than they need when they purchase fortified products, while those in most need of the added nutrients may not be able to afford to buy enough fortified foods.	https://www.wikidoc.org/index.php/Nutrification
04d0e3f6948aa5049e9469cd82cba05f587309db	wikidoc	Octane rating	Octane rating # Overview The octane rating is a measure of the autoignition resistance of gasoline and other fuels used in spark-ignition internal combustion engines. It is a measure of anti-detonation of a gasoline or fuel. Octane number is the number which gives the percentage, by volume, of iso-octane in a mixture of iso-octane and normal heptane, that would have the same anti-knocking capacity as the fuel which is under consideration. For example, gasoline with the same knocking characteristics as a mixture of 90% iso-octane and 10% heptane would have an octane rating of 90. # Definition of octane rating The octane rating of a spark ignition engine fuel is the knock resistance (anti-knock rating) compared to a mixture of iso-octane (2,2,4-trimethylpentane, an isomer of octane) and n-heptane. By definition, iso-octane is assigned an octane rating of 100 and heptane is assigned an octane rating of zero. An 87-octane gasoline, for example, possesses the same anti-knock rating of a mixture of 87% (by volume) iso-octane and 13% (by volume) n-heptane. This does not mean, however, that the gasoline actually contains these hydrocarbons in these proportions. It simply means that it has the same autoignition resistance as the described mixture. A high tendency to autoignite, or low octane rating, is undesirable in a spark ignition engine but desirable in a diesel engine. The standard for the combustion quality of diesel fuel is the cetane number. A diesel fuel with a high cetane number has a high tendency to autoignite, as is preferred. It should be noted that octane rating does not relate to the energy content of the fuel (see heating value), nor the speed at which the flame initiated by the spark plug propagates across the cylinder. It is only a measure of the fuel's resistance to autoignition. It is for this reason that one highly branched form, or isomer, of octane (2,2,4-trimethylpentane) has (by definition) an octane rating of 100, whereas n-octane (see octane), which has a linear arrangement of the 8 carbon atoms, has an octane rating of -10, even though the two fuels have exactly the same chemical formula and virtually identical heating values and flame speeds. ## Measurement methods The most common type of octane rating worldwide is the Research Octane Number (RON). RON is determined by running the fuel in a test engine with a variable compression ratio under controlled conditions, and comparing these results with those for mixtures of iso-octane and n-heptane. There is another type of octane rating, called Motor Octane Number (MON) or the aviation lean octane rating, which is a better measure of how the fuel behaves when under load. MON testing uses a similar test engine to that used in RON testing, but with a preheated fuel mixture, a higher engine speed, and variable ignition timing to further stress the fuel's knock resistance. Depending on the composition of the fuel, the MON of a modern gasoline will be about 8 to 10 points lower than the RON. Normally fuel specifications require both a minimum RON and a minimum MON. In most countries (including all of Europe and Australia) the "headline" octane that would be shown on the pump is the RON, but in the United States, Canada and some other countries the headline number is the average of the RON and the MON, sometimes called the Anti-Knock Index (AKI), Road Octane Number (RdON), Pump Octane Number (PON), or (R+M)/2. Because of the 8 to 10 point difference noted above, this means that the octane in the United States will be about 4 to 5 points lower than the same fuel elsewhere: 87 octane fuel, the "regular" gasoline in the US and Canada, would be 91-92 in Europe. However most European pumps deliver 95 (RON) as "regular", equivalent to 90-91 US (R+M)/2, and even deliver 98 (RON) or 100 (RON). The octane rating may also be a "trade name", with the actual figure being higher than the nominal rating. It is possible for a fuel to have a RON greater than 100, because iso-octane is not the most knock-resistant substance available. Racing fuels, straight ethanol, AvGas and liquified petroleum gas (LPG) typically have octane ratings of 110 or significantly higher - ethanol's RON is 129 (MON 102, AKI 116) reference. Typical "octane booster" additives include tetra-ethyl lead, MTBE and toluene. Tetra-ethyl lead is easily decomposed to its component radicals, which react with the radicals from the fuel and oxygen that would start the combustion, thereby delaying ignition. This is why leaded gasoline has a higher octane rating than unleaded. # Examples of octane ratings The octane ratings of n-heptane and iso-octane are respectively exactly 0 and 100, by definition. For some other hydrocarbons, the following table gives the 'AKI' ratings. *Hydrogen represents a paradox. As a fuel outright, it has low knock resistance, due to its low ignition energy (primarily due to its low dissociation energy) and extremely high flame speed. However, as a minor blending component (i.e., a bi-fuel vehicle), hydrogen raises overall knock resistance. Flame speed is limited by the rest of the component species; hydrogen may reduce knock by contributing its high thermal conductivity. These traits are highly desirable in rocket engines, but undesirable in Otto-cycle engines. # Effects of octane rating Higher octane ratings correlate to higher activation energies. Activation energy is the amount of energy necessary to start a chemical reaction. Since higher octane fuels have higher activation energies, it is less likely that a given compression will cause knocking. (Note that it is the absolute pressure (compression) in the combustion chamber which is important — not the compression ratio. The compression ratio only governs the maximum compression that can be achieved). Octane rating has no direct impact on the deflagration (burn) of the air/fuel mixture in the combustion chamber. Other properties of gasoline and engine design account for the manner at which deflagration takes place. In other words, the flame speed of a normally ignited mixture is not directly connected to octane rating. Deflagration is the type of combustion that constitutes the normal burn. Detonation is a different type of combustion and this is to be avoided in spark ignited gasoline engines. Octane rating is a measure of detonation resistance, not deflagration characteristics. It might seem odd that fuels with higher octane ratings explode less easily and are therefore more powerful. One simple explanation for the effect is that various fuels can provide different heat (therefore energy) at different compression levels. As the compression level increases on many fuels so does the heat (energy) per unit of measure of fuel. Fuels burned in normal sea level pressure produce less energy than ones burned at the point of pre-ignition. The best energy pressure (compression ratio) for a fuel is at the point of where the engine "pings". Each fuel with its own resistance to pre-ignition requires its own ideal compression ratio. This is not always what emission levels require however. A motor must be constructed to work within a fuels compression ratio and emission levels. Another simple explanation is that carbon-carbon bonds contain more energy than carbon-hydrogen bonds. Hence a fuel with a greater number of carbon bonds will carry more energy regardless of the octane rating. A premium motor fuel will often be formulated to have both higher octane as well as more energy. A counter example to this rule is that ethanol blend fuels have a higher octane rating, but carry a lower energy content by volume (per litre or per gallon). This is because ethanol is a partially oxidized hydrocarbon which can be seen by noting the presence of oxygen in the chemical formula: C2H5OH. Note the substitution of the OH hydroxyl group for a H hydrogen which transforms the gas ethane (C2H6) into ethanol. To a certain extent a fuel with a higher carbon ratio will be more dense than a fuel with a lower carbon ratio. Thus it is possible to formulate high octane fuels that carry less energy per liter than lower octane fuels. This is certainly true of ethanol blend fuels (gasohol), however fuels with no ethanol and indeed no oxygen are also possible. Alcohol fuels such as methanol and ethanol, are partially oxidized fuels and need to be run at much richer mixtures than gasoline. As a consequence, the total volume of fuel burned per cycle counterbalances the lower energy per unit volume, and the net energy released per cycle is higher. If gasoline is run at its preferred maximum power air/fuel mixture of 12.5:1, it will release approximately 20 MJ (about 19,000 BTU) of energy, where ethanol run at its preferred maximum power mixture of 6.5:1 will liberate approximately 25.7 MJ (24,400 BTU), and methanol at a 4.5:1 AFR liberates about 29.1 MJ (27,650 BTU). To account for these differences, a measure called the fuel's specific energy is sometimes used. It is defined as the energy released per air/fuel ratio. Using a fuel with a higher octane lets an engine run at a higher compression ratio without having problems with knock. Actual compression in the combustion chamber is determined by the compression ratio as well as the amount of air restriction in the intake manifold (manifold vacuum) as well as the barometric pressure, which is a function of elevation and weather conditions. Compression is directly related to power (see engine tuning), so engines that require higher octane usually deliver more power. Engine power is a function of the fuel as well as the engine design and is related to octane ratings of the fuel. Power is limited by the maximum amount of fuel-air mixture that can be forced into the combustion chamber. At partial load, only a small fraction of the total available power is produced because the manifold is operating at pressures far below atmospheric. In this case, the octane requirement is far lower than what is available. It is only when the throttle is opened fully and the manifold pressure increases to atmospheric (or higher in the case of supercharged or turbocharged engines) that the full octane requirement is achieved. Many high-performance engines are designed to operate with a high maximum compression and thus need a high quality (high energy) fuel usually associated with high octane numbers and thus demand high-octane premium gasoline. Ethanol with an octane of 116 could be a high performance fuel if engines were designed with a 14 to 1 compression ratio, possibly improving the mileage to compete with gasoline. The Offenhauser engine had a 15 to 1 ratio and burned methanol. The power output of an engine depends on the energy content of its fuel, and this bears no simple relationship to the octane rating. A common understanding that may apply in only limited circumstances amongst petrol consumers is that adding a higher octane fuel to a vehicle's engine will increase its performance and/or lessen its fuel consumption; this may be false under most conditions — while engines perform best when using fuel with the octane rating for which they were designed and any increase in performance by using a fuel with a different octane rating is minimal or even imaginary, unless there are carbon hotspots, fuel injector clogging or other conditions that may cause a lean situation that can cause knocking that are more common in high mileage vehicles, which would cause modern cars to retard timing thus leading to a loss of both responsiveness and fuel economy. This also does not apply to turbocharged vehicles, which may be allowed to run greater advance in certain circumstances due to external temperatures. Using high octane fuel for an engine makes a difference when the engine is producing its maximum power or when under a high load such as climbing a large hill or carrying excessive weight. This will occur when the intake manifold has no air restriction and is running at minimum vacuum. Depending on the engine design, this particular circumstance can be anywhere along the RPM range, but is usually easy to pinpoint if you can examine a printout of the power output (torque values) of an engine. On a typical high-revving motorcycle engine, for example, the maximum power occurs at a point where the movements of the intake and exhaust valves are timed in such a way to maximize the compression loading of the cylinder; although the piston is already rising at the time the intake valve closes, the forward speed of the charge coming into the cylinder is high enough to continue to load the air-fuel mixture in. When this occurs, if a fuel with below recommended octane is used, the engine will knock. Modern engines have anti-knock provisions built into the control systems and this is usually achieved by dynamically de-tuning the engine while under load by increasing the fuel-air mixture and retarding the spark. Here is a link to a white paper that gives an example: . In this example, the engine maximum power is reduced by about 4% with a fuel switch from 93 to 91 octane (11 hp, from 291 to 280 hp). If the engine is being run below maximum load, the difference in octane will have even less effect. The example cited does not indicate at what elevation the test is being conducted or what the barometric pressure is. For each 1000 feet of altitude the atmospheric pressure will drop by a little less than 11 kPa/km (1 inHg). An engine that might require 93 octane at sea level may perform at maximum on a fuel rated at 91 octane if the elevation is over, say, 1000 feet. See also the APC article. The octane rating was developed by chemist Russell Marker at the Ethyl Corporation c1926. The selection of n-heptane as the zero point of the scale was due to the availability of very high purity n-heptane, not mixed with other isomers of heptane or octane, distilled from the resin of the Jeffrey Pine. Other sources of heptane produced from crude oil contain a mixture of different isomers with greatly differing ratings, which would not give a precise zero point. # Regional variations Octane ratings can vary greatly from region to region. For example, the minimum octane rating available in much of the United States is 87 AKI and the highest is 93. However this does not mean that the gas is different. In the Rocky Mountain (high altitude) states, 85 octane is the minimum octane and 91 is the maximum octane available in fuel. The reason for this is that in higher-altitude areas, a typical combustion engine draws in less air per cycle due to the reduced density of the atmosphere. This directly translates to reduced absolute compression in the cylinder, therefore deterring knock. It is safe to fill up a car with a carburetor that normally takes 87 AKI fuel at sea level with 85 AKI fuel in the mountains, but at sea level the fuel may cause damage to the engine. A disadvantage to this strategy is that most turbocharged vehicles are unable to produce full power, even when using the "premium" 91 AKI fuel. In some east coast states, up to 94 AKI is available . In parts of the Midwest (primarily Minnesota, Illinois and Missouri) ethanol based E-85 fuel with 105 AKI is available . California fuel stations will offer 87, 89, and 91 octane fuels, and at some stations, 100 or higher octane, sold as racing fuel. Until 2003 or 2004, 92 octane was offered in lieu of 91. Generally, octane ratings are higher in Europe than they are in North America and most other parts of the world. This is especially true when comparing the lowest available octane level in each country. In many parts of Europe, 95 RON (90-91 AKI) is the minimum available standard, with 97/98 being higher specification (being called Super Unleaded). In Germany, big suppliers like Shell or Aral offer 100 octane gasoline (Shell V-Power, Aral Ultimate) at almost every gas station. In Australia, "regular" unleaded fuel is RON 91, "premium" unleaded with RON 95 is widely available, and RON 98 fuel is also reasonably common. Shell sells RON 100 petrol from a small number of service stations, most of which are located in capital cities. In Malaysia, the "regular" unleaded fuel is RON92 while "premium" fuel is rated at RON97. In other countries "regular" unleaded gasoline, when available, is sometimes as low as 85 RON (still with the more regular fuel - 95 - and premium around 98 available). In Russia and CIS countries 80 RON (76 AKI) is the minimum available and the standard. It should be noted that this higher rating seen in Europe is an artifact of a different underlying measuring procedure. In most countries (including all of Europe and Australia) the "headline" octane that would be shown on the pump is the RON, but in the United States, Canada and some other countries the headline number is the average of the RON and the MON, sometimes called the Anti-Knock Index (AKI), Road Octane Number (RdON), Pump Octane Number (PON), or (R+M)/2. Because of the 8 to 10 point difference noted above, this means that the octane in the United States will be about 4 to 5 points lower than the same fuel elsewhere: 87 octane fuel, the "regular" gasoline in the US and Canada, would be 91-92 in Europe. However most European pumps deliver 95 (RON) as "regular", equivalent to 90-91 US (R+M)/2, and deliver 98 (RON), 99 or 100 (RON) labeled as Super Unleaded. In the United Kingdom the oil company BP is currently trialling the public selling of the super-high octane petrol BP Ultimate Unleaded 102, which as the name suggests, has an octane rating of RON 102. Although BP Ultimate Unleaded (with an octane rating of RON 97) and BP Ultimate Diesel are both widely available throughout the UK, BP Ultimate Unleaded 102 is (as of October 2007) only available throughout the UK in 10 filling stations.	Octane rating # Overview The octane rating is a measure of the autoignition resistance of gasoline and other fuels used in spark-ignition internal combustion engines. It is a measure of anti-detonation of a gasoline or fuel. Octane number is the number which gives the percentage, by volume, of iso-octane in a mixture of iso-octane and normal heptane, that would have the same anti-knocking capacity as the fuel which is under consideration. For example, gasoline with the same knocking characteristics as a mixture of 90% iso-octane and 10% heptane would have an octane rating of 90. [1] # Definition of octane rating The octane rating of a spark ignition engine fuel is the knock resistance (anti-knock rating) compared to a mixture of iso-octane (2,2,4-trimethylpentane, an isomer of octane) and n-heptane. By definition, iso-octane is assigned an octane rating of 100 and heptane is assigned an octane rating of zero. An 87-octane gasoline, for example, possesses the same anti-knock rating of a mixture of 87% (by volume) iso-octane and 13% (by volume) n-heptane. This does not mean, however, that the gasoline actually contains these hydrocarbons in these proportions. It simply means that it has the same autoignition resistance as the described mixture. A high tendency to autoignite, or low octane rating, is undesirable in a spark ignition engine but desirable in a diesel engine. The standard for the combustion quality of diesel fuel is the cetane number. A diesel fuel with a high cetane number has a high tendency to autoignite, as is preferred. It should be noted that octane rating does not relate to the energy content of the fuel (see heating value), nor the speed at which the flame initiated by the spark plug propagates across the cylinder. It is only a measure of the fuel's resistance to autoignition. It is for this reason that one highly branched form, or isomer, of octane (2,2,4-trimethylpentane) has (by definition) an octane rating of 100, whereas n-octane (see octane), which has a linear arrangement of the 8 carbon atoms, has an octane rating of -10, even though the two fuels have exactly the same chemical formula and virtually identical heating values and flame speeds. ## Measurement methods The most common type of octane rating worldwide is the Research Octane Number (RON). RON is determined by running the fuel in a test engine with a variable compression ratio under controlled conditions, and comparing these results with those for mixtures of iso-octane and n-heptane. There is another type of octane rating, called Motor Octane Number (MON) or the aviation lean octane rating, which is a better measure of how the fuel behaves when under load. MON testing uses a similar test engine to that used in RON testing, but with a preheated fuel mixture, a higher engine speed, and variable ignition timing to further stress the fuel's knock resistance. Depending on the composition of the fuel, the MON of a modern gasoline will be about 8 to 10 points lower than the RON. Normally fuel specifications require both a minimum RON and a minimum MON. In most countries (including all of Europe and Australia) the "headline" octane that would be shown on the pump is the RON, but in the United States, Canada and some other countries the headline number is the average of the RON and the MON, sometimes called the Anti-Knock Index (AKI), Road Octane Number (RdON), Pump Octane Number (PON), or (R+M)/2. Because of the 8 to 10 point difference noted above, this means that the octane in the United States will be about 4 to 5 points lower than the same fuel elsewhere: 87 octane fuel, the "regular" gasoline in the US and Canada, would be 91-92 in Europe. However most European pumps deliver 95 (RON) as "regular", equivalent to 90-91 US (R+M)/2, and even deliver 98 (RON) or 100 (RON). The octane rating may also be a "trade name", with the actual figure being higher than the nominal rating.[citation needed] It is possible for a fuel to have a RON greater than 100, because iso-octane is not the most knock-resistant substance available. Racing fuels, straight ethanol, AvGas and liquified petroleum gas (LPG) typically have octane ratings of 110 or significantly higher - ethanol's RON is 129 (MON 102, AKI 116) reference[1]. Typical "octane booster" additives include tetra-ethyl lead, MTBE and toluene. Tetra-ethyl lead is easily decomposed to its component radicals, which react with the radicals from the fuel and oxygen that would start the combustion, thereby delaying ignition. This is why leaded gasoline has a higher octane rating than unleaded. # Examples of octane ratings The octane ratings of n-heptane and iso-octane are respectively exactly 0 and 100, by definition. For some other hydrocarbons, the following table[2][3] gives the 'AKI' ratings. *Hydrogen represents a paradox. As a fuel outright, it has low knock resistance[2][3], due to its low ignition energy (primarily due to its low dissociation energy) and extremely high flame speed. However, as a minor blending component (i.e., a bi-fuel vehicle), hydrogen raises overall knock resistance. Flame speed is limited by the rest of the component species; hydrogen may reduce knock by contributing its high thermal conductivity. These traits are highly desirable in rocket engines, but undesirable in Otto-cycle engines. # Effects of octane rating Template:Refimprovesect Higher octane ratings correlate to higher activation energies. Activation energy is the amount of energy necessary to start a chemical reaction. Since higher octane fuels have higher activation energies, it is less likely that a given compression will cause knocking. (Note that it is the absolute pressure (compression) in the combustion chamber which is important — not the compression ratio. The compression ratio only governs the maximum compression that can be achieved). Octane rating has no direct impact on the deflagration (burn) of the air/fuel mixture in the combustion chamber. Other properties of gasoline and engine design account for the manner at which deflagration takes place. In other words, the flame speed of a normally ignited mixture is not directly connected to octane rating. Deflagration is the type of combustion that constitutes the normal burn. Detonation is a different type of combustion and this is to be avoided in spark ignited gasoline engines. Octane rating is a measure of detonation resistance, not deflagration characteristics. It might seem odd that fuels with higher octane ratings explode less easily and are therefore more powerful. One simple explanation for the effect is that various fuels can provide different heat (therefore energy) at different compression levels. As the compression level increases on many fuels so does the heat (energy) per unit of measure of fuel. Fuels burned in normal sea level pressure produce less energy than ones burned at the point of pre-ignition. The best energy pressure (compression ratio) for a fuel is at the point of where the engine "pings". Each fuel with its own resistance to pre-ignition requires its own ideal compression ratio. This is not always what emission levels require however. A motor must be constructed to work within a fuels compression ratio and emission levels. Another simple explanation is that carbon-carbon bonds contain more energy than carbon-hydrogen bonds. Hence a fuel with a greater number of carbon bonds will carry more energy regardless of the octane rating. A premium motor fuel will often be formulated to have both higher octane as well as more energy. A counter example to this rule is that ethanol blend fuels have a higher octane rating, but carry a lower energy content by volume (per litre or per gallon). This is because ethanol is a partially oxidized hydrocarbon which can be seen by noting the presence of oxygen in the chemical formula: C2H5OH. Note the substitution of the OH hydroxyl group for a H hydrogen which transforms the gas ethane (C2H6) into ethanol. To a certain extent a fuel with a higher carbon ratio will be more dense than a fuel with a lower carbon ratio. Thus it is possible to formulate high octane fuels that carry less energy per liter than lower octane fuels. This is certainly true of ethanol blend fuels (gasohol), however fuels with no ethanol and indeed no oxygen are also possible. Alcohol fuels such as methanol and ethanol, are partially oxidized fuels and need to be run at much richer mixtures than gasoline. As a consequence, the total volume of fuel burned per cycle counterbalances the lower energy per unit volume, and the net energy released per cycle is higher. If gasoline is run at its preferred maximum power air/fuel mixture of 12.5:1, it will release approximately 20 MJ (about 19,000 BTU) of energy, where ethanol run at its preferred maximum power mixture of 6.5:1 will liberate approximately 25.7 MJ (24,400 BTU), and methanol at a 4.5:1 AFR liberates about 29.1 MJ (27,650 BTU).[citation needed] To account for these differences, a measure called the fuel's specific energy is sometimes used. It is defined as the energy released per air/fuel ratio. Using a fuel with a higher octane lets an engine run at a higher compression ratio without having problems with knock. Actual compression in the combustion chamber is determined by the compression ratio as well as the amount of air restriction in the intake manifold (manifold vacuum) as well as the barometric pressure, which is a function of elevation and weather conditions. Compression is directly related to power (see engine tuning), so engines that require higher octane usually deliver more power. Engine power is a function of the fuel as well as the engine design and is related to octane ratings of the fuel. Power is limited by the maximum amount of fuel-air mixture that can be forced into the combustion chamber. At partial load, only a small fraction of the total available power is produced because the manifold is operating at pressures far below atmospheric. In this case, the octane requirement is far lower than what is available. It is only when the throttle is opened fully and the manifold pressure increases to atmospheric (or higher in the case of supercharged or turbocharged engines) that the full octane requirement is achieved. Many high-performance engines are designed to operate with a high maximum compression and thus need a high quality (high energy) fuel usually associated with high octane numbers and thus demand high-octane premium gasoline. Ethanol with an octane of 116 could be a high performance fuel if engines were designed with a 14 to 1 compression ratio, possibly improving the mileage to compete with gasoline. The Offenhauser engine had a 15 to 1 ratio and burned methanol. The power output of an engine depends on the energy content of its fuel, and this bears no simple relationship to the octane rating. A common understanding that may apply in only limited circumstances amongst petrol consumers is that adding a higher octane fuel to a vehicle's engine will increase its performance and/or lessen its fuel consumption; this may be false under most conditions — while engines perform best when using fuel with the octane rating for which they were designed and any increase in performance by using a fuel with a different octane rating is minimal or even imaginary, unless there are carbon hotspots, fuel injector clogging or other conditions that may cause a lean situation that can cause knocking that are more common in high mileage vehicles, which would cause modern cars to retard timing thus leading to a loss of both responsiveness and fuel economy. This also does not apply to turbocharged vehicles, which may be allowed to run greater advance in certain circumstances due to external temperatures. Using high octane fuel for an engine makes a difference when the engine is producing its maximum power or when under a high load such as climbing a large hill or carrying excessive weight. This will occur when the intake manifold has no air restriction and is running at minimum vacuum. Depending on the engine design, this particular circumstance can be anywhere along the RPM range, but is usually easy to pinpoint if you can examine a printout of the power output (torque values) of an engine. On a typical high-revving motorcycle engine, for example, the maximum power occurs at a point where the movements of the intake and exhaust valves are timed in such a way to maximize the compression loading of the cylinder; although the piston is already rising at the time the intake valve closes, the forward speed of the charge coming into the cylinder is high enough to continue to load the air-fuel mixture in. When this occurs, if a fuel with below recommended octane is used, the engine will knock. Modern engines have anti-knock provisions built into the control systems and this is usually achieved by dynamically de-tuning the engine while under load by increasing the fuel-air mixture and retarding the spark. Here is a link to a white paper that gives an example: [4]. In this example, the engine maximum power is reduced by about 4% with a fuel switch from 93 to 91 octane (11 hp, from 291 to 280 hp). If the engine is being run below maximum load, the difference in octane will have even less effect. The example cited does not indicate at what elevation the test is being conducted or what the barometric pressure is. For each 1000 feet of altitude the atmospheric pressure will drop by a little less than 11 kPa/km (1 inHg). An engine that might require 93 octane at sea level may perform at maximum on a fuel rated at 91 octane if the elevation is over, say, 1000 feet. See also the APC article. The octane rating was developed by chemist Russell Marker at the Ethyl Corporation c1926. The selection of n-heptane as the zero point of the scale was due to the availability of very high purity n-heptane, not mixed with other isomers of heptane or octane, distilled from the resin of the Jeffrey Pine. Other sources of heptane produced from crude oil contain a mixture of different isomers with greatly differing ratings, which would not give a precise zero point. # Regional variations Octane ratings can vary greatly from region to region. For example, the minimum octane rating available in much of the United States is 87 AKI and the highest is 93. However this does not mean that the gas is different. In the Rocky Mountain (high altitude) states, 85 octane is the minimum octane and 91 is the maximum octane available in fuel. The reason for this is that in higher-altitude areas, a typical combustion engine draws in less air per cycle due to the reduced density of the atmosphere. This directly translates to reduced absolute compression in the cylinder, therefore deterring knock. It is safe to fill up a car with a carburetor that normally takes 87 AKI fuel at sea level with 85 AKI fuel in the mountains, but at sea level the fuel may cause damage to the engine. A disadvantage to this strategy is that most turbocharged vehicles are unable to produce full power, even when using the "premium" 91 AKI fuel. In some east coast states, up to 94 AKI is available [5]. In parts of the Midwest (primarily Minnesota, Illinois and Missouri) ethanol based E-85 fuel with 105 AKI is available [6]. California fuel stations will offer 87, 89, and 91 octane fuels, and at some stations, 100 or higher octane, sold as racing fuel. Until 2003 or 2004, 92 octane was offered in lieu of 91. Generally, octane ratings are higher in Europe than they are in North America and most other parts of the world. This is especially true when comparing the lowest available octane level in each country. In many parts of Europe, 95 RON (90-91 AKI) is the minimum available standard, with 97/98 being higher specification (being called Super Unleaded). In Germany, big suppliers like Shell or Aral offer 100 octane gasoline (Shell V-Power, Aral Ultimate) at almost every gas station. In Australia, "regular" unleaded fuel is RON 91, "premium" unleaded with RON 95 is widely available, and RON 98 fuel is also reasonably common. Shell sells RON 100 petrol from a small number of service stations, most of which are located in capital cities. In Malaysia, the "regular" unleaded fuel is RON92 while "premium" fuel is rated at RON97. In other countries "regular" unleaded gasoline, when available, is sometimes as low as 85 RON (still with the more regular fuel - 95 - and premium around 98 available). In Russia and CIS countries 80 RON (76 AKI) is the minimum available and the standard. It should be noted that this higher rating seen in Europe is an artifact of a different underlying measuring procedure. In most countries (including all of Europe and Australia) the "headline" octane that would be shown on the pump is the RON, but in the United States, Canada and some other countries the headline number is the average of the RON and the MON, sometimes called the Anti-Knock Index (AKI), Road Octane Number (RdON), Pump Octane Number (PON), or (R+M)/2. Because of the 8 to 10 point difference noted above, this means that the octane in the United States will be about 4 to 5 points lower than the same fuel elsewhere: 87 octane fuel, the "regular" gasoline in the US and Canada, would be 91-92 in Europe. However most European pumps deliver 95 (RON) as "regular", equivalent to 90-91 US (R+M)/2, and deliver 98 (RON), 99 or 100 (RON) labeled as Super Unleaded. In the United Kingdom the oil company BP is currently trialling the public selling of the super-high octane petrol BP Ultimate Unleaded 102, which as the name suggests, has an octane rating of RON 102. Although BP Ultimate Unleaded (with an octane rating of RON 97) and BP Ultimate Diesel are both widely available throughout the UK, BP Ultimate Unleaded 102 is (as of October 2007) only available throughout the UK in 10 filling stations.	https://www.wikidoc.org/index.php/Octane_number
f729938a1d59ba35fa2072059bc8e1003c8ad32f	wikidoc	Off-label use	Off-label use # Overview Off-label use is the practice of prescribing drugs for a purpose outside the scope of the drug's approved label, most often concerning the drug's indication. In the United States, the Food and Drug Administration (FDA) requires numerous clinical trials to prove a drug's safety and efficacy in treating a given disease or condition. If satisfied that the drug is safe and effective, the drug's manufacturer and the FDA agree on specific language describing dosage, route and other information to be included on the drug's label. More detail is included in the drug's package insert. However, once the FDA approves a drug for prescription use, they do not attempt to regulate the practice of medicine, and so the physician makes decisions based on her or his best judgment. It is entirely legal in the United States and in many other countries to use drugs off-label. Exceptions to this are certain controlled substances, such as opiates, which cannot be legally prescribed except for approved purposes (at least in the U.S.). In Australia, amphetamines are included in these drugs which cannot be prescribed off-label. Some drugs are used more frequently off-label than for their original, FDA-approved indications. A 1991 study by the U.S. General Accounting Office found that one-third of all drug administrations to cancer patients were off label and more than half of cancer patients received at least one drug for an off-label indication. Frequently the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs. An example is the use of tricyclic antidepressants to treat neuropathic pain. This old class of antidepressants is now rarely used for clinical depression due to side effects, but the tricyclics are often effective for treating pain. # Off-label use and the law In the United States, FDA regulations permit physicians to prescribe approved medications for other than their intended indications. Marketing information for the drug will list one or more indications, i.e., illnesses or medical conditions for which the drug has been shown to be both safe and effective. Pharmaceutical companies are not allowed to promote a drug for any other purpose without formal FDA approval. However, once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective; they are not limited to its official, FDA-approved indications. This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is usually extensive medical literature to support the off-label use. Access to pharmaceutical industry documents have revealed marketing strategies used to promote drugs for off-label use. In 1993, the US Food and Drug Administration (FDA) approved gabapentin (Neurontin®, Pfizer) only for treatment of seizures. Pfizer subsidiary Warner-Lambert used activities not usually associated with sales promotion, including continuing medical education and research, to promote gabapentin, so that within 5 years the drug was being widely used for the off-label treatment of pain and psychiatric conditions. In 2004, Warner-Lambert admitted to charges that it violated FDA regulations by promoting the drug for pain, psychiatric conditions, migraine, and other unapproved uses. The United States federal government is aggressively pursuing criminal and civil cases against pharmaceutical companies and their employees for promoting off-label uses of prescription drugs. In 2004, Pfizer/Warner-Lambert paid $430 million to the federal government to settle a whistleblower case that alleged the company engaged in a scheme to promote the epilepsy drug, Neurontin, for off-label uses such as for patients with bipolar disorder and Lou Gehrig's disease. The position of the British General Medical Council on off-label prescribing may be found here. # Off-label use of narcotics While off-label administration of non-narcotic medications is generally tolerated by U.S. authorities, prescription of DEA scheduled narcotics for unapproved purposes is not. Medical license revocation, asset seizure, and incarceration are all common consequences borne by doctors in violation of the prohibition laws. # Off-label use in Veterinary Medicine The veterinarian has a much smaller pharmacopea available than does the human practitioner. Therefore, drugs are more likely to be used "off label" - typically, this involves the use of a human medication in an animal, where there is no corresponding medication licenced for that species. This problem is compounded in "exotic" species (such as reptiles and rodents) where there are very few, if any licenced medications. In addition, (especially in Europe), equine veterinarians are forced to use a lot of drugs off label, as the horse is classified as a food-producing animal. # Examples of off-label use (and non-use) - Botulin toxin is approved for the treatment of muscle spasms. Under the tradename Botox, it has become the basis of a popular cosmetic anti-wrinkle procedure, which is much more economically important than the approved use. - Bevacizumab has been used against Age Related Macular Degeneration, but the evidence for its use is anecdotal. - Carbamazepine, has been used as a mood stabilizer and is accepted treatment for bipolar disorder. - Methotrexate (MTX), approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy. There is no FDA-approved drug for this purpose and there is little incentive to sponsor an unpatented drug such as MTX for FDA-approval. - The SSRI medication sertraline is approved as an anti-depressant. It is also commonly prescribed off-label to help men suffering from Premature ejaculation. - Buprenorphine has been shown experimentally (1982-1995) to be effective against psychiatric problems. Since buprenorphine is an opioid (narcotic) not approved for psychological use, prescription for psychiatric problems is prohibited. Apparently exceptions to the prohibition were allowed for the various experiments. - Stimulants such as Amphetamine (Adderall) and Methylphenidate (Ritalin) are indicated for childhood attention deficit disorder (ADD/ADHD), but are often prescribed to treat adults as well. Atomoxetine (Strattera), a non-stimulant norepinephrine reuptake inhibitor is currently the only drug (In the United States) indicated for adult ADD. In Australia dextroamphetamine is indicated for adult ADHD treatment. While Atomoxetine is also indicated for the treatment in Australia, it only has a minor percentage of the drugs prescribed for the condition, due to its prohibitively high price, as it is currently not subsidised by the Government's Pharmaceutical Benefits Scheme, whereas the stimulant medications methylphenidate and dextroamphetamine are.	Off-label use # Overview Off-label use is the practice of prescribing drugs for a purpose outside the scope of the drug's approved label, most often concerning the drug's indication. In the United States, the Food and Drug Administration (FDA) requires numerous clinical trials to prove a drug's safety and efficacy in treating a given disease or condition. If satisfied that the drug is safe and effective, the drug's manufacturer and the FDA agree on specific language describing dosage, route and other information to be included on the drug's label. More detail is included in the drug's package insert. However, once the FDA approves a drug for prescription use, they do not attempt to regulate the practice of medicine, and so the physician makes decisions based on her or his best judgment. It is entirely legal in the United States and in many other countries to use drugs off-label. Exceptions to this are certain controlled substances, such as opiates, which cannot be legally prescribed except for approved purposes (at least in the U.S.). In Australia, amphetamines are included in these drugs which cannot be prescribed off-label. Some drugs are used more frequently off-label than for their original, FDA-approved indications. A 1991 study by the U.S. General Accounting Office found that one-third of all drug administrations to cancer patients were off label and more than half of cancer patients received at least one drug for an off-label indication. Frequently the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs. An example is the use of tricyclic antidepressants to treat neuropathic pain. This old class of antidepressants is now rarely used for clinical depression due to side effects, but the tricyclics are often effective for treating pain. # Off-label use and the law In the United States, FDA regulations permit physicians to prescribe approved medications for other than their intended indications. Marketing information for the drug will list one or more indications, i.e., illnesses or medical conditions for which the drug has been shown to be both safe and effective. Pharmaceutical companies are not allowed to promote a drug for any other purpose without formal FDA approval. However, once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective; they are not limited to its official, FDA-approved indications. This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is usually extensive medical literature to support the off-label use. Access to pharmaceutical industry documents have revealed marketing strategies used to promote drugs for off-label use. [1] In 1993, the US Food and Drug Administration (FDA) approved gabapentin (Neurontin®, Pfizer) only for treatment of seizures. Pfizer subsidiary Warner-Lambert used activities not usually associated with sales promotion, including continuing medical education and research, to promote gabapentin, so that within 5 years the drug was being widely used for the off-label treatment of pain and psychiatric conditions. In 2004, Warner-Lambert admitted to charges that it violated FDA regulations by promoting the drug for pain, psychiatric conditions, migraine, and other unapproved uses. [2] [3] The United States federal government is aggressively pursuing criminal and civil cases against pharmaceutical companies and their employees for promoting off-label uses of prescription drugs.[4] In 2004, Pfizer/Warner-Lambert paid $430 million to the federal government to settle a whistleblower case that alleged the company engaged in a scheme to promote the epilepsy drug, Neurontin, for off-label uses such as for patients with bipolar disorder and Lou Gehrig's disease. The position of the British General Medical Council on off-label prescribing may be found here. # Off-label use of narcotics While off-label administration of non-narcotic medications is generally tolerated by U.S. authorities, prescription of DEA scheduled narcotics for unapproved purposes is not. Medical license revocation, asset seizure, and incarceration are all common consequences borne by doctors in violation of the prohibition laws. # Off-label use in Veterinary Medicine The veterinarian has a much smaller pharmacopea available than does the human practitioner. Therefore, drugs are more likely to be used "off label" - typically, this involves the use of a human medication in an animal, where there is no corresponding medication licenced for that species. This problem is compounded in "exotic" species (such as reptiles and rodents) where there are very few, if any licenced medications. In addition, (especially in Europe), equine veterinarians are forced to use a lot of drugs off label, as the horse is classified as a food-producing animal. # Examples of off-label use (and non-use) - Botulin toxin is approved for the treatment of muscle spasms. Under the tradename Botox, it has become the basis of a popular cosmetic anti-wrinkle procedure, which is much more economically important than the approved use. - Bevacizumab has been used against Age Related Macular Degeneration, but the evidence for its use is anecdotal.[2] - Carbamazepine, has been used as a mood stabilizer and is accepted treatment for bipolar disorder. - Methotrexate (MTX), approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy. There is no FDA-approved drug for this purpose and there is little incentive to sponsor an unpatented drug such as MTX for FDA-approval. - The SSRI medication sertraline is approved as an anti-depressant. It is also commonly prescribed off-label to help men suffering from Premature ejaculation. - Buprenorphine has been shown experimentally (1982-1995) to be effective against psychiatric problems. Since buprenorphine is an opioid (narcotic) not approved for psychological use, prescription for psychiatric problems is prohibited. Apparently exceptions to the prohibition were allowed for the various experiments. - Stimulants such as Amphetamine (Adderall) and Methylphenidate (Ritalin) are indicated for childhood attention deficit disorder (ADD/ADHD), but are often prescribed to treat adults as well. Atomoxetine (Strattera), a non-stimulant norepinephrine reuptake inhibitor is currently the only drug (In the United States) indicated for adult ADD. In Australia dextroamphetamine is indicated for adult ADHD treatment. While Atomoxetine is also indicated for the treatment in Australia, it only has a minor percentage of the drugs prescribed for the condition, due to its prohibitively high price, as it is currently not subsidised by the Government's Pharmaceutical Benefits Scheme, whereas the stimulant medications methylphenidate and dextroamphetamine are.	https://www.wikidoc.org/index.php/Off-label
8f91abdb026bdabaec479eb0c8bd909e1ab4d94f	wikidoc	Oil of cloves	Oil of cloves Oil of cloves, also known as Clove oil, is an essential oil from the clove plant, Syzygium aromaticum. It is a natural analgaesic used primarily in dentistry for its active ingredient eugenol. It can also be purchased in pharmacies over the counter, as a home remedy for dental pain relief, mainly toothache; it is also often found in the aromatherapy section of health food stores. The oil produced by cloves can be used in many things from flavouring medicine to remedies for bronchitis, the common cold, a cough, fever, sore throat and tending to infections. The main oil-producing countries are Madagascar and Indonesia. There are three types of clove oil: - Bud oil is derived form the flower-buds of S.aromaticum. It consists of 60-90% eugenol, eugenol acetate, caryophyllene and other minor constituents. - Leaf oil is derived from the leaves of S.aromaticum. It consists of 82-88% eugenol with little or no eugenol acetate, and minor constituents. - Stem oil is derived from the twigs of S.aromaticum. It consists of 90-95% eugenol, with other minor constituents. # Oral use Oil of cloves is known best for its anaesthetic properties. It is widely reported to be effective, and prior to the availability of safe, approved topical anaesthetic drugs, was used by some dentists. Clove oil is often used to relieve pain caused by dry socket, a possible complication of tooth extraction. Clove oil has an unpleasant taste, so it is advised to prevent the oil from touching the tongue. It is considered safe in very small quantities (<1500 p.p.m.) as a food additive. However, clove oil is toxic to human cells. If ingested in sufficient quantity or injected, it has been shown to cause life-threatening complications, including Acute Respiratory Distress Syndrome, Fulminant Hepatic (Liver) Failure, and Central Nervous System Depression; the lethal oral dose is 3.752 g per kg body weight # Topical use When applied to stop a toothache, it is best done with a cotton swab, applied directly to the side of the tooth, or directly on to the tooth, on the instance if a hole is present, to allow for the oil to absorb into the affected area. # Other uses It is also used for anesthetizing fish. Clove oil is also used in an all natural herbicide called "Perfectly Natural Weed & Grass Killer". The clove oil is the only active ingredient, and it is very effective at killing many types of plants. Clove oil has uses for antimicrobial and antifungal. It can be used for acne, warts, scars and parasites. Research has shown that clove oil is an effective mosquito repellent. # Footnotes - ↑ Lawless, J., The Illustrated Encyclopedia of Essential Oils, 1995, ISBN 1-85230-661-0 - ↑ Lawless, J., The Illustrated Encyclopedia of Essential Oils, 1995, ISBN 1-85230-661-0 - ↑ Bruneton, J (1995). Pharmacognosy, Phytochemistry, Medicinal Plants. Hampshire, U.K.: Intercept Ltd..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Jump up to: 4.0 4.1 Prashar A, Locke IC, Evans CS (2006). "Cytotoxicity of clove (Syzygium aromaticum) oil and its major components to human skin cells". Cell Prolif. 39: 241–248.CS1 maint: Multiple names: authors list (link) - ↑ "Oxford Physical and Theoretical Chemistry Lab Material Safety Data Sheets". - ↑ Hartnoll G, Moore D, Douek D (1993). "Near fatal ingestion of oil of cloves". Arch Dis Child. 69 (3): 392–393.CS1 maint: Multiple names: authors list (link) - ↑ Brown SA, Biggerstaff J, Savidge GF (1992). "Disseminated intravascular coagulation and hepatocellular necrosis due to clove oil". Blood Coagul Fibrinolysis. 3 (5): 665–668.CS1 maint: Multiple names: authors list (link) - ↑ Lane BW, Ellenhorn MH, Hulbert TV, McCarron M. (1991). "Clove oil ingestion in an infant". Human Exp Toxicol. 10 (4): 291–294.CS1 maint: Multiple names: authors list (link) - ↑ Kirsch CM; et al. (1990). "Non-cardiogenic pulmonary edema due to the intravenous administration of clove oil". Thorax. 45 (3): 235–236.CS1 maint: Explicit use of et al. (link) - ↑ Trongtokit Y, Rongsriyan Y, Komalamisra N, Apiwathnasom L, Comparative repellency of 38 essential oils against mosquito bites, Phytother Res. 2005 Apr;19(4):303-9	Oil of cloves Oil of cloves, also known as Clove oil, is an essential oil from the clove plant, Syzygium aromaticum. It is a natural analgaesic used primarily in dentistry for its active ingredient eugenol. It can also be purchased in pharmacies over the counter, as a home remedy for dental pain relief, mainly toothache; it is also often found in the aromatherapy section of health food stores. The oil produced by cloves can be used in many things from flavouring medicine to remedies for bronchitis, the common cold, a cough, fever, sore throat and tending to infections. The main oil-producing countries are Madagascar and Indonesia.[1] There are three types of clove oil:[2] - Bud oil is derived form the flower-buds of S.aromaticum. It consists of 60-90% eugenol, eugenol acetate, caryophyllene and other minor constituents. - Leaf oil is derived from the leaves of S.aromaticum. It consists of 82-88% eugenol with little or no eugenol acetate, and minor constituents. - Stem oil is derived from the twigs of S.aromaticum. It consists of 90-95% eugenol, with other minor constituents. # Oral use Oil of cloves is known best for its anaesthetic properties. It is widely reported to be effective, and prior to the availability of safe, approved topical anaesthetic drugs, was used by some dentists. Clove oil is often used to relieve pain caused by dry socket, a possible complication of tooth extraction. Clove oil has an unpleasant taste, so it is advised to prevent the oil from touching the tongue. It is considered safe in very small quantities (<1500 p.p.m.) as a food additive. [3] However, clove oil is toxic to human cells[4]. If ingested in sufficient quantity or injected, it has been shown to cause life-threatening complications, including Acute Respiratory Distress Syndrome, Fulminant Hepatic (Liver) Failure, and Central Nervous System Depression; the lethal oral dose is 3.752 g per kg body weight[5][6][7][8][9] # Topical use When applied to stop a toothache, it is best done with a cotton swab, applied directly to the side of the tooth, or directly on to the tooth, on the instance if a hole is present, to allow for the oil to absorb into the affected area.[4] # Other uses It is also used for anesthetizing fish. Clove oil is also used in an all natural herbicide called "Perfectly Natural Weed & Grass Killer". The clove oil is the only active ingredient, and it is very effective at killing many types of plants. Clove oil has uses for antimicrobial and antifungal. It can be used for acne, warts, scars and parasites. Research has shown that clove oil is an effective mosquito repellent.[10] # Footnotes - ↑ Lawless, J., The Illustrated Encyclopedia of Essential Oils, 1995, ISBN 1-85230-661-0 - ↑ Lawless, J., The Illustrated Encyclopedia of Essential Oils, 1995, ISBN 1-85230-661-0 - ↑ Bruneton, J (1995). Pharmacognosy, Phytochemistry, Medicinal Plants. Hampshire, U.K.: Intercept Ltd..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Jump up to: 4.0 4.1 Prashar A, Locke IC, Evans CS (2006). "Cytotoxicity of clove (Syzygium aromaticum) oil and its major components to human skin cells". Cell Prolif. 39: 241–248.CS1 maint: Multiple names: authors list (link) - ↑ "Oxford Physical and Theoretical Chemistry Lab Material Safety Data Sheets". - ↑ Hartnoll G, Moore D, Douek D (1993). "Near fatal ingestion of oil of cloves". Arch Dis Child. 69 (3): 392–393.CS1 maint: Multiple names: authors list (link) - ↑ Brown SA, Biggerstaff J, Savidge GF (1992). "Disseminated intravascular coagulation and hepatocellular necrosis due to clove oil". Blood Coagul Fibrinolysis. 3 (5): 665–668.CS1 maint: Multiple names: authors list (link) - ↑ Lane BW, Ellenhorn MH, Hulbert TV, McCarron M. (1991). "Clove oil ingestion in an infant". Human Exp Toxicol. 10 (4): 291–294.CS1 maint: Multiple names: authors list (link) - ↑ Kirsch CM; et al. (1990). "Non-cardiogenic pulmonary edema due to the intravenous administration of clove oil". Thorax. 45 (3): 235–236.CS1 maint: Explicit use of et al. (link) - ↑ Trongtokit Y, Rongsriyan Y, Komalamisra N, Apiwathnasom L, Comparative repellency of 38 essential oils against mosquito bites, Phytother Res. 2005 Apr;19(4):303-9 [1]	https://www.wikidoc.org/index.php/Oil_of_cloves
f5ed367dd76d4457bc4b63b76427e378ffefba19	wikidoc	Oil of guaiac	Oil of guaiac Oil of guaiac is a fragrance used in soap. It comes from the palo santo tree (Bulnesia sarmientoi). Oil of guaiac is produced through steam distillation of a mixture of wood and sawdust from palo santo. It is sometimes incorrectly called guaiac wood concrete. It is a yellow to greenish yellow semi-solid mass which melts around 40-50º C. Once melted, it can be cooled back to room temperature yet remain liquid for a long time. Oil of guaiac has a soft roselike odour, similar to the odour of Hybrid tea roses or violets. Because of this similarity, it has sometimes been used as an adulterant for rose oil. Oil of guaiac is primarily composed of 42-72% guaiol, bulnesol, d-bulnesene, b-bulnesene, a-guaiene, guaioxide and b-patchoulene. It is considered non-irritating, non-sensitizing, and non phototoxic to human skin. Oil of guaiac was also a pre-Renaissance remedy to syphilis.	Oil of guaiac Oil of guaiac is a fragrance used in soap. It comes from the palo santo tree (Bulnesia sarmientoi). Oil of guaiac is produced through steam distillation of a mixture of wood and sawdust from palo santo. It is sometimes incorrectly called guaiac wood concrete. It is a yellow to greenish yellow semi-solid mass which melts around 40-50º C. Once melted, it can be cooled back to room temperature yet remain liquid for a long time. Oil of guaiac has a soft roselike odour, similar to the odour of Hybrid tea roses or violets. Because of this similarity, it has sometimes been used as an adulterant for rose oil. Oil of guaiac is primarily composed of 42-72% guaiol, bulnesol, d-bulnesene, b-bulnesene, a-guaiene, guaioxide and b-patchoulene. It is considered non-irritating, non-sensitizing, and non phototoxic to human skin. Oil of guaiac was also a pre-Renaissance remedy to syphilis.	https://www.wikidoc.org/index.php/Oil_of_guaiac
f68be642f197c96e1ceca87d559a78f22a9c5339	wikidoc	Older drivers	Older drivers # Introduction Driving safety is a public health issue that is paramount in the context of an aging society. Motor vehicle injuries are the leading cause of injury-related deaths among 65 to 74 year olds, and the second leading cause, after falls, among 75 to 84 year olds . Additionally, drivers over 80 have higher crash rates per mile driven than any other age group except teenage drivers . Common effects of aging, such as vision deficits and changes in cognition and musculoskeletal abilities, can affect driving safety. Age-related health problems (e.g. stroke, diabetes) and medication side effects can also impact driving safety . There is a challenge of balancing safety and independence. Driving for many is perceived to be a right rather than a privilege. Especially in American culture, driving remains an important part of an elder’s identity. Possession of a driver’s license has been referred to as an “asphalt identikit” . # Elders & Driving ## Guidelines License renewal policies vary from state to state. The American Medical Association set guidelines in 1999 and 2003 encouraging physicians to notify the Department of Motor Vehicles (in their state) when they are concerned about medical conditions that could make driving unsafe for patients they treat. A survey revealed that across stakeholder groups of physicians, policemen, and community members, there is not agreement regarding the type of assessment needed to determine driving competence . ## Risk Factors for Continued Driving Risks for continuing driving when it is no longer safe to do so include being male, living alone, and having dementia . ## Risks of Driving Cessation There are risks associated with driving cessation given poor transportation alternatives. Elders tend not to increase their use of public transit as they age, and the majority of elders who cease driving rely on private cars for transport . Driving cessation is associated with a loss of mobility, decreased engagement in activities, reduced access to proper health care, and a greater likelihood of health problems like depression . # Driving Management Options There are medical, functional, and psychosocial management options available for elder drivers with safety concerns. ## Medical Options - Reducing or elimination alcohol use - Minimizing prescription drug use - Managing underlying medical problems such as diabetes ## Functional Options - Self-limiting driving (based on the time of day, weather conditions, distance and familiarity of locations) - Wearing a seat-belt - Using a “co-pilot” ## Psychosocial Options - Reframing giving up the keys to driving retirement - Avoiding using “good” and “bad” driving language, focusing instead on “safety” - Using medical (as opposed to age-related) explanations - Highlighting the risk to self and others, and the potential legal/insurance repercussions to crashes - Identifying transportation resources. ## Other Options Last resort authoritarian options include reporting the driver to the RMV, hiding or removing car keys or changing the lock, disabling or removing the car, and obtaining an official letter from the MD to stop driving. A more proactive approach involves making a transportation plan that includes alternative resources before it is necessary to use them, considering relocating to a more supportive environment, and making a formal driving contract. # DriveWise at Beth Israel Deaconess Medical Center ## DriveWise Program Because driving is important to one’s independence and self-esteem, health care providers and family members are careful not to end driving privileges prematurely. On the other hand, delaying this decision may jeopardize safety. No one likes being “the bad guy” when it comes to making decisions about a person’s future driving. The DriveWise program at Beth Israel Deaconess Medical Center (BIDMC) was created in 1996 to help families and health care providers with this difficult decision making process. The program aims to confront the issue of driving safety in a manner that is both compassionate and evidence based . Recognized as a national model and the first of its kind, the DriveWise program offers an objective evaluation of driving safety for people of all ages who have experienced neurological, psychological, and/or physical impairments. Many DriveWise patients suffer from mild dementia; other patients have been evaluated with problems such as: head injury, brain tumors, seizures, Multiple Sclerosis and Parkinson’s Disease. The program, which was developed by the divisions of Behavioral Neurology and Occupational Therapy at BIDMC, is comprised of a multidisciplinary team, including social workers, occupational therapists, certified driving instructors, and neuropsychologists. This unique team approach results in a thorough examination of driving performance and provides support to patients and their families through the process. The DriveWise assessment reassures health professionals about those patients who, despite medical problems, are safe to continue driving. It also identifies those individuals whose compromised skills make driving no longer safe. By engaging in research and community education, the DriveWise team has opportunity to influence public policy affecting the older driver. The program has consulted countless physicians, family members, and community agencies to help resolve or to offer approaches to difficult driving dilemmas. To date, the program has assessed over 400 participants. ## DriveWise Evaluation and Follow Up The multidisciplinary team conducts a thorough evaluation that includes: - A clinical social work assessment; - In-clinic occupational therapy assessment; - On-road driving assessment with an occupational therapist and driving instructor, an element not offered by other driving evaluation programs; - Patient/family feedback meetings with the clinical social worker. Written recommendations summarize the finding of the evaluation. Some drivers benefit from remediation. Others are trained in the use of adaptations for the car or strategies for safer driving. When untreated medical issues, such as vision problems, compromise driving, referrals are made to hospital specialists. Alternative transportation resources in a community are identified as needed. If cessation of driving is recommended, the emotional impact of this loss is explored and support is provided to the driver and family. Consent forms allow contact with the RMV when appropriate. ## Referral to DriveWise Family members, primary care physicians, or specialists may make referrals by calling Beth Israel Deaconess Medical Center’s Division of Behavioral Neurology at (617) 667-4074. DriveWise follows a private pay model (not covered by Medicare).	Older drivers # Introduction Driving safety is a public health issue that is paramount in the context of an aging society. Motor vehicle injuries are the leading cause of injury-related deaths among 65 to 74 year olds, and the second leading cause, after falls, among 75 to 84 year olds [1]. Additionally, drivers over 80 have higher crash rates per mile driven than any other age group except teenage drivers [2]. Common effects of aging, such as vision deficits and changes in cognition and musculoskeletal abilities, can affect driving safety. Age-related health problems (e.g. stroke, diabetes) and medication side effects can also impact driving safety [3]. There is a challenge of balancing safety and independence. Driving for many is perceived to be a right rather than a privilege. Especially in American culture, driving remains an important part of an elder’s identity. Possession of a driver’s license has been referred to as an “asphalt identikit” [4]. # Elders & Driving ## Guidelines License renewal policies vary from state to state. The American Medical Association set guidelines in 1999 and 2003 encouraging physicians to notify the Department of Motor Vehicles (in their state) when they are concerned about medical conditions that could make driving unsafe for patients they treat. A survey revealed that across stakeholder groups of physicians, policemen, and community members, there is not agreement regarding the type of assessment needed to determine driving competence [5]. ## Risk Factors for Continued Driving Risks for continuing driving when it is no longer safe to do so include being male, living alone, and having dementia [6] [7]. ## Risks of Driving Cessation There are risks associated with driving cessation given poor transportation alternatives. Elders tend not to increase their use of public transit as they age, and the majority of elders who cease driving rely on private cars for transport [8]. Driving cessation is associated with a loss of mobility, decreased engagement in activities, reduced access to proper health care, and a greater likelihood of health problems like depression [9] [10]. # Driving Management Options There are medical, functional, and psychosocial management options available for elder drivers with safety concerns. ## Medical Options - Reducing or elimination alcohol use - Minimizing prescription drug use - Managing underlying medical problems such as diabetes ## Functional Options - Self-limiting driving (based on the time of day, weather conditions, distance and familiarity of locations) - Wearing a seat-belt - Using a “co-pilot” ## Psychosocial Options - Reframing giving up the keys to driving retirement - Avoiding using “good” and “bad” driving language, focusing instead on “safety” - Using medical (as opposed to age-related) explanations - Highlighting the risk to self and others, and the potential legal/insurance repercussions to crashes - Identifying transportation resources. ## Other Options Last resort authoritarian options include reporting the driver to the RMV, hiding or removing car keys or changing the lock, disabling or removing the car, and obtaining an official letter from the MD to stop driving. A more proactive approach involves making a transportation plan that includes alternative resources before it is necessary to use them, considering relocating to a more supportive environment, and making a formal driving contract. # DriveWise at Beth Israel Deaconess Medical Center ## DriveWise Program Because driving is important to one’s independence and self-esteem, health care providers and family members are careful not to end driving privileges prematurely. On the other hand, delaying this decision may jeopardize safety. No one likes being “the bad guy” when it comes to making decisions about a person’s future driving. The DriveWise program at Beth Israel Deaconess Medical Center (BIDMC) was created in 1996 to help families and health care providers with this difficult decision making process. The program aims to confront the issue of driving safety in a manner that is both compassionate and evidence based [11]. Recognized as a national model and the first of its kind, the DriveWise program offers an objective evaluation of driving safety for people of all ages who have experienced neurological, psychological, and/or physical impairments. Many DriveWise patients suffer from mild dementia; other patients have been evaluated with problems such as: head injury, brain tumors, seizures, Multiple Sclerosis and Parkinson’s Disease. The program, which was developed by the divisions of Behavioral Neurology and Occupational Therapy at BIDMC, is comprised of a multidisciplinary team, including social workers, occupational therapists, certified driving instructors, and neuropsychologists. This unique team approach results in a thorough examination of driving performance and provides support to patients and their families through the process. The DriveWise assessment reassures health professionals about those patients who, despite medical problems, are safe to continue driving. It also identifies those individuals whose compromised skills make driving no longer safe. By engaging in research and community education, the DriveWise team has opportunity to influence public policy affecting the older driver. The program has consulted countless physicians, family members, and community agencies to help resolve or to offer approaches to difficult driving dilemmas. To date, the program has assessed over 400 participants. ## DriveWise Evaluation and Follow Up The multidisciplinary team conducts a thorough evaluation that includes: - A clinical social work assessment; - In-clinic occupational therapy assessment; - On-road driving assessment with an occupational therapist and driving instructor, an element not offered by other driving evaluation programs; - Patient/family feedback meetings with the clinical social worker. Written recommendations summarize the finding of the evaluation. Some drivers benefit from remediation. Others are trained in the use of adaptations for the car or strategies for safer driving. When untreated medical issues, such as vision problems, compromise driving, referrals are made to hospital specialists. Alternative transportation resources in a community are identified as needed. If cessation of driving is recommended, the emotional impact of this loss is explored and support is provided to the driver and family. Consent forms allow contact with the RMV when appropriate. ## Referral to DriveWise Family members, primary care physicians, or specialists may make referrals by calling Beth Israel Deaconess Medical Center’s Division of Behavioral Neurology at (617) 667-4074. DriveWise follows a private pay model (not covered by Medicare).	https://www.wikidoc.org/index.php/Older_Drivers
84419974d23407fc62427e6c89752d2e0759710d	wikidoc	Oldest people	Oldest people The longest unambiguously documented lifespan is that of Jeanne Calment of France (1875–1997), who was aged 122 years. She met Vincent van Gogh when aged 14. This led to her being noticed by the media in 1988, at age 113. Subsequent investigation found that her life was documented in the records of her native city of Arles beyond reasonable question. More evidence for the Calment case has been produced than for any other supercentenarian case, which makes her case a "gold standard" among the "oldest people" recordholders. This is contrasted with the now-disputed claim of age 120 for the oldest man ever, Shigechiyo Izumi. While this case is currently still recognized by Guinness World Records, the Japanese authorities have hinted that his age was not certain. This claim was accepted in 1978, but subsequent additional research (as early as 1984) has raised doubt as to whether his birth date was confused with that of a brother who died at a young age. Currently (since the death of Yone Minagawa on 13 August, 2007), the oldest living person is 114-year-old Edna Parker of the U.S., born on 20 April, 1893. Parker, Maria de Jesus and Bertha Fry are the only validated people born in 1893 who are still alive. # Oldest living people The following is a list of the people who have held the title of oldest recognized person in the world since 1955 (the year Guinness Records began). This list does not reflect the original lists, but is instead "retroactive" – for example, the Betsy Baker case was not verified until the 2000s. The longest consecutive time with the title of "World's Oldest Person" held was by Shigechiyo Izumi of Japan for 3384 days from November 16, 1976 to February 21, 1986. The shortest consecutive time was by Emma Tillman of the United States for 4 days from January 24, 2007 to January 28, 2007. The average length of time served as "World's Oldest Person" for the 36 people following Betsy Baker (not including the current serving person, Edna Parker) has been approximately 525.5 days. The country with the most people on the list is the United States with 12, followed by the United Kingdom with 9, and Japan with 6. # Oldest living men (since 1961) Note: Guinness World Records has only maintained the category of 'oldest living man' intermittently over the years, not establishing it permanently until the year 2000. Persons listed prior to 2000 may be based on an historical reconstruction. The longest consecutive time with the title of "World's Oldest Man" held was by Shigechiyo Izumi of Japan for 4367 days from March 9, 1974 to February 21, 1986. The shortest consecutive time was by Henri Pérignon of France for 8 days from June 10, 1990 to June 18, 1990. The country with the most people on the list is the United States with 9, followed by Japan with 4, and the United Kingdom with 3. # Oldest people ever (115+) # Oldest men ever (top 10) # Oldest people currently living (top 10) # Oldest men currently living (top 10) # Supercentenarians who died before 1955 # National longevity recordholders ## Nation of death (oldest first) ## Emigrant records (oldest first) Note: listed for countries where an emigrant lived longer than any lifelong resident # Gerontology and the verification of age claims Gerontology involves the tracking of the longest-lived proven individuals as the bio-markers of the human life span. The study of gerontology is usually credited to Michel Eugène Chevreul, a French chemist who died in 1889, aged 102. In the early years of the twenty first century gerontology is benefiting from the improvements in record-keeping in the industrialized world from the latter part of the nineteenth century. As a result, verification standards have evolved and multiple independent documentary confirmations of birth-date are now required to substantiate a claim, rather than evidence deriving only from the claimant. For claims that have not been satisfactorily confirmed by Guinness World Records, considered the authority, see longevity claims. # Current trends in the lifespans of the oldest humans The population and lifespans of the world's oldest people are continually increasing due to improvements in healthcare and lifestyle during the nineteenth and twentieth centuries and the increasing world population. Additionally, better record-keeping, both 100+ years ago and today, is increasing the percentage of the world's population whose age can be tracked and verified. This increase has been matched by efforts to harness this data. While in 1837 the oldest verified person was aged 108 years, it is now no longer unheard of for individuals, especially females, to have lived 110 years and more. The term supercentenarian has been coined to describe this emerging population group.	Oldest people The longest unambiguously documented lifespan is that of Jeanne Calment of France (1875–1997), who was aged 122 years. She met Vincent van Gogh when aged 14. This led to her being noticed by the media in 1988, at age 113. Subsequent investigation found that her life was documented in the records of her native city of Arles beyond reasonable question. More evidence for the Calment case has been produced than for any other supercentenarian case, which makes her case a "gold standard" among the "oldest people" recordholders. This is contrasted with the now-disputed claim of age 120 for the oldest man ever, Shigechiyo Izumi. While this case is currently still recognized by Guinness World Records, the Japanese authorities have hinted that his age was not certain.[citation needed] This claim was accepted in 1978, but subsequent additional research (as early as 1984) has raised doubt as to whether his birth date was confused with that of a brother who died at a young age. Currently (since the death of Yone Minagawa on 13 August, 2007), the oldest living person is 114-year-old Edna Parker of the U.S., born on 20 April, 1893. [1] Parker, Maria de Jesus and Bertha Fry are the only validated people born in 1893 who are still alive. # Oldest living people The following is a list of the people who have held the title of oldest recognized person in the world since 1955 (the year Guinness Records began). This list does not reflect the original lists, but is instead "retroactive" – for example, the Betsy Baker case was not verified until the 2000s. The longest consecutive time with the title of "World's Oldest Person" held was by Shigechiyo Izumi of Japan for 3384 days from November 16, 1976 to February 21, 1986. The shortest consecutive time was by Emma Tillman of the United States for 4 days from January 24, 2007 to January 28, 2007. The average length of time served as "World's Oldest Person" for the 36 people following Betsy Baker (not including the current serving person, Edna Parker) has been approximately 525.5 days. The country with the most people on the list is the United States with 12, followed by the United Kingdom with 9, and Japan with 6. # Oldest living men (since 1961) Note: Guinness World Records has only maintained the category of 'oldest living man' intermittently over the years, not establishing it permanently until the year 2000. Persons listed prior to 2000 may be based on an historical reconstruction. The longest consecutive time with the title of "World's Oldest Man" held was by Shigechiyo Izumi of Japan for 4367 days from March 9, 1974 to February 21, 1986. The shortest consecutive time was by Henri Pérignon of France for 8 days from June 10, 1990 to June 18, 1990. The country with the most people on the list is the United States with 9, followed by Japan with 4, and the United Kingdom with 3. # Oldest people ever (115+) # Oldest men ever (top 10) # Oldest people currently living (top 10) # Oldest men currently living (top 10) # Supercentenarians who died before 1955 # National longevity recordholders ## Nation of death (oldest first) ## Emigrant records (oldest first) Note: listed for countries where an emigrant lived longer than any lifelong resident # Gerontology and the verification of age claims Gerontology involves the tracking of the longest-lived proven individuals as the bio-markers of the human life span. The study of gerontology is usually credited to Michel Eugène Chevreul, a French chemist who died in 1889, aged 102. In the early years of the twenty first century gerontology is benefiting from the improvements in record-keeping in the industrialized world from the latter part of the nineteenth century. As a result, verification standards have evolved and multiple independent documentary confirmations of birth-date are now required to substantiate a claim, rather than evidence deriving only from the claimant. For claims that have not been satisfactorily confirmed by Guinness World Records, considered the authority, see longevity claims. # Current trends in the lifespans of the oldest humans The population and lifespans of the world's oldest people are continually increasing due to improvements in healthcare and lifestyle during the nineteenth and twentieth centuries and the increasing world population. Additionally, better record-keeping, both 100+ years ago and today, is increasing the percentage of the world's population whose age can be tracked and verified. This increase has been matched by efforts to harness this data. While in 1837 the oldest verified person was aged 108 years, it is now no longer unheard of for individuals, especially females, to have lived 110 years and more. The term supercentenarian has been coined to describe this emerging population group.	https://www.wikidoc.org/index.php/Oldest_people
115251331a7da6b12463056cb61d4f74c9acf110	wikidoc	Olfactory pit	Olfactory pit By the upgrowth of the surrounding parts the olfactory areas are converted into pits, the olfactory pits, which indent the fronto-nasal process and divide it into a medial and two lateral nasal processes. # Additional images - Head end of human embryo of about thirty to thirty-one days. - Same embryo as shown in Fig. 45, with front wall of pharynx removed. - The roof of the mouth of a human embryo, aged about two and a half months, showing the mode of formation of the palate. - The head and neck of a human embryo thirty-two days old, seen from the ventral surface.	Olfactory pit Template:Infobox Embryology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] By the upgrowth of the surrounding parts the olfactory areas are converted into pits, the olfactory pits, which indent the fronto-nasal process and divide it into a medial and two lateral nasal processes. # Additional images - Head end of human embryo of about thirty to thirty-one days. - Same embryo as shown in Fig. 45, with front wall of pharynx removed. - The roof of the mouth of a human embryo, aged about two and a half months, showing the mode of formation of the palate. - The head and neck of a human embryo thirty-two days old, seen from the ventral surface. # External links - Template:EmbryologyUNC Template:Gray's Template:Embryology Template:Embryology of head and neck Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Olfactory_pit
f74aaf468b0aa74c0681d1936fcfb8c336adfa12	wikidoc	Oliver's sign	Oliver's sign Synonyms and keywords: Tracheal tug sign # Overview Oliver's sign is an abnormal downward movement of the trachea during systole that can indicate a dilation or aneurysm of the aortic arch. Oliver's sign is elicited by gently grasping the cricoid cartilage and applying upward pressure while the patient stands with his or her chin extended upward. Due to the anatomic position of the aortic arch, which overrides the left main bronchus, a downward tug of the trachea may be felt if an aneurysm is present. # Historical Perspective The sign was first described by English military surgeon William Silver Oliver in 1878. # Causes ## Life Threatening Causes Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. - Aortic aneurysm - Aortic dissection ## Common Causes - Aortic aneurysm - Aortic dissection - Atherosclerosis - Cystic medial necrosis - Marfan's syndrome - Trauma ## Causes by Organ System ## Causes in Alphabetical Order	Oliver's sign Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Mugilan Poongkunran M.B.B.S [2] Synonyms and keywords: Tracheal tug sign # Overview Oliver's sign is an abnormal downward movement of the trachea during systole that can indicate a dilation or aneurysm of the aortic arch. Oliver's sign is elicited by gently grasping the cricoid cartilage and applying upward pressure while the patient stands with his or her chin extended upward. Due to the anatomic position of the aortic arch, which overrides the left main bronchus, a downward tug of the trachea may be felt if an aneurysm is present. # Historical Perspective The sign was first described by English military surgeon William Silver Oliver in 1878. # Causes ## Life Threatening Causes Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. - Aortic aneurysm - Aortic dissection ## Common Causes - Aortic aneurysm - Aortic dissection - Atherosclerosis - Cystic medial necrosis - Marfan's syndrome - Trauma ## Causes by Organ System ## Causes in Alphabetical Order	https://www.wikidoc.org/index.php/Oliver%27s_sign
1ab5daa8d4d8fa99ab33b6ba0fbc3b906b4e99e0	wikidoc	Ootidogenesis	Ootidogenesis The succeeding ootidogenesis is the step in which the primary oocyte turns into an ootid. It is achieved by meiosis. The primary oocyte is even defined from its role to undergo meiosis. However, although this process begins at prenatal age, it stops at prophase I. In late fetal life, all oocytes, still primary oocytes, have taken this halt in development, called dictyate. First after menarche they continue to develop, although only a few does so every menstrual cycle. # Meiosis I Meiosis I of ootidogenesis starts at embryonic age, but halts in diplotene of prophase I until puberty. For those primary oocytes continuing to develop in each menstrual cycle, however, synapsis occurs and tetrads form, enabling and crossing over. As a result of meiosis I, the primary oocyte becomes the secondary oocyte and the first polar body. # Meiosis II Immediately after meiosis I, the haploid secondary oocyte initiates meiosis II. However, this, too is halted in metaphase II. However, this only lasts until fertilization, if such occurs. When meiosis II is completed, an ootid and another polar body is created. - ↑ Biochem	Ootidogenesis The succeeding ootidogenesis is the step in which the primary oocyte turns into an ootid. It is achieved by meiosis. The primary oocyte is even defined from its role to undergo meiosis[1]. However, although this process begins at prenatal age, it stops at prophase I. In late fetal life, all oocytes, still primary oocytes, have taken this halt in development, called dictyate. First after menarche they continue to develop, although only a few does so every menstrual cycle. ## Meiosis I Meiosis I of ootidogenesis starts at embryonic age, but halts in diplotene of prophase I until puberty. For those primary oocytes continuing to develop in each menstrual cycle, however, synapsis occurs and tetrads form, enabling and crossing over. As a result of meiosis I, the primary oocyte becomes the secondary oocyte and the first polar body. ## Meiosis II Immediately after meiosis I, the haploid secondary oocyte initiates meiosis II. However, this, too is halted in metaphase II. However, this only lasts until fertilization, if such occurs. When meiosis II is completed, an ootid and another polar body is created. Template:WH Template:WS - ↑ Biochem	https://www.wikidoc.org/index.php/Ootidogenesis
e7c0c8820c23bf877a26ebc3c8adfb2a89ec8406	wikidoc	Ophthalmology	Ophthalmology # Overview Ophthalmology is the branch of medicine which deals with the diseases and surgery of the visual pathways, including the eye, brain, and areas surrounding the eye, such as the lacrimal system and eyelids. The word ophthalmology comes from the Greek roots ophthalmos meaning eye and logos meaning word, thought or discourse; ophthalmology literally means "The science of eyes." As a discipline it applies to animal eyes also, since the differences from human practice are surprisingly minor and are related mainly to differences in anatomy or prevalence, not differences in disease processes. However, veterinary medicine is regulated separately in many countries and states/provinces resulting in few ophthalmologists treating both humans and animals. By convention the term ophthalmologist is more restricted and implies a medically trained specialist. Since ophthalmologists perform operations on eyes, they are generally categorized as surgeons. # History of ophthalmology The eye, including its structure and mechanism, has fascinated scientists and the public in general since ancient times. The majority of all input to the brain comes from vision. Many of the expressions in the english language that mean to understand are equivalent vision terms. "I see", to mean I understand. Many patients when told that they may have an eye problem will be more concerned about diseases that affect vision than other, more lethal diseases. Being deprived of sight can have a devastating effect on the psyche, as well as economic and social effects, as many blind individuals require significant assistance with activities of daily living and are often unable to continue gainful employment previously held while seeing. The maintenance of ocular health, and correction of eye problems that decrease vision contributes greatly to the ability to appreciate the longer lifespan that all of medicine continues to allow. As a bonus, it is incredibly rewarding to be able to restore sight to a patient! As detailed below, advances in diagnosis and treatment of disease, and improved surgical techniques have extended our abilities to restore vision like never before. ## Sushruta Sushruta wrote Sushruta Samhita in about fifth Century BCE in India. He described about 72 ocular diseases as well as several ophthalmological surgical instruments and techniques. Sushruta has been described as the first Indian cataract surgeon. Arab scientists are some of the earliest to have written about and drawn the anatomy of the eye—the earliest known diagram being in Hunain ibn Is-hâq's Book of the Ten Treatises on the Eye. Earlier manuscripts exist which refer to diagrams which are not known to have survived. Current knowledge of the Græco-Roman understanding of the eye is limited, as many manuscripts lacked diagrams. In fact, there are very few Græco-Roman diagrams of the eye still in existence. Thus, it is not clear to which structures the texts refer, and what purpose they were thought to have. ## Pre-Hippocrates The pre-Hippocratics largely based their anatomical conceptions of the eye on speculation, rather than empiricism. They recognized the sclera and transparent cornea running flushly as the outer coating of the eye, with an inner layer with pupil, and a fluid at the centre. It was believed, by Alcamaeon and others, that this fluid was the medium of vision and flowed from the eye to the brain via a tube. Aristotle advanced such ideas with empiricism. He dissected the eyes of animals, and discovering three layers (not two), found that the fluid was of a constant consistency with the lens forming (or congealing) after death, and the surrounding layers were seen to be juxtaposed. He, and his contemporaries, further put forth the existence of three tubes leading from the eye, not one. One tube from each eye met within the skull. ## Alexandrian studies Alexandrian studies extensively contributed to knowledge of the eye. Aëtius tells us that Herophilus dedicated an entire study to the eye which no longer exists. In fact, no manuscripts from the region and time are known to have survived, leading us to rely on Celsius' account—which is seen as a confused account written by a man who did not know the subject matter. From Celsius it is known that the lens had been recognised, and they no longer saw a fluid flowing to the brain through some hollow tube, but likely a continuation of layers of tissue into the brain. Celsius failed to recognise the retina's role, and did not think it was the tissue that continued into the brain. ## Rufus Rufus recognised a more modern eye, with conjunctiva, extending as a fourth epithelial layer over the eye. Rufus was the first to recognise a two chambered eye - with one chamber from cornea to lens (filled with water), the other from lens to retina (filled with an egg-white-like substance). Galen remedied some mistakes including the curvature of the cornea and lens, the nature of the optic nerve, and the existence of a posterior chamber. Though this model was roughly a correct but simplistic modern model of the eye, it contained errors. Yet it was not advanced upon again until after Vesalius. A ciliary body was then discovered and the sclera, retina, choroid and cornea were seen to meet at the same point. The two chambers were seen to hold the same fluid as well as the lens being attached to the choroid. Galen continued the notion of a central canal, though he dissected the optic nerve, and saw it was solid, He mistakenly counted seven optical muscles, one too many. He also knew of the tear ducts. ## After Galen After Galen a period of speculation is again noted by Arab scientists - the lens modified Galen's model to place the lens in the middle of the eye, a notion which lasted until Vesalius reversed the era of speculation. However, Vesalius was not an ophthalmologist and taught that the eye was a more primitive notion than the notion of both Galen and the Arabian scientists - the cornea was not seen as being of greater curvature and the posterior side of the lens wasn't seen to be larger. Understanding of the eye had been so slow to develop because for a long time the lens was perceived to be the seat of vision, not as part of the pathway for vision. This mistake was corrected when Fabricius and his successors correctly placed the lens and developed the modern notion of the structure of the eye. They removed the idea of Galen's seventh muscle (the retractor bulbi) and reinstated the correct curvatures of the lens and cornea, as well as stating the ciliary body as a connective structure between the lens and the choroid. ## Muslim ophthalmology Of all the branches of Islamic medicine, ophthalmology was considered the foremost. The specialized instruments used in their operations ran into scores. Innovations such as the “injection syringe”, invented by Ammar ibn Ali of Mosul, which was used for the extraction by suction of soft cataracts, were quite common. Ibn al-Haytham, the "father of optics", studied the anatomy of the eye extensively. ## Seventeenth and eighteenth century The seventeenth and eighteenth century saw the use of hand-lenses (by Malpighi), microscopes (van Leeuwenhoek), preparations for fixing the eye for study (Ruysch) and later the freezing of the eye (Petit). This allowed for detailed study of the eye and an advanced model. Some mistakes persisted such as: why the pupil changed size (seen to be vessels of the iris filling with blood), the existence of the posterior chamber, and of course the nature of the retina. In 1722 Leeuwenhoek noted the existence of rods and cones though they were not properly discovered until Gottfried Reinhold Treviranus in 1834 by use of a microscope. ## First ophthalmic surgeon The first ophthalmic surgeon was John Freke, appointed to the position by the Governors of St Bartholomew's Hospital in 1727, but the establishment of the first dedicated ophthalmic hospital in 1805 - now called Moorfields Eye Hospital in London, England was a transforming event in modern ophthalmology. Clinical developments at Moorfields and the founding of the Institute of Ophthalmology by Sir Stewart Duke-Elder established the site as the largest eye hospital in the world and a nexus for ophthalmic research. # Professional requirements Ophthalmologists are medical doctors (M.D.) or Doctors of Osteopathy (D.O.) who have completed medical school and completed a further four years post-graduate training in ophthalmology in many countries. Many ophthalmologists also undergo additional specialized training in one of the many subspecialities. Ophthalmology was the first branch of medicine to offer board certification, now a standard practice among all specialties. ## United States In the United States, four years of training after medical school are required, with the first year being an internship in surgery, internal medicine, pediatrics, or a general transition year. The scope of a physician's licensure is such that he or she need not be board certified in ophthalmology to practice as an ophthalmologist. The American Academy of Ophthalmology (AAO) promotes the use of the phrase "Eye MD" to distinguish ophthalmologists from optometrists who hold the degree OD (Doctor of Optometry). This, however, can lead to confusion among patients, since a few ophthalmologists' are DOs, or Doctors of Osteopathic Medicine, rather than MDs. In both cases, the same residency and certification requirements must be fulfilled. Completing the requirements of continuing medical education is mandatory for continuing licensure and re-certification. Professional bodies like the AAO and ASCRS organize conferences and help members through CME programs to maintain certification, in addition to political advocacy and peer support. ## United Kingdom In the United Kingdom, there are four colleges that grant postgraduate degrees in ophthalmology. The Royal College of Ophthalmologists grants MRCOphth and FRCOphth (postgraduate exams), the Royal College of Edinburgh grants MRCSEd, the Royal College of Glasgow grants FRCS and Royal College of Ireland grants FRCSI. Work experience as a specialist registrar and one of these degrees is required for specialisation in eye diseases. ## Australia and New Zealand In Australia and New Zealand, the FRACO/FRANZCO is the equivalent postgraduate specialist qualification. They do not generally accept overseas-trained Ophthalmologists as having equivalent qualifications, except those who have completed their formal training in the UK. On case by case basis, they will allow suitably-qualified Ophthalmologists to work in Area of Need positions, usually in regional areas. However, such appointments are generally only limited to South African/Canadian trained Ophthalmologists. ## India In India, after completing MBBS degree, post-graduation in Ophthalmology is required. The degrees are Doctor of Medicine (MD), Master of Surgery (MS), Diploma in Ophthalmic Medicine and Surgery (DOMS) or Diplomate of National Board (DNB). The concurrent training and work experience is in the form of a Junior Residency at a Medical College, Eye Hospital or Institution under the supervision of experienced faculty. Further work experience in form of fellowship, registrar or senior resident refines the skills of these eye surgeons. All India Ophthalmological Society (AIOS) and various state level Ophthalmological Societies (like DOS) hold regular conferences and actively promote continuing medical education. ## Pakistan In Pakistan, there is a residency program leading into FCPS which is composed of two parts. ## Canada In Canada, an Ophthalmology residency after medical school. A minimum of 5 years after the MD. degree although subspecialty training is undertaken by about 30% of fellows (FRCSC). There are about 30 vacancies per year for ophthalmology training in all of Canada. ## Finland In Finland, physicians willing to become ophthalmologists must undergo a 5 year specialization which includes practical training and theoretical studies. ## Veterinary Formal specialty training programs in veterinary ophthalmology now exist in some countries . # Distinction from Optometry Ophthalmologists are trained and licensed to perform surgery and prescribe ocular, oral and systemic medications. They can manage diseases and conditions of the eye, the visual pathway, and structures surrounding the eye, with medical and/or surgical treatments. For example this may include: - cataract extraction with intra-ocular lens replacement for cataracts, - laser refractive surgery on cornea for refractive error remediation - extra-ocular muscle surgery for strabismus, - prescribing topical medication, performing trabeculoplasty or iridotomy surgery for glaucoma (in all 50 states in the USA, optometrists are licensed to prescribe topical ocular medications and treat glaucoma) - laser surgery for some retinal diseases - excision or biopsy of tumors on eyelid or in the eye - prescribing temporary topical medical treatment for amblyopia(optometrists are permitted to do this as well) Optometrists, or optometric physicians, are not medical doctors. Instead, optometrists usually receive 4-5 years training in vision science, eye health and optometry-related areas, sometimes following a bachelor's degree (usually in science) in some countries. (In the USA, all optometrists attend optometry school for 4 years FOLLOWING their bachelors degree) While both ophthalmologists and optometrists are trained in refraction, it is generally accepted that optometrists receive more thorough training in prescribing optical aids such as spectacles, contact lens and magnifiers. The two fields often have a mutually beneficial relationship. - Ophthalmologists may refer patients to optometrists for optical aids or low vision rehabilitation whilst continuing to treat the ocular disease/condition that may have reduced vision. - Both optometrists and ophthalmologists perform screening for common ocular problems affecting children (i.e., amblyopia and strabismus) and the adult population (cataract, glaucoma, and diabetic retinopathy). Optometrists may refer to ophthalmology for further assessment and medical treatment of ocular disease or condition, however in the USA, most optometrists now treat many medical conditions, including glaucoma. - Optometrists and ophthalmologists sometimes co-manage treatment of strabismus and amblyopia with a combination of vision therapy, medical or surgical treatment. # Sub-specialities Ophthalmology includes sub-specialities which deal either with certain diseases or diseases of certain parts of the eye. Some of them are: - Anterior segment surgery - Cataract - not considered a subspecialty per se, since most general ophthalmologists do surgery for this. - Cornea, ocular surface, and external disease - Glaucoma - Neuro-ophthalmology - Ocular oncology - Oculoplastics & Orbit surgery - Ophthalmic pathology - Pediatric ophthalmology/Strabismus (squint) - Refractive surgery - Medical retina , deals with treatment of retinal problems conservatively. - Vitreoretinal Surgery, deals with surgical management of retinal and posterio segment diseases and disorders. Medical retina and vitreoretinal surgery sometimes together called posterior segment subspecialisation. - Uveitis/Immunology # Ophthalmic surgery	Ophthalmology # Overview Ophthalmology is the branch of medicine which deals with the diseases and surgery of the visual pathways, including the eye, brain, and areas surrounding the eye, such as the lacrimal system and eyelids. The word ophthalmology comes from the Greek roots ophthalmos meaning eye and logos meaning word, thought or discourse; ophthalmology literally means "The science of eyes." As a discipline it applies to animal eyes also, since the differences from human practice are surprisingly minor and are related mainly to differences in anatomy or prevalence, not differences in disease processes. However, veterinary medicine is regulated separately in many countries and states/provinces resulting in few ophthalmologists treating both humans and animals. By convention the term ophthalmologist is more restricted and implies a medically trained specialist. Since ophthalmologists perform operations on eyes, they are generally categorized as surgeons. # History of ophthalmology The eye, including its structure and mechanism, has fascinated scientists and the public in general since ancient times. The majority of all input to the brain comes from vision. Many of the expressions in the english language that mean to understand are equivalent vision terms. "I see", to mean I understand. Many patients when told that they may have an eye problem will be more concerned about diseases that affect vision than other, more lethal diseases. Being deprived of sight can have a devastating effect on the psyche, as well as economic and social effects, as many blind individuals require significant assistance with activities of daily living and are often unable to continue gainful employment previously held while seeing. The maintenance of ocular health, and correction of eye problems that decrease vision contributes greatly to the ability to appreciate the longer lifespan that all of medicine continues to allow. As a bonus, it is incredibly rewarding to be able to restore sight to a patient! As detailed below, advances in diagnosis and treatment of disease, and improved surgical techniques have extended our abilities to restore vision like never before. ## Sushruta Sushruta wrote Sushruta Samhita in about fifth Century BCE in India. He described about 72 ocular diseases as well as several ophthalmological surgical instruments and techniques. Sushruta has been described as the first Indian cataract surgeon. [1] [2] [3] Arab scientists are some of the earliest to have written about and drawn the anatomy of the eye—the earliest known diagram being in Hunain ibn Is-hâq's Book of the Ten Treatises on the Eye. Earlier manuscripts exist which refer to diagrams which are not known to have survived. Current knowledge of the Græco-Roman understanding of the eye is limited, as many manuscripts lacked diagrams. In fact, there are very few Græco-Roman diagrams of the eye still in existence. Thus, it is not clear to which structures the texts refer, and what purpose they were thought to have. ## Pre-Hippocrates The pre-Hippocratics largely based their anatomical conceptions of the eye on speculation, rather than empiricism. They recognized the sclera and transparent cornea running flushly as the outer coating of the eye, with an inner layer with pupil, and a fluid at the centre. It was believed, by Alcamaeon and others, that this fluid was the medium of vision and flowed from the eye to the brain via a tube. Aristotle advanced such ideas with empiricism. He dissected the eyes of animals, and discovering three layers (not two), found that the fluid was of a constant consistency with the lens forming (or congealing) after death, and the surrounding layers were seen to be juxtaposed. He, and his contemporaries, further put forth the existence of three tubes leading from the eye, not one. One tube from each eye met within the skull. ## Alexandrian studies Alexandrian studies extensively contributed to knowledge of the eye. Aëtius tells us that Herophilus dedicated an entire study to the eye which no longer exists. In fact, no manuscripts from the region and time are known to have survived, leading us to rely on Celsius' account—which is seen as a confused account written by a man who did not know the subject matter. From Celsius it is known that the lens had been recognised, and they no longer saw a fluid flowing to the brain through some hollow tube, but likely a continuation of layers of tissue into the brain. Celsius failed to recognise the retina's role, and did not think it was the tissue that continued into the brain. ## Rufus Rufus recognised a more modern eye, with conjunctiva, extending as a fourth epithelial layer over the eye. Rufus was the first to recognise a two chambered eye - with one chamber from cornea to lens (filled with water), the other from lens to retina (filled with an egg-white-like substance). Galen remedied some mistakes including the curvature of the cornea and lens, the nature of the optic nerve, and the existence of a posterior chamber. Though this model was roughly a correct but simplistic modern model of the eye, it contained errors. Yet it was not advanced upon again until after Vesalius. A ciliary body was then discovered and the sclera, retina, choroid and cornea were seen to meet at the same point. The two chambers were seen to hold the same fluid as well as the lens being attached to the choroid. Galen continued the notion of a central canal, though he dissected the optic nerve, and saw it was solid, He mistakenly counted seven optical muscles, one too many. He also knew of the tear ducts. ## After Galen After Galen a period of speculation is again noted by Arab scientists - the lens modified Galen's model to place the lens in the middle of the eye, a notion which lasted until Vesalius reversed the era of speculation. However, Vesalius was not an ophthalmologist and taught that the eye was a more primitive notion than the notion of both Galen and the Arabian scientists - the cornea was not seen as being of greater curvature and the posterior side of the lens wasn't seen to be larger. Understanding of the eye had been so slow to develop because for a long time the lens was perceived to be the seat of vision, not as part of the pathway for vision. This mistake was corrected when Fabricius and his successors correctly placed the lens and developed the modern notion of the structure of the eye. They removed the idea of Galen's seventh muscle (the retractor bulbi) and reinstated the correct curvatures of the lens and cornea, as well as stating the ciliary body as a connective structure between the lens and the choroid. ## Muslim ophthalmology Of all the branches of Islamic medicine, ophthalmology was considered the foremost. The specialized instruments used in their operations ran into scores. Innovations such as the “injection syringe”, invented by Ammar ibn Ali of Mosul, which was used for the extraction by suction of soft cataracts, were quite common. Ibn al-Haytham, the "father of optics", studied the anatomy of the eye extensively. ## Seventeenth and eighteenth century The seventeenth and eighteenth century saw the use of hand-lenses (by Malpighi), microscopes (van Leeuwenhoek), preparations for fixing the eye for study (Ruysch) and later the freezing of the eye (Petit). This allowed for detailed study of the eye and an advanced model. Some mistakes persisted such as: why the pupil changed size (seen to be vessels of the iris filling with blood), the existence of the posterior chamber, and of course the nature of the retina. In 1722 Leeuwenhoek noted the existence of rods and cones though they were not properly discovered until Gottfried Reinhold Treviranus in 1834 by use of a microscope. ## First ophthalmic surgeon The first ophthalmic surgeon was John Freke, appointed to the position by the Governors of St Bartholomew's Hospital in 1727, but the establishment of the first dedicated ophthalmic hospital in 1805 - now called Moorfields Eye Hospital in London, England was a transforming event in modern ophthalmology. Clinical developments at Moorfields and the founding of the Institute of Ophthalmology by Sir Stewart Duke-Elder established the site as the largest eye hospital in the world and a nexus for ophthalmic research. # Professional requirements Ophthalmologists are medical doctors (M.D.) or Doctors of Osteopathy (D.O.) who have completed medical school and completed a further four years post-graduate training in ophthalmology in many countries. Many ophthalmologists also undergo additional specialized training in one of the many subspecialities. Ophthalmology was the first branch of medicine to offer board certification, now a standard practice among all specialties. ## United States In the United States, four years of training after medical school are required, with the first year being an internship in surgery, internal medicine, pediatrics, or a general transition year. The scope of a physician's licensure is such that he or she need not be board certified in ophthalmology to practice as an ophthalmologist. The American Academy of Ophthalmology (AAO) promotes the use of the phrase "Eye MD" to distinguish ophthalmologists from optometrists who hold the degree OD (Doctor of Optometry). This, however, can lead to confusion among patients, since a few ophthalmologists' are DOs, or Doctors of Osteopathic Medicine, rather than MDs. In both cases, the same residency and certification requirements must be fulfilled. Completing the requirements of continuing medical education is mandatory for continuing licensure and re-certification. Professional bodies like the AAO and ASCRS organize conferences and help members through CME programs to maintain certification, in addition to political advocacy and peer support. ## United Kingdom In the United Kingdom, there are four colleges that grant postgraduate degrees in ophthalmology. The Royal College of Ophthalmologists grants MRCOphth and FRCOphth (postgraduate exams), the Royal College of Edinburgh grants MRCSEd, the Royal College of Glasgow grants FRCS and Royal College of Ireland grants FRCSI. Work experience as a specialist registrar and one of these degrees is required for specialisation in eye diseases. ## Australia and New Zealand In Australia and New Zealand, the FRACO/FRANZCO is the equivalent postgraduate specialist qualification. They do not generally accept overseas-trained Ophthalmologists as having equivalent qualifications, except those who have completed their formal training in the UK. On case by case basis, they will allow suitably-qualified Ophthalmologists to work in Area of Need positions, usually in regional areas. However, such appointments are generally only limited to South African/Canadian trained Ophthalmologists. ## India In India, after completing MBBS degree, post-graduation in Ophthalmology is required. The degrees are Doctor of Medicine (MD), Master of Surgery (MS), Diploma in Ophthalmic Medicine and Surgery (DOMS) or Diplomate of National Board (DNB). The concurrent training and work experience is in the form of a Junior Residency at a Medical College, Eye Hospital or Institution under the supervision of experienced faculty. Further work experience in form of fellowship, registrar or senior resident refines the skills of these eye surgeons. All India Ophthalmological Society (AIOS) and various state level Ophthalmological Societies (like DOS) hold regular conferences and actively promote continuing medical education. ## Pakistan In Pakistan, there is a residency program leading into FCPS which is composed of two parts. ## Canada In Canada, an Ophthalmology residency after medical school. A minimum of 5 years after the MD. degree although subspecialty training is undertaken by about 30% of fellows (FRCSC). There are about 30 vacancies per year for ophthalmology training in all of Canada. ## Finland In Finland, physicians willing to become ophthalmologists must undergo a 5 year specialization which includes practical training and theoretical studies. ## Veterinary Formal specialty training programs in veterinary ophthalmology now exist in some countries [4] [5] [6]. # Distinction from Optometry Ophthalmologists are trained and licensed to perform surgery and prescribe ocular, oral and systemic medications. They can manage diseases and conditions of the eye, the visual pathway, and structures surrounding the eye, with medical and/or surgical treatments. For example this may include: - cataract extraction with intra-ocular lens replacement for cataracts, - laser refractive surgery on cornea for refractive error remediation - extra-ocular muscle surgery for strabismus, - prescribing topical medication, performing trabeculoplasty or iridotomy surgery for glaucoma (in all 50 states in the USA, optometrists are licensed to prescribe topical ocular medications and treat glaucoma) - laser surgery for some retinal diseases - excision or biopsy of tumors on eyelid or in the eye - prescribing temporary topical medical treatment for amblyopia(optometrists are permitted to do this as well) Optometrists, or optometric physicians, are not medical doctors. Instead, optometrists usually receive 4-5 years training in vision science, eye health and optometry-related areas, sometimes following a bachelor's degree (usually in science) in some countries. (In the USA, all optometrists attend optometry school for 4 years FOLLOWING their bachelors degree) While both ophthalmologists and optometrists are trained in refraction, it is generally accepted that optometrists receive more thorough training in prescribing optical aids such as spectacles, contact lens and magnifiers. The two fields often have a mutually beneficial relationship. - Ophthalmologists may refer patients to optometrists for optical aids or low vision rehabilitation whilst continuing to treat the ocular disease/condition that may have reduced vision. - Both optometrists and ophthalmologists perform screening for common ocular problems affecting children (i.e., amblyopia and strabismus) and the adult population (cataract, glaucoma, and diabetic retinopathy). Optometrists may refer to ophthalmology for further assessment and medical treatment of ocular disease or condition, however in the USA, most optometrists now treat many medical conditions, including glaucoma. - Optometrists and ophthalmologists sometimes co-manage treatment of strabismus and amblyopia with a combination of vision therapy, medical or surgical treatment. # Sub-specialities Ophthalmology includes sub-specialities which deal either with certain diseases or diseases of certain parts of the eye. Some of them are: - Anterior segment surgery - Cataract - not considered a subspecialty per se, since most general ophthalmologists do surgery for this. - Cornea, ocular surface, and external disease - Glaucoma - Neuro-ophthalmology - Ocular oncology - Oculoplastics & Orbit surgery - Ophthalmic pathology - Pediatric ophthalmology/Strabismus (squint) - Refractive surgery - Medical retina , deals with treatment of retinal problems conservatively. - Vitreoretinal Surgery, deals with surgical management of retinal and posterio segment diseases and disorders. Medical retina and vitreoretinal surgery sometimes together called posterior segment subspecialisation. - Uveitis/Immunology # Ophthalmic surgery	https://www.wikidoc.org/index.php/Ophthalmologic
29baf48e4f69de2fde2cc1ce75e91c0f4fe891c7	wikidoc	Optimism bias	Optimism bias Optimism bias is the demonstrated systematic tendency for people to be over-optimistic about the outcome of planned actions. This includes over-estimating the likelihood of positive events and under-estimating the likelihood of negative events. It is one of several kinds of positive illusion to which people are generally susceptible. # Experimental demonstration Armor and Taylor review a number of studies that have found optimism bias in different kinds of judgement. These include: - Second-year MBA students overestimated the number of job offers they would receive and their starting salary. - Students overestimated the scores they would achieve on exams. - Almost all the newlyweds in a US study expected their marriage to last a lifetime, even while aware of the divorce statistics. - Professional financial analysts consistently overestimated corporate earnings. - Most smokers believe they are less at risk of developing smoking-related diseases than others who smoke. Students in one study rated themselves as much less likely than their peers (students of the same sex at the same college) to experience negative life events such as developing a drinking problem, having a heart attack, being fired from a job or divorcing a few years after getting married. Optimism bias does not apply universally. For example, people overestimate their chances of experiencing very low-frequency events, including negative events. # Effects of overconfidence ## Example: Increased risk taking and insufficient preventive care Optimistic overconfidence bias can induce people to underinvest in primary and preventative care and other risk reducing behaviors, like abstinence from smoking. ## Example: Credit card borrowing and penalty rates and fees Overconfidence causes many individuals to grossly underestimate their odds of making a payment late. Statistically, many people are quite likely to make at least one or more payments late due to the normal range of difficulties and delays in day-to-day life. Overconfidence bias causes these individuals to grossly underestimate the odds of this happening, and therefore to accept grossly punitive fees and rates (for example an interest rate of nearly 30 %) as a result of otherwise minor transgressions like a late payment. Other companies now have extended on this approach, by increasing interest rates to punitive rates for any late payment even if it is to another creditor. Overconfidence bias makes these terms more acceptable to borrowers than if they were accurately calibrated. Overconfidence bias also causes many individuals to substantially underestimate the probability of having serious financial or liquidity problems - for example from a sudden job loss or severe illness. This can cause individuals to take on excessive debt under the expectation that they will do "better than average" in the future and be readily able to pay it off. ## Overconfidence, locus of control and depression Overconfidence bias may cause many individuals to overestimate their degree of control as well as their odds of success. This may be protective against depression - since Seligman and Maier's model of depression includes a sense of learned helplessness and loss of predictability and control. Depressives tend to be more accurate, and less overconfident in their assessments of the probabilities of good and bad events occurring to others but they tend to overestimate the probability of bad events happening to them. This has caused some researchers to consider that overconfidence bias may be adaptive and/or protective in some situations. ## Optimism bias and planning Optimism bias arises in relation to estimates of costs and benefits and duration of tasks. It must be accounted for explicitly in appraisals, if these are to be realistic. Optimism bias typically results in cost overruns, benefit shortfalls, and delays, when plans are implemented. The UK government explicitly acknowledges that optimism bias is a problem in planning and budgeting and has developed measures for how to deal with optimism bias in government (HM Treasury 2003 ). The UK Department for Transport requires project planners to use so-called "optimism bias uplifts" for large transport projects in order to arrive at accurate budgets for planned ventures (Flyvbjerg and Cowi 2004). In a debate in Harvard Business Review, between Daniel Kahneman, Dan Lovallo, and Bent Flyvbjerg, Flyvbjerg (2003) – while acknowledging the existence of optimism bias – pointed out that what appears to be optimism bias may on closer examination be strategic misrepresentation. Planners may deliberately underestimate costs and overestimate benefits in order to get their projects approved, especially when projects are large and when organizational and political pressures are high. Kahneman and Lovallo (2003) maintained that optimism bias is the main problem. # Mechanisms A brain-imaging study found that, when imagining negative future events, signals in the amygdala, an emotion centre of the brain, are weaker than when remembering past negative events. This weakened consideration of possible negative outcomes is one possible mechanism for optimism bias.	Optimism bias Optimism bias is the demonstrated systematic tendency for people to be over-optimistic about the outcome of planned actions. This includes over-estimating the likelihood of positive events and under-estimating the likelihood of negative events. It is one of several kinds of positive illusion to which people are generally susceptible. # Experimental demonstration Armor and Taylor review a number of studies that have found optimism bias in different kinds of judgement.[1] These include: - Second-year MBA students overestimated the number of job offers they would receive and their starting salary. - Students overestimated the scores they would achieve on exams. - Almost all the newlyweds in a US study expected their marriage to last a lifetime, even while aware of the divorce statistics. - Professional financial analysts consistently overestimated corporate earnings. - Most smokers believe they are less at risk of developing smoking-related diseases than others who smoke. Students in one study rated themselves as much less likely than their peers (students of the same sex at the same college) to experience negative life events such as developing a drinking problem, having a heart attack, being fired from a job or divorcing a few years after getting married.[2] Optimism bias does not apply universally. For example, people overestimate their chances of experiencing very low-frequency events, including negative events. # Effects of overconfidence ## Example: Increased risk taking and insufficient preventive care Optimistic overconfidence bias can induce people to underinvest in primary and preventative care and other risk reducing behaviors, like abstinence from smoking.[3] ## Example: Credit card borrowing and penalty rates and fees Overconfidence causes many individuals to grossly underestimate their odds of making a payment late. Statistically, many people are quite likely to make at least one or more payments late due to the normal range of difficulties and delays in day-to-day life. Overconfidence bias causes these individuals to grossly underestimate the odds of this happening, and therefore to accept grossly punitive fees and rates (for example an interest rate of nearly 30 %) as a result of otherwise minor transgressions like a late payment. Other companies now have extended on this approach, by increasing interest rates to punitive rates for any late payment even if it is to another creditor. Overconfidence bias makes these terms more acceptable to borrowers than if they were accurately calibrated. Overconfidence bias also causes many individuals to substantially underestimate the probability of having serious financial or liquidity problems - for example from a sudden job loss or severe illness. This can cause individuals to take on excessive debt under the expectation that they will do "better than average" in the future and be readily able to pay it off. ## Overconfidence, locus of control and depression Overconfidence bias may cause many individuals to overestimate their degree of control as well as their odds of success. This may be protective against depression - since Seligman and Maier's model of depression includes a sense of learned helplessness and loss of predictability and control. Depressives tend to be more accurate, and less overconfident in their assessments of the probabilities of good and bad events occurring to others but they tend to overestimate the probability of bad events happening to them[citation needed]. This has caused some researchers to consider that overconfidence bias may be adaptive and/or protective in some situations. ## Optimism bias and planning Optimism bias arises in relation to estimates of costs and benefits and duration of tasks. It must be accounted for explicitly in appraisals, if these are to be realistic. Optimism bias typically results in cost overruns, benefit shortfalls, and delays, when plans are implemented. The UK government explicitly acknowledges that optimism bias is a problem in planning and budgeting and has developed measures for how to deal with optimism bias in government (HM Treasury 2003[dead link] ). The UK Department for Transport requires project planners to use so-called "optimism bias uplifts" for large transport projects in order to arrive at accurate budgets for planned ventures (Flyvbjerg and Cowi 2004). In a debate in Harvard Business Review, between Daniel Kahneman, Dan Lovallo, and Bent Flyvbjerg, Flyvbjerg (2003) – while acknowledging the existence of optimism bias – pointed out that what appears to be optimism bias may on closer examination be strategic misrepresentation. Planners may deliberately underestimate costs and overestimate benefits in order to get their projects approved, especially when projects are large and when organizational and political pressures are high. Kahneman and Lovallo (2003) maintained that optimism bias is the main problem. # Mechanisms A brain-imaging study found that, when imagining negative future events, signals in the amygdala, an emotion centre of the brain, are weaker than when remembering past negative events. This weakened consideration of possible negative outcomes is one possible mechanism for optimism bias.[4]	https://www.wikidoc.org/index.php/Optimism_bias
5060be4eb0dbbf75491c2362c3c0f082241c7d3f	wikidoc	Orthogonality	Orthogonality # Overview In mathematics, orthogonal, as a simple adjective not part of a longer phrase, is a generalization of perpendicular. It means "at right angles". The word comes from the Greek Template:Polytonic (orthos), meaning "straight", and Template:Polytonic (gonia), meaning "angle". Two streets that cross each other at a right angle are orthogonal to one another. In recent years, "perpendicular" has come to be used more in relation to right angles outside of a coordinate plane context, whereas "orthogonal" is used when discussing vectors or coordinate geometry. # Explanation Formally, two vectors x and y in an inner product space V are orthogonal if their inner product \langle x, y \rangle is zero. This situation is denoted x \perp y. Two vector subspaces A and B of vector space V are called orthogonal subspaces if each vector in A is orthogonal to each vector in B. The largest subspace that is orthogonal to a given subspace is its orthogonal complement. A linear transformation T : V \rightarrow V is called an orthogonal linear transformation if it preserves the inner product. That is, for all pairs of vectors x and y in the inner product space V, This means that T preserves the angle between x and y, and that the lengths of Tx and x are equal. A term rewriting system is said to be orthogonal if it is left-linear and is non-ambiguous. Orthogonal term rewriting systems are confluent. The word normal is sometimes also used in place of orthogonal. However, normal can also refer to unit vectors. In particular, orthonormal refers to a collection of vectors that are both orthogonal and normal (of unit length). So, using the term normal to mean "orthogonal" is often avoided. # In Euclidean vector spaces In 2- or 3-dimensional Euclidean space, two vectors are orthogonal if their dot product is zero, i.e. they make an angle of 90° or π/2 radians. Hence orthogonality of vectors is a generalization of the concept of perpendicular. In terms of Euclidean subspaces, the orthogonal complement of a line is the plane perpendicular to it, and vice versa. Note however that there is no correspondence with regards to perpendicular planes, because vectors in subspaces start from the origin. In 4-dimensional Euclidean space, the orthogonal complement of a line is a hyperplane and vice versa, and that of a plane is a plane. Several vectors are called pairwise orthogonal if any two of them are orthogonal, and a set of such vectors is called an orthogonal set. Such a set is an orthonormal set if all its vectors are unit vectors. Non-zero pairwise orthogonal vectors are always linearly independent. # Orthogonal functions It is common to use the following inner product for two functions f and g: Here we introduce a nonnegative weight function w(x) in the definition of this inner product. We say that those functions are orthogonal if that inner product is zero: We write the norms with respect to this inner product and the weight function as The members of a sequence { fi : i = 1, 2, 3, ... } are: - orthogonal if - orthonormal where is the Kronecker delta. In other words, any two of them are orthogonal, and the norm of each is 1 in the case of the orthonormal sequence. See in particular orthogonal polynomials. # Examples - The vectors (1, 3, 2), (3, −1, 0), (1/3, 1, −5/3) are orthogonal to each other, since (1)(3) + (3)(−1) + (2)(0) = 0, (3)(1/3) + (−1)(1) + (0)(−5/3) = 0, (1)(1/3) + (3)(1) − (2)(5/3) = 0. Observe also that the dot product of the vectors with themselves are the norms of those vectors, so to check for orthogonality, we need only check the dot product with every other vector. - The vectors (1, 0, 1, 0, ...)T and (0, 1, 0, 1, ...)T are orthogonal to each other. Clearly the dot product of these vectors is 0. We can then make the obvious generalization to consider the vectors in Z2n: - Take two quadratic functions 2t + 3 and 5t2 + t − 17/9. These functions are orthogonal with respect to a unit weight function on the interval from −1 to 1. The product of these two functions is 10t3 + 17t2 − 7/9 t − 17/3, and now, - The functions 1, sin(nx), cos(nx) : n = 1, 2, 3, ... are orthogonal with respect to Lebesgue measure on the interval from 0 to 2π. This fact is basic in the theory of Fourier series. - Various eponymously named polynomial sequences are sequences of orthogonal polynomials. In particular: The Hermite polynomials are orthogonal with respect to the normal distribution with expected value 0. The Legendre polynomials are orthogonal with respect to the uniform distribution on the interval from −1 to 1. The Laguerre polynomials are orthogonal with respect to the exponential distribution. Somewhat more general Laguerre polynomial sequences are orthogonal with respect to gamma distributions. The Chebyshev polynomials of the first kind are orthogonal with respect to the measure 1/\sqrt{1-x^2}. The Chebyshev polynomials of the second kind are orthogonal with respect to the Wigner semicircle distribution. - The Hermite polynomials are orthogonal with respect to the normal distribution with expected value 0. - The Legendre polynomials are orthogonal with respect to the uniform distribution on the interval from −1 to 1. - The Laguerre polynomials are orthogonal with respect to the exponential distribution. Somewhat more general Laguerre polynomial sequences are orthogonal with respect to gamma distributions. - The Chebyshev polynomials of the first kind are orthogonal with respect to the measure 1/\sqrt{1-x^2}. - The Chebyshev polynomials of the second kind are orthogonal with respect to the Wigner semicircle distribution. - In quantum mechanics, two eigenstates of a wavefunction, \psi_m and \psi_n , are orthogonal if they correspond to different eigenvalues. This means, in Dirac notation, that \langle \psi_m \| \psi_n \rangle = 0 unless \psi_m and \psi_n correspond to the same eigenvalue. This follows from that Schrödinger's equation is a Sturm-Liouville equation (in Schrödinger's formulation) or that observables are given by hermitian operators (in Heisenberg's formulation). # Derived meanings Other meanings of the word orthogonal evolved from its earlier use in mathematics. ## Art In art the perspective imagined lines pointing to the vanishing point are referred to as 'orthogonal lines'. ## Computer science Orthogonality is a system design property facilitating feasibility and compactness of complex designs. Orthogonality guarantees that modifying the technical effect produced by a component of a system neither creates nor propagates side effects to other components of the system. The emergent behavior of a system consisting of components should be controlled strictly by formal definitions of its logic and not by side effects resulting from poor integration, i.e. non-orthogonal design of modules and interfaces. Orthogonality reduces testing and development time because it is easier to verify designs that neither cause side effects nor depend on them. For example, a car has orthogonal components and controls (e.g. accelerating the vehicle does not influence anything else but the components involved exclusively with the acceleration function). On the other hand, a non-orthogonal design might have its steering influence its braking (e.g. Electronic Stability Control), or its speed tweak its suspension. Consequently, this usage is seen to be derived from the use of orthogonal in mathematics: One may project a vector onto a subspace by projecting it onto each member of a set of basis vectors separately and adding the projections if and only if the basis vectors are mutually orthogonal. An instruction set is said to be orthogonal if any instruction can use any register in any addressing mode. This terminology results from considering an instruction as a vector whose components are the instruction fields. One field identifies the registers to be operated upon, and another specifies the addressing mode. An orthogonal instruction set uniquely encodes all combinations of registers and addressing modes. ## Radio communications In radio communications, multiple-access schemes are orthogonal when an ideal receiver can completely reject arbitrarily strong unwanted signals using different basis functions than the desired signal. One such scheme is TDMA, where the orthogonal basis functions are non-overlapping rectangular pulses ("time slots"). Another scheme is orthogonal frequency-division multiplexing (OFDM), which refers to the use, by a single transmitter, of a set of frequency multiplexed signals with the exact minimum frequency spacing needed to make them orthogonal so that they do not interfere with each other. Well known examples include (a and g) versions of 802.11 Wi-Fi; Wimax; DVB-T, the terrestrial digital TV broadcast system used in most of the world outside North America; and DMT, the standard form of ADSL. ## Statistics, econometrics, and economics When performing statistical analysis, variables that affect a particular result are said to be orthogonal if they are uncorrelated. That is to say that by varying each separately, one can predict the combined effect of varying them jointly. If correlation is present, the factors are not orthogonal. In addition, orthogonality restrictions are necessary for inference. This meaning of orthogonality derives from the mathematical one, because orthogonal vectors are linearly independent. ## Taxonomy In taxonomy, an orthogonal classification is one in which no item is a member of more than one group, that is, the classifications are mutually exclusive. ## Combinatorics In combinatorics, two n×n Latin squares are said to be orthogonal if their superimposition yields all possible n2 combinations of entries. ## Chemistry In chemistry orthogonal protection is a strategy allowing the deprotection of functional groups independently of each other.	Orthogonality # Overview In mathematics, orthogonal, as a simple adjective not part of a longer phrase, is a generalization of perpendicular. It means "at right angles". The word comes from the Greek Template:Polytonic (orthos), meaning "straight", and Template:Polytonic (gonia), meaning "angle". Two streets that cross each other at a right angle are orthogonal to one another. In recent years, "perpendicular" has come to be used more in relation to right angles outside of a coordinate plane context, whereas "orthogonal" is used when discussing vectors or coordinate geometry. # Explanation Formally, two vectors <math>x</math> and <math>y</math> in an inner product space <math>V</math> are orthogonal if their inner product <math>\langle x, y \rangle</math> is zero. This situation is denoted <math>x \perp y</math>. Two vector subspaces <math>A</math> and <math>B</math> of vector space <math>V</math> are called orthogonal subspaces if each vector in <math>A</math> is orthogonal to each vector in <math>B</math>. The largest subspace that is orthogonal to a given subspace is its orthogonal complement. A linear transformation <math>T : V \rightarrow V</math> is called an orthogonal linear transformation if it preserves the inner product. That is, for all pairs of vectors <math>x</math> and <math>y</math> in the inner product space <math>V</math>, This means that <math>T</math> preserves the angle between <math>x</math> and <math>y</math>, and that the lengths of <math>Tx</math> and <math>x</math> are equal. A term rewriting system is said to be orthogonal if it is left-linear and is non-ambiguous. Orthogonal term rewriting systems are confluent. The word normal is sometimes also used in place of orthogonal. However, normal can also refer to unit vectors. In particular, orthonormal refers to a collection of vectors that are both orthogonal and normal (of unit length). So, using the term normal to mean "orthogonal" is often avoided. # In Euclidean vector spaces In 2- or 3-dimensional Euclidean space, two vectors are orthogonal if their dot product is zero, i.e. they make an angle of 90° or π/2 radians. Hence orthogonality of vectors is a generalization of the concept of perpendicular. In terms of Euclidean subspaces, the orthogonal complement of a line is the plane perpendicular to it, and vice versa. Note however that there is no correspondence with regards to perpendicular planes, because vectors in subspaces start from the origin. In 4-dimensional Euclidean space, the orthogonal complement of a line is a hyperplane and vice versa, and that of a plane is a plane. Several vectors are called pairwise orthogonal if any two of them are orthogonal, and a set of such vectors is called an orthogonal set. Such a set is an orthonormal set if all its vectors are unit vectors. Non-zero pairwise orthogonal vectors are always linearly independent. # Orthogonal functions It is common to use the following inner product for two functions f and g: Here we introduce a nonnegative weight function <math>w(x)</math> in the definition of this inner product. We say that those functions are orthogonal if that inner product is zero: We write the norms with respect to this inner product and the weight function as The members of a sequence { fi : i = 1, 2, 3, ... } are: - orthogonal if - orthonormal where is the Kronecker delta. In other words, any two of them are orthogonal, and the norm of each is 1 in the case of the orthonormal sequence. See in particular orthogonal polynomials. # Examples - The vectors (1, 3, 2), (3, −1, 0), (1/3, 1, −5/3) are orthogonal to each other, since (1)(3) + (3)(−1) + (2)(0) = 0, (3)(1/3) + (−1)(1) + (0)(−5/3) = 0, (1)(1/3) + (3)(1) − (2)(5/3) = 0. Observe also that the dot product of the vectors with themselves are the norms of those vectors, so to check for orthogonality, we need only check the dot product with every other vector. - The vectors (1, 0, 1, 0, ...)T and (0, 1, 0, 1, ...)T are orthogonal to each other. Clearly the dot product of these vectors is 0. We can then make the obvious generalization to consider the vectors in Z2n: - Take two quadratic functions 2t + 3 and 5t2 + t − 17/9. These functions are orthogonal with respect to a unit weight function on the interval from −1 to 1. The product of these two functions is 10t3 + 17t2 − 7/9 t − 17/3, and now, - The functions 1, sin(nx), cos(nx) : n = 1, 2, 3, ... are orthogonal with respect to Lebesgue measure on the interval from 0 to 2π. This fact is basic in the theory of Fourier series. - Various eponymously named polynomial sequences are sequences of orthogonal polynomials. In particular: The Hermite polynomials are orthogonal with respect to the normal distribution with expected value 0. The Legendre polynomials are orthogonal with respect to the uniform distribution on the interval from −1 to 1. The Laguerre polynomials are orthogonal with respect to the exponential distribution. Somewhat more general Laguerre polynomial sequences are orthogonal with respect to gamma distributions. The Chebyshev polynomials of the first kind are orthogonal with respect to the measure <math>1/\sqrt{1-x^2}.</math> The Chebyshev polynomials of the second kind are orthogonal with respect to the Wigner semicircle distribution. - The Hermite polynomials are orthogonal with respect to the normal distribution with expected value 0. - The Legendre polynomials are orthogonal with respect to the uniform distribution on the interval from −1 to 1. - The Laguerre polynomials are orthogonal with respect to the exponential distribution. Somewhat more general Laguerre polynomial sequences are orthogonal with respect to gamma distributions. - The Chebyshev polynomials of the first kind are orthogonal with respect to the measure <math>1/\sqrt{1-x^2}.</math> - The Chebyshev polynomials of the second kind are orthogonal with respect to the Wigner semicircle distribution. - In quantum mechanics, two eigenstates of a wavefunction, <math> \psi_m </math> and <math> \psi_n </math>, are orthogonal if they correspond to different eigenvalues. This means, in Dirac notation, that <math> \langle \psi_m \| \psi_n \rangle = 0 </math> unless <math> \psi_m </math> and <math> \psi_n </math> correspond to the same eigenvalue. This follows from that Schrödinger's equation is a Sturm-Liouville equation (in Schrödinger's formulation) or that observables are given by hermitian operators (in Heisenberg's formulation). # Derived meanings Other meanings of the word orthogonal evolved from its earlier use in mathematics. ## Art In art the perspective imagined lines pointing to the vanishing point are referred to as 'orthogonal lines'. ## Computer science Orthogonality is a system design property facilitating feasibility and compactness of complex designs. Orthogonality guarantees that modifying the technical effect produced by a component of a system neither creates nor propagates side effects to other components of the system. The emergent behavior of a system consisting of components should be controlled strictly by formal definitions of its logic and not by side effects resulting from poor integration, i.e. non-orthogonal design of modules and interfaces. Orthogonality reduces testing and development time because it is easier to verify designs that neither cause side effects nor depend on them. For example, a car has orthogonal components and controls (e.g. accelerating the vehicle does not influence anything else but the components involved exclusively with the acceleration function). On the other hand, a non-orthogonal design might have its steering influence its braking (e.g. Electronic Stability Control), or its speed tweak its suspension.[1] Consequently, this usage is seen to be derived from the use of orthogonal in mathematics: One may project a vector onto a subspace by projecting it onto each member of a set of basis vectors separately and adding the projections if and only if the basis vectors are mutually orthogonal. An instruction set is said to be orthogonal if any instruction can use any register in any addressing mode. This terminology results from considering an instruction as a vector whose components are the instruction fields. One field identifies the registers to be operated upon, and another specifies the addressing mode. An orthogonal instruction set uniquely encodes all combinations of registers and addressing modes. ## Radio communications In radio communications, multiple-access schemes are orthogonal when an ideal receiver can completely reject arbitrarily strong unwanted signals using different basis functions than the desired signal. One such scheme is TDMA, where the orthogonal basis functions are non-overlapping rectangular pulses ("time slots"). Another scheme is orthogonal frequency-division multiplexing (OFDM), which refers to the use, by a single transmitter, of a set of frequency multiplexed signals with the exact minimum frequency spacing needed to make them orthogonal so that they do not interfere with each other. Well known examples include (a and g) versions of 802.11 Wi-Fi; Wimax; DVB-T, the terrestrial digital TV broadcast system used in most of the world outside North America; and DMT, the standard form of ADSL. ## Statistics, econometrics, and economics When performing statistical analysis, variables that affect a particular result are said to be orthogonal if they are uncorrelated.[2] That is to say that by varying each separately, one can predict the combined effect of varying them jointly. If correlation is present, the factors are not orthogonal. In addition, orthogonality restrictions are necessary for inference. This meaning of orthogonality derives from the mathematical one, because orthogonal vectors are linearly independent. ## Taxonomy In taxonomy, an orthogonal classification is one in which no item is a member of more than one group, that is, the classifications are mutually exclusive. ## Combinatorics In combinatorics, two n×n Latin squares are said to be orthogonal if their superimposition yields all possible n2 combinations of entries. ## Chemistry In chemistry orthogonal protection is a strategy allowing the deprotection of functional groups independently of each other.	https://www.wikidoc.org/index.php/Orthogonal
ec54f9beae1fef2ae2141471d02ce08c16d5bfa2	wikidoc	Otic ganglion	Otic ganglion The otic ganglion is a small, ovalshaped, flattened parasympathetic ganglion of a reddish-gray color, located immediately below the foramen ovale. # Location and relations It is related to the maxillary and internal pterygoid nerves, to the cartilaginous part of the Eustachian tube, to the origin of the tensor palati muscle, and to the middle meningeal artery. It surrounds the origin of the nerve to the Pterygoideus internus. It is in relation, laterally, with the trunk of the mandibular nerve at the point where the motor and sensory roots join; medially, with the cartilaginous part of the auditory tube, and the origin of the Tensor veli palatini; posteriorly, with the middle meningeal artery. # Filaments Functionally, it gives off filaments: - posteriorly on the lateral surface of the Eustachian tube to the tensor tympani - anteriorly to the tensor palati muscle - to the inferior maxillary nerve, making up its motor root. - to the auriculotemporal nerve, making up its sensory root. ## Branches of Communication It is connected by two or three short filaments with the nerve to the Pterygoideus internus, from which it may obtain a motor, and possibly a sensory root. It communicates with the glossopharyngeal and facial nerves, through the lesser superficial petrosal nerve continued from the tympanic plexus, and through this nerve it probably receives a root from the glossopharyngeal and a motor root from the facial; its sympathetic root consists of a filament from the plexus surrounding the middle meningeal artery. The fibers from the glossopharyngeal which pass to the otic ganglion in the small superficial petrosal are supposed to be parasympathetic efferent (preganglionic) fibers from the dorsal nucleus or inferior salivatory nucleus of the medulla. Fibers (postganglionic) from the otic ganglion with which these form synapses are supposed to pass with the auriculotemporal nerve to the parotid gland. A slender filament (sphenoidal) ascends from it to the nerve of the Pterygoid canal, and a small branch connects it with the chorda tympani. ## Distribution Its branches of distribution are: a filament to the Tensor tympani, and one to the Tensor veli palatini. The former passes backward, lateral to the auditory tube; the latter arises from the ganglion, near the origin of the nerve to the Pterygoideus internus, and is directed forward. The fibers of these nerves are, however, mainly derived from the nerve to the Pterygoideus internus. # Additional images - Plan of the facial and intermediate nerves and their communication with other nerves. - Diagram of efferent sympathetic nervous system.	Otic ganglion Template:Infobox Nerve Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The otic ganglion is a small, ovalshaped, flattened parasympathetic ganglion of a reddish-gray color, located immediately below the foramen ovale. # Location and relations It is related to the maxillary and internal pterygoid nerves, to the cartilaginous part of the Eustachian tube, to the origin of the tensor palati muscle, and to the middle meningeal artery. It surrounds the origin of the nerve to the Pterygoideus internus. It is in relation, laterally, with the trunk of the mandibular nerve at the point where the motor and sensory roots join; medially, with the cartilaginous part of the auditory tube, and the origin of the Tensor veli palatini; posteriorly, with the middle meningeal artery. # Filaments Functionally, it gives off filaments: - posteriorly on the lateral surface of the Eustachian tube to the tensor tympani - anteriorly to the tensor palati muscle - to the inferior maxillary nerve, making up its motor root. - to the auriculotemporal nerve, making up its sensory root. ## Branches of Communication It is connected by two or three short filaments with the nerve to the Pterygoideus internus, from which it may obtain a motor, and possibly a sensory root. It communicates with the glossopharyngeal and facial nerves, through the lesser superficial petrosal nerve continued from the tympanic plexus, and through this nerve it probably receives a root from the glossopharyngeal and a motor root from the facial; its sympathetic root consists of a filament from the plexus surrounding the middle meningeal artery. The fibers from the glossopharyngeal which pass to the otic ganglion in the small superficial petrosal are supposed to be parasympathetic efferent (preganglionic) fibers from the dorsal nucleus or inferior salivatory nucleus of the medulla. Fibers (postganglionic) from the otic ganglion with which these form synapses are supposed to pass with the auriculotemporal nerve to the parotid gland. A slender filament (sphenoidal) ascends from it to the nerve of the Pterygoid canal, and a small branch connects it with the chorda tympani. ## Distribution Its branches of distribution are: a filament to the Tensor tympani, and one to the Tensor veli palatini. The former passes backward, lateral to the auditory tube; the latter arises from the ganglion, near the origin of the nerve to the Pterygoideus internus, and is directed forward. The fibers of these nerves are, however, mainly derived from the nerve to the Pterygoideus internus. # Additional images - Plan of the facial and intermediate nerves and their communication with other nerves. - Diagram of efferent sympathetic nervous system.	https://www.wikidoc.org/index.php/Otic_ganglion
46a61bfa3a19b757862317f9b8588fd0db610374	wikidoc	Oxcarbazepine	Oxcarbazepine # 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 Oxcarbazepine is an antiepileptic drug that is FDA approved for the treatment of partial seizures. Common adverse reactions include dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Adjunctive Therapy for Adults - Treatment with Oxcarbazepine should be initiated with a dose of 600 mg/day, given in a twice-a-day regimen. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects. It is recommended that the patient be observed closely and plasma levels of the concomitant AEDs be monitored during the period of Oxcarbazepine titration, as these plasma levels may be altered, especially at Oxcarbazepine doses greater than 1200 mg/day. - Conversion to Monotherapy for Adults - Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with Oxcarbazepine at 600 mg/day (given in a twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3-6 weeks, while the maximum dose of Oxcarbazepine should be reached in about 2-4 weeks. Oxcarbazepine may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the recommended daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with Oxcarbazepine. Patients should be observed closely during this transition phase. - Initiation of Monotherapy for Adults - Patients not currently being treated with AEDs may have monotherapy initiated with Oxcarbazepine. In these patients, Oxcarbazepine should be initiated at a dose of 600 mg/day (given in a twice-a-day regimen); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to Oxcarbazepine monotherapy ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oxcarbazepine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxcarbazepine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Adjunctive Therapy for Pediatric Patients (Aged 2-16 Years) - In pediatric patients aged 4-16 years, treatment should be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. The target maintenance dose of Oxcarbazepine should be achieved over two weeks, and is dependent upon patient weight, according to the following chart: 20-29 kg - 900 mg/day 29.1-39 kg - 1200 mg/day 39 kg – 1800 mg/day - 20-29 kg - 900 mg/day - 29.1-39 kg - 1200 mg/day - >39 kg – 1800 mg/day - In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6-51 mg/kg. - In pediatric patients aged 2-<4 years, treatment should also be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. For patients under 20 kg, a starting dose of 16-20 mg/kg may be considered. The maximum maintenance dose of Oxcarbazepine should be achieved over 2-4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen. - In the clinical trial in pediatric patients (2 to 4 years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day. - Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults. - Conversion to Monotherapy for Pediatric Patients (Aged 4-16 Years) - Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with Oxcarbazepine at approximately 8-10 mg/kg/day given in a twice-a-day regimen, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3-6 weeks while Oxcarbazepine may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase. - The recommended total daily dose of Oxcarbazepine is shown in the table below. - Initiation of Monotherapy for Pediatric Patients (Aged 4-16 Years) - Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with Oxcarbazepine. In these patients, Oxcarbazepine should be initiated at a dose of 8-10 mg/kg/day given in a twice-a-day regimen. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oxcarbazepine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxcarbazepine in pediatric patients. # Contraindications - Oxcarbazepine should not be used in patients with a known hypersensitivity to oxcarbazepine or to any of its components. # Warnings ### Precautions - Hyponatremia - Clinically significant hyponatremia (sodium <125 mmol/L) can develop during Oxcarbazepine use. In the 14 controlled epilepsy studies 2.5% of Oxcarbazepine-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first three months of treatment with Oxcarbazepine, although there were patients who first developed a serum sodium <125 mmol/L more than one year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their Oxcarbazepine dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia have been reported during post-marketing use. In clinical trials, patients whose treatment with Oxcarbazepine was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment. - Measurement of serum sodium levels should be considered for patients during maintenance treatment with Oxcarbazepine, particularly if the patient is receiving other medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity). - Anaphylactic Reactions and Angioedema - Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of Oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Oxcarbazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug. - Patients with a Past History of Hypersensitivity Reaction to Carbamazepine - Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of them will experience hypersensitivity reactions with Oxcarbazepine. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with Oxcarbazepine only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, Oxcarbazepine should be discontinued immediately. - Serious Dermatological Reactions - Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with Oxcarbazepine use. Such serious skin reactions may be life threatening, and some patients have required hospitalization, with very rare reports of fatal outcome. The median time of onset for reported cases was 19 days after treatment initiation. Recurrence of the serious skin reactions following rechallenge with Oxcarbazepine has also been reported. - The reporting rate of TEN and SJS associated with Oxcarbazepine use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking Oxcarbazepine, consideration should be given to discontinuing Oxcarbazepine use and prescribing another antiepileptic medication. - Association with HLA-B1502 - Patients carrying the HLA-B1502 allele may be at increased risk for SJS/TEN with oxcarbazepine treatment. - Human Leukocyte Antigen (HLA) allele B1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structure of oxcarbazepine is similar to that of carbamazepine. Available clinical evidence, and data from nonclinical studies showing a direct interaction between oxcarbazepine and HLA-B1502 protein, suggest that the HLA-B1502 allele may also increase the risk for SJS/TEN with oxcarbazepine. - The frequency of HLA-B1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines and in some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (<1%). - Testing for the presence of the HLA-B1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine. The use of oxcarbazepine should be avoided in patients positive for HLA-B1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B1502 is low, or in current oxcarbazepine users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B1502 status. - The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized. - Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including Oxcarbazepine, 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 2 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 Oxcarbazepine 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. - Withdrawal of AEDs - As with all antiepileptic drugs, Oxcarbazepine should be withdrawn gradually to minimize the potential of increased seizure frequency. - Cognitive/Neuropsychiatric Adverse Events - Use of Oxcarbazepine has been associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances. - In one large, fixed-dose study, Oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as Oxcarbazepine was added, reduction in Oxcarbazepine dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of Oxcarbazepine on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related. - In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse event. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about seven times greater on oxcarbazepine than on placebo. - In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of Oxcarbazepine, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance. - In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day Oxcarbazepine, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group. - A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which Oxcarbazepine was added to existing AED therapy (up to two concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as Oxcarbazepine was added. Oxcarbazepine was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient's body weight with fixed doses for predefined weight ranges). - Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse event or somnolence.). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances. - Drug Reaction with Eosinophilia and Systemic Symptoms (Dress syndrome/Multi-Organ Hypersensitivity) - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with oxcarbazepine. Some of these events have been fatal or life-threatening. DRESS syndrome typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Oxcarbazepine should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with DRESS/multi-organ hypersensitivity would indicate this to be a possibility. - Hematologic Events - Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with Oxcarbazepine during postmarketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develop. - Seizure Control During Pregnancy - Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period because MHD levels may return after delivery. - Laboratory Tests - Serum sodium levels below 125 mmol/L have been observed in patients treated with Oxcarbazepine. Experience from clinical trials indicates that serum sodium levels return toward normal when the Oxcarbazepine dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). - Laboratory data from clinical trials suggest that Oxcarbazepine use was associated with decreases in T4, without changes in T3 or TSH. # 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. - Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine and substantially more frequent than in placebo-treated patients were: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait. - Approximately 23% of these 1,537 adult patients discontinued treatment because of an adverse experience. The adverse reactions most commonly associated with discontinuation were: dizziness (6.4%), diplopia (5.9%), ataxia (5.2%), vomiting (5.1%), nausea (4.9%), somnolence (3.8%), headache (2.9%), fatigue (2.1%), abnormal vision (2.1%), tremor (1.8%), abnormal gait (1.7%), rash (1.4%), hyponatremia (1.0%). - Monotherapy in Adults Not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine in these patients were similar to those in previously treated patients. - Approximately 9% of these 295 adult patients discontinued treatment because of an adverse experience. The adverse reactions most commonly associated with discontinuation were: dizziness (1.7%), nausea (1.7%), rash (1.7%), headache (1.4%). - Adjunctive Therapy/Monotherapy in Pediatric Patients 4 Years Old and Above Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine in these patients were similar to those seen in adults. - Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse experience. The adverse reactions most commonly associated with discontinuation were: somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), nystagmus (1.1%). - Monotherapy in Pediatric Patients 4 Years Old and Above Not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine in these patients were similar to those in adults. - Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse experience. The adverse reactions most commonly associated (≥1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%). - Adjunctive Therapy/Monotherapy in Pediatric Patients 1 Month to <4 Years Old Previously Treated or Not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine in these patients were similar to those seen in older children and adults except for infections and infestations which were more frequently seen in these younger children. - Approximately 11% of these 241 pediatric patients discontinued treatment because of an adverse experience. The adverse reaction most commonly associated with discontinuation were: convulsions (3.7%), status epilepticus (1.2%), and ataxia (1.2%). - Incidence in Controlled Clinical Studies: The prescriber should be aware that the figures in Tables 3, 4, 5 and 6 cannot be used to predict the frequency of adverse reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. - Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: Table 3 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with epilepsy treated with Oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of Oxcarbazepine. Table 4 lists treatment-emergent signs and symptoms in patients converted from other AEDs to either high dose Oxcarbazepine or low dose (300 mg) Oxcarbazepine. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables. - Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with other AEDs: Table 5 lists treatment-emergent signs and symptoms in a controlled clinical study of monotherapy in adults not previously treated with other AEDs that occurred in at least 2% of adult patients with epilepsy treated with Oxcarbazepine or placebo and were numerically more common in the patients treated with Oxcarbazepine. - Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with other AEDs: Table 6 lists treatment-emergent signs and symptoms that occurred in at least 2% of pediatric patients with epilepsy treated with Oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with Oxcarbazepine. - Other Events Observed in Association with the Administration of Oxcarbazepine - In the paragraphs that follow, the adverse events, other than those in the preceding tables or text, that occurred in a total of 565 children and 1,574 adults exposed to Oxcarbazepine and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and events likely to reflect concomitant illness are omitted particularly if minor. They are listed in order of decreasing frequency. Because the reports cite events observed in open label and uncontrolled trials, the role of Oxcarbazepine in their causation cannot be reliably determined. Fever, malaise, pain chest precordial, rigors, weight decrease. Bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia. Appetite increased, blood in stool, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival bleeding, gum hyperplasia, hematemesis, rectal hemorrhage, hemorrhoids, hiccup, mouth dry, pain biliary, pain right hypochondrium, retching, sialoadenitis, stomatitis, stomatitis ulcerative. Thrombocytopenia. Gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased. Hypertonia muscle. Aggressive reaction, amnesia, anguish, anxiety, apathy, aphasia, aura, convulsions aggravated, delirium, delusion, depressed level of consciousness, dysphonia, dystonia, emotional lability, euphoria, extrapyramidal disorder, feeling drunk, hemiplegia, hyperkinesia, hyperreflexia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, hysteria, libido decreased, libido increased, manic reaction, migraine, muscle contractions involuntary, nervousness, neuralgia, oculogyric crisis, panic disorder, paralysis, paroniria, personality disorder, psychosis, ptosis, stupor, tetany. Asthma, dyspnea, epistaxis, laryngismus, pleurisy. Acne, alopecia, angioedema, bruising, contact dermatitis, eczema, facial rash, flushing, folliculitis, heat rash, hot flushes, photosensitivity reaction, pruritus genital, psoriasis, purpura, rash erythematous, rash maculopapular, vitiligo, urticaria. Accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia. Procedure dental oral, procedure female reproductive, procedure musculoskeletal, procedure skin. Dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus. Systemic lupus erythematosus. ## Postmarketing Experience - The following adverse events have been observed in named patient programs or postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pancreatitis and/or lipase and/or amylase increase Aplastic anemia Hypothyroidism Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, Acute Generalized Exanthematous Pustulosis (AGEP) There have been reports of decreased bone mineral density, osteoporosis and fractures in patients on long-term therapy with oxcarbazepine. # Drug Interactions - Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. The inhibition of CYP2C19 by oxcarbazepine and MHD can cause increased plasma concentrations of drugs that are substrates of CYP2C19. Oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs. - In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. No autoinduction has been observed with Oxcarbazepine. - Antiepileptic Drugs - Potential interactions between Oxcarbazepine and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in Table 7. - In vivo, the plasma levels of phenytoin increased by up to 40% when Oxcarbazepine was given at doses above 1200 mg/day. Therefore, when using doses of Oxcarbazepine greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbital level, however, is small (15%) when given with Oxcarbazepine. - Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29%-40%). - No autoinduction has been observed with Oxcarbazepine. - Hormonal Contraceptives - Coadministration of Oxcarbazepine with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% in one study and 52% in another study. The mean AUC values of LNG were decreased by 32% in one study and 52% in another study. Therefore, concurrent use of Oxcarbazepine with hormonal contraceptives may render these contraceptives less effective. Studies with other oral or implant contraceptives have not been conducted. - Calcium Antagonists - After repeated coadministration of Oxcarbazepine, the AUC of felodipine was lowered by 28% . Verapamil produced a decrease of 20% of the plasma levels of MHD. - Other Drug Interactions - Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of Oxcarbazepine. - Drug/Laboratory Test Interactions - There are no known interactions of Oxcarbazepine with commonly used laboratory tests. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled clinical studies of Oxcarbazepine in pregnant women; however, Oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Given this fact, and the results of the animal studies described, it is likely that Oxcarbazepine is a human teratogen. Oxcarbazepine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose. - When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the maximum recommended human dose on a mg/m2 basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥300 mg/kg were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects. - In a study in which pregnant rabbits were orally administered MHD (20, 100, or 200 mg/kg) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m2 basis). This dose produced only minimal maternal toxicity. - In a study in which female rats were dosed orally with oxcarbazepine (25, 50, or 150 mg/kg) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (0.6 times the MRHD on a mg/m2 basis). Oral administration of MHD (25, 75, or 250 mg/kg) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m2 basis). - To provide information regarding the effects of in utero exposure to Oxcarbazepine, physicians are advised to recommend that pregnant patients taking Oxcarbazepine enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website / Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxcarbazepine in women who are pregnant. ### Labor and Delivery - The effect of Oxcarbazepine on labor and delivery in humans has not been evaluated. ### Nursing Mothers - Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to Oxcarbazepine in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother. ### Pediatric Use - Oxcarbazepine is indicated for use as adjunctive therapy for partial seizures in patients aged 2-16 years. Oxcarbazepine is also indicated as monotherapy for partial seizures in patients aged 4-16 years. Oxcarbazepine has been given to 898 patients between the ages of 1 month-17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month-17 years in other trials. ### Geriatic Use - There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxcarbazepine in elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. ### Gender There is no FDA guidance on the use of Oxcarbazepine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Oxcarbazepine with respect to specific racial populations. ### Renal Impairment - In renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged with a corresponding two-fold increase in AUC. Oxcarbazepine therapy should be initiated at one-half the usual starting dose and increased, if necessary, at a slower than usual rate until the desired clinical response is achieved. ### Hepatic Impairment There is no FDA guidance on the use of Oxcarbazepine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Oxcarbazepine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Oxcarbazepine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Oxcarbazepine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Oxcarbazepine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Isolated cases of overdose with Oxcarbazepine have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment. ### Management - There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered. ## Chronic Overdose There is limited information regarding Chronic Overdose of Oxcarbazepine in the drug label. # Pharmacology ## Mechanism of Action - The pharmacological activity of oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine. The precise mechanism by which Oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated. ## Structure - Oxcarbazepine Tablet is an antiepileptic drug available as 150 mg, 300 mg and 600 mg film-coated tablets for oral administration. Oxcarbazepine is 10,11-Dihydro-10-oxo-5H-dibenzazepine-5-carboxamide, and its structural formula is - Oxcarbazepine is a white to faintly orange crystalline powder. It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether and water. Its molecular weight is 252.27. - Oxcarbazepine film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide yellow, iron oxide red, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. ## Pharmacodynamics - Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with oxcarbazepine or MHD. ## Pharmacokinetics - Following oral administration of Oxcarbazepine Tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites. - The half-life of the parent is about two hours, while the half-life of MHD is about nine hours, so that MHD is responsible for most antiepileptic activity. - Absorption - Based on MHD concentrations, Oxcarbazepine Tablets and suspension were shown to have similar bioavailability. - After single-dose administration of Oxcarbazepine Tablets to healthy male volunteers under fasted conditions, the median tmax was 4.5 (range 3 to 13) hours. - Steady-state plasma concentrations of MHD are reached within 2-3 days in patients when Oxcarbazepine Tablet is given twice a day. At steady state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day. - Effect of Food: Food has no effect on the rate and extent of absorption of Oxcarbazepine Tablets. Therefore, Oxcarbazepine Tablets can be taken with or without food. - Distribution - The apparent volume of distribution of MHD is 49L. - Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein. - Metabolism and Excretion - Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Oxcarbazepine. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD). - Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose. - The half-life of the parent is about two hours, while the half-life of MHD is about nine hours. - Special Populations - Hepatic Impairment - The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. No dose adjustment for Oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment and, therefore, caution should be exercised when dosing severely impaired patients. - Renal Impairment - There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Oxcarbazepine is administered as a single 300-mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUC. Dose adjustment for Oxcarbazepine is recommended in these patients. - Pediatrics - Weight-adjusted MHD clearance decreases as age and weight increases, approaching that of adults. The mean weight adjusted clearance in children 2 years-<4 years of age is approximately 80% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted clearance in children 4-12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults. - Pregnancy - Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy. - Geriatrics - Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxcarbazepine to elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. - Gender - No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly. - Race - No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine. - Drug Interactions: - In Vitro - Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. - Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD, is clinically relevant. - In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine). - In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs. - As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely. ## Nonclinical Toxicology - Carcinogenesis - In two-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg/day to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses ≥70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m2 basis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses ≥25 mg/kg/day (0.1 times the MRHD on a mg/m2 basis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/m2 basis) and ≥250 mg/kg/day (equivalent to the MRHD on a mg/m2 basis), respectively. There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at ≥250 mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day. - Mutagenesis - Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay. - Impairment of Fertility - In a fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately two times the MRHD on a mg/m2 basis). # Clinical Studies - The effectiveness of Oxcarbazepine as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 2-16 years was established in seven multicenter, randomized, controlled trials. - The effectiveness of Oxcarbazepine as monotherapy for partial seizures in children aged 4-16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations. - Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of Oxcarbazepine as monotherapy. Two trials compared Oxcarbazepine to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of Oxcarbazepine, after substituting Oxcarbazepine 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a twice-a-day schedule. A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose Oxcarbazepine treatment groups. - One placebo-controlled Oxcarbazepine trial was conducted in 102 patients (11-62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2-10 partial seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or Oxcarbazepine given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional nine days, or until one of the following three exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) two new-onset secondarily generalized seizures, where such seizures were not seen in the one-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of Oxcarbazepine (see Figure 1), p=0.0001. - The second placebo-controlled trial was conducted in 67 untreated patients (8-69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or Oxcarbazepine, initiated at 300 mg twice a day and titrated to 1200 mg/day (given as 600 mg twice a day) in six days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between-group comparison of the time to first seizure. The difference between the two treatments was statistically significant in favor of Oxcarbazepine (see Figure 2), p=0.046. - A third trial substituted Oxcarbazepine monotherapy at 2400 mg/day for carbamazepine in 143 patients (12-65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this Oxcarbazepine dose for 56 days (baseline phase). Patients who were able to tolerate titration of Oxcarbazepine to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of Oxcarbazepine or 2400 mg/day Oxcarbazepine. Patients were observed for 126 days or until one of the following four exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two-fold increase in the highest consecutive two-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the Oxcarbazepine 2400 mg/day group (see Figure 3), p=0.0001. - Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on one or two AEDs. Patients were randomized to either Oxcarbazepine 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first six weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until one of the four exit criteria described for the previous study occurred. The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the Oxcarbazepine 2400 mg/day group (14/34; 41.2%) compared to the Oxcarbazepine 300 mg/day group (42/45; 93.3%) (p<0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the Oxcarbazepine 2400 mg/day group (see Figure 4), p=0.0001. - A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures. Patients were hospitalized and randomized to either Oxcarbazepine 10 mg/kg/day or were titrated up to 40-60 mg/kg/day within three days while withdrawing the previous AED on the second day of Oxcarbazepine therapy. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-day treatment or met one of the two exit criteria: 1) three study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate), 2) a prolonged study-specific seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p=0.904). The majority of patients from both dose groups completed the 5-day study without exiting. - Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable. For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older. - The effectiveness of Oxcarbazepine as an adjunctive therapy for partial seizures was established in two multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15-66 years of age) and one in 264 pediatric patients (3-17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing two doses of Oxcarbazepine in 128 pediatric patients (1 month to <4 years of age). - Patients in the two placebo-controlled trials were on 1-3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1-4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of Oxcarbazepine in addition to their other AEDs. - In these studies, the dose was increased over a two-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period. - In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30-46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of Oxcarbazepine at all doses tested in both trials (p=0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 8. It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study, an outcome not seen in the monotherapy studies. - Subset analyses of the antiepileptic efficacy of Oxcarbazepine with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 in controlled trials, the effect of the drug in the elderly has not been adequately assessed. - The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial seizures on 1-2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either Oxcarbazepine10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days. Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period. The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline. For the entire group of patients enrolled, this comparison was statistically significant in favor of Oxcarbazepine 60 mg/kg/day. In this study, there was no evidence that Oxcarbazepine was effective in patients below the age of 2 years (N=75). # How Supplied - 150 mg Film-Coated Tablets: Oval, Orange yellow film coated tablet, scored on both sides, debossed with ‘J’ and ‘232’ on either side of the score line on one side. - Bottles of 100 NDC 59746-232-01. - Bottles of 500 NDC 59746-232-05. - 300 mg Film-Coated Tablets: Oval, Orange yellow film coated tablet, scored on both sides, debossed with ‘J’ and ‘233’ on either side of the score line on one side. - Bottles of 100 NDC 59746-233-01. - Bottles of 500 NDC 59746-233-05. - 600 mg Film-Coated Tablets: Oval, Orange yellow film coated tablet, scored on both sides, debossed with ‘J’ and ‘234’ on either side of the score line on one side. - Bottles of 100 NDC 59746-234-01. - Bottles of 500 NDC 59746-234-05 - Store at 20°C to 25°C (68°F - 77°F) excursions permitted to 15°-30°C (59°-86°F). Dispense in tight container (USP). ## Storage There is limited information regarding Oxcarbazepine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Oxcarbazepine Tablets. - Patients should be advised that Oxcarbazepine Tablets may reduce the serum sodium concentrations especially if they are taking other medications that can lower sodium. Patients should be advised to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures. - Anaphylactic reactions and angioedema may occur during treatment with Oxcarbazepine Tablets. Patients should be advised to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician. - Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of these patients may experience hypersensitivity reactions with Oxcarbazepine. Patients should be advised that if they experience a hypersensitivity reaction while taking Oxcarbazepine Tablets they should consult with their physician immediately. - Patients should be advised that serious skin reactions have been reported in association with Oxcarbazepine Tablets. In the event a skin reaction should occur while taking Oxcarbazepine Tablets, patients should consult with their physician immediately - Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug related and should be reported to the physician immediately - Patients should be advised that there have been rare reports of blood disorders reported in patients treated with Oxcarbazepine. Patients should be instructed to immediately consult with their physician if they experience symptoms suggestive of blood disorders. - Female patients of childbearing age should be warned that the concurrent use of Oxcarbazepine with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using Oxcarbazepine. - Patients, their caregivers, and families should be counseled that AEDs, including Oxcarbazepine Tablets, 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. - Caution should be exercised if alcohol is taken in combination with Oxcarbazepine therapy, due to a possible additive sedative effect. - Patients should be advised that Oxcarbazepine Tablets may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on Oxcarbazepine Tablets to gauge whether it adversely affects their ability to drive or operate machinery. - 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. # Precautions with Alcohol - Caution should be exercised if alcohol is taken in combination with Oxcarbazepine therapy, due to a possible additive sedative effect. # Brand Names - OXCARBAZEPINE® # Look-Alike Drug Names There is limited information regarding Oxcarbazepine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Oxcarbazepine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, 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 Oxcarbazepine is an antiepileptic drug that is FDA approved for the treatment of partial seizures. Common adverse reactions include dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Adjunctive Therapy for Adults - Treatment with Oxcarbazepine should be initiated with a dose of 600 mg/day, given in a twice-a-day regimen. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects. It is recommended that the patient be observed closely and plasma levels of the concomitant AEDs be monitored during the period of Oxcarbazepine titration, as these plasma levels may be altered, especially at Oxcarbazepine doses greater than 1200 mg/day. - Conversion to Monotherapy for Adults - Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with Oxcarbazepine at 600 mg/day (given in a twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3-6 weeks, while the maximum dose of Oxcarbazepine should be reached in about 2-4 weeks. Oxcarbazepine may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the recommended daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with Oxcarbazepine. Patients should be observed closely during this transition phase. - Initiation of Monotherapy for Adults - Patients not currently being treated with AEDs may have monotherapy initiated with Oxcarbazepine. In these patients, Oxcarbazepine should be initiated at a dose of 600 mg/day (given in a twice-a-day regimen); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to Oxcarbazepine monotherapy ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oxcarbazepine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxcarbazepine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Adjunctive Therapy for Pediatric Patients (Aged 2-16 Years) - In pediatric patients aged 4-16 years, treatment should be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. The target maintenance dose of Oxcarbazepine should be achieved over two weeks, and is dependent upon patient weight, according to the following chart: 20-29 kg - 900 mg/day 29.1-39 kg - 1200 mg/day >39 kg – 1800 mg/day - 20-29 kg - 900 mg/day - 29.1-39 kg - 1200 mg/day - >39 kg – 1800 mg/day - In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6-51 mg/kg. - In pediatric patients aged 2-<4 years, treatment should also be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. For patients under 20 kg, a starting dose of 16-20 mg/kg may be considered. The maximum maintenance dose of Oxcarbazepine should be achieved over 2-4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen. - In the clinical trial in pediatric patients (2 to 4 years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day. - Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults. - Conversion to Monotherapy for Pediatric Patients (Aged 4-16 Years) - Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with Oxcarbazepine at approximately 8-10 mg/kg/day given in a twice-a-day regimen, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3-6 weeks while Oxcarbazepine may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase. - The recommended total daily dose of Oxcarbazepine is shown in the table below. - Initiation of Monotherapy for Pediatric Patients (Aged 4-16 Years) - Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with Oxcarbazepine. In these patients, Oxcarbazepine should be initiated at a dose of 8-10 mg/kg/day given in a twice-a-day regimen. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oxcarbazepine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxcarbazepine in pediatric patients. # Contraindications - Oxcarbazepine should not be used in patients with a known hypersensitivity to oxcarbazepine or to any of its components. # Warnings ### Precautions - Hyponatremia - Clinically significant hyponatremia (sodium <125 mmol/L) can develop during Oxcarbazepine use. In the 14 controlled epilepsy studies 2.5% of Oxcarbazepine-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first three months of treatment with Oxcarbazepine, although there were patients who first developed a serum sodium <125 mmol/L more than one year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their Oxcarbazepine dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia have been reported during post-marketing use. In clinical trials, patients whose treatment with Oxcarbazepine was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment. - Measurement of serum sodium levels should be considered for patients during maintenance treatment with Oxcarbazepine, particularly if the patient is receiving other medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity). - Anaphylactic Reactions and Angioedema - Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of Oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Oxcarbazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug. - Patients with a Past History of Hypersensitivity Reaction to Carbamazepine - Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of them will experience hypersensitivity reactions with Oxcarbazepine. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with Oxcarbazepine only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, Oxcarbazepine should be discontinued immediately. - Serious Dermatological Reactions - Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with Oxcarbazepine use. Such serious skin reactions may be life threatening, and some patients have required hospitalization, with very rare reports of fatal outcome. The median time of onset for reported cases was 19 days after treatment initiation. Recurrence of the serious skin reactions following rechallenge with Oxcarbazepine has also been reported. - The reporting rate of TEN and SJS associated with Oxcarbazepine use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking Oxcarbazepine, consideration should be given to discontinuing Oxcarbazepine use and prescribing another antiepileptic medication. - Association with HLA-B1502 - Patients carrying the HLA-B1502 allele may be at increased risk for SJS/TEN with oxcarbazepine treatment. - Human Leukocyte Antigen (HLA) allele B1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structure of oxcarbazepine is similar to that of carbamazepine. Available clinical evidence, and data from nonclinical studies showing a direct interaction between oxcarbazepine and HLA-B1502 protein, suggest that the HLA-B1502 allele may also increase the risk for SJS/TEN with oxcarbazepine. - The frequency of HLA-B1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines and in some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (<1%). - Testing for the presence of the HLA-B1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine. The use of oxcarbazepine should be avoided in patients positive for HLA-B1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B1502 is low, or in current oxcarbazepine users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B1502 status. - The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized. - Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including Oxcarbazepine, 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 2 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 Oxcarbazepine 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. - Withdrawal of AEDs - As with all antiepileptic drugs, Oxcarbazepine should be withdrawn gradually to minimize the potential of increased seizure frequency. - Cognitive/Neuropsychiatric Adverse Events - Use of Oxcarbazepine has been associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances. - In one large, fixed-dose study, Oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as Oxcarbazepine was added, reduction in Oxcarbazepine dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of Oxcarbazepine on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related. - In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse event. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about seven times greater on oxcarbazepine than on placebo. - In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of Oxcarbazepine, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance. - In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day Oxcarbazepine, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group. - A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which Oxcarbazepine was added to existing AED therapy (up to two concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as Oxcarbazepine was added. Oxcarbazepine was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient's body weight with fixed doses for predefined weight ranges). - Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse event or somnolence.). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances. - Drug Reaction with Eosinophilia and Systemic Symptoms (Dress syndrome/Multi-Organ Hypersensitivity) - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with oxcarbazepine. Some of these events have been fatal or life-threatening. DRESS syndrome typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Oxcarbazepine should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with DRESS/multi-organ hypersensitivity would indicate this to be a possibility. - Hematologic Events - Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with Oxcarbazepine during postmarketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develop. - Seizure Control During Pregnancy - Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period because MHD levels may return after delivery. - Laboratory Tests - Serum sodium levels below 125 mmol/L have been observed in patients treated with Oxcarbazepine. Experience from clinical trials indicates that serum sodium levels return toward normal when the Oxcarbazepine dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). - Laboratory data from clinical trials suggest that Oxcarbazepine use was associated with decreases in T4, without changes in T3 or TSH. # 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. - Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine and substantially more frequent than in placebo-treated patients were: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait. - Approximately 23% of these 1,537 adult patients discontinued treatment because of an adverse experience. The adverse reactions most commonly associated with discontinuation were: dizziness (6.4%), diplopia (5.9%), ataxia (5.2%), vomiting (5.1%), nausea (4.9%), somnolence (3.8%), headache (2.9%), fatigue (2.1%), abnormal vision (2.1%), tremor (1.8%), abnormal gait (1.7%), rash (1.4%), hyponatremia (1.0%). - Monotherapy in Adults Not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine in these patients were similar to those in previously treated patients. - Approximately 9% of these 295 adult patients discontinued treatment because of an adverse experience. The adverse reactions most commonly associated with discontinuation were: dizziness (1.7%), nausea (1.7%), rash (1.7%), headache (1.4%). - Adjunctive Therapy/Monotherapy in Pediatric Patients 4 Years Old and Above Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine in these patients were similar to those seen in adults. - Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse experience. The adverse reactions most commonly associated with discontinuation were: somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), nystagmus (1.1%). - Monotherapy in Pediatric Patients 4 Years Old and Above Not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine in these patients were similar to those in adults. - Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse experience. The adverse reactions most commonly associated (≥1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%). - Adjunctive Therapy/Monotherapy in Pediatric Patients 1 Month to <4 Years Old Previously Treated or Not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse reactions seen in association with Oxcarbazepine in these patients were similar to those seen in older children and adults except for infections and infestations which were more frequently seen in these younger children. - Approximately 11% of these 241 pediatric patients discontinued treatment because of an adverse experience. The adverse reaction most commonly associated with discontinuation were: convulsions (3.7%), status epilepticus (1.2%), and ataxia (1.2%). - Incidence in Controlled Clinical Studies: The prescriber should be aware that the figures in Tables 3, 4, 5 and 6 cannot be used to predict the frequency of adverse reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. - Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: Table 3 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with epilepsy treated with Oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of Oxcarbazepine. Table 4 lists treatment-emergent signs and symptoms in patients converted from other AEDs to either high dose Oxcarbazepine or low dose (300 mg) Oxcarbazepine. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables. - Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with other AEDs: Table 5 lists treatment-emergent signs and symptoms in a controlled clinical study of monotherapy in adults not previously treated with other AEDs that occurred in at least 2% of adult patients with epilepsy treated with Oxcarbazepine or placebo and were numerically more common in the patients treated with Oxcarbazepine. - Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with other AEDs: Table 6 lists treatment-emergent signs and symptoms that occurred in at least 2% of pediatric patients with epilepsy treated with Oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with Oxcarbazepine. - Other Events Observed in Association with the Administration of Oxcarbazepine - In the paragraphs that follow, the adverse events, other than those in the preceding tables or text, that occurred in a total of 565 children and 1,574 adults exposed to Oxcarbazepine and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and events likely to reflect concomitant illness are omitted particularly if minor. They are listed in order of decreasing frequency. Because the reports cite events observed in open label and uncontrolled trials, the role of Oxcarbazepine in their causation cannot be reliably determined. Fever, malaise, pain chest precordial, rigors, weight decrease. Bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia. Appetite increased, blood in stool, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival bleeding, gum hyperplasia, hematemesis, rectal hemorrhage, hemorrhoids, hiccup, mouth dry, pain biliary, pain right hypochondrium, retching, sialoadenitis, stomatitis, stomatitis ulcerative. Thrombocytopenia. Gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased. Hypertonia muscle. Aggressive reaction, amnesia, anguish, anxiety, apathy, aphasia, aura, convulsions aggravated, delirium, delusion, depressed level of consciousness, dysphonia, dystonia, emotional lability, euphoria, extrapyramidal disorder, feeling drunk, hemiplegia, hyperkinesia, hyperreflexia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, hysteria, libido decreased, libido increased, manic reaction, migraine, muscle contractions involuntary, nervousness, neuralgia, oculogyric crisis, panic disorder, paralysis, paroniria, personality disorder, psychosis, ptosis, stupor, tetany. Asthma, dyspnea, epistaxis, laryngismus, pleurisy. Acne, alopecia, angioedema, bruising, contact dermatitis, eczema, facial rash, flushing, folliculitis, heat rash, hot flushes, photosensitivity reaction, pruritus genital, psoriasis, purpura, rash erythematous, rash maculopapular, vitiligo, urticaria. Accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia. Procedure dental oral, procedure female reproductive, procedure musculoskeletal, procedure skin. Dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus. Systemic lupus erythematosus. ## Postmarketing Experience - The following adverse events have been observed in named patient programs or postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pancreatitis and/or lipase and/or amylase increase Aplastic anemia Hypothyroidism Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, Acute Generalized Exanthematous Pustulosis (AGEP) There have been reports of decreased bone mineral density, osteoporosis and fractures in patients on long-term therapy with oxcarbazepine. # Drug Interactions - Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. The inhibition of CYP2C19 by oxcarbazepine and MHD can cause increased plasma concentrations of drugs that are substrates of CYP2C19. Oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs. - In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. No autoinduction has been observed with Oxcarbazepine. - Antiepileptic Drugs - Potential interactions between Oxcarbazepine and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in Table 7. - In vivo, the plasma levels of phenytoin increased by up to 40% when Oxcarbazepine was given at doses above 1200 mg/day. Therefore, when using doses of Oxcarbazepine greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbital level, however, is small (15%) when given with Oxcarbazepine. - Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29%-40%). - No autoinduction has been observed with Oxcarbazepine. - Hormonal Contraceptives - Coadministration of Oxcarbazepine with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% [90% CI: 22-65] in one study and 52% [90% CI: 38-52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20-45] in one study and 52% [90% CI: 42-52] in another study. Therefore, concurrent use of Oxcarbazepine with hormonal contraceptives may render these contraceptives less effective. Studies with other oral or implant contraceptives have not been conducted. - Calcium Antagonists - After repeated coadministration of Oxcarbazepine, the AUC of felodipine was lowered by 28% [90% CI: 20-33]. Verapamil produced a decrease of 20% [90% CI: 18-27] of the plasma levels of MHD. - Other Drug Interactions - Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of Oxcarbazepine. - Drug/Laboratory Test Interactions - There are no known interactions of Oxcarbazepine with commonly used laboratory tests. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled clinical studies of Oxcarbazepine in pregnant women; however, Oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Given this fact, and the results of the animal studies described, it is likely that Oxcarbazepine is a human teratogen. Oxcarbazepine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose. - When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥300 mg/kg were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects. - In a study in which pregnant rabbits were orally administered MHD (20, 100, or 200 mg/kg) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m2 basis). This dose produced only minimal maternal toxicity. - In a study in which female rats were dosed orally with oxcarbazepine (25, 50, or 150 mg/kg) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (0.6 times the MRHD on a mg/m2 basis). Oral administration of MHD (25, 75, or 250 mg/kg) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m2 basis). - To provide information regarding the effects of in utero exposure to Oxcarbazepine, physicians are advised to recommend that pregnant patients taking Oxcarbazepine enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxcarbazepine in women who are pregnant. ### Labor and Delivery - The effect of Oxcarbazepine on labor and delivery in humans has not been evaluated. ### Nursing Mothers - Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to Oxcarbazepine in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother. ### Pediatric Use - Oxcarbazepine is indicated for use as adjunctive therapy for partial seizures in patients aged 2-16 years. Oxcarbazepine is also indicated as monotherapy for partial seizures in patients aged 4-16 years. Oxcarbazepine has been given to 898 patients between the ages of 1 month-17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month-17 years in other trials. ### Geriatic Use - There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxcarbazepine in elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. ### Gender There is no FDA guidance on the use of Oxcarbazepine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Oxcarbazepine with respect to specific racial populations. ### Renal Impairment - In renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged with a corresponding two-fold increase in AUC. Oxcarbazepine therapy should be initiated at one-half the usual starting dose and increased, if necessary, at a slower than usual rate until the desired clinical response is achieved. ### Hepatic Impairment There is no FDA guidance on the use of Oxcarbazepine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Oxcarbazepine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Oxcarbazepine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Oxcarbazepine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Oxcarbazepine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Isolated cases of overdose with Oxcarbazepine have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment. ### Management - There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered. ## Chronic Overdose There is limited information regarding Chronic Overdose of Oxcarbazepine in the drug label. # Pharmacology ## Mechanism of Action - The pharmacological activity of oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine. The precise mechanism by which Oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated. ## Structure - Oxcarbazepine Tablet is an antiepileptic drug available as 150 mg, 300 mg and 600 mg film-coated tablets for oral administration. Oxcarbazepine is 10,11-Dihydro-10-oxo-5H-dibenz[b,ƒ]azepine-5-carboxamide, and its structural formula is - Oxcarbazepine is a white to faintly orange crystalline powder. It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether and water. Its molecular weight is 252.27. - Oxcarbazepine film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide yellow, iron oxide red, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. ## Pharmacodynamics - Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with oxcarbazepine or MHD. ## Pharmacokinetics - Following oral administration of Oxcarbazepine Tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites. - The half-life of the parent is about two hours, while the half-life of MHD is about nine hours, so that MHD is responsible for most antiepileptic activity. - Absorption - Based on MHD concentrations, Oxcarbazepine Tablets and suspension were shown to have similar bioavailability. - After single-dose administration of Oxcarbazepine Tablets to healthy male volunteers under fasted conditions, the median tmax was 4.5 (range 3 to 13) hours. - Steady-state plasma concentrations of MHD are reached within 2-3 days in patients when Oxcarbazepine Tablet is given twice a day. At steady state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day. - Effect of Food: Food has no effect on the rate and extent of absorption of Oxcarbazepine Tablets. Therefore, Oxcarbazepine Tablets can be taken with or without food. - Distribution - The apparent volume of distribution of MHD is 49L. - Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein. - Metabolism and Excretion - Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Oxcarbazepine. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD). - Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose. - The half-life of the parent is about two hours, while the half-life of MHD is about nine hours. - Special Populations - Hepatic Impairment - The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. No dose adjustment for Oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment and, therefore, caution should be exercised when dosing severely impaired patients. - Renal Impairment - There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Oxcarbazepine is administered as a single 300-mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUC. Dose adjustment for Oxcarbazepine is recommended in these patients. - Pediatrics - Weight-adjusted MHD clearance decreases as age and weight increases, approaching that of adults. The mean weight adjusted clearance in children 2 years-<4 years of age is approximately 80% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted clearance in children 4-12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults. - Pregnancy - Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy. - Geriatrics - Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxcarbazepine to elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. - Gender - No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly. - Race - No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine. - Drug Interactions: - In Vitro - Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. - Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD, is clinically relevant. - In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine). - In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs. - As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely. ## Nonclinical Toxicology - Carcinogenesis - In two-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg/day to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses ≥70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m2 basis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses ≥25 mg/kg/day (0.1 times the MRHD on a mg/m2 basis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/m2 basis) and ≥250 mg/kg/day (equivalent to the MRHD on a mg/m2 basis), respectively. There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at ≥250 mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day. - Mutagenesis - Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay. - Impairment of Fertility - In a fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately two times the MRHD on a mg/m2 basis). # Clinical Studies - The effectiveness of Oxcarbazepine as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 2-16 years was established in seven multicenter, randomized, controlled trials. - The effectiveness of Oxcarbazepine as monotherapy for partial seizures in children aged 4-16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations. - Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of Oxcarbazepine as monotherapy. Two trials compared Oxcarbazepine to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of Oxcarbazepine, after substituting Oxcarbazepine 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a twice-a-day schedule. A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose Oxcarbazepine treatment groups. - One placebo-controlled Oxcarbazepine trial was conducted in 102 patients (11-62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2-10 partial seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or Oxcarbazepine given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional nine days, or until one of the following three exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) two new-onset secondarily generalized seizures, where such seizures were not seen in the one-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of Oxcarbazepine (see Figure 1), p=0.0001. - The second placebo-controlled trial was conducted in 67 untreated patients (8-69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or Oxcarbazepine, initiated at 300 mg twice a day and titrated to 1200 mg/day (given as 600 mg twice a day) in six days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between-group comparison of the time to first seizure. The difference between the two treatments was statistically significant in favor of Oxcarbazepine (see Figure 2), p=0.046. - A third trial substituted Oxcarbazepine monotherapy at 2400 mg/day for carbamazepine in 143 patients (12-65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this Oxcarbazepine dose for 56 days (baseline phase). Patients who were able to tolerate titration of Oxcarbazepine to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of Oxcarbazepine or 2400 mg/day Oxcarbazepine. Patients were observed for 126 days or until one of the following four exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two-fold increase in the highest consecutive two-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the Oxcarbazepine 2400 mg/day group (see Figure 3), p=0.0001. - Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on one or two AEDs. Patients were randomized to either Oxcarbazepine 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first six weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until one of the four exit criteria described for the previous study occurred. The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the Oxcarbazepine 2400 mg/day group (14/34; 41.2%) compared to the Oxcarbazepine 300 mg/day group (42/45; 93.3%) (p<0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the Oxcarbazepine 2400 mg/day group (see Figure 4), p=0.0001. - A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures. Patients were hospitalized and randomized to either Oxcarbazepine 10 mg/kg/day or were titrated up to 40-60 mg/kg/day within three days while withdrawing the previous AED on the second day of Oxcarbazepine therapy. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-day treatment or met one of the two exit criteria: 1) three study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate), 2) a prolonged study-specific seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p=0.904). The majority of patients from both dose groups completed the 5-day study without exiting. - Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable. For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older. - The effectiveness of Oxcarbazepine as an adjunctive therapy for partial seizures was established in two multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15-66 years of age) and one in 264 pediatric patients (3-17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing two doses of Oxcarbazepine in 128 pediatric patients (1 month to <4 years of age). - Patients in the two placebo-controlled trials were on 1-3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1-4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of Oxcarbazepine in addition to their other AEDs. - In these studies, the dose was increased over a two-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period. - In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30-46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of Oxcarbazepine at all doses tested in both trials (p=0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 8. It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study, an outcome not seen in the monotherapy studies. - Subset analyses of the antiepileptic efficacy of Oxcarbazepine with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 in controlled trials, the effect of the drug in the elderly has not been adequately assessed. - The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial seizures on 1-2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either Oxcarbazepine10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days. Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period. The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline. For the entire group of patients enrolled, this comparison was statistically significant in favor of Oxcarbazepine 60 mg/kg/day. In this study, there was no evidence that Oxcarbazepine was effective in patients below the age of 2 years (N=75). # How Supplied - 150 mg Film-Coated Tablets: Oval, Orange yellow film coated tablet, scored on both sides, debossed with ‘J’ and ‘232’ on either side of the score line on one side. - Bottles of 100 NDC 59746-232-01. - Bottles of 500 NDC 59746-232-05. - 300 mg Film-Coated Tablets: Oval, Orange yellow film coated tablet, scored on both sides, debossed with ‘J’ and ‘233’ on either side of the score line on one side. - Bottles of 100 NDC 59746-233-01. - Bottles of 500 NDC 59746-233-05. - 600 mg Film-Coated Tablets: Oval, Orange yellow film coated tablet, scored on both sides, debossed with ‘J’ and ‘234’ on either side of the score line on one side. - Bottles of 100 NDC 59746-234-01. - Bottles of 500 NDC 59746-234-05 - Store at 20°C to 25°C (68°F - 77°F) excursions permitted to 15°-30°C (59°-86°F). Dispense in tight container (USP). ## Storage There is limited information regarding Oxcarbazepine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Oxcarbazepine Tablets. - Patients should be advised that Oxcarbazepine Tablets may reduce the serum sodium concentrations especially if they are taking other medications that can lower sodium. Patients should be advised to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures. - Anaphylactic reactions and angioedema may occur during treatment with Oxcarbazepine Tablets. Patients should be advised to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician. - Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of these patients may experience hypersensitivity reactions with Oxcarbazepine. Patients should be advised that if they experience a hypersensitivity reaction while taking Oxcarbazepine Tablets they should consult with their physician immediately. - Patients should be advised that serious skin reactions have been reported in association with Oxcarbazepine Tablets. In the event a skin reaction should occur while taking Oxcarbazepine Tablets, patients should consult with their physician immediately - Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug related and should be reported to the physician immediately - Patients should be advised that there have been rare reports of blood disorders reported in patients treated with Oxcarbazepine. Patients should be instructed to immediately consult with their physician if they experience symptoms suggestive of blood disorders. - Female patients of childbearing age should be warned that the concurrent use of Oxcarbazepine with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using Oxcarbazepine. - Patients, their caregivers, and families should be counseled that AEDs, including Oxcarbazepine Tablets, 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. - Caution should be exercised if alcohol is taken in combination with Oxcarbazepine therapy, due to a possible additive sedative effect. - Patients should be advised that Oxcarbazepine Tablets may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on Oxcarbazepine Tablets to gauge whether it adversely affects their ability to drive or operate machinery. - 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. # Precautions with Alcohol - Caution should be exercised if alcohol is taken in combination with Oxcarbazepine therapy, due to a possible additive sedative effect. # Brand Names - OXCARBAZEPINE®[1] # Look-Alike Drug Names There is limited information regarding Oxcarbazepine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Oxcarbazepine
73ba41bf48ec9e79d06a086e4533e20a5e0266db	wikidoc	Oxpheneridine	Oxpheneridine Oxpheneridine (Carbamethidine) is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine). Oxpheneridine is not currently used in medicine. Presumably it has similar effects to other opioid derivatives, such as analgesia, sedation, nausea and respiratory depression. Unlike most opioid derivatives, oxpheneridine is not specifically listed as an illegal drug. In the UNODC narcotics report of 1958, they state that it was not possible to administer oxpheneridine in high doses as it is poorly soluble and highly irritating, and at the low doses administered it did not produce addiction in animals. This appears to be the only time oxpheneridine has been investigated, and so its pharmacological properties have not been well established. Oxpheneridine would probably be regarded as a a controlled substance analogue of pethidine on the grounds of its related chemical structure in some jurisdictions such as the USA, Australia and New Zealand. In Canada, Oxpheneridine is specifically excluded from the illegal drugs list on the Controlled Drugs and Substances Act schedules, presumably on the basis of the lack of addictive potential found by the UNODC. Canada also lists "Carbamethidine" as another excluded drug on its schedule, but this appears to be a double entry as the chemical name listed for carbamethidine is actually the chemical name of oxpheneridine, and the chemical name given for oxpheneridine on the Canadian drug schedules is chemically incorrect and does not correspond to a compound that could exist.	Oxpheneridine Oxpheneridine (Carbamethidine) is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine). Oxpheneridine is not currently used in medicine. Presumably it has similar effects to other opioid derivatives, such as analgesia, sedation, nausea and respiratory depression. Unlike most opioid derivatives, oxpheneridine is not specifically listed as an illegal drug. In the UNODC narcotics report of 1958, they state that it was not possible to administer oxpheneridine in high doses as it is poorly soluble and highly irritating, and at the low doses administered it did not produce addiction in animals. This appears to be the only time oxpheneridine has been investigated, and so its pharmacological properties have not been well established. Oxpheneridine would probably be regarded as a a controlled substance analogue of pethidine on the grounds of its related chemical structure in some jurisdictions such as the USA, Australia and New Zealand. In Canada, Oxpheneridine is specifically excluded from the illegal drugs list on the Controlled Drugs and Substances Act schedules, presumably on the basis of the lack of addictive potential found by the UNODC. Canada also lists "Carbamethidine" as another excluded drug on its schedule, but this appears to be a double entry as the chemical name listed for carbamethidine is actually the chemical name of oxpheneridine, and the chemical name given for oxpheneridine on the Canadian drug schedules is chemically incorrect and does not correspond to a compound that could exist. Template:Pharm-stub	https://www.wikidoc.org/index.php/Oxpheneridine
79c1cddbd200720bec79fc8a0e6af031c68d0d0d	wikidoc	Oxybuprocaine	Oxybuprocaine # Overview Oxybuprocaine (INN), also known as benoxinate or BNX, is an ester-type local anesthetic, which is used especially in ophthalmology and otolaryngology. Oxybuprocaine is sold by Novartis under the brand names Novesine or Novesin. Safety for use in pregnancy and lactation has not been established. # Uses - In ophthalmology in order to numb the surface of the eye (the outermost layers of the cornea and conjunctiva) for the following purposes: in order to perform a contact/applanation tonometry, for small operations, in order to remove small foreign objects from the uppermost layer of the cornea or conjunctiva; - in order to perform a contact/applanation tonometry, - for small operations, - in order to remove small foreign objects from the uppermost layer of the cornea or conjunctiva; - in otolaryngology for numbing the mucous membranes of the nostrils and pharynx, for diagnostic purposes and small operations, - for numbing the mucous membranes of bronchi, for example in bronchoscopy, - and the oesophagus, for example in intubation. # Pharmacokinetics Anaesthesia starts with a latency of 30 to 50 seconds and lasts for about 10 to 30 minutes, depending on perfusion. The drug is metabolised by esterases in blood plasma and liver. # Adverse effects When used excessively, oxybuprocaine like any other topical anesthetic used in the eye and on mucous membranes (like for example tetracaine, proxymetacaine and proparacaine) can cause irritation, hypersensitivity, anaphylaxis, irreversible corneal damage and even complete destruction of the cornea. (Excessive use means several times a day during several days or even weeks.) # Interactions Oxybuprocaine is incompatible with silver and mercury salts, as well as basic substances. It also reduces the antimicrobial action of sulfonamides.	Oxybuprocaine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Oxybuprocaine (INN), also known as benoxinate or BNX, is an ester-type local anesthetic, which is used especially in ophthalmology and otolaryngology. Oxybuprocaine is sold by Novartis under the brand names Novesine or Novesin. Safety for use in pregnancy and lactation has not been established. # Uses - In ophthalmology in order to numb the surface of the eye (the outermost layers of the cornea and conjunctiva) for the following purposes:[1] in order to perform a contact/applanation tonometry, for small operations, in order to remove small foreign objects from the uppermost layer of the cornea or conjunctiva; - in order to perform a contact/applanation tonometry, - for small operations, - in order to remove small foreign objects from the uppermost layer of the cornea or conjunctiva; - in otolaryngology for numbing the mucous membranes of the nostrils and pharynx, for diagnostic purposes and small operations,[2] - for numbing the mucous membranes of bronchi, for example in bronchoscopy,[2] - and the oesophagus, for example in intubation.[2] # Pharmacokinetics Anaesthesia starts with a latency of 30 to 50 seconds and lasts for about 10 to 30 minutes, depending on perfusion. The drug is metabolised by esterases in blood plasma and liver.[2] # Adverse effects When used excessively, oxybuprocaine like any other topical anesthetic used in the eye and on mucous membranes (like for example tetracaine, proxymetacaine and proparacaine) can cause irritation, hypersensitivity, anaphylaxis, irreversible corneal damage and even complete destruction of the cornea.[1][3] (Excessive use means several times a day during several days or even weeks.) # Interactions Oxybuprocaine is incompatible with silver and mercury salts, as well as basic substances. It also reduces the antimicrobial action of sulfonamides.[2]	https://www.wikidoc.org/index.php/Oxybuprocaine
d1489f9dc1b3a5caa982b5d54e08a1c55d44e5c3	wikidoc	Oxymetazoline	Oxymetazoline # 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 Oxymetazoline is a nasal decongestant, opthalmologic agent that is FDA approved for the treatment of nasal congestion, ocular irritation in conjunctivitis. Common adverse reactions include headache, insomnia, feeling nervous, rebound nasal congestion, dry nasal mucosa , nasal stinging/burning, sneezing. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - temporarily relieves nasal congestion due to: - common cold - hay fever - upper respiratory allergies - temporarily relieves sinus congestion and pressure - shrinks swollen nasal membranes so you can breathe more freely - Dosing Information - For CONJUNCTIVITIS, the usual adult dose of oxymetazoline for adults and children 6 years old or greater is 1 to 2 drops of 0.025% ophthalmic solution instilled into the affected eye(s) every 6 hours. - Contact lens wear during ophthalmic use is not recommended - Dosing Information - For RHINITIS, the usual intranasal dose of oxymetazoline in adults and children 6 years old or greater is 2 to 3 drops or sprays of 0.05% solution in each nostril twice a day for up to 3 days ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Oxymetazoline in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxymetazoline in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - For RHINITIS, the usual dose of oxymetazoline in children 2 to 5 years old is 2 to 3 drops of a 0.025% solution in each nostril twice a day for up to 3 days. Drops are preferred to spray dosage forms since dosage can be more easily controlled with the former. - Use should be limited to less than 5 days to minimize occurrence of rebound congestion. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Oxymetazoline in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxymetazoline in pediatric patients. # Contraindications There is limited information regarding Oxymetazoline Contraindications in the drug label. # Warnings - Ask a doctor before use if you have - heart disease - high blood pressure - diabetes - thyroid disease - trouble urinating due to an enlarged prostate gland - When using this product - do not use more than directed - do not use for more than 3 days. Use only as directed. Frequent or prolonged use may cause nasal congestion to recur or worsen. - temporary discomfort such as burning, stinging, sneezing or an increase in nasal discharge may occur - use of this container by more than one person may spread infection - Stop use and ask a doctor if - symptoms persist - If pregnant or breast-feeding, - ask a health professional before use. - Keep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center right away. (1-800-222-1222) # Adverse Reactions ## Clinical Trials Experience - There is limited information regarding Clinical Trial Experience of Oxymetazoline in the drug label. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Oxymetazoline in the drug label. # Drug Interactions There is limited information regarding Oxymetazoline Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxymetazoline in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Oxymetazoline during labor and delivery. ### Nursing Mothers - There is no FDA guidance on the use of Oxymetazoline with respect to nursing mothers. ### Pediatric Use - There is no FDA guidance on the use of Oxymetazoline with respect to pediatric patients. ### Geriatic Use - There is no FDA guidance on the use of Oxymetazoline with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Oxymetazoline with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Oxymetazoline with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Oxymetazoline in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Oxymetazoline in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Oxymetazoline in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Oxymetazoline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - There is limited information regarding Monitoring of Oxymetazoline in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Oxymetazoline in the drug label. # Overdosage - There is limited information regarding Chronic Overdose of Oxymetazoline in the drug label. # Pharmacology ## Mechanism of Action ## Structure ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Oxymetazoline in the drug label. ## Pharmacokinetics - There is limited information regarding Pharmacokinetics of Oxymetazoline in the drug label. ## Nonclinical Toxicology - There is limited information regarding Nonclinical Toxicology of Oxymetazoline in the drug label. # Clinical Studies - There is limited information regarding Clinical Studies of Oxymetazoline in the drug label. # How Supplied ## Storage - store at 20°-25°C (68°-77°F) - retain carton for future reference on full labeling # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - adults and children 6 to under 12 years of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours. Do not exceed 2 doses in any 24-hour period. - children under 6 years of age: ask a doctor - To spray, squeeze bottle quickly and firmly. Do not tilt head backward while spraying. Wipe nozzle clean after use. Replace cap tightly to maintain child resistance. # Precautions with Alcohol Alcohol-Oxymetazoline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Afrin, 4-Way Long Lasting, Neo-Synephrine 12 Hour, Vicks Sinex 12 Hour, Visine L.R., Nasacon, Sinarest Nasal, Duramist Plus. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Oxymetazoline Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [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 Oxymetazoline is a nasal decongestant, opthalmologic agent that is FDA approved for the treatment of nasal congestion, ocular irritation in conjunctivitis. Common adverse reactions include headache, insomnia, feeling nervous, rebound nasal congestion, dry nasal mucosa , nasal stinging/burning, sneezing. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - temporarily relieves nasal congestion due to: - common cold - hay fever - upper respiratory allergies - temporarily relieves sinus congestion and pressure - shrinks swollen nasal membranes so you can breathe more freely - Dosing Information - For CONJUNCTIVITIS, the usual adult dose of oxymetazoline for adults and children 6 years old or greater is 1 to 2 drops of 0.025% ophthalmic solution instilled into the affected eye(s) every 6 hours. - Contact lens wear during ophthalmic use is not recommended - Dosing Information - For RHINITIS, the usual intranasal dose of oxymetazoline in adults and children 6 years old or greater is 2 to 3 drops or sprays of 0.05% solution in each nostril twice a day for up to 3 days ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Oxymetazoline in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxymetazoline in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - For RHINITIS, the usual dose of oxymetazoline in children 2 to 5 years old is 2 to 3 drops of a 0.025% solution in each nostril twice a day for up to 3 days. Drops are preferred to spray dosage forms since dosage can be more easily controlled with the former. - Use should be limited to less than 5 days to minimize occurrence of rebound congestion. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Oxymetazoline in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxymetazoline in pediatric patients. # Contraindications There is limited information regarding Oxymetazoline Contraindications in the drug label. # Warnings - Ask a doctor before use if you have - heart disease - high blood pressure - diabetes - thyroid disease - trouble urinating due to an enlarged prostate gland - When using this product - do not use more than directed - do not use for more than 3 days. Use only as directed. Frequent or prolonged use may cause nasal congestion to recur or worsen. - temporary discomfort such as burning, stinging, sneezing or an increase in nasal discharge may occur - use of this container by more than one person may spread infection - Stop use and ask a doctor if - symptoms persist - If pregnant or breast-feeding, - ask a health professional before use. - Keep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center right away. (1-800-222-1222) # Adverse Reactions ## Clinical Trials Experience - There is limited information regarding Clinical Trial Experience of Oxymetazoline in the drug label. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Oxymetazoline in the drug label. # Drug Interactions There is limited information regarding Oxymetazoline Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxymetazoline in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Oxymetazoline during labor and delivery. ### Nursing Mothers - There is no FDA guidance on the use of Oxymetazoline with respect to nursing mothers. ### Pediatric Use - There is no FDA guidance on the use of Oxymetazoline with respect to pediatric patients. ### Geriatic Use - There is no FDA guidance on the use of Oxymetazoline with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Oxymetazoline with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Oxymetazoline with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Oxymetazoline in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Oxymetazoline in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Oxymetazoline in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Oxymetazoline in patients who are immunocompromised. # Administration and Monitoring ### Administration - - Intravenous ### Monitoring - There is limited information regarding Monitoring of Oxymetazoline in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Oxymetazoline in the drug label. # Overdosage - There is limited information regarding Chronic Overdose of Oxymetazoline in the drug label. # Pharmacology ## Mechanism of Action - ## Structure - ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Oxymetazoline in the drug label. ## Pharmacokinetics - There is limited information regarding Pharmacokinetics of Oxymetazoline in the drug label. ## Nonclinical Toxicology - There is limited information regarding Nonclinical Toxicology of Oxymetazoline in the drug label. # Clinical Studies - There is limited information regarding Clinical Studies of Oxymetazoline in the drug label. # How Supplied - ## Storage - store at 20°-25°C (68°-77°F) - retain carton for future reference on full labeling # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - adults and children 6 to under 12 years of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours. Do not exceed 2 doses in any 24-hour period. - children under 6 years of age: ask a doctor - To spray, squeeze bottle quickly and firmly. Do not tilt head backward while spraying. Wipe nozzle clean after use. Replace cap tightly to maintain child resistance. # Precautions with Alcohol Alcohol-Oxymetazoline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Afrin, 4-Way Long Lasting, Neo-Synephrine 12 Hour, Vicks Sinex 12 Hour, Visine L.R., Nasacon, Sinarest Nasal, Duramist Plus. # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Oxymetazoline
844a7d8c1c58b0bdf587fc09ca7f77f4d2aad7ad	wikidoc	Oxyntomodulin	Oxyntomodulin Oxyntomodulin is a naturally occurring 37 amino acid peptide hormone found in the colon, produced by the oxyntic (fundic) cells of the oxyntic (fundic) mucosa. It has been found to suppress appetite. A recent study has found that it can be used as a weight loss treatment. The mechanism of action of oxyntomodulin is not well understood. It is known to bind both the GLP-1 receptor and the glucagon receptor but it is not known whether the effects of the hormone are mediated through these receptors or through an unidentified receptor. Thiakis , a biotechnology company based in London and founded by Professor Steve Bloom and Dr John Burt, is developing a novel analogue of oxyntomodulin for the treatment of obesity.	Oxyntomodulin Oxyntomodulin is a naturally occurring 37 amino acid peptide hormone found in the colon, produced by the oxyntic (fundic) cells of the oxyntic (fundic) mucosa. It has been found to suppress appetite. A recent study has found that it can be used as a weight loss treatment.[1][2][3][4] The mechanism of action of oxyntomodulin is not well understood. It is known to bind both the GLP-1 receptor and the glucagon receptor but it is not known whether the effects of the hormone are mediated through these receptors or through an unidentified receptor. Thiakis [1], a biotechnology company based in London and founded by Professor Steve Bloom and Dr John Burt, is developing a novel analogue of oxyntomodulin for the treatment of obesity.	https://www.wikidoc.org/index.php/Oxyntomodulin
51e206fd3968a7c047b70d7c7c33fcdcfb9bbb95	wikidoc	P-type ATPase	P-type ATPase P-type (or E1-E2-type) ATPases constitute a superfamily of cation transport enzymes, present both in prokaryota and eukaryota, whose members mediate membrane flux of all common biologically relevant cations. The ATPases, that form an aspartyl phosphate intermediate in the course of ATP hydrolysis, can be divided into 4 major groups: - (1) Ca2+-transporting ATPases; - (2) Na+/K+- and gastric H+/K+-transporting ATPases; - (3) Plasma membrane H+-transporting ATPases (proton pumps) of plants, fungi and lower eukaryotes; and - (4) all bacterial P-type ATPases, except the Mg2+-ATPase of Salmonella typhimurium, which is more similar to the eukaryotic sequences. # Human proteins containing this domain - Na+/K+ transporting: ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B1, ATP1B2, ATP1B3, ATP1B4 - Ca++ transporting: ATP2A1, ATP2A2, ATP2A3, ATP2B1, ATP2B2, ATP2B3, ATP2B4, ATP2C1 - Cu++ transporting: ATP7A, ATP7B - Class I, type 8: ATP8A1, ATP8B1, ATP8B2, ATP8B3, ATP8B4 - Class II, type 9: ATP9A, ATP9B - Class V, type 10: ATP10A, ATP10B, ATP10D - Class VI, type 11: ATP11A, ATP11B, ATP11C - H+/K+ transporting, nongastric: ATP12A - type 13: ATP13A1, ATP13A2, ATP13A3, ATP13A4, ATP13A5 - ATP2C2; - ATP4A; - KIAA0195	P-type ATPase P-type (or E1-E2-type) ATPases constitute a superfamily of cation transport enzymes, present both in prokaryota and eukaryota, whose members mediate membrane flux of all common biologically relevant cations[1]. The ATPases, that form an aspartyl phosphate intermediate in the course of ATP hydrolysis, can be divided into 4 major groups[2]: - (1) Ca2+-transporting ATPases; - (2) Na+/K+- and gastric H+/K+-transporting ATPases; - (3) Plasma membrane H+-transporting ATPases (proton pumps) of plants, fungi and lower eukaryotes; and - (4) all bacterial P-type ATPases, except the Mg2+-ATPase of Salmonella typhimurium, which is more similar to the eukaryotic sequences. # Human proteins containing this domain - Na+/K+ transporting: ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B1, ATP1B2, ATP1B3, ATP1B4 - Ca++ transporting: ATP2A1, ATP2A2, ATP2A3, ATP2B1, ATP2B2, ATP2B3, ATP2B4, ATP2C1 - Cu++ transporting: ATP7A, ATP7B - Class I, type 8: ATP8A1, ATP8B1, ATP8B2, ATP8B3, ATP8B4 - Class II, type 9: ATP9A, ATP9B - Class V, type 10: ATP10A, ATP10B, ATP10D - Class VI, type 11: ATP11A, ATP11B, ATP11C - H+/K+ transporting, nongastric: ATP12A - type 13: ATP13A1, ATP13A2, ATP13A3, ATP13A4, ATP13A5 - ATP2C2; - ATP4A; - KIAA0195	https://www.wikidoc.org/index.php/P-ATPase
9255c3760ee71a6dab4e58ef5bddb16774600fce	wikidoc	P53 (protein)	P53 (protein) # Overview p53, also known as protein 53 (TP53), is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. It is important in multicellular organisms as it helps to suppress cancer. p53 has been described as "the guardian of the genome", "the guardian angel gene", or the "master watchman", referring to its role in conserving stability by preventing genome mutation. The name p53 is in reference to its apparent molecular mass: it runs as a 53-kilodalton (kDa) protein on SDS-PAGE. But different ways of measuring molecular mass can produce different results. Based on calculations from its amino acid residues, p53's mass is actually only 43.7 kilodaltons. This difference is due to the high number of amino-acid proline residues in the p53 protein which slow p53's migration on SDS-PAGE, thus making it appear larger. This observation is also seen in p53 from other species including rodents, frogs, and fish. # Names - Official protein name: Cellular tumor antigen p53 Synonyms: - Tumor suppressor p53 - Phosphoprotein p53 - Antigen NY-CO-13 # Gene The human gene that encodes for p53 is TP53. The gene is named TP53 after the protein it codes for (TP53 is another name for p53). Italics are used to distinguish the TP53 gene name from the TP53 protein name. The gene is located on the human chromosome 17 (17p13.1). The location has also been mapped on other model animals: - Mouse - chromosome 11 - Rat - chromosome 10 - Dog - chromosome 5 - Pig - chromosome 12 # Structure Human p53 is 393 amino acids long and has five domains: - An N-terminal transcription-activation domain (TAD), which activates transcription factors : residues 1-42 - A Proline rich domain important for the apoptotic activity of p53 : residues 80-94 - A central DNA-binding core domain (DBD). Contains one zinc atom and several Arginine Amino Acid : Residues 100-300. - A homo-oligomerisation domain (OD) : residues 307-.355 Tetramerization is essential for the activity of p53 in vivo. - A C-terminal involved in downregulation of DNA binding of the central domain : residues 356-393. Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore OD mutations have a dominant negative effect on the function of p53. Wild-type p53 is a labile protein, comprising folded and unstructured regions which function in a synergistic manner. # Functional significance p53 has many anti-cancer mechanisms: - It can activate DNA repair proteins when DNA has sustained damage. - It can also hold the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.) - It can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irreparable. p53 is central to many of the cell's anti-cancer mechanisms. It can induce growth arrest, apoptosis and cell senescence. In normal cells p53 is usually inactive, bound to the protein MDM2 (HDM2 in humans), which prevents its action and promotes its degradation by acting as ubiquitin ligase. Active p53 is induced after the effects of various cancer-causing agents such as UV radiation, oncogenes and some DNA-damaging drugs. DNA damage is sensed by 'checkpoints' in a cell's cycle, and causes proteins such as ATM, CHK1 and CHK2 to phosphorylate p53 at sites that are close to or within the MDM2-binding region and p300-binding region of the protein. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. Some oncogenes can also stimulate the transcription of proteins which bind to MDM2 and inhibit its activity. Once activated p53 activates expression of several genes including one encoding for p21. p21 binds to the G1-S/CDK and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. p53 has many anticancer mechanisms, and plays a role in apoptosis, genetic stability, and inhibition of angiogenesis. Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other. Research published in 2007 showed when p53 expression is stimulated by sunlight, it begins the chain of events leading to tanning. # Regulation of p53 activity p53 becomes activated in response to a myriad of stress types, which include but is not limited to DNA damage (induced by either UV, IR or chemical agents,such as hydrogen peroxide), oxidative stress, osmotic shock, ribonucleotide depletion and deregulated oncogene expression. This activation is marked by two major events. Firstly, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Secondly, a conformational change forces p53 to take on an active role as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-Terminal domain. The N-Terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. The protein kinases which are known to target this transcriptional activation domain of p53, can roughly be divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc... A second group of protein kinases (ATR, ATM, Chk1, Chk2, DNA-PK, CAK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 binds to p53 and transports it from the nucleus to the cytosol where it becomes degraded by the proteasome. Phosphorylation of the N-terminal end of p53 by the above mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53 which prevents Mdm2-binding even more. Trancriptional coactivators, like p300 or PCAF, then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. # Role in disease If the TP53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disease known as Li-Fraumeni syndrome. The TP53 gene can also be damaged in cells by mutagens (chemicals, radiation or viruses), increasing the likelihood that the cell will begin uncontrolled division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Increasing the amount of p53, which may initially seem a good way to treat tumors or prevent them from spreading, is in actuality not a usable method of treatment, since it can cause premature aging. However, restoring endogenous p53 function holds a lot of promise. Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, the Human papillomavirus (HPV), encodes a protein, E6, which binds the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, p105RB, allows for repeated cell division manifestested in the clinical disease of warts. In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop MDM2 is itself induced by the p53 protein. However mutant p53 proteins often don't induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels. Originally P53 was thought to be an oncogene because well over half of all cancer cells tested showed high levels of P53 protein. However, these were all mutated forms of P53. # History p53 was identified in 1979 by Arnold Levine, David Lane, and Lloyd Old, working at Princeton University, Imperial Cancer Research Fund (UK), and Sloan-Kettering Memorial Hospital, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Moscow Academy of Sciences in 1982, and independently in 1983 by Moshe Oren (Weizmann Institute). It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumour cell mRNA. Its character as a tumor suppressor gene was finally revealed in 1989 by Bert Vogelstein working at Johns Hopkins School of Medicine. Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation. In a series of publications in 1991-92, Michael Kastan, Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage. In 1993, p53 was voted molecule of the year by Science magazine. Its role in sun tanning was published in March 2007.	P53 (protein) Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview p53, also known as protein 53 (TP53), is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. It is important in multicellular organisms as it helps to suppress cancer. p53 has been described as "the guardian of the genome", "the guardian angel gene", or the "master watchman", referring to its role in conserving stability by preventing genome mutation.[1] The name p53 is in reference to its apparent molecular mass: it runs as a 53-kilodalton (kDa) protein on SDS-PAGE. But different ways of measuring molecular mass can produce different results. Based on calculations from its amino acid residues, p53's mass is actually only 43.7 kilodaltons. This difference is due to the high number of amino-acid proline residues in the p53 protein which slow p53's migration on SDS-PAGE, thus making it appear larger. This observation is also seen in p53 from other species including rodents, frogs, and fish. # Names - Official protein name: Cellular tumor antigen p53 Synonyms: - Tumor suppressor p53 - Phosphoprotein p53 - Antigen NY-CO-13 # Gene The human gene that encodes for p53 is TP53. The gene is named TP53 after the protein it codes for (TP53 is another name for p53). Italics are used to distinguish the TP53 gene name from the TP53 protein name. The gene is located on the human chromosome 17 (17p13.1). The location has also been mapped on other model animals: - Mouse - chromosome 11 - Rat - chromosome 10 - Dog - chromosome 5 - Pig - chromosome 12 # Structure Human p53 is 393 amino acids long and has five domains: - An N-terminal transcription-activation domain (TAD), which activates transcription factors : residues 1-42 - A Proline rich domain important for the apoptotic activity of p53 : residues 80-94 - A central DNA-binding core domain (DBD). Contains one zinc atom and several Arginine Amino Acid : Residues 100-300. - A homo-oligomerisation domain (OD) : residues 307-.355 Tetramerization is essential for the activity of p53 in vivo. - A C-terminal involved in downregulation of DNA binding of the central domain : residues 356-393. Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore OD mutations have a dominant negative effect on the function of p53. Wild-type p53 is a labile protein, comprising folded and unstructured regions which function in a synergistic manner.[2] # Functional significance p53 has many anti-cancer mechanisms: - It can activate DNA repair proteins when DNA has sustained damage. - It can also hold the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.) - It can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irreparable. p53 is central to many of the cell's anti-cancer mechanisms. It can induce growth arrest, apoptosis and cell senescence. In normal cells p53 is usually inactive, bound to the protein MDM2 (HDM2 in humans), which prevents its action and promotes its degradation by acting as ubiquitin ligase. Active p53 is induced after the effects of various cancer-causing agents such as UV radiation, oncogenes and some DNA-damaging drugs. DNA damage is sensed by 'checkpoints' in a cell's cycle, and causes proteins such as ATM, CHK1 and CHK2 to phosphorylate p53 at sites that are close to or within the MDM2-binding region and p300-binding region of the protein. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. Some oncogenes can also stimulate the transcription of proteins which bind to MDM2 and inhibit its activity. Once activated p53 activates expression of several genes including one encoding for p21. p21 binds to the G1-S/CDK and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. p53 has many anticancer mechanisms, and plays a role in apoptosis, genetic stability, and inhibition of angiogenesis. Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other.[3] Research published in 2007 showed when p53 expression is stimulated by sunlight, it begins the chain of events leading to tanning.[4] # Regulation of p53 activity p53 becomes activated in response to a myriad of stress types, which include but is not limited to DNA damage (induced by either UV, IR or chemical agents,such as hydrogen peroxide), oxidative stress, osmotic shock, ribonucleotide depletion and deregulated oncogene expression. This activation is marked by two major events. Firstly, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Secondly, a conformational change forces p53 to take on an active role as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-Terminal domain. The N-Terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. The protein kinases which are known to target this transcriptional activation domain of p53, can roughly be divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc... A second group of protein kinases (ATR, ATM, Chk1, Chk2, DNA-PK, CAK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 binds to p53 and transports it from the nucleus to the cytosol where it becomes degraded by the proteasome. Phosphorylation of the N-terminal end of p53 by the above mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53 which prevents Mdm2-binding even more. Trancriptional coactivators, like p300 or PCAF, then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. # Role in disease If the TP53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disease known as Li-Fraumeni syndrome. The TP53 gene can also be damaged in cells by mutagens (chemicals, radiation or viruses), increasing the likelihood that the cell will begin uncontrolled division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Increasing the amount of p53, which may initially seem a good way to treat tumors or prevent them from spreading, is in actuality not a usable method of treatment, since it can cause premature aging.[5] However, restoring endogenous p53 function holds a lot of promise.[6] Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, the Human papillomavirus (HPV), encodes a protein, E6, which binds the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, p105RB, allows for repeated cell division manifestested in the clinical disease of warts. In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop MDM2 is itself induced by the p53 protein. However mutant p53 proteins often don't induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels. Originally P53 was thought to be an oncogene because well over half of all cancer cells tested showed high levels of P53 protein. However, these were all mutated forms of P53. # History p53 was identified in 1979 by Arnold Levine, David Lane, and Lloyd Old, working at Princeton University, Imperial Cancer Research Fund (UK), and Sloan-Kettering Memorial Hospital, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Moscow Academy of Sciences in 1982,[7] and independently in 1983 by Moshe Oren (Weizmann Institute). It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumour cell mRNA. Its character as a tumor suppressor gene was finally revealed in 1989 by Bert Vogelstein working at Johns Hopkins School of Medicine. Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.[8] In a series of publications in 1991-92, Michael Kastan, Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage. In 1993, p53 was voted molecule of the year by Science magazine. Its role in sun tanning was published in March 2007.	https://www.wikidoc.org/index.php/P53_(protein)
f6fa8ed03ea995889d012bfbae95b6ee1a1b7465	wikidoc	PAH clearance	PAH clearance # Overview Para aminohippurate clearance or PAH clearance is a method used in renal physiology to measure renal plasma flow, which, in turn, is a measure of renal function. The concentration of para aminohippurate (PAH) is measured in one arterial blood sample (PPAH) and one urine sample(UPAH). The urine flow (V) as also measured. Renal perfusion flow is then calculated by: What in fact is calculated is the effective renal plasma flow (eRPF). However, since the renal extraction ratio of PAH almost equals 1, then eRPF almost equals RPF. # Precision The renal extraction ratio of PAH is a normal individual is approximately 0.92, and thus not exactly 1.0. Thus, this method usually underestimates RPF by approximately 10%. This margin of error is generally acceptable considering the ease with which eRPF is measured.	PAH clearance Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Para aminohippurate clearance or PAH clearance is a method used in renal physiology to measure renal plasma flow, which, in turn, is a measure of renal function. The concentration of para aminohippurate (PAH) is measured in one arterial blood sample (PPAH) and one urine sample(UPAH). The urine flow (V) as also measured. Renal perfusion flow is then calculated by: What in fact is calculated is the effective renal plasma flow (eRPF). However, since the renal extraction ratio of PAH almost equals 1, then eRPF almost equals RPF. # Precision The renal extraction ratio of PAH is a normal individual is approximately 0.92[1], and thus not exactly 1.0. Thus, this method usually underestimates RPF by approximately 10%. This margin of error is generally acceptable considering the ease with which eRPF is measured.	https://www.wikidoc.org/index.php/PAH_clearance
1ddb738f00218841c6108e0d9c445594ab2276a8	wikidoc	Pineoblastoma	Pineoblastoma Synonyms and keywords: Pineoblastomas; Pinealoblastoma; Pinealoblastomas; PB; Pineal parenchymal tumor # Overview Pineoblastoma is a rare, malignant pineal parenchymal tumor. It is a supratentorial midline primitive neuroectodermal tumor. It is considered as a WHO grade IV tumor according to the WHO classification of tumors of the central nervous system. # Pathophysiology ## Pathogenesis Pineoblastoma originates from the neuroectodermal cells. It is the least differentiated pineal gland tumors, with pineocytoma and pineal parenchymal tumour with intermediate differentiation representing better differentiated tumors along the same spectrum. ## Associated Conditions - Pineoblastoma may occur in patients with hereditary uni- or bilateral retinoblastoma. - When retinoblastoma patients present with pineoblastoma, this is characterized as "trilateral retinoblastoma". ## Gross Pathology On gross pathology, pineoblastoma is characterized by solid, large poorly defined masses. ## Microscopic Pathology On microscopic histopathological analysis, pineoblastoma is characterized by: - Hypercellular appearance - Tightly packed small round blue cells (high nuclear to cytoplasmic ratio) - Oval and angulated hyperchromatic nuclei with atypia - Mitoses - Homer-Wright & Flexner-Winterstein rosettes - Fleurettes ## Immunohistochemistry Pineoblastoma is demonstrated by positivity to tumor markers such as: - GFAP - Neurofilament - Synaptophysin - MIB-1 - Ki-67 # Differentiating Pineoblastoma from other Diseases Pineoblastoma must be differentiated from: - Pineocytoma - Pineal parenchymal tumor with intermediate differentiation - Papillary tumor of the pineal region - Pineal germinoma - Pineal embryonal carcinoma - Pineal choriocarcinoma - Pineal yolk sac carcinoma (endodermal sinus tumor) - Pineal teratoma - Pineal cyst - Astrocytoma of the pineal gland - Meningioma near pineal gland - Pineal metastasis - Cavernoma in pineal region - Aneurysm in pineal region # Epidemiology and Demographics ## Prevalence - Pineoblastoma constitutes approximately 0.1% of the intracranial neoplasms. - Pineoblastoma together with germ cell tumors are the most common pineal tumors in children. ## Age Pineoblastoma is a disease that tends to affect children and young adults. ## Gender Pineoblastoma affects men and women equally. # Natural History, Complications and Prognosis ## Natural History - Pineoblastoma is the most agressive pineal parenchymal tumor. - If left untreated, patients with pineoblastoma may progress to develop seizures, obstructive hydrocephalus, local recurrence, and cerebrospinal fluid (CSF) metastasis. ## Complications Common complications of pineoblastoma include: - Obstructive hydrocephalus - Local recurrence - CSF metastasis ## Prognosis Prognosis is generally poor, and the 5-year survival rate of patients with pineoblastoma is approximately 58%. # History and Symptoms ## History The clinical presentation of pineoblastoma is mainly from the obstructive hydrocephalus secondary to compression of the tectum of the midbrain and obstruction of the aqueduct. ## Symptoms - Symptoms of pineoblastoma include: - Headaches - Nausea - Vomiting - Seizures - Tinnitus - Hearing loss - Sleepiness - Irritability - Personality changes - Double vision - Trouble coordinating motor movements - Difficulty walking - Slowed growth # Physical Examination - Compression of the superior colliculi can lead to a characteristic upward gaze palsy, known as Parinaud syndrome. - Common physical examination findings of pineoblastoma include: ## HEENT - Bulging soft spots (fontanelles) - Eyes that are constantly looking down (sunsetting sign) - Upward gaze palsy - Pupillary light-near dissociation (pupils respond to near stimuli but not light) - Convergence-retraction nystagmus - Papilledema ## Neurological - Mental retardation - Muscle spasms - Loss of bladder control - Ataxia - Cranioneuropathies - VIth nerve palsy ## Laboratory Diagnosis There are no specific laboratory findings for pineocytoma. However, the following findings are of significant - Both serum and CSF should be assayed for alpha-fetoprotein and beta human chorionic gonadotropin (beta-hCG) to help diagnose a germ cell tumor. - Immunohistochemistry may be of value in detecting these markers or placental alkaline phosphatase. ## CT Scan - Head CT scan may be diagnostic of pineoblastoma. - Findings on CT scan suggestive of pineoblastoma include a mass with a solid component that tends to be slightly hyperdense compared to adjacent brain due to high cellularity. Calcification is present that is peripherally disperse or "exploded", similar to pineocytoma. ## MRI - Brain MRI may be diagnostic of pineoblastoma. - Features on MRI suggestive of pineoblastoma include: ## Other Imaging Findings Other imaging studies for pineoblastoma include magnetic resonance spectroscopy (MR spectroscopy), which demonstrates: - Elevation of the choline and lipid lactate peaks - Depression of the neural markers (N-acetyl aspartate (NAA) and creatine (Cr) - Prominent glutamate and taurine peaks at 3.4 ppm with shot TE signal voxel MR spectroscopy ## Other Diagnostic Studies Stereotactic biopsy - A direct, visually guided biopsy of the pineal gland mass with open or neuroendoscopic surgery has been preferred due to concerns about injury to the deep cerebral veins. - An open procedure also allows CSF to be obtained for Tumor marker studies Permits direct visualization of the third ventricle for staging purposes Sllows a third ventriculostomy to be performed for CSF diversion if needed. - Tumor marker studies - Permits direct visualization of the third ventricle for staging purposes - Sllows a third ventriculostomy to be performed for CSF diversion if needed. - The diagnostic yield of stereotactic biopsy ranges from 94 to 100 percent. - If the biopsy is nondiagnostic, equivocal, or suggests a benign tumor such as mature teratoma or meningioma, surgery is recommended to establish a definitive diagnosis or to identify focal areas of malignant disease # Treatment - The predominant therapy for pineoblastoma is surgical resection. Adjunctive chemotherapy and radiation may be required. - The main goal of open surgery on pineoblastoma is the complete tumor removal with minimal morbidity, whenever possible. However, even if gross total excision cannot be achieved, establishment of an accurate diagnosis, maximal cytoreduction, and restoration of the CSF pathway may be achieved. - Gross total resection has been associated with improved survival, similar to treatment with craniospinal irradiation and multi-agent chemotherapy. - Children under the age of 36 months with pineoblastoma should be treated with multi-agent chemotherapy for 12 to 24 months with the goal of delaying radiation past the age of 36 months. Craniospinal irradiation before this age of 3 has been associated with significant cognitive and neuroendocrine sequelae. - Subtotal tumor resection in children under 5 years of age is associated with markedly worsened patient survival. According to the Children's Oncology Group trials, these tumors require craniospinal irradiation (with local tumor doses of at least 50 Gy) and adjuvant chemotherapy. When carboplatin and vincristine were administered during craniospinal irradiation followed by 6 months of non-intensive non-cisplatin chemotherapy, it significantly reduces tumor progression. - Patients with pineoblastoma will develop hydrocephalus in majority of the cases and they will require CSF diversion. Ventriculo-peritoneal (V-P) shunt placement is associated with low morbidity and mortality rate. However, shunt malfunction in this population is as high as 20%. In addition, tumor metastasis through a CSF shunt has been reported. Endoscopic third ventriculostomy (ETVC) is an alternative option, which also permits a biopsy of the tumor in the same procedure. Ahn et al. reported that the biopsy samples, obtained in the lateral ventricle or pineal region, were more favorable towards a successful diagnosis than those in the thalamus or tectal region. Neuroendoscopic biopsy procedures have been proven safe with low complication rates.	Pineoblastoma Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2] Aditya Ganti M.B.B.S. [3] Synonyms and keywords: Pineoblastomas; Pinealoblastoma; Pinealoblastomas; PB; Pineal parenchymal tumor # Overview Pineoblastoma is a rare, malignant pineal parenchymal tumor. It is a supratentorial midline primitive neuroectodermal tumor. It is considered as a WHO grade IV tumor according to the WHO classification of tumors of the central nervous system. # Pathophysiology ## Pathogenesis Pineoblastoma originates from the neuroectodermal cells. It is the least differentiated pineal gland tumors, with pineocytoma and pineal parenchymal tumour with intermediate differentiation representing better differentiated tumors along the same spectrum.[1] ## Associated Conditions - Pineoblastoma may occur in patients with hereditary uni- or bilateral retinoblastoma. - When retinoblastoma patients present with pineoblastoma, this is characterized as "trilateral retinoblastoma".[2] ## Gross Pathology On gross pathology, pineoblastoma is characterized by solid, large poorly defined masses.[3] ## Microscopic Pathology On microscopic histopathological analysis, pineoblastoma is characterized by:[1][5][6] - Hypercellular appearance - Tightly packed small round blue cells (high nuclear to cytoplasmic ratio) - Oval and angulated hyperchromatic nuclei with atypia - Mitoses - Homer-Wright & Flexner-Winterstein rosettes - Fleurettes ## Immunohistochemistry Pineoblastoma is demonstrated by positivity to tumor markers such as:[6][7] - GFAP - Neurofilament - Synaptophysin - MIB-1 - Ki-67 # Differentiating Pineoblastoma from other Diseases Pineoblastoma must be differentiated from:[8][9] - Pineocytoma - Pineal parenchymal tumor with intermediate differentiation - Papillary tumor of the pineal region - Pineal germinoma - Pineal embryonal carcinoma - Pineal choriocarcinoma - Pineal yolk sac carcinoma (endodermal sinus tumor) - Pineal teratoma - Pineal cyst - Astrocytoma of the pineal gland - Meningioma near pineal gland - Pineal metastasis - Cavernoma in pineal region - Aneurysm in pineal region # Epidemiology and Demographics ## Prevalence - Pineoblastoma constitutes approximately 0.1% of the intracranial neoplasms.[10] - Pineoblastoma together with germ cell tumors are the most common pineal tumors in children.[11] ## Age Pineoblastoma is a disease that tends to affect children and young adults.[12] ## Gender Pineoblastoma affects men and women equally.[13] # Natural History, Complications and Prognosis ## Natural History - Pineoblastoma is the most agressive pineal parenchymal tumor. - If left untreated, patients with pineoblastoma may progress to develop seizures, obstructive hydrocephalus, local recurrence, and cerebrospinal fluid (CSF) metastasis.[14] ## Complications Common complications of pineoblastoma include:[14][15] - Obstructive hydrocephalus - Local recurrence - CSF metastasis ## Prognosis Prognosis is generally poor, and the 5-year survival rate of patients with pineoblastoma is approximately 58%.[16] # History and Symptoms ## History The clinical presentation of pineoblastoma is mainly from the obstructive hydrocephalus secondary to compression of the tectum of the midbrain and obstruction of the aqueduct.[14] ## Symptoms - Symptoms of pineoblastoma include:[10][14] - Headaches - Nausea - Vomiting - Seizures - Tinnitus - Hearing loss - Sleepiness - Irritability - Personality changes - Double vision - Trouble coordinating motor movements - Difficulty walking - Slowed growth # Physical Examination - Compression of the superior colliculi can lead to a characteristic upward gaze palsy, known as Parinaud syndrome. - Common physical examination findings of pineoblastoma include:[10][14] ## HEENT - Bulging soft spots (fontanelles) - Eyes that are constantly looking down (sunsetting sign) - Upward gaze palsy - Pupillary light-near dissociation (pupils respond to near stimuli but not light) - Convergence-retraction nystagmus - Papilledema ## Neurological - Mental retardation - Muscle spasms - Loss of bladder control - Ataxia - Cranioneuropathies - VIth nerve palsy ## Laboratory Diagnosis There are no specific laboratory findings for pineocytoma. However, the following findings are of significant - Both serum and CSF should be assayed for alpha-fetoprotein and beta human chorionic gonadotropin (beta-hCG) to help diagnose a germ cell tumor. - Immunohistochemistry may be of value in detecting these markers or placental alkaline phosphatase. ## CT Scan - Head CT scan may be diagnostic of pineoblastoma. - Findings on CT scan suggestive of pineoblastoma include a mass with a solid component that tends to be slightly hyperdense compared to adjacent brain due to high cellularity. Calcification is present that is peripherally disperse or "exploded", similar to pineocytoma.[17] ## MRI - Brain MRI may be diagnostic of pineoblastoma. - Features on MRI suggestive of pineoblastoma include:[18] ## Other Imaging Findings Other imaging studies for pineoblastoma include magnetic resonance spectroscopy (MR spectroscopy), which demonstrates:[19] - Elevation of the choline and lipid lactate peaks - Depression of the neural markers (N-acetyl aspartate (NAA) and creatine (Cr) - Prominent glutamate and taurine peaks at 3.4 ppm with shot TE signal voxel MR spectroscopy ## Other Diagnostic Studies Stereotactic biopsy - A direct, visually guided biopsy of the pineal gland mass with open or neuroendoscopic surgery has been preferred due to concerns about injury to the deep cerebral veins. - An open procedure also allows CSF to be obtained for Tumor marker studies Permits direct visualization of the third ventricle for staging purposes Sllows a third ventriculostomy to be performed for CSF diversion if needed. - Tumor marker studies - Permits direct visualization of the third ventricle for staging purposes - Sllows a third ventriculostomy to be performed for CSF diversion if needed. - The diagnostic yield of stereotactic biopsy ranges from 94 to 100 percent. - If the biopsy is nondiagnostic, equivocal, or suggests a benign tumor such as mature teratoma or meningioma, surgery is recommended to establish a definitive diagnosis or to identify focal areas of malignant disease # Treatment - The predominant therapy for pineoblastoma is surgical resection. Adjunctive chemotherapy and radiation may be required.[11][16] - The main goal of open surgery on pineoblastoma is the complete tumor removal with minimal morbidity, whenever possible. However, even if gross total excision cannot be achieved, establishment of an accurate diagnosis, maximal cytoreduction, and restoration of the CSF pathway may be achieved. - Gross total resection has been associated with improved survival, similar to treatment with craniospinal irradiation and multi-agent chemotherapy.[11] - Children under the age of 36 months with pineoblastoma should be treated with multi-agent chemotherapy for 12 to 24 months with the goal of delaying radiation past the age of 36 months. Craniospinal irradiation before this age of 3 has been associated with significant cognitive and neuroendocrine sequelae. - Subtotal tumor resection in children under 5 years of age is associated with markedly worsened patient survival. According to the Children's Oncology Group trials, these tumors require craniospinal irradiation (with local tumor doses of at least 50 Gy) and adjuvant chemotherapy. When carboplatin and vincristine were administered during craniospinal irradiation followed by 6 months of non-intensive non-cisplatin chemotherapy, it significantly reduces tumor progression. - Patients with pineoblastoma will develop hydrocephalus in majority of the cases and they will require CSF diversion. Ventriculo-peritoneal (V-P) shunt placement is associated with low morbidity and mortality rate. However, shunt malfunction in this population is as high as 20%. In addition, tumor metastasis through a CSF shunt has been reported. Endoscopic third ventriculostomy (ETVC) is an alternative option, which also permits a biopsy of the tumor in the same procedure. Ahn et al. reported that the biopsy samples, obtained in the lateral ventricle or pineal region, were more favorable towards a successful diagnosis than those in the thalamus or tectal region. Neuroendoscopic biopsy procedures have been proven safe with low complication rates.[11]	https://www.wikidoc.org/index.php/PB
b7e939c728d45eda99937e11a664b7506a73d994	wikidoc	PM20D1 (gene)	PM20D1 (gene) Peptidase M20 domain containing 1 is a circulating enzyme of the mammalian M20 peptidase family. It is encoded by the PM20D1 gene. PM20D1 catalyzes the synthesis of N-acyl amino acids from free fatty acids and free amino acids as well as the reverse hydrolytic reaction. PM20D1, along with FAAH, constitute the two dominant mammalian enzymes that physiologically regulate the fatty acid amide family of signaling metabolites. In mice, PM20D1 is highly expressed in liver, kidney, small intestine, and brown fat. Its expression in adipose tissues is increased under hypermetabolic conditions. Genetic elevation of circulating PM20D1 in mice leads to accumulation of multiple circulating N-acyl amino acid species and a hypermetabolic phenotype. PM20D1-KO mice exhibit a bidirectional dysregulation of a distinct set of circulating N-acyl amino acids and range of phenotypes, including insulin resistance, altered body temperature in cold, and anti-nociceptive behaviors to inflammatory pain. # Clinical significance In humans, the PM20D1 locus has been associated with Alzheimer's disease. Elevation of brain PM20D1 is neuroprotective in rodent models of AD.	PM20D1 (gene) Peptidase M20 domain containing 1 is a circulating enzyme of the mammalian M20 peptidase family. It is encoded by the PM20D1 gene.[1] PM20D1 catalyzes the synthesis of N-acyl amino acids from free fatty acids and free amino acids as well as the reverse hydrolytic reaction.[2] PM20D1, along with FAAH, constitute the two dominant mammalian enzymes that physiologically regulate the fatty acid amide family of signaling metabolites. In mice, PM20D1 is highly expressed in liver, kidney, small intestine, and brown fat. Its expression in adipose tissues is increased under hypermetabolic conditions. Genetic elevation of circulating PM20D1 in mice leads to accumulation of multiple circulating N-acyl amino acid species and a hypermetabolic phenotype.[2] PM20D1-KO mice exhibit a bidirectional dysregulation of a distinct set of circulating N-acyl amino acids and range of phenotypes, including insulin resistance, altered body temperature in cold, and anti-nociceptive behaviors to inflammatory pain.[3] # Clinical significance In humans, the PM20D1 locus has been associated with Alzheimer's disease. Elevation of brain PM20D1 is neuroprotective in rodent models of AD.[4]	https://www.wikidoc.org/index.php/PM20D1_(gene)
2f6369ae3848ef95216e32d7f6aa3ccd7c9931bd	wikidoc	PROLONG Study	PROLONG Study # Official Title D-Dimer Test to Establish Duration of Anticoagulation After a First Idiopathic Episode of Venous Thromboembolism; the Prospective Randomized “Prolong” Study # Objective The optimal duration of oral anticoagulant treatment in patients with idiopathic venous thromboembolism is still uncertain. The present study addresses the possible role of the D-dimer test in assessing the need for continuation of anticoagulation. The study aims at assessing whether D-dimer assay may have a role in guiding the duration of anticoagulation in these patients. # Sponsor St. Orsola Hospital # Timeline The previous information was derived from ClinicalTrials.gov on 09/25/2013 using the identification number NCT00264277. # Study Description The previous information was derived from ClinicalTrials.gov on 09/25/2013 using the identification number NCT00264277. # Eligibility Criteria ## Inclusion Criteria - Age > 18 years - After a first documented idiopathic proximal deep vein thrombosis and/or pulmonary embolism - After at least 3 months of oral anticoagulation - After written informed consent ## Exclusion Criteria - If the Venous thromboembolism occurred: During pregnancy or puerperium After recent (i.e. within three months) fracture or plaster casting of a leg, After immobilization with confinement to bed for three consecutive days After surgery with general anesthesia lasting longer than 30 minutes - During pregnancy or puerperium - After recent (i.e. within three months) fracture or plaster casting of a leg, - After immobilization with confinement to bed for three consecutive days - After surgery with general anesthesia lasting longer than 30 minutes - Patients with: Active cancer Antiphospholipid antibody syndrome Antithrombin deficiency Serious liver disease or renal insufficiency (creatininemia > 2 mg/dL), Other indications for anticoagulation or contraindications for this treatment Limited life expectation - Active cancer - Antiphospholipid antibody syndrome - Antithrombin deficiency - Serious liver disease or renal insufficiency (creatininemia > 2 mg/dL), - Other indications for anticoagulation or contraindications for this treatment - Limited life expectation - Patients who live too far from the clinical center # Outcomes ## Primary Outcomes - Confirmed recurrent proximal deep vein thrombosis and/or pulmonary embolism at 18 months follow up - Confirmed major bleeding events at 18 months follow up ## Secondary Outcomes Not provided # Publications ## Results ## Conclusion	PROLONG Study Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Official Title D-Dimer Test to Establish Duration of Anticoagulation After a First Idiopathic Episode of Venous Thromboembolism; the Prospective Randomized “Prolong” Study # Objective The optimal duration of oral anticoagulant treatment in patients with idiopathic venous thromboembolism is still uncertain. The present study addresses the possible role of the D-dimer test in assessing the need for continuation of anticoagulation. The study aims at assessing whether D-dimer assay may have a role in guiding the duration of anticoagulation in these patients. # Sponsor St. Orsola Hospital # Timeline The previous information was derived from ClinicalTrials.gov on 09/25/2013 using the identification number NCT00264277. # Study Description The previous information was derived from ClinicalTrials.gov on 09/25/2013 using the identification number NCT00264277. # Eligibility Criteria ## Inclusion Criteria - Age > 18 years - After a first documented idiopathic proximal deep vein thrombosis and/or pulmonary embolism - After at least 3 months of oral anticoagulation - After written informed consent ## Exclusion Criteria - If the Venous thromboembolism occurred: During pregnancy or puerperium After recent (i.e. within three months) fracture or plaster casting of a leg, After immobilization with confinement to bed for three consecutive days After surgery with general anesthesia lasting longer than 30 minutes - During pregnancy or puerperium - After recent (i.e. within three months) fracture or plaster casting of a leg, - After immobilization with confinement to bed for three consecutive days - After surgery with general anesthesia lasting longer than 30 minutes - Patients with: Active cancer Antiphospholipid antibody syndrome Antithrombin deficiency Serious liver disease or renal insufficiency (creatininemia > 2 mg/dL), Other indications for anticoagulation or contraindications for this treatment Limited life expectation - Active cancer - Antiphospholipid antibody syndrome - Antithrombin deficiency - Serious liver disease or renal insufficiency (creatininemia > 2 mg/dL), - Other indications for anticoagulation or contraindications for this treatment - Limited life expectation - Patients who live too far from the clinical center # Outcomes ## Primary Outcomes - Confirmed recurrent proximal deep vein thrombosis and/or pulmonary embolism at 18 months follow up - Confirmed major bleeding events at 18 months follow up ## Secondary Outcomes Not provided # Publications ## Results ## Conclusion	https://www.wikidoc.org/index.php/PROLONG_Study
ac625fd7717ecd563b527a0a9232062e01352b6e	wikidoc	Packaging gas	Packaging gas A packaging gas is a gas used to pack sensitive materials in a modified atmosphere. It is usually inert, or of a nature that protects the packaged goods, thus inhibiting reactions such as spoilage. Some may also serve as propellant for aerosols like whipped cream. For packaging food, various gases are approved. Their E numbers are in parenthesis: - argon (E938), used for canned products - helium (E939), used for canned products - nitrogen (E941) - oxygen (E948), used eg. for packaging of vegetables - hydrogen (E949) - carbon dioxide (E290, also propellant) Specific kind of packaging gases are aerosol propellants: - dichlorodifluoromethane known as CFC (E940), rarely used because of the damage that it does to the ozone layer - nitrous oxide (E942), used for aerosol whipped cream canisters (see Nitrous oxide: Aerosol propellant) - butane (E943a) - isobutane (E943b) - propane (E944)	Packaging gas A packaging gas is a gas used to pack sensitive materials in a modified atmosphere. It is usually inert, or of a nature that protects the packaged goods, thus inhibiting reactions such as spoilage. Some may also serve as propellant for aerosols like whipped cream. For packaging food, various gases are approved. Their E numbers are in parenthesis: - argon (E938), used for canned products - helium (E939), used for canned products - nitrogen (E941) - oxygen (E948), used eg. for packaging of vegetables - hydrogen (E949) - carbon dioxide (E290, also propellant) Specific kind of packaging gases are aerosol propellants: - dichlorodifluoromethane known as CFC (E940), rarely used because of the damage that it does to the ozone layer[1] - nitrous oxide (E942), used for aerosol whipped cream canisters (see Nitrous oxide: Aerosol propellant) - butane (E943a) - isobutane (E943b) - propane (E944) Template:E number infobox 930-949	https://www.wikidoc.org/index.php/Packaging_gas
a7f5f1ba6478ab75c75393e80bd10373e2d41940	wikidoc	Padilla Miami	Padilla Miami Padilla Miami 8 &11 is a brand of hand-made premium cigar owned by Padilla Cigar Company. # History and Background The blend for this brand was created by José "Pepin" Garcia and the cigars are manufactured at the El Rey de los Habanos factory in the Little Havana section of Miami, Florida. The name refers to the location of the factory, which is near the corner of 8th Street & 11th Avenue in Miami. # Description A full-strength cigar, the Padilla Miami has a wrapper of Nicaraguan grown Cuban-seed Corojo surrounding a filler blend of Nicaraguan Criollo and Corojo and a binder of Nicaraguan Criollo. The band is black with gold lettering, with a large monogram "P" surrounded by a gold border in the center, with "Miami" in gold on a red background below the monogram. They are packed uncelloed in boxes of 20. # Models/Vitolas ## Honors/Awards The Padilla Miami 8 & 11 Robusto was named the thirteenth top-rated cigar of 2005 by Cigar Aficionado ("...a full-bodied masterpiece"). # Notes 1. One size is an exclusive to a single retailer, and is not given above (the Belicoso Fino, 5 x 52). 2. The Salomons are rolled exclusively by Don Pepin himself.	Padilla Miami Padilla Miami 8 &11 is a brand of hand-made premium cigar owned by Padilla Cigar Company. # History and Background The blend for this brand was created by José "Pepin" Garcia and the cigars are manufactured at the El Rey de los Habanos factory in the Little Havana section of Miami, Florida. The name refers to the location of the factory, which is near the corner of 8th Street & 11th Avenue in Miami.[1] # Description A full-strength cigar, the Padilla Miami has a wrapper of Nicaraguan grown Cuban-seed Corojo surrounding a filler blend of Nicaraguan Criollo and Corojo and a binder of Nicaraguan Criollo. The band is black with gold lettering, with a large monogram "P" surrounded by a gold border in the center, with "Miami" in gold on a red background below the monogram. They are packed uncelloed in boxes of 20. # Models/Vitolas ## Honors/Awards The Padilla Miami 8 & 11 Robusto was named the thirteenth top-rated cigar of 2005 by Cigar Aficionado ("...a full-bodied masterpiece").[1] # Notes 1. One size is an exclusive to a single retailer, and is not given above (the Belicoso Fino, 5 x 52). 2. The Salomons are rolled exclusively by Don Pepin himself.[2]	https://www.wikidoc.org/index.php/Padilla_Miami
97356b9f4b865c145d45951189148be7cd8ab14b	wikidoc	Paget Disease	Paget Disease Synonyms and keywords: PD; commonly known as Paget's disease or historically, osteitis deformans # Overview # Historical Perspective # Classification # Pathophysiology # Causes # Differentiating Paget Disease from other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications and Prognosis # Diagnosis Diagnostic Criteria \| History and Symptoms \| Physical Examination \| Laboratory Findings \| X Ray \| CT \| MRI \| Other Imaging Findings \| Other Diagnostic Studies # Treatment Medical Therapy \| Surgery \| Primary Prevention \| Secondary Prevention \| Cost-Effectiveness of Therapy \| Future or Investigational Therapies \| Stem cell # Case Studies # Related Chapters - Back pain - Chronic pain - Osteoimmunology bg:Артроза ca:Artrosi cs:Osteoartróza de:Arthrose he:דלקת מפרקים ניוונית lt:Osteoartritas nl:Artrose no:Artrose sv:Artros	Paget Disease For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou [2]; Synonyms and keywords: PD; commonly known as Paget's disease or historically, osteitis deformans # Overview # Historical Perspective # Classification # Pathophysiology # Causes # Differentiating Paget Disease from other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications and Prognosis # Diagnosis Diagnostic Criteria \| History and Symptoms \| Physical Examination \| Laboratory Findings \| X Ray \| CT \| MRI \| Other Imaging Findings \| Other Diagnostic Studies # Treatment Medical Therapy \| Surgery \| Primary Prevention \| Secondary Prevention \| Cost-Effectiveness of Therapy \| Future or Investigational Therapies \| Stem cell # Case Studies # Related Chapters - Back pain - Chronic pain - Osteoimmunology Template:Diseases of the musculoskeletal system and connective tissue bg:Артроза ca:Artrosi cs:Osteoartróza de:Arthrose he:דלקת מפרקים ניוונית lt:Osteoartritas nl:Artrose no:Artrose sv:Artros Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Paget_Disease
66c2cf55a0f43096135b81af2fdccc0c208ce3cb	wikidoc	Pain	Pain overview # Overview Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm. Individuals experience pain by various daily hurts and aches, and occasionally through more serious injuries or illnesses. For scientific and clinical purposes, pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Pain is highly subjective to the individual experiencing it. A definition that is widely used in nursing was first given as early as 1968 by Margo McCaffery: "'Pain is whatever the experiencing person says it is, existing whenever he says it does". Pain of any type is the most frequent reason for physician consultation in the United States, prompting half of all Americans to seek medical care annually. It is a major symptom in many medical conditions, significantly interfering with a person's quality of life and general functioning. Diagnosis is based on characterizing pain in various ways, according to duration, intensity, type (dull, burning or stabbing), source, or location in body. Usually pain stops without treatment or responds to simple measures such as resting or taking an analgesic, and it is then called ‘acute’ pain. But it may also become intractable and develop into a condition called chronic pain, in which pain is no longer considered a symptom but an illness by itself. The study of pain has in recent years attracted many different fields such as pharmacology, neurobiology, nursing sciences, dentistry, physiotherapy, and psychology. Pain medicine is a separate subspecialty figuring under some medical specialties like anesthesiology, physiatry, neurology, psychiatry. Pain is part of the body's defense system, triggering a reflex reaction to retract from a painful stimulus, and helps adjust behaviour to increase avoidance of that particular harmful situation in the future. Given its significance, physical pain is also linked to various cultural, religious, philosophical, or social issues. # Historical Perspective "Pain (n.) 1297, "punishment," especially for a crime; also (c.1300) "condition one feels when hurt, opposite of pleasure," from O.Fr. peine, from L. poena "punishment, penalty" (in L.L. also "torment, hardship, suffering"), from Gk. poine "punishment," from PIE *kwei- "to pay, atone, compensate" (...)." # Pathophysiology Stimulation of a nociceptor, due to a chemical, thermal, or mechanical event that has the potential to damage body tissue, may cause nociceptivepain. # Diagnosis ## X Ray X-rays produce pictures of the body's structures, such as bones and joints ## MRI Imaging, especially magnetic resonance imaging or MRI, provides physicians with pictures of the body's structures and tissues. MRI uses magnetic fields and radio waves to differentiate between healthy and diseased tissue. ## Other Diagnostic Studies Electrodiagnostic procedures include electromyography (EMG), nerve conduction studies, and evoked potential (EP) studies. Information from EMG can help physicians tell precisely which muscles or nerves are affected by weakness or pain. Thin needles are inserted in muscles and a physician can see or listen to electrical signals displayed on an EMG machine. With nerve conduction studies the doctor uses two sets of electrodes (similar to those used during an electrocardiogram) that are placed on the skin over the muscles. The first set gives the patient a mild shock that stimulates the nerve that runs to that muscle. The second set of electrodes is used to make a recording of the nerve's electrical signals, and from this information the doctor can determine if there is nerve damage. EP tests also involve two sets of electrodes-one set for stimulating a nerve (these electrodes are attached to a limb) and another set on the scalp for recording the speed of nerve signal transmission to the brain.	Pain overview Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Pain, in the sense of physical pain,[1] is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm. Individuals experience pain by various daily hurts and aches, and occasionally through more serious injuries or illnesses. For scientific and clinical purposes, pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage".[2][3] Pain is highly subjective to the individual experiencing it. A definition that is widely used in nursing was first given as early as 1968 by Margo McCaffery: "'Pain is whatever the experiencing person says it is, existing whenever he says it does".[4][5] Pain of any type is the most frequent reason for physician consultation in the United States, prompting half of all Americans to seek medical care annually.[6] It is a major symptom in many medical conditions, significantly interfering with a person's quality of life and general functioning. Diagnosis is based on characterizing pain in various ways, according to duration, intensity, type (dull, burning or stabbing), source, or location in body. Usually pain stops without treatment or responds to simple measures such as resting or taking an analgesic, and it is then called ‘acute’ pain. But it may also become intractable and develop into a condition called chronic pain, in which pain is no longer considered a symptom but an illness by itself. The study of pain has in recent years attracted many different fields such as pharmacology, neurobiology, nursing sciences, dentistry, physiotherapy, and psychology. Pain medicine is a separate subspecialty[7] figuring under some medical specialties like anesthesiology, physiatry, neurology, psychiatry. Pain is part of the body's defense system, triggering a reflex reaction to retract from a painful stimulus, and helps adjust behaviour to increase avoidance of that particular harmful situation in the future. Given its significance, physical pain is also linked to various cultural, religious, philosophical, or social issues. # Historical Perspective "Pain (n.) 1297, "punishment," especially for a crime; also (c.1300) "condition one feels when hurt, opposite of pleasure," from O.Fr. peine, from L. poena "punishment, penalty" (in L.L. also "torment, hardship, suffering"), from Gk. poine "punishment," from PIE *kwei- "to pay, atone, compensate" (...)." [8] # Pathophysiology Stimulation of a nociceptor, due to a chemical, thermal, or mechanical event that has the potential to damage body tissue, may cause nociceptivepain. # Diagnosis ## X Ray X-rays produce pictures of the body's structures, such as bones and joints ## MRI Imaging, especially magnetic resonance imaging or MRI, provides physicians with pictures of the body's structures and tissues. MRI uses magnetic fields and radio waves to differentiate between healthy and diseased tissue. ## Other Diagnostic Studies Electrodiagnostic procedures include electromyography (EMG), nerve conduction studies, and evoked potential (EP) studies. Information from EMG can help physicians tell precisely which muscles or nerves are affected by weakness or pain. Thin needles are inserted in muscles and a physician can see or listen to electrical signals displayed on an EMG machine. With nerve conduction studies the doctor uses two sets of electrodes (similar to those used during an electrocardiogram) that are placed on the skin over the muscles. The first set gives the patient a mild shock that stimulates the nerve that runs to that muscle. The second set of electrodes is used to make a recording of the nerve's electrical signals, and from this information the doctor can determine if there is nerve damage. EP tests also involve two sets of electrodes-one set for stimulating a nerve (these electrodes are attached to a limb) and another set on the scalp for recording the speed of nerve signal transmission to the brain.	https://www.wikidoc.org/index.php/Pain_overview
18cf9e664873f67c4850810ec785ecd462c0aeda	wikidoc	Pants Pankuro	Pants Pankuro # Overview "Pants Pankuro" (Japanese: パンツぱんくろう) is the name of a series of animated shorts (each just over a minute in length) that air on Japanese public television. The series is geared to toddlers and young children, and most episodes focus on the issues involved with toilet training. It features a number of anthropomorphic characters, including talking toilets and washing machines, who instruct children about how to use the restroom and what to do in case of an accident. # Characters - Pants Pankuro, the protagonist, is about three years old. He has just started to wear underpants and use the toilet. - Komingo is Pankuro's little sister. She is not yet toilet trained. - Koricchi is a boy the same age as Pankuro; the two are intensely competitive. - Koin is a girl about the same age as Pankuro, who likes to spin and dance. - Toire-sama is Pankuro's friendly household toilet. Pankuro usually treats Toire-sama with great respect, as though he were an older relative. - Kamiko-san is the toilet roll holder. - Sentako Hacchan is Pankuro's eight-legged washing machine, who is very eager to do the laundry. (The name is a combination of "sentaku," which means laundry, and "tako," which means octopus.) - Koricchi's family also has an old-fashioned squat toilet (name unknown).	Pants Pankuro # Overview "Pants Pankuro" (Japanese: パンツぱんくろう) is the name of a series of animated shorts (each just over a minute in length) that air on Japanese public television. The series is geared to toddlers and young children, and most episodes focus on the issues involved with toilet training. It features a number of anthropomorphic characters, including talking toilets and washing machines, who instruct children about how to use the restroom and what to do in case of an accident. # Characters - Pants Pankuro, the protagonist, is about three years old. He has just started to wear underpants and use the toilet. - Komingo is Pankuro's little sister. She is not yet toilet trained. - Koricchi is a boy the same age as Pankuro; the two are intensely competitive. - Koin is a girl about the same age as Pankuro, who likes to spin and dance. - Toire-sama is Pankuro's friendly household toilet. Pankuro usually treats Toire-sama with great respect, as though he were an older relative. - Kamiko-san is the toilet roll holder. - Sentako Hacchan is Pankuro's eight-legged washing machine, who is very eager to do the laundry. (The name is a combination of "sentaku," which means laundry, and "tako," which means octopus.) - Koricchi's family also has an old-fashioned squat toilet (name unknown). # External links - Official "Pants Pankuro" site at NHK - "Pants Pankuro" shorts on YouTube Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Pants_Pankuro
5572d5b4d80bb1e57119c73de2e5908011f5e646	wikidoc	Paramagnetism	Paramagnetism # Overview Paramagnetism is a form of magnetism which occurs only in the presence of an externally applied magnetic field. Paramagnetic materials are attracted to magnetic fields, hence have a relative magnetic permeability greater than one (or, equivalently, a positive magnetic susceptibility). The force of attraction generated by the applied field is linear in the field strength and rather weak. It typically requires a sensitive analytical balance to detect the effect. Unlike ferromagnets paramagnets do not retain any magnetization in the absence of an externally applied magnetic field, because thermal motion causes the spins to become randomly oriented without it. Thus the total magnetization will drop to zero when the applied field is removed. Even in the presence of the field there is only a small induced magnetization because only a small fraction of the spins will be oriented by the field. This fraction is proportional to the field strength and this explains the linear dependency. The attraction experienced by ferromagnets is non-linear and much stronger, so that it is easily observed on the door of one's fridge. # Curie's law For low levels of magnetisation, the magnetisation of paramagnets follows Curie's law to good approximation: where This law indicates that the susceptibility χ of paramagnetic materials is inversely proportional to their temperature. Curie's law is only valid under conditions of low magnetisation, since it does not consider the saturation of magnetisation that occurs when the atomic dipoles are all aligned in parallel. After everything is aligned, increasing the external field will not increase the total magnetisation since there can be no further alignment. However such saturation typically requires very strong magnetic fields. # Relation to electron spins Constituent atoms or molecules of paramagnetic materials have permanent magnetic moments (dipoles), even in the absence of an applied field. This generally occurs due to the presence of unpaired electrons in the atomic/molecular electron orbitals. In pure paramagnetism, the dipoles do not interact with one another and are randomly oriented in the absence of an external field due to thermal agitation, resulting in zero net magnetic moment. When a magnetic field is applied, the dipoles will tend to align with the applied field, resulting in a net magnetic moment in the direction of the applied field. In the classical description, this alignment can be understood to occur due to a torque being provided on the magnetic moments by an applied field, which tries to align the dipoles parallel to the applied field. However, the truer origins of the alignment can only be understood via the quantum-mechanical properties of spin and angular momentum. If there is sufficient energy exchange between neighbouring dipoles they will interact, and may spontaneously align or anti-align and form magnetic domains, resulting in ferromagnetism (permanent magnets) or antiferromagnetism, respectively. Paramagnetic behavior can also be observed in ferromagnetic materials that are above their Curie temperature, and in antiferromagnets above their Néel temperature. At these temperatures the available thermal energy simply overcomes the interaction energy between the spins. In general paramagnetic effects are quite small: the magnetic susceptibility is of the order of 10−3 to 10−5 for most paramagnets, but may be as high as 10-1 for synthetic paramagnets such as ferrofluids. ## Delocalization In many metallic materials the electrons are itinerant, i.e. they travel through the solid more or less as an electron gas. This is the result of very strong interactions (overlap) between the wave functions of neighboring atoms in the extended lattice structure. The wave functions of the valence electrons thus form a band with equal numbers of spins up and down. When exposed to an external field only those electrons close to the Fermi-level will respond and a small surplus of one type of spins will result. This effect is a weak form of paramagnetism known as Pauli-paramagnetism. The effect always competes with a diamagentic response of opposite sign due to all the core electrons of the atoms. Stronger forms of magnetism usually require localized rather than itinerant electrons. However in some cases a bandstructure can result in which there are two delocalized subbands with states of opposite spins that have different energies. If one subband is preferentially filled over the other one can have itinerant ferromagnetic order. This usually only happens in relatively narrow (d-)bands that are poorly delocalized. ### s and p electrons In general one can say that strong delocalization in a solid due to large overlap with neighboring wave functions tends to lead to pairing of spins (quenching) and thus weak magnetism. This is why s- and p-type metals are typically either Pauli-paramagnetic or as in the case gold even diamagnetic. In the latter case the diamagnetic contribution from the closed shell inner electrons simply wins from the weak paramagnetic term of the almost free electrons. ### d and f electrons Stronger magnetic effects are typically only observed when d or f-electrons are involved. Particularly the latter are usually strongly localized. Moreover the size of the magnetic moment on a lanthanide atom can be quite large as it can carry up to 7 unpaired electrons. This is one reason why superstrong magnets are typically based on lanthanide elements like Nd or Sm. ### Molecular localization Of course the above picture is a generalization as it pertains to materials with an extended lattice rather than a molecular structure. Molecular structure can also lead to localization of electrons. Although there are usually energetic reasons why a molecular structure results such that it does not exhibit partly filled orbitals (i.e. unpaired spins), some non-closed shell moieties do occur in nature. Molecular oxygen is a good example. Even in the frozen solid it contains di-radical molecules resulting in paramagnetic behavior. The unpaired spins reside in orbitals derived from oxygen p wave functions, but the overlap is limited to the one neighbor in the O2 molecules. The distances to other oxygen atoms in the lattice remain too large to lead to delocalisation and the magnetic moments remain unpaired. # Examples of paramagnets It is not easy to identify which materials should be called 'paramagnets', because the term is often used for rather different systems. In principle any system that contains atoms, ions or molecules with unpaired spins can be called a paramagnet, but the interactions between them do need consideration. ## Systems with minimal interactions The narrowest definition would be: a system with unpaired spins that do not interact with each other. In this narrowest sense, the only pure paramagnet is a dilute gas of hydrogen atoms. Each atom has one non-interacting unpaired electron. Of course, the latter could be said about a gas of lithium atoms but these already possess two paired core electrons that produce a diamagnetic response of opposite sign. Strictly speaking Li is a mixed system therefore, although admittedly the diamagnetic component is weak and often neglected. In the case of heavier elements the diamagnetic contribution becomes more important and in the case of metallic gold it dominates the properties. However, even the element hydrogen is usually not called a 'paramagnet' because at lower temperatures the monatomic gas is not stable. Two atoms will combine to form molecular H2 and in that interaction the magnetic moments are lost (quenched), because the spins will pair. As a substance hydrogen is therefore usually considered a diamagnet. This holds true for many elements. Although the electronic configuration of the individual atoms (and ions) of most elements contain unpaired spins, it is not correct to call these elements 'paramagnets' because at lower temperatures quenching is the rule rather than the exception. As pointed out above the quenching tendency is weakest for f-electrons. Thus, consensed phase paramagnets are only possible if the interactions of the spins that lead either to quenching or to ordering are somehow kept at bay. There are two classes of materials for which this holds: - Molecular materials with a (isolated) paramagnetic center. Good examples are organometallic compounds of d- or f-metals or proteins with such centers, e.g. myoglobin. In such materials the organic part of the molecule acts as an envelope shielding the spins from their neighbors. Small molecules can be stable in radical form, oxygen O2 is a good example. Such systems are quite rare because they tend to be rather reactive. - Good examples are organometallic compounds of d- or f-metals or proteins with such centers, e.g. myoglobin. In such materials the organic part of the molecule acts as an envelope shielding the spins from their neighbors. - Small molecules can be stable in radical form, oxygen O2 is a good example. Such systems are quite rare because they tend to be rather reactive. - Dilute systems. Dissolving a paramagnetic species in a diamagnetic lattice at small concentrations, e.g. Nd3+ in CaCl2 will separate the neodymium ions at large enough distances that they do not interact. Such systems are of prime importance for what can be considered the most sensitive method to study paramagnetic systems: EPR. - Dissolving a paramagnetic species in a diamagnetic lattice at small concentrations, e.g. Nd3+ in CaCl2 will separate the neodymium ions at large enough distances that they do not interact. Such systems are of prime importance for what can be considered the most sensitive method to study paramagnetic systems: EPR. ## Systems with interactions As stated above many materials that contain d- or f-elements do retain unquenched spins. Salts of such elements often show paramagnetic behavior but at low enough temperatures the magnetic moments may order. It is not uncommon to call such materials 'paramagnets', when referring to their paramagnetic behavior above their Curie or Néel-points, particularly if such temperatures are very low or have never been properly measured. Even for iron it is not uncommon to say that iron becomes a paramagnet above its relatively high Curie-point. In that case the Curie-point is seen as a phase transition between a ferromagnet and a 'paramagnet'. The word paramagnet now merely refers to the linear response of the system to an applied field, the temperature dependence of which requires an amended version of Curie's law, known as the Curie-Weiss law. \boldsymbol{M} = C \frac{\boldsymbol{B}}{T- \theta} . This amended law includes a term θ that describes the exchange interaction that is present albeit overcome by thermal motion. The sign of θ depends on whether ferro- or antiferromagnetic interactions dominate and it is seldom exactly zero, except in the dilute, isolated cases mentioned above. Obviously, the paramagnetic Curie-Weiss description above TN or TC is a rather different interpretation of the word 'paramagnet' as it does not imply the absence of interactions, but rather that the magnetic structure is random in the absence of an external field at these sufficiently high temperatures. Even if θ is close to zero this does not mean that there are no interactions, just that the aligning ferro- and the anti-aligning antiferromagnetic ones cancel. An additional complication is that the interactions are often different in different directions of the crystalline lattice (anisotropy), leading to complicated magnetic structures once ordered. Randomness of the structure also applies to the many metals that show a net paramagnetic response over a broad temperature range. They do not follow a Curie type law as function of temperature however, often they are more or less temperature independent. This type of behavior is of an itinerant nature and better called Pauli-paramagnetism, but it is not unusual to see e.g. the metal Aluminium called a 'paramagnet', even though interactions are strong enough to give this element very good electrical conductivity. ## Superparamagnets There are materials that show induced magnetic behavior that follows a Curie type law but with exceptionally large values for the Curie constants. These materials are known as superparamagnets. They are characterized by a strong ferro- or ferrimagnetic type of coupling into domains of a limited size that behave independently from one another. The bulk properties of such a system resembles that of a paramagnet, but on a microsopic level they are ordered. The materials do show an ordering temperature above which the behavior reverts to ordinary paramagnetism (with interaction). Ferrofluids are a good example, but the phenomenon can also occur inside solids, e.g. when dilute paramagnetic centers are introduced in a strong itinerant medium of ferromagnetic coupling such as when Fe is substituted in TlCu2Se2 or the alloy AuFe. Such systems contain ferromagnetically coupled clusters that freeze out at lower temperatures. They are also called mictomagnets	Paramagnetism # Overview Paramagnetism is a form of magnetism which occurs only in the presence of an externally applied magnetic field. Paramagnetic materials are attracted to magnetic fields, hence have a relative magnetic permeability greater than one (or, equivalently, a positive magnetic susceptibility). The force of attraction generated by the applied field is linear in the field strength and rather weak. It typically requires a sensitive analytical balance to detect the effect. Unlike ferromagnets paramagnets do not retain any magnetization in the absence of an externally applied magnetic field, because thermal motion causes the spins to become randomly oriented without it. Thus the total magnetization will drop to zero when the applied field is removed. Even in the presence of the field there is only a small induced magnetization because only a small fraction of the spins will be oriented by the field. This fraction is proportional to the field strength and this explains the linear dependency. The attraction experienced by ferromagnets is non-linear and much stronger, so that it is easily observed on the door of one's fridge. # Curie's law For low levels of magnetisation, the magnetisation of paramagnets follows Curie's law to good approximation: where This law indicates that the susceptibility χ of paramagnetic materials is inversely proportional to their temperature. Curie's law is only valid under conditions of low magnetisation, since it does not consider the saturation of magnetisation that occurs when the atomic dipoles are all aligned in parallel. After everything is aligned, increasing the external field will not increase the total magnetisation since there can be no further alignment. However such saturation typically requires very strong magnetic fields. # Relation to electron spins Constituent atoms or molecules of paramagnetic materials have permanent magnetic moments (dipoles), even in the absence of an applied field. This generally occurs due to the presence of unpaired electrons in the atomic/molecular electron orbitals. In pure paramagnetism, the dipoles do not interact with one another and are randomly oriented in the absence of an external field due to thermal agitation, resulting in zero net magnetic moment. When a magnetic field is applied, the dipoles will tend to align with the applied field, resulting in a net magnetic moment in the direction of the applied field. In the classical description, this alignment can be understood to occur due to a torque being provided on the magnetic moments by an applied field, which tries to align the dipoles parallel to the applied field. However, the truer origins of the alignment can only be understood via the quantum-mechanical properties of spin and angular momentum. If there is sufficient energy exchange between neighbouring dipoles they will interact, and may spontaneously align or anti-align and form magnetic domains, resulting in ferromagnetism (permanent magnets) or antiferromagnetism, respectively. Paramagnetic behavior can also be observed in ferromagnetic materials that are above their Curie temperature, and in antiferromagnets above their Néel temperature. At these temperatures the available thermal energy simply overcomes the interaction energy between the spins. In general paramagnetic effects are quite small: the magnetic susceptibility is of the order of 10−3 to 10−5 for most paramagnets, but may be as high as 10-1 for synthetic paramagnets such as ferrofluids. ## Delocalization In many metallic materials the electrons are itinerant, i.e. they travel through the solid more or less as an electron gas. This is the result of very strong interactions (overlap) between the wave functions of neighboring atoms in the extended lattice structure. The wave functions of the valence electrons thus form a band with equal numbers of spins up and down. When exposed to an external field only those electrons close to the Fermi-level will respond and a small surplus of one type of spins will result. This effect is a weak form of paramagnetism known as Pauli-paramagnetism. The effect always competes with a diamagentic response of opposite sign due to all the core electrons of the atoms. Stronger forms of magnetism usually require localized rather than itinerant electrons. However in some cases a bandstructure can result in which there are two delocalized subbands with states of opposite spins that have different energies. If one subband is preferentially filled over the other one can have itinerant ferromagnetic order. This usually only happens in relatively narrow (d-)bands that are poorly delocalized. ### s and p electrons In general one can say that strong delocalization in a solid due to large overlap with neighboring wave functions tends to lead to pairing of spins (quenching) and thus weak magnetism. This is why s- and p-type metals are typically either Pauli-paramagnetic or as in the case gold even diamagnetic. In the latter case the diamagnetic contribution from the closed shell inner electrons simply wins from the weak paramagnetic term of the almost free electrons. ### d and f electrons Stronger magnetic effects are typically only observed when d or f-electrons are involved. Particularly the latter are usually strongly localized. Moreover the size of the magnetic moment on a lanthanide atom can be quite large as it can carry up to 7 unpaired electrons. This is one reason why superstrong magnets are typically based on lanthanide elements like Nd or Sm. ### Molecular localization Of course the above picture is a generalization as it pertains to materials with an extended lattice rather than a molecular structure. Molecular structure can also lead to localization of electrons. Although there are usually energetic reasons why a molecular structure results such that it does not exhibit partly filled orbitals (i.e. unpaired spins), some non-closed shell moieties do occur in nature. Molecular oxygen is a good example. Even in the frozen solid it contains di-radical molecules resulting in paramagnetic behavior. The unpaired spins reside in orbitals derived from oxygen p wave functions, but the overlap is limited to the one neighbor in the O2 molecules. The distances to other oxygen atoms in the lattice remain too large to lead to delocalisation and the magnetic moments remain unpaired. # Examples of paramagnets It is not easy to identify which materials should be called 'paramagnets', because the term is often used for rather different systems. In principle any system that contains atoms, ions or molecules with unpaired spins can be called a paramagnet, but the interactions between them do need consideration. ## Systems with minimal interactions The narrowest definition would be: a system with unpaired spins that do not interact with each other. In this narrowest sense, the only pure paramagnet is a dilute gas of hydrogen atoms. Each atom has one non-interacting unpaired electron. Of course, the latter could be said about a gas of lithium atoms but these already possess two paired core electrons that produce a diamagnetic response of opposite sign. Strictly speaking Li is a mixed system therefore, although admittedly the diamagnetic component is weak and often neglected. In the case of heavier elements the diamagnetic contribution becomes more important and in the case of metallic gold it dominates the properties. However, even the element hydrogen is usually not called a 'paramagnet' because at lower temperatures the monatomic gas is not stable. Two atoms will combine to form molecular H2 and in that interaction the magnetic moments are lost (quenched), because the spins will pair. As a substance hydrogen is therefore usually considered a diamagnet. This holds true for many elements. Although the electronic configuration of the individual atoms (and ions) of most elements contain unpaired spins, it is not correct to call these elements 'paramagnets' because at lower temperatures quenching is the rule rather than the exception. As pointed out above the quenching tendency is weakest for f-electrons. Thus, consensed phase paramagnets are only possible if the interactions of the spins that lead either to quenching or to ordering are somehow kept at bay. There are two classes of materials for which this holds: - Molecular materials with a (isolated) paramagnetic center. Good examples are organometallic compounds of d- or f-metals or proteins with such centers, e.g. myoglobin. In such materials the organic part of the molecule acts as an envelope shielding the spins from their neighbors. Small molecules can be stable in radical form, oxygen O2 is a good example. Such systems are quite rare because they tend to be rather reactive. - Good examples are organometallic compounds of d- or f-metals or proteins with such centers, e.g. myoglobin. In such materials the organic part of the molecule acts as an envelope shielding the spins from their neighbors. - Small molecules can be stable in radical form, oxygen O2 is a good example. Such systems are quite rare because they tend to be rather reactive. - Dilute systems. Dissolving a paramagnetic species in a diamagnetic lattice at small concentrations, e.g. Nd3+ in CaCl2 will separate the neodymium ions at large enough distances that they do not interact. Such systems are of prime importance for what can be considered the most sensitive method to study paramagnetic systems: EPR. - Dissolving a paramagnetic species in a diamagnetic lattice at small concentrations, e.g. Nd3+ in CaCl2 will separate the neodymium ions at large enough distances that they do not interact. Such systems are of prime importance for what can be considered the most sensitive method to study paramagnetic systems: EPR. ## Systems with interactions As stated above many materials that contain d- or f-elements do retain unquenched spins. Salts of such elements often show paramagnetic behavior but at low enough temperatures the magnetic moments may order. It is not uncommon to call such materials 'paramagnets', when referring to their paramagnetic behavior above their Curie or Néel-points, particularly if such temperatures are very low or have never been properly measured. Even for iron it is not uncommon to say that iron becomes a paramagnet above its relatively high Curie-point. In that case the Curie-point is seen as a phase transition between a ferromagnet and a 'paramagnet'. The word paramagnet now merely refers to the linear response of the system to an applied field, the temperature dependence of which requires an amended version of Curie's law, known as the Curie-Weiss law. <math> \boldsymbol{M} = C \frac{\boldsymbol{B}}{T- \theta} </math>. This amended law includes a term θ that describes the exchange interaction that is present albeit overcome by thermal motion. The sign of θ depends on whether ferro- or antiferromagnetic interactions dominate and it is seldom exactly zero, except in the dilute, isolated cases mentioned above. Obviously, the paramagnetic Curie-Weiss description above TN or TC is a rather different interpretation of the word 'paramagnet' as it does not imply the absence of interactions, but rather that the magnetic structure is random in the absence of an external field at these sufficiently high temperatures. Even if θ is close to zero this does not mean that there are no interactions, just that the aligning ferro- and the anti-aligning antiferromagnetic ones cancel. An additional complication is that the interactions are often different in different directions of the crystalline lattice (anisotropy), leading to complicated magnetic structures once ordered. Randomness of the structure also applies to the many metals that show a net paramagnetic response over a broad temperature range. They do not follow a Curie type law as function of temperature however, often they are more or less temperature independent. This type of behavior is of an itinerant nature and better called Pauli-paramagnetism, but it is not unusual to see e.g. the metal Aluminium called a 'paramagnet', even though interactions are strong enough to give this element very good electrical conductivity. ## Superparamagnets There are materials that show induced magnetic behavior that follows a Curie type law but with exceptionally large values for the Curie constants. These materials are known as superparamagnets. They are characterized by a strong ferro- or ferrimagnetic type of coupling into domains of a limited size that behave independently from one another. The bulk properties of such a system resembles that of a paramagnet, but on a microsopic level they are ordered. The materials do show an ordering temperature above which the behavior reverts to ordinary paramagnetism (with interaction). Ferrofluids are a good example, but the phenomenon can also occur inside solids, e.g. when dilute paramagnetic centers are introduced in a strong itinerant medium of ferromagnetic coupling such as when Fe is substituted in TlCu2Se2 or the alloy AuFe. Such systems contain ferromagnetically coupled clusters that freeze out at lower temperatures. They are also called mictomagnets	https://www.wikidoc.org/index.php/Paramagnetic
79f09c5ca75211ac1a5a3dfa15f8d54fd60dbe86	wikidoc	Paramyxovirus	Paramyxovirus # Overview Paramyxoviruses are viruses of the Paramyxoviridae family of the Mononegavirales order; they are negative-sense single-stranded RNA viruses responsible for a number of human and animal diseases. ## Genera - Subfamily Paramyxovirinae Genus Avulavirus (type species Newcastle disease virus) Genus Henipavirus (type species Hendravirus; others include Nipahvirus) Genus Morbillivirus (type species Measles virus; others include Rinderpest virus, Canine distemper virus, phocine distemper virus) Genus Respirovirus (type species Sendai virus; others include Human parainfluenza viruses 1 and 3, as well some of the viruses of the common cold) Genus Rubulavirus (type species Mumps virus; others include Simian parainfluenza virus 5, Menangle virus, Tioman virus) Genus TPMV-like viruses (type species Tupaia paramyxovirus) - Genus Avulavirus (type species Newcastle disease virus) - Genus Henipavirus (type species Hendravirus; others include Nipahvirus) - Genus Morbillivirus (type species Measles virus; others include Rinderpest virus, Canine distemper virus, phocine distemper virus) - Genus Respirovirus (type species Sendai virus; others include Human parainfluenza viruses 1 and 3, as well some of the viruses of the common cold) - Genus Rubulavirus (type species Mumps virus; others include Simian parainfluenza virus 5, Menangle virus, Tioman virus) - Genus TPMV-like viruses (type species Tupaia paramyxovirus) - Subfamily Pneumovirinae Genus Pneumovirus (type species Human respiratory syncytial virus, others include Bovine respiratory syncytial virus) Genus Metapneumovirus (type species Avian pneumovirus, Human metapneumovirus) - Genus Pneumovirus (type species Human respiratory syncytial virus, others include Bovine respiratory syncytial virus) - Genus Metapneumovirus (type species Avian pneumovirus, Human metapneumovirus) - Unassigned viruses Fer-de-Lance virus Nariva virus Tupaia paramyxovirus Salem virus J virus Mossman virus Beilong virus - Fer-de-Lance virus - Nariva virus - Tupaia paramyxovirus - Salem virus - J virus - Mossman virus - Beilong virus # Physical structure Virions are enveloped and can be spherical, filamentous or pleomorphic. Fusion proteins and attachment proteins appear as spikes on the virion surface. Matrix proteins inside the envelope stabilise virus structure. The nucleocapsid core is composed of the genomic RNA, nucleocapsid proteins, phosphoproteins and polymerase proteins. # Genome structure The genome consists of a single segment of negative-sense RNA, 15-19 kilobases in length and containing 6-10 genes. Extracistronic (non-coding) regions include: - A 3’ leader sequence, 50 nucleotides in length which acts as a transcriptional promoter. - A 5’ trailer sequence, 50-161 nucleotides long - Intergenomic regions between each gene which are three nucleotides long for morbillivirus, respirovirus and henipavirus, variable length (1-56 nucleotides) for rubulavirus and pneumovirinae. Each gene contains transcription start/stop signals at the beginning and end which are transcribed as part of the gene. Gene sequence within the genome is conserved across the family due to a phenomenon known as transcriptional polarity (see Mononegavirales) in which genes closest to the 3’ end of the genome are transcribed in greater abundance than those towards the 5’ end. This mechanism acts as a form of transcriptional regulation. The gene sequence is: - Nucleocapsid – Phosphoprotein – Matrix – Fusion – Attachment – Large (polymerase) # Proteins - N – the nucleocapsid protein associates with genomic RNA (one molecule per hexamer) and protects the RNA from nuclease digestion - P – the phosphoprotein binds to the N and L proteins and forms part of the RNA polymerase complex - M – the matrix protein assembles between the envelope and the nucleocapsid core, it organizes and maintains virion structure - F – the fusion protein projects from the envelope surface as a trimer, and mediates cell entry by inducing fusion between the viral envelope and the cell membrane by class I fusion. One of the defining characteristics of members of the paramyxoviridae family is the requirement for a neutral pH for fusogenic activity. - H/HN/G – the cell attachment proteins span the viral envelope and project from the surface as spikes. They bind to sialic acid on the cell surface and facilitate cell entry. Note that the receptor for measles virus is unknown. Proteins are designated H for morbilliviruses and henipaviruses as they possess haemagglutination activity, observed as an ability to cause red blood cells to clump. HN attachment proteins occur in respiroviruses and rubulaviruses. These possess both haemagglutination and neuraminidase activity which cleaves sialic acid on the cell surface, preventing viral particles from reattaching to previously infected cells. Attachment proteins with neither haemagglutination nor neuraminidase activity are designated G (glycoprotein). These occur in members of pneumovirinae. - L – the large protein is the catalytic subunit of RNA dependent RNA polymerase (RDRP) - Accessory proteins – a mechanism known as RNA editing (see Mononegavirales) allows multiple proteins to be produced from the P gene. These are not essential for replication but may aid in survival in vitro or may be involved in regulating the switch from mRNA synthesis to antigenome synthesis. # Pathogenic paramyxoviruses A number of important human diseases are caused by paramyxoviruses. These include mumps, measles, which caused 745,000 deaths in 2001 and respiratory syncytial virus (RSV) which is the major cause of bronchiolitis and pneumonia in infants and children. The parainfluenza viruses are the second most common causes of respiratory tract disease in infants and children. They can cause pneumonia, bronchitis and croup in children and the elderly. Human metapneumovirus, initially described in about 2001, is also implicated in bronchitis, especially in children. Paramyxoviruses are also responsible for a range of diseases in other animal species, for example canine distemper virus (dogs), phocine distemper virus (seals), cetacean morbillivirus (dolphins and porpoises) Newcastle disease virus (birds) and rinderpest virus (cattle). Some paramyxoviruses such as the henipaviruses are zoonotic pathogens, occurring naturally in an animal host, but also able to infect humans. Hendra virus (HeV) and Nipah virus (NiV) in the genus Henipavirus have emerged in humans and livestock in Australia and Southeast Asia. Both viruses are contagious, highly virulent, and capable of infecting a number of mammalian species and causing potentially fatal disease. Due to the lack of a licensed vaccine or antiviral therapies, HeV and NiV are designated as biosafety level (BSL) 4 agents. The genomic structure of both viruses is that of a typical paramyxovirus. # Related chapters - Animal viruses - Virology - Henipavirus # Resources - Paramyxoviruses (1998) — morphology, genome, replication, pathogenesis - Hendra virus has a growing family tree (2001) CSIRO Paramyxovirus press release - Animal viruses	Paramyxovirus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Paramyxoviruses are viruses of the Paramyxoviridae family of the Mononegavirales order; they are negative-sense single-stranded RNA viruses responsible for a number of human and animal diseases. ## Genera - Subfamily Paramyxovirinae Genus Avulavirus (type species Newcastle disease virus) Genus Henipavirus (type species Hendravirus; others include Nipahvirus) Genus Morbillivirus (type species Measles virus; others include Rinderpest virus, Canine distemper virus, phocine distemper virus) Genus Respirovirus (type species Sendai virus; others include Human parainfluenza viruses 1 and 3, as well some of the viruses of the common cold) Genus Rubulavirus (type species Mumps virus; others include Simian parainfluenza virus 5, Menangle virus, Tioman virus) Genus TPMV-like viruses (type species Tupaia paramyxovirus) - Genus Avulavirus (type species Newcastle disease virus) - Genus Henipavirus (type species Hendravirus; others include Nipahvirus) - Genus Morbillivirus (type species Measles virus; others include Rinderpest virus, Canine distemper virus, phocine distemper virus) - Genus Respirovirus (type species Sendai virus; others include Human parainfluenza viruses 1 and 3, as well some of the viruses of the common cold) - Genus Rubulavirus (type species Mumps virus; others include Simian parainfluenza virus 5, Menangle virus, Tioman virus) - Genus TPMV-like viruses (type species Tupaia paramyxovirus) - Subfamily Pneumovirinae Genus Pneumovirus (type species Human respiratory syncytial virus, others include Bovine respiratory syncytial virus) Genus Metapneumovirus (type species Avian pneumovirus, Human metapneumovirus) - Genus Pneumovirus (type species Human respiratory syncytial virus, others include Bovine respiratory syncytial virus) - Genus Metapneumovirus (type species Avian pneumovirus, Human metapneumovirus) - Unassigned viruses Fer-de-Lance virus Nariva virus Tupaia paramyxovirus Salem virus J virus Mossman virus Beilong virus - Fer-de-Lance virus - Nariva virus - Tupaia paramyxovirus - Salem virus - J virus - Mossman virus - Beilong virus # Physical structure Virions are enveloped and can be spherical, filamentous or pleomorphic. Fusion proteins and attachment proteins appear as spikes on the virion surface. Matrix proteins inside the envelope stabilise virus structure. The nucleocapsid core is composed of the genomic RNA, nucleocapsid proteins, phosphoproteins and polymerase proteins. # Genome structure The genome consists of a single segment of negative-sense RNA, 15-19 kilobases in length and containing 6-10 genes. Extracistronic (non-coding) regions include: - A 3’ leader sequence, 50 nucleotides in length which acts as a transcriptional promoter. - A 5’ trailer sequence, 50-161 nucleotides long - Intergenomic regions between each gene which are three nucleotides long for morbillivirus, respirovirus and henipavirus, variable length (1-56 nucleotides) for rubulavirus and pneumovirinae. Each gene contains transcription start/stop signals at the beginning and end which are transcribed as part of the gene. Gene sequence within the genome is conserved across the family due to a phenomenon known as transcriptional polarity (see Mononegavirales) in which genes closest to the 3’ end of the genome are transcribed in greater abundance than those towards the 5’ end. This mechanism acts as a form of transcriptional regulation. The gene sequence is: - Nucleocapsid – Phosphoprotein – Matrix – Fusion – Attachment – Large (polymerase) # Proteins - N – the nucleocapsid protein associates with genomic RNA (one molecule per hexamer) and protects the RNA from nuclease digestion - P – the phosphoprotein binds to the N and L proteins and forms part of the RNA polymerase complex - M – the matrix protein assembles between the envelope and the nucleocapsid core, it organizes and maintains virion structure - F – the fusion protein projects from the envelope surface as a trimer, and mediates cell entry by inducing fusion between the viral envelope and the cell membrane by class I fusion. One of the defining characteristics of members of the paramyxoviridae family is the requirement for a neutral pH for fusogenic activity. - H/HN/G – the cell attachment proteins span the viral envelope and project from the surface as spikes. They bind to sialic acid on the cell surface and facilitate cell entry. Note that the receptor for measles virus is unknown. Proteins are designated H for morbilliviruses and henipaviruses as they possess haemagglutination activity, observed as an ability to cause red blood cells to clump. HN attachment proteins occur in respiroviruses and rubulaviruses. These possess both haemagglutination and neuraminidase activity which cleaves sialic acid on the cell surface, preventing viral particles from reattaching to previously infected cells. Attachment proteins with neither haemagglutination nor neuraminidase activity are designated G (glycoprotein). These occur in members of pneumovirinae. - L – the large protein is the catalytic subunit of RNA dependent RNA polymerase (RDRP) - Accessory proteins – a mechanism known as RNA editing (see Mononegavirales) allows multiple proteins to be produced from the P gene. These are not essential for replication but may aid in survival in vitro or may be involved in regulating the switch from mRNA synthesis to antigenome synthesis. # Pathogenic paramyxoviruses A number of important human diseases are caused by paramyxoviruses. These include mumps, measles, which caused 745,000 deaths in 2001 and respiratory syncytial virus (RSV) which is the major cause of bronchiolitis and pneumonia in infants and children. The parainfluenza viruses are the second most common causes of respiratory tract disease in infants and children. They can cause pneumonia, bronchitis and croup in children and the elderly. Human metapneumovirus, initially described in about 2001, is also implicated in bronchitis, especially in children. Paramyxoviruses are also responsible for a range of diseases in other animal species, for example canine distemper virus (dogs), phocine distemper virus (seals), cetacean morbillivirus (dolphins and porpoises) Newcastle disease virus (birds) and rinderpest virus (cattle). Some paramyxoviruses such as the henipaviruses are zoonotic pathogens, occurring naturally in an animal host, but also able to infect humans. Hendra virus (HeV) and Nipah virus (NiV) in the genus Henipavirus have emerged in humans and livestock in Australia and Southeast Asia. Both viruses are contagious, highly virulent, and capable of infecting a number of mammalian species and causing potentially fatal disease. Due to the lack of a licensed vaccine or antiviral therapies, HeV and NiV are designated as biosafety level (BSL) 4 agents. The genomic structure of both viruses is that of a typical paramyxovirus.[1] # Related chapters - Animal viruses - Virology - Henipavirus # Resources - Paramyxoviruses (1998) — morphology, genome, replication, pathogenesis - Hendra virus has a growing family tree (2001) CSIRO Paramyxovirus press release - Animal viruses	https://www.wikidoc.org/index.php/Paramyxoviridae
3efae218579fcaa9591c8e0e2a65e5ce37765b1e	wikidoc	Parapsoriasis	Parapsoriasis # Overview Parapsoriasis refers to one of a group of skin disorders that are characterized primarily by their resemblance to psoriasis (red, scaly lesions), rather than by their underlying etiology. Neoplasms can devleop from parapsoriasis. For example, it can develop into cutaneous T-cell lymphoma. The term "Parapsoriasis" was formed in 1902. # Examples of parapsoriases - Pityriasis lichenoides chronica - Pityriasis lichenoides et varioliformis acuta # Differentiating parapsoriasis from other dieases Parapsoriasis should be differentiated from other diseases that cause papulosquamous or erythmatosquamous rash. The differentials include:	Parapsoriasis # Overview Parapsoriasis refers to one of a group of skin disorders that are characterized primarily by their resemblance to psoriasis (red, scaly lesions), rather than by their underlying etiology. Neoplasms can devleop from parapsoriasis.[1] For example, it can develop into cutaneous T-cell lymphoma. The term "Parapsoriasis" was formed in 1902.[2] # Examples of parapsoriases - Pityriasis lichenoides chronica - Pityriasis lichenoides et varioliformis acuta # Differentiating parapsoriasis from other dieases Parapsoriasis should be differentiated from other diseases that cause papulosquamous or erythmatosquamous rash. The differentials include:	https://www.wikidoc.org/index.php/Parapsoriasis
2824917daac626d1e4c8c1db27e790d35d74e033	wikidoc	Parietal lobe	Parietal lobe The parietal lobe is a lobe in the brain. It is positioned above (superior to) the occipital lobe and behind (posterior to) the frontal lobe. The parietal lobe integrates sensory information from different modalities, particularly determining spatial sense and navigation. For example, it comprises somatosensory cortex and the dorsal stream of the visual system. This enables regions of the parietal cortex to map objects perceived visually into body coordinate positions. # Anatomy The parietal lobe is defined by four anatomical boundaries: the central sulcus separates the parietal lobe from the frontal lobe; the parieto-occipital sulcus separates the parietal and occipital lobe; the lateral sulcus (sylvian fissure) is the most lateral boundary separating it from the temporal lobe; and the medial longitudinal fissure divides the two hemispheres. Immediately posterior to the central sulcus, and the most anterior part of the parietal lobe, is the postcentral gyrus (Brodmann area 3), the primary somatosensory cortical area. Dividing this and the posterior parietal cortex is the postcentral sulcus. The posterior parietal cortex can be subdivided into the superior parietal lobule (Brodmann areas 5 + 7) and the inferior parietal lobule (39 + 40), separated by the intraparietal sulcus (IP). The intraparietal sulcus and adjacent gyri are essential in guidance of limb and eye movement, and based on cytoarchitectural and functional differences is further divided into medial (MIP), lateral (LIP), ventral (VIP), and anterior (AIP) areas. # Function The parietal lobe plays important roles in integrating sensory information from various parts of the body, knowledge of numbers and their relations, and in the manipulation of objects. Portions of the parietal lobe are involved with visuospatial processing. Much less is known about this lobe than the other three in the cerebrum. Various studies in the 1990s found that different regions of the parietal cortex in Macaques represent different parts of space. - The lateral intraparietal (LIP) contains a 2-dimensional topographic map of retinotopically-coded space representing the saliency of spatial locations. It can be used by the oculomotor system for targeting eye movements, when appropriate. - The ventral intraparietal (VIP) area receives input from a number of senses (visual, somatosensory, auditory, and vestibular). Neurons with tactile receptive fields represented space in a head-centered reference frame. The cells with visual receptive fields also fire with head-centered reference frames but possibly also with eye-centered coordinates - The medial intraparietal (MIP) area neurons encode the location of a reach target in eye-centered coordinates. - The anterior intraparietal (AIP) area contains neurons responsive to shape, size, and orientation of objects to be grasped as well as for manipulation of hands themselves, both to viewed and remembered stimuli. # Pathology Gerstmann's syndrome is associated with lesion to the dominant (usually left) parietal lobe. Balint's syndrome is associated with bilateral lesions. The syndrome of hemispatial neglect is usually associated with large deficits of attention of the non-dominant hemisphere. # Additional images - Lobes - Drawing to illustrate the relations of the brain to the skull.	Parietal lobe Template:Infobox Brain Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The parietal lobe is a lobe in the brain. It is positioned above (superior to) the occipital lobe and behind (posterior to) the frontal lobe. The parietal lobe integrates sensory information from different modalities, particularly determining spatial sense and navigation. For example, it comprises somatosensory cortex and the dorsal stream of the visual system. This enables regions of the parietal cortex to map objects perceived visually into body coordinate positions. # Anatomy The parietal lobe is defined by four anatomical boundaries: the central sulcus separates the parietal lobe from the frontal lobe; the parieto-occipital sulcus separates the parietal and occipital lobe; the lateral sulcus (sylvian fissure) is the most lateral boundary separating it from the temporal lobe; and the medial longitudinal fissure divides the two hemispheres. Immediately posterior to the central sulcus, and the most anterior part of the parietal lobe, is the postcentral gyrus (Brodmann area 3), the primary somatosensory cortical area. Dividing this and the posterior parietal cortex is the postcentral sulcus. The posterior parietal cortex can be subdivided into the superior parietal lobule (Brodmann areas 5 + 7) and the inferior parietal lobule (39 + 40), separated by the intraparietal sulcus (IP). The intraparietal sulcus and adjacent gyri are essential in guidance of limb and eye movement, and based on cytoarchitectural and functional differences is further divided into medial (MIP), lateral (LIP), ventral (VIP), and anterior (AIP) areas. # Function The parietal lobe plays important roles in integrating sensory information from various parts of the body, knowledge of numbers and their relations[1], and in the manipulation of objects. Portions of the parietal lobe are involved with visuospatial processing. Much less is known about this lobe than the other three in the cerebrum. Various studies in the 1990s found that different regions of the parietal cortex in Macaques represent different parts of space. - The lateral intraparietal (LIP) contains a 2-dimensional topographic map of retinotopically-coded space representing the saliency of spatial locations. It can be used by the oculomotor system for targeting eye movements, when appropriate. - The ventral intraparietal (VIP) area receives input from a number of senses (visual, somatosensory, auditory, and vestibular[2]). Neurons with tactile receptive fields represented space in a head-centered reference frame[2]. The cells with visual receptive fields also fire with head-centered reference frames[3] but possibly also with eye-centered coordinates[2] - The medial intraparietal (MIP) area neurons encode the location of a reach target in eye-centered coordinates.[4] - The anterior intraparietal (AIP) area contains neurons responsive to shape, size, and orientation of objects to be grasped[5] as well as for manipulation of hands themselves, both to viewed[5] and remembered stimuli. [6] # Pathology Gerstmann's syndrome is associated with lesion to the dominant (usually left) parietal lobe. Balint's syndrome is associated with bilateral lesions. The syndrome of hemispatial neglect is usually associated with large deficits of attention of the non-dominant hemisphere. # Additional images - Lobes - Drawing to illustrate the relations of the brain to the skull.	https://www.wikidoc.org/index.php/Parietal_cortex
771c42b733f4cfad6e97d76258bca6dc54dfcb95	wikidoc	Parotid gland	Parotid gland # Overview The parotid gland is the largest of the salivary glands. It is found wrapped around the mandibular ramus, and it secretes saliva through Stensen's duct into the oral cavity, to facilitate mastication and swallowing. # Anatomy ## Location The parotid gland is found in the subcutaneous tissue of the face, overlying the mandibular ramus and anterior and inferior to the external ear. The gland occupies the parotid fascial space, an area posterior to the mandibular ramus, anterior and inferior to the ear. The gland extends irregularly from the zygomatic arch to the angle of the mandible. This gland is effectively palpated bilaterally. Start anterior to each ear and move to the cheek area and then inferior to the angle of the mandible. (Illustrated Head and Neck Anatomy, Fehrenbach and Herring, Elsevier, 2007, p. 170-1). The facial nerve and its branches pass through the parotid gland as do the external carotid artery and its branches. ## Excretory portion The duct to this gland (also known as Stensen's duct) empties within the buccal cavity (the inside of the cheek) opposite the upper second molar. The parotid papilla is a small elevation of tissue that marks the opening of the parotid duct on the inner surface of the cheek (Illustrated Dental Embryology, Histology, and Anatomy, Bath-Balogh and Fehrenbach, Elsevier, 2006, p. 166). Serous fluid (as opposed to mucous fluid) is produced by the parotid gland. ## Innervation Although the facial nerve (CN VII) runs through this gland, it does not control it. Secretion of saliva by the parotid gland is controlled by presynaptic parasympathetic fibres originating in the inferior salivatory nucleus; these leave the brain via the glossopharyngeal nerve (CN IX), travel along the tympanic nerve (of Jacobson), pass through the tympanic plexus (located in the middle ear), and then travel in the lesser petrosal nerve until they reach the otic ganglion. After synapsing, the postganglionic fibers travel as part of the auriculotemporal nerve, a branch of the mandibular nerve (V3) to reach the parotid gland. Sympathetic nerves originating from Superior Cervical Ganglion reach the gland with blood vessels. Parasympathetic stimulation produces a water rich mucus saliva. Sympathetic stimulation leads to the production of low volume enzyme rich saliva. There is no inhibitory nerve supply to the gland. ## Vascularization Branches of the external carotid artery traverse the glandular tissue and supply the parotid gland with oxygenated blood, whereas numerous local veins drain the organ. These veins drain into tributaries of external and internal jugular veins. The maxillary vein and superficial temporal vein meet to form the retromandibular vein within the parotid gland but are not responsible for draining it. Lymphatics mainly comprise pre-auricular lymph nodes. # Pathology Inflammation of one or both parotid glands is known as parotitis. The most common cause of parotitis was mumps. Widespread vaccination against mumps has markedly reduced the incidence of mumps parotitis. Other infections such as bacterial infections can cause parotitis as may blockage of the duct, whether from salivary duct calculi or external compression. Stones mainly occur within the main confluence of the ducts and within the main parotid duct. The patient usually complains of intense pain when salivating and tends to avoid foods which produce this symptom. In addition the parotid gland may become enlarged upon trying to eat. The pain can be reproduced in clinic via squirting lemon juice into the patient's mouth. Surgery depends upon the situation of the stone, if within the anterior aspect of the duct a simple incision into the buccal mucosa with sphinterotomy may allow removal, however if further posterior within the main duct, complete gland excision may be necessary. The most common of tumors in the parotid gland are benign and only affect the superficial gland. These include pleomorphic adenoma and adenolymphoma. Their importance is in relation to their anatomical position. The tumorous growth can also change the consistency of the gland and cause facial pain on the involved side since the facial nerve travels through the gland (Illustrated Head and Neck Anatomy, Fehrenbach and Herring, Elsevier, 2007, p. 172). Critically, the relationship of the tumor to the branches of the facial nerve (CN VII) must be defined because resection may damage the nerves, resulting in paralysis of the muscles of facial expression. If the tumor is deep within the gland, the patient should give consent for potential damage of the facial nerve. # Additional images - Mandibular division of the trifacial nerve. - Sympathetic connections of the otic and superior cervical ganglia. - Horizontal section through left ear; upper half of section. - Outline of side of face, showing chief surface markings. - microscopic ducts surrounded by connective tissue	Parotid gland Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Template:Infobox Anatomy The parotid gland is the largest of the salivary glands. It is found wrapped around the mandibular ramus, and it secretes saliva through Stensen's duct into the oral cavity, to facilitate mastication and swallowing. # Anatomy ## Location The parotid gland is found in the subcutaneous tissue of the face, overlying the mandibular ramus and anterior and inferior to the external ear. The gland occupies the parotid fascial space, an area posterior to the mandibular ramus, anterior and inferior to the ear. The gland extends irregularly from the zygomatic arch to the angle of the mandible. This gland is effectively palpated bilaterally. Start anterior to each ear and move to the cheek area and then inferior to the angle of the mandible. (Illustrated Head and Neck Anatomy, Fehrenbach and Herring, Elsevier, 2007, p. 170-1). The facial nerve and its branches pass through the parotid gland as do the external carotid artery and its branches. ## Excretory portion The duct to this gland (also known as Stensen's duct) empties within the buccal cavity (the inside of the cheek) opposite the upper second molar. The parotid papilla is a small elevation of tissue that marks the opening of the parotid duct on the inner surface of the cheek (Illustrated Dental Embryology, Histology, and Anatomy, Bath-Balogh and Fehrenbach, Elsevier, 2006, p. 166). Serous fluid (as opposed to mucous fluid) is produced by the parotid gland. ## Innervation Although the facial nerve (CN VII) runs through this gland, it does not control it. Secretion of saliva by the parotid gland is controlled by presynaptic parasympathetic fibres originating in the inferior salivatory nucleus; these leave the brain via the glossopharyngeal nerve (CN IX), travel along the tympanic nerve (of Jacobson), pass through the tympanic plexus (located in the middle ear), and then travel in the lesser petrosal nerve until they reach the otic ganglion. After synapsing, the postganglionic fibers travel as part of the auriculotemporal nerve, a branch of the mandibular nerve (V3) to reach the parotid gland. Sympathetic nerves originating from Superior Cervical Ganglion reach the gland with blood vessels. Parasympathetic stimulation produces a water rich mucus saliva. Sympathetic stimulation leads to the production of low volume enzyme rich saliva. There is no inhibitory nerve supply to the gland. ## Vascularization Branches of the external carotid artery traverse the glandular tissue and supply the parotid gland with oxygenated blood, whereas numerous local veins drain the organ. These veins drain into tributaries of external and internal jugular veins. The maxillary vein and superficial temporal vein meet to form the retromandibular vein within the parotid gland but are not responsible for draining it. Lymphatics mainly comprise pre-auricular lymph nodes. # Pathology Inflammation of one or both parotid glands is known as parotitis. The most common cause of parotitis was mumps. Widespread vaccination against mumps has markedly reduced the incidence of mumps parotitis. Other infections such as bacterial infections can cause parotitis as may blockage of the duct, whether from salivary duct calculi or external compression. Stones mainly occur within the main confluence of the ducts and within the main parotid duct. The patient usually complains of intense pain when salivating and tends to avoid foods which produce this symptom. In addition the parotid gland may become enlarged upon trying to eat. The pain can be reproduced in clinic via squirting lemon juice into the patient's mouth. Surgery depends upon the situation of the stone, if within the anterior aspect of the duct a simple incision into the buccal mucosa with sphinterotomy may allow removal, however if further posterior within the main duct, complete gland excision may be necessary. The most common of tumors in the parotid gland are benign and only affect the superficial gland. These include pleomorphic adenoma and adenolymphoma. Their importance is in relation to their anatomical position. The tumorous growth can also change the consistency of the gland and cause facial pain on the involved side since the facial nerve travels through the gland (Illustrated Head and Neck Anatomy, Fehrenbach and Herring, Elsevier, 2007, p. 172). Critically, the relationship of the tumor to the branches of the facial nerve (CN VII) must be defined because resection may damage the nerves, resulting in paralysis of the muscles of facial expression. If the tumor is deep within the gland, the patient should give consent for potential damage of the facial nerve. # Additional images - Mandibular division of the trifacial nerve. - Sympathetic connections of the otic and superior cervical ganglia. - Horizontal section through left ear; upper half of section. - Outline of side of face, showing chief surface markings. - microscopic ducts surrounded by connective tissue # External links - Illustration at yoursurgery.com - Template:NormanAnatomy - Histology at usc.edu - Template:EMedicineDictionary Template:Head and neck general de:Ohrspeicheldrüse it:Ghiandola parotide sr:Доушна жлезда Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Parotid
91c9bdb091e83368ce47cef013e5f771b46c9f39	wikidoc	Pars compacta	Pars compacta The pars compacta is a portion of the substantia nigra. # Anatomy The pars compacta contains neurons which, in humans, are coloured black by the pigment neuromelanin that increases with age. This pigmentation is visible as a distinctive black stripe in brain sections and is the origin of the name given to this area. The neurons have particularly long and thick dendrites (François et al.). The ventral dendrites, particularly, go down deeply in the pars reticulata. Other similar neurons are more sparsely distributed in the mesencephalon and constitute "groups" with no clear borders, although continuous to the pars compacta, in a prerubral position. These have been given in early works in rats with not much respect for the anatomical subdivions the name of "area A8" and "A10". The pars compacta itself ("A9") is usually subdivided into a ventral and a dorsal tier, the last being calbindin positive. The ventral tier is considered as A9v. The dorsal tier A9d is linked to an ensemble comprising also A8 and A10, A8, A9d and A10 representing 28% of dopaminergic neurons. The long dendrites of compacta neurons receive striatal information. This cannot be the case for the more posterior groups that are located outside the striato-pallidonigral bundle territory. Neurons of the pars compacta receive inhibiting signals from the collateral axons from the neurons of the pars reticulata. All these neurons send their axons along the nigrostriatal pathway to the striatum where they release the neurotransmitter dopamine. There is an organization in which dopaminergic neurons of the fringes (the lowest) go to the sensorimotor striatum and the highest to the associative striatum. Dopaminergic axons also innervate other elements of the basal ganglia system including the lateral and medial pallidum, substantia nigra pars reticulata, and the subthalamic nucleus. # Function The function of the dopamine neurons in the substantia nigra pars compacta is complex. Contrary to what was thought initially it is not directly linked to movements. "Dopamine neurons are activated by novel, unexpected stimuli, by primary rewards in the absence of predictive stimuli and during learning". Dopamine neurons are thought to be involved in learning to predict which behaviours will lead to a reward (for example food or sex). In particular, it is suggested that dopamine neurons fire when a reward is greater than that previously expected; a key component of many reinforcement learning models. This signal can then be used to update the expected value of that action. Many drugs of abuse, such as cocaine, mimic this reward response—providing an explanation for their addictive nature. # Pathology Degeneration of pigmented neurons in this region is the principal pathology that underlies Parkinson's disease. In a few people, the cause of Parkinson's disease is genetic, but in most cases, the reason for the death of these dopamine neurons is unknown. Parkinsonism can also be produced by viral infections such as encephalitis or a number of toxins, such as MPTP, an industrial toxin which can be mistakenly produced during synthesis of the meperidine analog MPPP. Many such toxins appear to work by producing reactive oxygen species. Binding to neuromelanin by means of charge transfer complexes may concentrate radical-generating toxins in the substantia nigra. Pathological changes to the dopaminergic neurons of the pars compacta are also thought to be involved in schizophrenia (see the dopamine hypothesis of schizophrenia) and psychomotor retardation sometimes seen in clinical depression.	Pars compacta Template:Infobox Brain The pars compacta is a portion of the substantia nigra. ## Anatomy The pars compacta contains neurons which, in humans, are coloured black by the pigment neuromelanin that increases with age. This pigmentation is visible as a distinctive black stripe in brain sections and is the origin of the name given to this area. The neurons have particularly long and thick dendrites (François et al.). The ventral dendrites, particularly, go down deeply in the pars reticulata. Other similar neurons are more sparsely distributed in the mesencephalon and constitute "groups" with no clear borders, although continuous to the pars compacta, in a prerubral position. These have been given in early works in rats with not much respect for the anatomical subdivions the name of "area A8" and "A10". The pars compacta itself ("A9") is usually subdivided into a ventral and a dorsal tier, the last being calbindin positive.[1] The ventral tier is considered as A9v. The dorsal tier A9d is linked to an ensemble comprising also A8 and A10,[2] A8, A9d and A10 representing 28% of dopaminergic neurons. The long dendrites of compacta neurons receive striatal information. This cannot be the case for the more posterior groups that are located outside the striato-pallidonigral bundle territory. Neurons of the pars compacta receive inhibiting signals from the collateral axons from the neurons of the pars reticulata.[3] All these neurons send their axons along the nigrostriatal pathway to the striatum where they release the neurotransmitter dopamine. There is an organization in which dopaminergic neurons of the fringes (the lowest) go to the sensorimotor striatum and the highest to the associative striatum. Dopaminergic axons also innervate other elements of the basal ganglia system including the lateral and medial pallidum,[4] substantia nigra pars reticulata, and the subthalamic nucleus.[5] ## Function The function of the dopamine neurons in the substantia nigra pars compacta is complex. Contrary to what was thought initially it is not directly linked to movements. "Dopamine neurons are activated by novel, unexpected stimuli, by primary rewards in the absence of predictive stimuli and during learning".[6] Dopamine neurons are thought to be involved in learning to predict which behaviours will lead to a reward (for example food or sex). In particular, it is suggested that dopamine neurons fire when a reward is greater than that previously expected; a key component of many reinforcement learning models. This signal can then be used to update the expected value of that action. Many drugs of abuse, such as cocaine, mimic this reward response—providing an explanation for their addictive nature. ## Pathology Degeneration of pigmented neurons in this region is the principal pathology that underlies Parkinson's disease. In a few people, the cause of Parkinson's disease is genetic, but in most cases, the reason for the death of these dopamine neurons is unknown. Parkinsonism can also be produced by viral infections such as encephalitis or a number of toxins, such as MPTP, an industrial toxin which can be mistakenly produced during synthesis of the meperidine analog MPPP. Many such toxins appear to work by producing reactive oxygen species. Binding to neuromelanin by means of charge transfer complexes may concentrate radical-generating toxins in the substantia nigra. Pathological changes to the dopaminergic neurons of the pars compacta are also thought to be involved in schizophrenia (see the dopamine hypothesis of schizophrenia) and psychomotor retardation sometimes seen in clinical depression.	https://www.wikidoc.org/index.php/Pars_compacta
6cf3b2b4b94ea7b1f8446b58ae915df4d87d03f8	wikidoc	Paternal bond	Paternal bond The paternal bond is typically the relationship between a father and his child. In the U.S., legal paternity is presumed for the husband of the mother unless a separate action is taken; an unmarried man may establish paternity by signing a voluntary recognition of paternity or by taking court action. Paternity may also be established between a man and a younger person, commonly in adoption, without the two being related to each other. # Fatherhood The father of a child can develop the bond during the pregnancy of his partner, feeling attachment to the developing child. Research indicates that this may have some biological basis. Statistics show that fathers' levels of testosterone tend to decline several months before the birth of the child (due, perhaps, to an inverse pheromonal chemical produced by the mother during pregnancy). Since high testosterone levels seem to encourage more aggressive behaviour, low levels may enhance the ability to develop a new relationship bond (for example, with the child). Fathers find many ways to bond with their children, such as soothing, consoling, feeding (expressed breast milk, infant formula or baby food), changing diapers, bathing, dressing, playing, and cuddling. Carrying the infant in a sling or backpack or pushing them in a baby transport can build the bond, as can participating in the baby's bedtime routine.	Paternal bond The paternal bond is typically the relationship between a father and his child.[1] In the U.S., legal paternity is presumed for the husband of the mother unless a separate action is taken; an unmarried man may establish paternity by signing a voluntary recognition of paternity or by taking court action.[2] Paternity may also be established between a man and a younger person, commonly in adoption, without the two being related to each other. # Fatherhood The father of a child can develop the bond during the pregnancy of his partner, feeling attachment to the developing child. Research indicates that this may have some biological basis.[3] Statistics show that fathers' levels of testosterone tend to decline several months before the birth of the child (due, perhaps, to an inverse pheromonal chemical produced by the mother during pregnancy). Since high testosterone levels seem to encourage more aggressive behaviour, low levels may enhance the ability to develop a new relationship bond (for example, with the child).[4] Fathers find many ways to bond with their children, such as soothing, consoling, feeding (expressed breast milk, infant formula or baby food), changing diapers, bathing, dressing, playing, and cuddling. Carrying the infant in a sling or backpack or pushing them in a baby transport can build the bond, as can participating in the baby's bedtime routine.	https://www.wikidoc.org/index.php/Paternal_bond
887ee2b1fd50596ccc042eb1dfedb794809c9346	wikidoc	Pathergy test	Pathergy test Synonyms and keywords: Pathergy # Overview The pathergy test, is a non-specific skin or mucus membrane reaction to trauma that is observed in patients with Behçet disease. This reaction is classified as a hypersensitivity reaction. The positive pathergy test is one of the minor diagnostic criteria of Behçet’s disease. # Historical Perspective Skin pathergy test was first reported by Blobner in 1937. # Procedure Skin Pathergy test There is no standardized method for performing the pathergy test. However, the method below is one of the suggested ways. Procedure The area of the skin should not be cleaned with disinfectant and the needle should be blunted against the inside surface of its sterile plastic sheath before using. The needle is inserted carefully at an angle of 30° to the skin into the dermis at a depth of 1.5–2 mm. The needle should not be observed beneath the epidermis and then it should be withdrawn with a twisting movement. The test is read between 24 to 48 hours after the procedure. One of the suggested scales for the degree of positivity is a three-point scale as follows: - Negative Result: only needle mark (scored 0) - Positive Result: the presence of papule or pustule 1+ papule only 2+ pustule - 1+ papule only - 2+ pustule Another scale for the interpretation of the test, known as Dilsen pathergy test, is indicated in the table below: To increase the sensitivity of the test: - make at least two needle pricks on the glabrous skin of the forearm - Use a large hypodermic needle (21 gauge or less) - Use four needle pricks in total - Use a blunt needle to prick Oral pathergy test To perform the test, a 20-gauge (0.9 mm) blunt disposable needle is used to prick the mucous membrane of the lower lip to the submucosa. The test is then read 48 hours later. The result is interpreted as below: - Positive Result: Presence of pustule and/or ulcer - Negative Result: Absence of aforementioned lesions This method is more accessible than the traditional skin test, as there is no need to measure the size of the lesion and pustule or ulcer of any size turn the test positive. Additionally, it has similar sensitivity to Dilsen skin pathergy test. # Associated Conditions The following disorders are associated with positive pathergy test: - Behçet’s disease (the skin pathergy test is a specific diagnostic tool for this disorder) - Pyoderma gangrenosum - Sweet’s syndrome - Atypical eosinophilic pustular folliculitis - Neonates with Down syndrome - Myeloproliferative disorders - Non-Hodgkin’s lymphoma - Chronic myeloid leukemia treated with interferon α - Inflammatory bowel disease - spondyloarthropathies (rarely)	Pathergy test Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Synonyms and keywords: Pathergy # Overview The pathergy test, is a non-specific skin or mucus membrane reaction to trauma that is observed in patients with Behçet disease. This reaction is classified as a hypersensitivity reaction. The positive pathergy test is one of the minor diagnostic criteria of Behçet’s disease. # Historical Perspective Skin pathergy test was first reported by Blobner in 1937.[1] # Procedure Skin Pathergy test There is no standardized method for performing the pathergy test. However, the method below is one of the suggested ways.[2][3] Procedure The area of the skin should not be cleaned with disinfectant and the needle should be blunted against the inside surface of its sterile plastic sheath before using. The needle is inserted carefully at an angle of 30° to the skin into the dermis at a depth of 1.5–2 mm. The needle should not be observed beneath the epidermis and then it should be withdrawn with a twisting movement. The test is read between 24 to 48 hours after the procedure. One of the suggested scales for the degree of positivity is a three-point scale as follows: - Negative Result: only needle mark (scored 0) - Positive Result: the presence of papule or pustule 1+ papule only 2+ pustule - 1+ papule only - 2+ pustule Another scale for the interpretation of the test, known as Dilsen pathergy test, is indicated in the table below:[4] To increase the sensitivity of the test:[1][2] - make at least two needle pricks on the glabrous skin of the forearm - Use a large hypodermic needle (21 gauge or less) - Use four needle pricks in total - Use a blunt needle to prick Oral pathergy test To perform the test, a 20-gauge (0.9 mm) blunt disposable needle is used to prick the mucous membrane of the lower lip to the submucosa. The test is then read 48 hours later. The result is interpreted as below:[4] - Positive Result: Presence of pustule and/or ulcer - Negative Result: Absence of aforementioned lesions This method is more accessible than the traditional skin test, as there is no need to measure the size of the lesion and pustule or ulcer of any size turn the test positive. Additionally, it has similar sensitivity to Dilsen skin pathergy test. # Associated Conditions The following disorders are associated with positive pathergy test:[2][5] - Behçet’s disease (the skin pathergy test is a specific diagnostic tool for this disorder) - Pyoderma gangrenosum - Sweet’s syndrome - Atypical eosinophilic pustular folliculitis - Neonates with Down syndrome - Myeloproliferative disorders - Non-Hodgkin’s lymphoma - Chronic myeloid leukemia treated with interferon α - Inflammatory bowel disease - spondyloarthropathies (rarely)	https://www.wikidoc.org/index.php/Pathergy
73a0bb190ebf65a75d8398ef419f8602f47a51be	wikidoc	Pathogenicity	Pathogenicity Pathogenicity is the ability of an organism to cause disease in another organism, thus called Pathogen. It is often used interchangeably with the term "virulence", although some authors prefer to reserve the latter term for descriptions of the relative degree of damage done by a pathogen. Pathogens are infectious agents that cause disease and include viruses, bacteria, fungi, protozoa and higher parasites. The agents responsible for the CJD and BSE are also pathogenic. The term used to describe the capacity of microbes to cause disease. he:פתוגניות	Pathogenicity Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Pathogenicity is the ability of an organism to cause disease in another organism, thus called Pathogen. It is often used interchangeably with the term "virulence", although some authors prefer to reserve the latter term for descriptions of the relative degree of damage done by a pathogen. Pathogens are infectious agents that cause disease and include viruses, bacteria, fungi, protozoa and higher parasites. The agents responsible for the CJD and BSE are also pathogenic. The term used to describe the capacity of microbes to cause disease. [Source: Talaro, Kathleen P. Foundations in Microbioligy / Kathleen Park Talaro. - 6th edition. 2008] he:פתוגניות Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Pathogenicity
cb7c07b673f6c0b2b29101f5e3e745471f6684bb	wikidoc	Pathognomonic	Pathognomonic Pathognomonic (often misspelled as pathognomic) is an adjective of Greek origin (παθογνωμονικό ), often used in medicine, which means diagnostic for a particular disease. A pathognomonic sign is a particular sign whose presence means, beyond any doubt, that a particular disease is present. It is derived from the Greek páthos (πάθος, disease) and gnōmon (γνώμον, "judge"). Labelling a sign or symptom "pathognomonic" represents a marked intensification of a "diagnostic" sign or symptom. While some findings may be classic, typical or highly suggestive in a certain condition, they may not occur uniquely in this condition and therefore may not directly imply a specific diagnosis. A pathognomonic finding on the other hand allows immediate diagnosing, since there are no other conditions in the differential diagnosis. A pathognomonic sign or symptom can sometimes be absent in a certain disease, since the term only implies that when it is present, the doctor instantly knows the patient's illness. Singular pathognomonic signs are relatively uncommon. Examples of pathognomonic findings include Koplik's spots inside the mouth in measles, the palmar xanthomata seen on the hands of people suffering from hyperlipoproteinemia, or a tetrad of rash, arthralgia, abdominal pain and kidney disease in a child with Henoch-Schönlein purpura. # Pathognomonic signs	Pathognomonic Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Pathognomonic (often misspelled as pathognomic) is an adjective of Greek origin (παθογνωμονικό [σύμπτωμα]), often used in medicine, which means diagnostic for a particular disease. A pathognomonic sign is a particular sign whose presence means, beyond any doubt, that a particular disease is present. It is derived from the Greek páthos (πάθος, disease) and gnōmon (γνώμον, "judge"). Labelling a sign or symptom "pathognomonic" represents a marked intensification of a "diagnostic" sign or symptom. While some findings may be classic, typical or highly suggestive in a certain condition, they may not occur uniquely in this condition and therefore may not directly imply a specific diagnosis. A pathognomonic finding on the other hand allows immediate diagnosing, since there are no other conditions in the differential diagnosis. A pathognomonic sign or symptom can sometimes be absent in a certain disease, since the term only implies that when it is present, the doctor instantly knows the patient's illness. Singular pathognomonic signs are relatively uncommon. Examples of pathognomonic findings include Koplik's spots inside the mouth in measles, the palmar xanthomata seen on the hands of people suffering from hyperlipoproteinemia, or a tetrad of rash, arthralgia, abdominal pain and kidney disease in a child with Henoch-Schönlein purpura. # Pathognomonic signs	https://www.wikidoc.org/index.php/Pathognomonic
db37f9cfac33d6259e0f1bbb5ab9167b20b4b893	wikidoc	Pectoral fins	Pectoral fins Fish anatomy is primarily governed by the physical characteristics of water, which is much denser than air, holds a relatively small amount of dissolved oxygen, and absorbs light more than air does. # Body Fish have a variety of different body plans. Their body is divided into head, trunk, and tail, although the divisions are not always externally visible. The body is often fusiform, a streamlined body plan often found in fast-moving fish. They may also be filiform (eel-shaped) or vermiform (worm-shaped). Also, fish are often either laterally compressed (thin) or vertically depressed (flat). The caudal peduncle is the narrow part of the fish's body to which the caudal or tail fin is attached. The hypural joint is the joint between the caudal fin and the last of the vertebrae. The hypural is often fan-shaped. Photophores are light-emitting organs which appears as luminous spots on some fishes. The light can be produced from compounds during the digestion of prey, from specialized mitochondrial cells in the organism called photocytes, or associated with symbiotic bacteria, and are used for attracting food or confusing predators. The lateral line is a sense organ used to detect movement and vibration in the surrounding water. In most species, it consists of a line of receptors running along each side of the fish. The ampullae of Lorenzini allow sharks to sense electrical discharges. The genital papilla is a small, fleshy tube behind the anus in some fishes, from which the sperm or eggs are released; the sex of a fish often can be determined by the shape of its papilla. ## Head The head includes the snout, from the eye to the forwardmost point of the upper jaw, the operculum or gill cover (absent in sharks), and the cheek, which extends from eye to preopercle. The operculum and preopercle may or may not have spines. The lower jaw defines a chin. In lampreys, the mouth is formed into an oral disk. In most jawed fish, however, there are three general configurations. The mouth may be on the forward end of the head (terminal), may be upturned (superior), or may be turned downwards or on the bottom of the fish (subterminal or inferior). The mouth may be modified into a suckermouth adapted for clinging onto objects in fast-moving water. The head may have several fleshy structures known as barbels, which may be very long and resemble whiskers. Many fish species also have a variety of protrusions or spines on the head. The nostrils or nares of almost all fishes do not connect to the oral cavity, but are pits of varying shape and depth. # Fins The fins are the most distinctive features of a fish. ## Spines and rays In bony fish, most fins may have spines or rays. A fin can contain only spiny rays, only soft rays, or a combination of both. If both are present, the spiny rays are always anterior. Spines are generally stiff and sharp. Rays are generally soft, flexible, segmented, and may be branched. This segmentation of rays is the main difference that separates them from spines; spines may be flexible in certain species, but they will never be segmented. The caudal fin is what is connected to the end of each fin. Spines have a variety of uses. In catfish, they are used as a form of defense; many catfish have the ability to lock their spines outwards. Triggerfish also use spines to lock themselves in crevices to prevent being pulled out. ## Types of fin - dorsal fins are located on the back. A fish can have up to three of them. The dorsal fins serve to protect the fish against rolling, and assists in sudden turns and stops. In anglerfish, the anterior of the dorsal fin is modified into an illicium and esca, a biological equivalent to a fishing pole and a lure. The bones that support the dorsal fin are called Pterygiophore. There are two to three of them: "proximal", "middle", and "distal". In spinous fins the distal is often fused to the middle, or not present at all. - In anglerfish, the anterior of the dorsal fin is modified into an illicium and esca, a biological equivalent to a fishing pole and a lure. - The bones that support the dorsal fin are called Pterygiophore. There are two to three of them: "proximal", "middle", and "distal". In spinous fins the distal is often fused to the middle, or not present at all. - The caudal fin is the tail fin, located at the end of the caudal peduncle. File:PletwyRyb.svgtypes of caudal fin :(A) - Heterocercal, (B) - Protocercal, (C) - Homocercal, (D) - Diphycercal The tail can be heterocercal, which means that the vertebrae extend into a larger lobe of the tail or that the tail is asymmetrical Epicercal means that the upper lobe is longer (as in sharks) Hypocercal means that the lower lobe is longer (as in flying fish) Protocercal means that the caudal fin extends around the vertebral column, present in embryonic fish and hagfish. This is not to be confused with a caudal fin that has fused with the dorsal and anal fins to form a contiguous fin. Diphycercal refers to the special, three-lobed caudal fin of the coelacanth and lungfish where the vertebrae extend all the way to the end of the tail. Most fish have a homocercal tail, where the vertebrae do not extend into a lobe and the fin is more or less symmetrical. This can be expressed in a variety of shapes. The tail fin may be rounded at the end. The tail fin may be truncated, or end in a more-or-less vertical edge (such as in salmon). The fin may be forked, or end in two prongs. The tail fin may be emarginate, or with a slight inward curve. The tail fin may be lunate, or shaped like a crescent moon. - The tail can be heterocercal, which means that the vertebrae extend into a larger lobe of the tail or that the tail is asymmetrical Epicercal means that the upper lobe is longer (as in sharks) Hypocercal means that the lower lobe is longer (as in flying fish) - Epicercal means that the upper lobe is longer (as in sharks) - Hypocercal means that the lower lobe is longer (as in flying fish) - Protocercal means that the caudal fin extends around the vertebral column, present in embryonic fish and hagfish. This is not to be confused with a caudal fin that has fused with the dorsal and anal fins to form a contiguous fin. - Diphycercal refers to the special, three-lobed caudal fin of the coelacanth and lungfish where the vertebrae extend all the way to the end of the tail. - Most fish have a homocercal tail, where the vertebrae do not extend into a lobe and the fin is more or less symmetrical. This can be expressed in a variety of shapes. The tail fin may be rounded at the end. The tail fin may be truncated, or end in a more-or-less vertical edge (such as in salmon). The fin may be forked, or end in two prongs. The tail fin may be emarginate, or with a slight inward curve. The tail fin may be lunate, or shaped like a crescent moon. - The tail fin may be rounded at the end. - The tail fin may be truncated, or end in a more-or-less vertical edge (such as in salmon). - The fin may be forked, or end in two prongs. - The tail fin may be emarginate, or with a slight inward curve. - The tail fin may be lunate, or shaped like a crescent moon. - The anal fin is located on the ventral surface behind the anus. This fin is used to stabilize the fish while swimming. - The paired pectoral fins are located on each side, usually just behind the operculum, and are homologous to the forelimbs of tetrapods. A peculiar function of pectoral fins, highly developed in some fish, is the creation of the dynamic lifting force that assists some fish, such as sharks, in maintaining depth and also enables the "flight" for flying fish.File:Thunnus obesus (Bigeye tuna) diagram cropped.GIFBigeye tuna Thunnus obesus showing finlets and keels.Drawing by Dr Tony Ayling In many fish, the pectoral fins aid in walking, especially in the lobe-like fins of some anglerfish and in the mudskipper. Certain rays of the pectoral fins may be adapted into finger-like projections, such as in sea robins and flying gurnards. The "horns" of manta rays and their relatives are called cephalic fins; this is actually a modification of the anterior portion of the pectoral fin. - A peculiar function of pectoral fins, highly developed in some fish, is the creation of the dynamic lifting force that assists some fish, such as sharks, in maintaining depth and also enables the "flight" for flying fish.File:Thunnus obesus (Bigeye tuna) diagram cropped.GIFBigeye tuna Thunnus obesus showing finlets and keels.Drawing by Dr Tony Ayling - In many fish, the pectoral fins aid in walking, especially in the lobe-like fins of some anglerfish and in the mudskipper. - Certain rays of the pectoral fins may be adapted into finger-like projections, such as in sea robins and flying gurnards. The "horns" of manta rays and their relatives are called cephalic fins; this is actually a modification of the anterior portion of the pectoral fin. - The "horns" of manta rays and their relatives are called cephalic fins; this is actually a modification of the anterior portion of the pectoral fin. - The paired pelvic or ventral fins are located ventrally below the pectoral fins. They are homologous to the hindlimbs of tetrapods. The pelvic fin assists the fish in going up or down through the water, turning sharply, and stopping quickly. In gobies, the pelvic fins are often fused into a single sucker disk. This can be used to attach to objects. - In gobies, the pelvic fins are often fused into a single sucker disk. This can be used to attach to objects. - The adipose fin is a soft, fleshy fin found on the back behind the dorsal fin and just forward of the caudal fin. It is absent in many fish families, but is found in Salmonidae, characins and catfishes. - Some types of fast-swimming fish have a horizontal caudal keel just forward of the tail fin. This is a lateral ridge on the caudal peduncle, usually composed of scutes (see below), that provides stability and support to the caudal fin. There may be a single paired keel, one on each side, or two pairs above and below. - Finlets are small fins, generally behind the dorsal and anal fins (in bichirs, there are only finlets on the dorsal surface and no dorsal fin). In some fish such as tuna or sauries, they are rayless, non-retractable, and found between the last dorsal and/or anal fin and the caudal fin. For every fin, there are a number of fish species in which this particular fin has been lost during evolution. ## Internal fertilization In many species of fish, fins have been modified to allow internal fertilization. A gonopodium is an anal fin that is modified into an intromittent organ in males of certain species of live-bearing fish in the families Anablepidae and Poeciliidae. It is movable and used to impregnate females during mating. The male's anal fin’s 3rd, 4th and 5th rays are formed into a tube like structure in which the sperm of the fish is ejected. In some species, the gonopodium may be as much as 50% of the total body length. Occasionally the fin is too long to be used, as in the "lyretail" breeds of Xiphophorus helleri. Hormone treated females may develop gonopodia. These are useless for breeding. One finds similar organs having the same characteristics in other types of fish, for example the andropodium in the Hemirhamphodon or in the Goodeidae. When ready for mating, the gonopodium becomes “erect” and points forward, towards the female. The male shortly inserts the organ into the sex opening of the female, with hook-like adaptations that allow the fish to grip onto the female to insure impregnation. If a female remains stationary and her partner contacts her vent with his gonopodium, she is fertilized. The sperm is preserved in the female's oviduct. This allows females to, at any time, fertilize themselves without further assistance of males. Male cartilaginous fish have claspers modified from pelvic fins. These are intromittent organs, used to channel semen into the female's cloaca during copulation. # Skin The outer body of many fish is covered with scales. Some species are covered instead by scutes. Others have no outer covering on the skin; these are called naked fish. Most fish are covered in a protective layer of slime (mucus). There are four types of fish scales. - Placoid scales, also called dermal denticles, are similar to teeth in that they are made of dentin covered by enamel. They are typical of sharks and rays. - Ganoid scales are flat, basal-looking scales that cover a fish body with little overlapping. They are typical of gar and bichirs. - Cycloid scales are small oval-shaped scales with growth rings. Bowfin and remora have cycloid scales. - Ctenoid scales are similar to the cycloid scales, with growth rings. They are distinguished by spines that cover one edge. Halibut have this type of scale. Another, less common, type of scale is the scute, which is: - an external shield-like bony plate, or - a modified, thickened scale that often is keeled or spiny, or - a projecting, modified (rough and strongly ridged) scale, usually associated with the lateral line, or on the caudal peduncle forming caudal keels, or along the ventral profile. Some fish, such as pineconefish, are completely or partially covered in scutes. # Internal organs - The gas bladder, or swim bladder, is an internal organ that contributes to the ability of a fish to control its buoyancy, and thus to stay at the current water depth, ascend, or descend without having to waste energy in swimming. It is often absent in fast swimming fishes such as the tuna and mackerel families. - Certain groups of fish have modifications to allow them to hear, such as the Weberian apparatus of Ostariophysians. - The gills, located under the operculum, are a respiratory organ for the extraction of oxygen from water and for the excretion of carbon dioxide. They are not usually visible, but can be seen in some species, such as the frilled shark. - The labyrinth organ of Anabantoidei and Clariidae is used to allow the fish to extract oxygen from the air. - Gill rakers are bony, finger-like projections of the gill arch filaments which function in filter-feeders in retaining food organisms. - Electric fish are able to produce electric fields by modified muscles in their body. - Many fish species are hermaphrodites. Synchronous hermaphrodites possess both ovaries and testes at the same time. Sequential hermaphrodites have both types of tissue in their gonads, with one type being predominant while the fish belongs to the corresponding gender.	Pectoral fins Fish anatomy is primarily governed by the physical characteristics of water, which is much denser than air, holds a relatively small amount of dissolved oxygen, and absorbs light more than air does. # Body Fish have a variety of different body plans. Their body is divided into head, trunk, and tail, although the divisions are not always externally visible. The body is often fusiform, a streamlined body plan often found in fast-moving fish. They may also be filiform (eel-shaped) or vermiform (worm-shaped). Also, fish are often either laterally compressed (thin) or vertically depressed (flat). The caudal peduncle is the narrow part of the fish's body to which the caudal or tail fin is attached. The hypural joint is the joint between the caudal fin and the last of the vertebrae. The hypural is often fan-shaped. Photophores are light-emitting organs which appears as luminous spots on some fishes. The light can be produced from compounds during the digestion of prey, from specialized mitochondrial cells in the organism called photocytes, or associated with symbiotic bacteria, and are used for attracting food or confusing predators. The lateral line is a sense organ used to detect movement and vibration in the surrounding water. In most species, it consists of a line of receptors running along each side of the fish. The ampullae of Lorenzini allow sharks to sense electrical discharges. The genital papilla is a small, fleshy tube behind the anus in some fishes, from which the sperm or eggs are released; the sex of a fish often can be determined by the shape of its papilla. ## Head The head includes the snout, from the eye to the forwardmost point of the upper jaw, the operculum or gill cover (absent in sharks), and the cheek, which extends from eye to preopercle. The operculum and preopercle may or may not have spines. The lower jaw defines a chin. In lampreys, the mouth is formed into an oral disk. In most jawed fish, however, there are three general configurations. The mouth may be on the forward end of the head (terminal), may be upturned (superior), or may be turned downwards or on the bottom of the fish (subterminal or inferior). The mouth may be modified into a suckermouth adapted for clinging onto objects in fast-moving water. The head may have several fleshy structures known as barbels, which may be very long and resemble whiskers. Many fish species also have a variety of protrusions or spines on the head. The nostrils or nares of almost all fishes do not connect to the oral cavity, but are pits of varying shape and depth. # Fins The fins are the most distinctive features of a fish. ## Spines and rays In bony fish, most fins may have spines or rays. A fin can contain only spiny rays, only soft rays, or a combination of both. If both are present, the spiny rays are always anterior. Spines are generally stiff and sharp. Rays are generally soft, flexible, segmented, and may be branched. This segmentation of rays is the main difference that separates them from spines; spines may be flexible in certain species, but they will never be segmented. The caudal fin is what is connected to the end of each fin. Spines have a variety of uses. In catfish, they are used as a form of defense; many catfish have the ability to lock their spines outwards. Triggerfish also use spines to lock themselves in crevices to prevent being pulled out. ## Types of fin - dorsal fins are located on the back. A fish can have up to three of them. The dorsal fins serve to protect the fish against rolling, and assists in sudden turns and stops. In anglerfish, the anterior of the dorsal fin is modified into an illicium and esca, a biological equivalent to a fishing pole and a lure. The bones that support the dorsal fin are called Pterygiophore. There are two to three of them: "proximal", "middle", and "distal". In spinous fins the distal is often fused to the middle, or not present at all. - In anglerfish, the anterior of the dorsal fin is modified into an illicium and esca, a biological equivalent to a fishing pole and a lure. - The bones that support the dorsal fin are called Pterygiophore. There are two to three of them: "proximal", "middle", and "distal". In spinous fins the distal is often fused to the middle, or not present at all. - The caudal fin is the tail fin, located at the end of the caudal peduncle. File:PletwyRyb.svgtypes of caudal fin :(A) - Heterocercal, (B) - Protocercal, (C) - Homocercal, (D) - Diphycercal The tail can be heterocercal, which means that the vertebrae extend into a larger lobe of the tail or that the tail is asymmetrical Epicercal means that the upper lobe is longer (as in sharks) Hypocercal means that the lower lobe is longer (as in flying fish) Protocercal means that the caudal fin extends around the vertebral column, present in embryonic fish and hagfish. This is not to be confused with a caudal fin that has fused with the dorsal and anal fins to form a contiguous fin. Diphycercal refers to the special, three-lobed caudal fin of the coelacanth and lungfish where the vertebrae extend all the way to the end of the tail. Most fish have a homocercal tail, where the vertebrae do not extend into a lobe and the fin is more or less symmetrical. This can be expressed in a variety of shapes. The tail fin may be rounded at the end. The tail fin may be truncated, or end in a more-or-less vertical edge (such as in salmon). The fin may be forked, or end in two prongs. The tail fin may be emarginate, or with a slight inward curve. The tail fin may be lunate, or shaped like a crescent moon. - The tail can be heterocercal, which means that the vertebrae extend into a larger lobe of the tail or that the tail is asymmetrical Epicercal means that the upper lobe is longer (as in sharks) Hypocercal means that the lower lobe is longer (as in flying fish) - Epicercal means that the upper lobe is longer (as in sharks) - Hypocercal means that the lower lobe is longer (as in flying fish) - Protocercal means that the caudal fin extends around the vertebral column, present in embryonic fish and hagfish. This is not to be confused with a caudal fin that has fused with the dorsal and anal fins to form a contiguous fin. - Diphycercal refers to the special, three-lobed caudal fin of the coelacanth and lungfish where the vertebrae extend all the way to the end of the tail. - Most fish have a homocercal tail, where the vertebrae do not extend into a lobe and the fin is more or less symmetrical. This can be expressed in a variety of shapes. The tail fin may be rounded at the end. The tail fin may be truncated, or end in a more-or-less vertical edge (such as in salmon). The fin may be forked, or end in two prongs. The tail fin may be emarginate, or with a slight inward curve. The tail fin may be lunate, or shaped like a crescent moon. - The tail fin may be rounded at the end. - The tail fin may be truncated, or end in a more-or-less vertical edge (such as in salmon). - The fin may be forked, or end in two prongs. - The tail fin may be emarginate, or with a slight inward curve. - The tail fin may be lunate, or shaped like a crescent moon. - The anal fin is located on the ventral surface behind the anus. This fin is used to stabilize the fish while swimming. - The paired pectoral fins are located on each side, usually just behind the operculum, and are homologous to the forelimbs of tetrapods. A peculiar function of pectoral fins, highly developed in some fish, is the creation of the dynamic lifting force that assists some fish, such as sharks, in maintaining depth and also enables the "flight" for flying fish.File:Thunnus obesus (Bigeye tuna) diagram cropped.GIFBigeye tuna Thunnus obesus showing finlets and keels.Drawing by Dr Tony Ayling In many fish, the pectoral fins aid in walking, especially in the lobe-like fins of some anglerfish and in the mudskipper. Certain rays of the pectoral fins may be adapted into finger-like projections, such as in sea robins and flying gurnards. The "horns" of manta rays and their relatives are called cephalic fins; this is actually a modification of the anterior portion of the pectoral fin. - A peculiar function of pectoral fins, highly developed in some fish, is the creation of the dynamic lifting force that assists some fish, such as sharks, in maintaining depth and also enables the "flight" for flying fish.File:Thunnus obesus (Bigeye tuna) diagram cropped.GIFBigeye tuna Thunnus obesus showing finlets and keels.Drawing by Dr Tony Ayling - In many fish, the pectoral fins aid in walking, especially in the lobe-like fins of some anglerfish and in the mudskipper. - Certain rays of the pectoral fins may be adapted into finger-like projections, such as in sea robins and flying gurnards. The "horns" of manta rays and their relatives are called cephalic fins; this is actually a modification of the anterior portion of the pectoral fin. - The "horns" of manta rays and their relatives are called cephalic fins; this is actually a modification of the anterior portion of the pectoral fin. - The paired pelvic or ventral fins are located ventrally below the pectoral fins. They are homologous to the hindlimbs of tetrapods. The pelvic fin assists the fish in going up or down through the water, turning sharply, and stopping quickly. In gobies, the pelvic fins are often fused into a single sucker disk. This can be used to attach to objects. - In gobies, the pelvic fins are often fused into a single sucker disk. This can be used to attach to objects. - The adipose fin is a soft, fleshy fin found on the back behind the dorsal fin and just forward of the caudal fin. It is absent in many fish families, but is found in Salmonidae, characins and catfishes. - Some types of fast-swimming fish have a horizontal caudal keel just forward of the tail fin. This is a lateral ridge on the caudal peduncle, usually composed of scutes (see below), that provides stability and support to the caudal fin. There may be a single paired keel, one on each side, or two pairs above and below. - Finlets are small fins, generally behind the dorsal and anal fins (in bichirs, there are only finlets on the dorsal surface and no dorsal fin). In some fish such as tuna or sauries, they are rayless, non-retractable, and found between the last dorsal and/or anal fin and the caudal fin. For every fin, there are a number of fish species in which this particular fin has been lost during evolution. ## Internal fertilization In many species of fish, fins have been modified to allow internal fertilization. A gonopodium is an anal fin that is modified into an intromittent organ in males of certain species of live-bearing fish in the families Anablepidae and Poeciliidae. It is movable and used to impregnate females during mating. The male's anal fin’s 3rd, 4th and 5th rays are formed into a tube like structure in which the sperm of the fish is ejected. In some species, the gonopodium may be as much as 50% of the total body length. Occasionally the fin is too long to be used, as in the "lyretail" breeds of Xiphophorus helleri. Hormone treated females may develop gonopodia. These are useless for breeding. One finds similar organs having the same characteristics in other types of fish, for example the andropodium in the Hemirhamphodon or in the Goodeidae. When ready for mating, the gonopodium becomes “erect” and points forward, towards the female. The male shortly inserts the organ into the sex opening of the female, with hook-like adaptations that allow the fish to grip onto the female to insure impregnation. If a female remains stationary and her partner contacts her vent with his gonopodium, she is fertilized. The sperm is preserved in the female's oviduct. This allows females to, at any time, fertilize themselves without further assistance of males. Male cartilaginous fish have claspers modified from pelvic fins. These are intromittent organs, used to channel semen into the female's cloaca during copulation. # Skin The outer body of many fish is covered with scales. Some species are covered instead by scutes. Others have no outer covering on the skin; these are called naked fish. Most fish are covered in a protective layer of slime (mucus). There are four types of fish scales. - Placoid scales, also called dermal denticles, are similar to teeth in that they are made of dentin covered by enamel. They are typical of sharks and rays. - Ganoid scales are flat, basal-looking scales that cover a fish body with little overlapping. They are typical of gar and bichirs. - Cycloid scales are small oval-shaped scales with growth rings. Bowfin and remora have cycloid scales. - Ctenoid scales are similar to the cycloid scales, with growth rings. They are distinguished by spines that cover one edge. Halibut have this type of scale. Another, less common, type of scale is the scute, which is: - an external shield-like bony plate, or - a modified, thickened scale that often is keeled or spiny, or - a projecting, modified (rough and strongly ridged) scale, usually associated with the lateral line, or on the caudal peduncle forming caudal keels, or along the ventral profile. Some fish, such as pineconefish, are completely or partially covered in scutes. # Internal organs - The gas bladder, or swim bladder, is an internal organ that contributes to the ability of a fish to control its buoyancy, and thus to stay at the current water depth, ascend, or descend without having to waste energy in swimming. It is often absent in fast swimming fishes such as the tuna and mackerel families. - Certain groups of fish have modifications to allow them to hear, such as the Weberian apparatus of Ostariophysians. - The gills, located under the operculum, are a respiratory organ for the extraction of oxygen from water and for the excretion of carbon dioxide. They are not usually visible, but can be seen in some species, such as the frilled shark. - The labyrinth organ of Anabantoidei and Clariidae is used to allow the fish to extract oxygen from the air. - Gill rakers are bony, finger-like projections of the gill arch filaments which function in filter-feeders in retaining food organisms. - Electric fish are able to produce electric fields by modified muscles in their body. - Many fish species are hermaphrodites. Synchronous hermaphrodites possess both ovaries and testes at the same time. Sequential hermaphrodites have both types of tissue in their gonads, with one type being predominant while the fish belongs to the corresponding gender.[1]	https://www.wikidoc.org/index.php/Pectoral_fins
9e818ec48057fa4634786ce3b45d257f4cedd868	wikidoc	Pediatric BLS	Pediatric BLS Synonyms and keywords: BLS, Basic life support in children, Pediatric BLS. # Overview Pediatric Basic Life Support is a life-saving skill comprising of high quality CPR (Cardiopulmonary Resuscitation) and Rescue Breadths with Artificial External Defibrillator (AED). Bystander CPR - Bystander resuscitation plays a key role in out of hospital CPR. A study done by Maryam Y Naim et al on communities practicing bystander CPR showed better survival outcomes in children less than 18 years from out of hospital cardiac arrest(CA). According to two studies done on a total of 781 children, about half of the Cardio-Respiratory arrests occur outside the hospital in children under 12 months. Good Prognostic Factor upon arrival at the emergency department include short interval between arrest and arrival at the hospital, less than 20 minutes of resuscitation in the emergency department, and less than 2 doses of epinephrine. # Classification - Pediatric Basic Life Support is classified according to age: Age - Less than 1 year - Infant Basic Life Support Age - 1 year to Puberty - Child Basic Life Support Age - After Puberty - Adult Basic Life Support - Age - Less than 1 year - Infant Basic Life Support - Age - 1 year to Puberty - Child Basic Life Support - Age - After Puberty - Adult Basic Life Support - BLS can be classified as: BLS in Out of hospital cardiac arrest (OHCA) BLS inpatient cardiac arrest (IHCA) - BLS in Out of hospital cardiac arrest (OHCA) - BLS inpatient cardiac arrest (IHCA) # Causes of Cardiac Arrest in Children - Following is a list of common causes of cardiac arrest (CA) in children: Ventricular Fibrillation Pulseless Ventricular tachycardia Children with preexisting cardiac disorders such as: Hypertrophic cardiomyopathy Anomalous coronary artery (from the pulmonary artery) Long QT syndrome Myocarditis Drug intoxication including the following drugs: Tricyclic antidepressants Digoxin Cocaine Commotio cordis - Ventricular Fibrillation - Pulseless Ventricular tachycardia - Children with preexisting cardiac disorders such as: Hypertrophic cardiomyopathy Anomalous coronary artery (from the pulmonary artery) Long QT syndrome Myocarditis - Hypertrophic cardiomyopathy - Anomalous coronary artery (from the pulmonary artery) - Long QT syndrome - Myocarditis - Drug intoxication including the following drugs: Tricyclic antidepressants Digoxin Cocaine - Tricyclic antidepressants - Digoxin - Cocaine - Commotio cordis # Goals of Resuscitation - The goal of resuscitation is to perform high quality CPR and have a better neurological outcome post-discharge. High quality CPR - Cardiopulmonary resuscitation comprises of effective chest compression and ventilation by rescue breath. According to the AHA guidelines 2015,2017,2010, the following are the steps for high-quality CPR. Rate - Rate of CPR is the frequency of the chest compressions in a minute the AHA guidelines recommend 100 compressions per minute. Depth- For high-quality CPR, the depth of the compressions should be 4 cm for infants and 5 cm for children more than 1 year of age. Chest recoil- Allow the chest to recoil during chest compression which allows blood to flow back to the heart and hence the to the other vital organs. CPR with rescue breaths- The above guidelines suggest better neurological complications in children more than 1 year of age who were given CPR with the rescue breaths as compared to children who received Compression- only CPR for cardiac arrest - According to the AHA guidelines 2015,2017,2010, the following are the steps for high-quality CPR. Rate - Rate of CPR is the frequency of the chest compressions in a minute the AHA guidelines recommend 100 compressions per minute. Depth- For high-quality CPR, the depth of the compressions should be 4 cm for infants and 5 cm for children more than 1 year of age. Chest recoil- Allow the chest to recoil during chest compression which allows blood to flow back to the heart and hence the to the other vital organs. CPR with rescue breaths- The above guidelines suggest better neurological complications in children more than 1 year of age who were given CPR with the rescue breaths as compared to children who received Compression- only CPR for cardiac arrest - Rate - Rate of CPR is the frequency of the chest compressions in a minute the AHA guidelines recommend 100 compressions per minute. - Depth- For high-quality CPR, the depth of the compressions should be 4 cm for infants and 5 cm for children more than 1 year of age. - Chest recoil- Allow the chest to recoil during chest compression which allows blood to flow back to the heart and hence the to the other vital organs. - CPR with rescue breaths- The above guidelines suggest better neurological complications in children more than 1 year of age who were given CPR with the rescue breaths as compared to children who received Compression- only CPR for cardiac arrest ## Variables with the good prognostic outcome Variables: - Age >1 year - Shockable rhythm like ventricular fibrillation - Less duration of CPR - Reactive pupil at 24 hours after ROSC - Lower serum lactate levels at 0 to 12 hours after ROSC is associated with improved outcomes. The following tables provide the details of the different studies done to determine which factors during pediatric cardiac arrest resuscitation have a superior prognosis. OHCA - Out of hospital cardiac arrest. ROSC- Return of spontaneous circulation. # Approach to a Suspected Patient of Cardiac or Respiratory Arrest Following is the list of AHA guidelines for a suspected patient of cardiac or respiratory arrest: - Look out for the safety of yourself as a bystander and the child/infant. - Call for help if alone and if 2 rescuers are present send one person to call the EMS (Emergency medical service) and get the AED (Automated external defibrillator). - Check for response ask "What is your name?" ''Can you hear me?" - Check if the child is breathing: If the child is breathing normally, don't do CPR. If the child is not breathing or is gasping for air, start CPR. - If the child is breathing normally, don't do CPR. - If the child is not breathing or is gasping for air, start CPR. - Check for a pulse in an infant, it is the Brachial pulse. For children above 1 year of age, check the femoral artery pulse or the Brachial pulse, for not more than 10 seconds. - The new 2010 and 2015 AHA guidelines have changed the order from "ABC" Airway, Breathing/ventilation, and Chest compressions (or Circulation) to "CAB" Compression (Circulation), Airway and Breathing/Ventilation. - High-quality chest compressions: For infants - Place 2 fingers below the intermammary line not compressing any rib or xiphoid process and start compressions 100/minute and up to 4 cm or 1.5-inch depth in infants and 5 cm or 2-inch depth in children above 1 year. Use two hands wrapped around the thorax for better grip depending on the size of the child to avoid exhaustion especially if its a lone rescuer. If 2 people are there give 15 chest compressions followed by 2 rescue breaths. Interchange the position every 2 minutes if 2 people are present to avoid exhaustion and ensure high-quality CPR. If there is a single person for CPR give 30 chest compressions followed by 2 rescue breaths. CPR with rescue breaths has more survival benefit in children vs CPR- Only Compressions. In children the majority of the cause for cardiac arrest is Asphyxia . If the lone rescuer is not trained in ventilation then Compression only CPR can be done. - For infants - Place 2 fingers below the intermammary line not compressing any rib or xiphoid process and start compressions 100/minute and up to 4 cm or 1.5-inch depth in infants and 5 cm or 2-inch depth in children above 1 year. - Use two hands wrapped around the thorax for better grip depending on the size of the child to avoid exhaustion especially if its a lone rescuer. - If 2 people are there give 15 chest compressions followed by 2 rescue breaths. Interchange the position every 2 minutes if 2 people are present to avoid exhaustion and ensure high-quality CPR. - If there is a single person for CPR give 30 chest compressions followed by 2 rescue breaths. - CPR with rescue breaths has more survival benefit in children vs CPR- Only Compressions. - In children the majority of the cause for cardiac arrest is Asphyxia . - If the lone rescuer is not trained in ventilation then Compression only CPR can be done. - Ventilation: If you are a lone rescuer, follow 30 x 2 cycle which is 30 compressions with 2 breaths. Observe for a chest rise as you are giving ventilation. Use the head tilt and chin lift method to open the airway for injured and non-injured children. If there is no chest rise after mouth to mouth ventilation adjust the neck. Infants- Follow mouth to mouth ventilation, pinch the nose to prevent air movement out of the nose. Mouth to nose ventilation can also be administered, close the mouth to prevent air being lost in the mouth. Children- Follow Mouth to Mouth ventilation with pinching the nose. In each of the rescue breaths make sure the chest rises and quickly resume immediately compressions in 30 x 2 cycle if you are a lone rescuer for improving the survival. - If you are a lone rescuer, follow 30 x 2 cycle which is 30 compressions with 2 breaths. Observe for a chest rise as you are giving ventilation. - Use the head tilt and chin lift method to open the airway for injured and non-injured children. - If there is no chest rise after mouth to mouth ventilation adjust the neck. - Infants- Follow mouth to mouth ventilation, pinch the nose to prevent air movement out of the nose. Mouth to nose ventilation can also be administered, close the mouth to prevent air being lost in the mouth. - Mouth to nose ventilation can also be administered, close the mouth to prevent air being lost in the mouth. - Children- Follow Mouth to Mouth ventilation with pinching the nose. - In each of the rescue breaths make sure the chest rises and quickly resume immediately compressions in 30 x 2 cycle if you are a lone rescuer for improving the survival. # Basic Life Support Guidelines (Revised American Heart Association 2010 Guidelines) Changes made in the new AHA guidelines 2010, 2015, 2017, 2019 According to the 2010,2015,2017,2019 Pediatric BLS Guidelines, the following changes were made and are followed: Pediatric BLS algorithm for single and 2 or more rescuers - For single rescuers start with 30 compressions followed by 2 rescue breaths. - For 2 or more rescuers start with 15 compressions followed by 2 rescue breaths and then both rescuers should change the positions alternating between compressions and breathing every 2 minutes. Change of order of A-B-C TO C-A-B - A-B-C is airway, breathing, and compressions in that order. C-A-B is compression, airway, and breathing. - This change was advised by the 2010 guidelines but in 2015 there is more evidence supporting this sequence of CPR. - Evidence: Manikin studies in both adults and children show a decrease in time to achieve the first chest compressions by following C-A-B compared to A-B-C. The delay in getting to ventilation was of 6 seconds compared with the new C-A-B compared to A-B-C. - Manikin studies in both adults and children show a decrease in time to achieve the first chest compressions by following C-A-B compared to A-B-C. - The delay in getting to ventilation was of 6 seconds compared with the new C-A-B compared to A-B-C. Chest compression rate and the depth - Adult model for compression rate and depth is to be followed for pediatrics cases due to lack of evidence. - More studies need to be found for the pediatric rate of compressions. - A study by Sutton RM et al reported among 87 pediatric CPR of more than 8 years of age, found that compression depth greater than 51 mm for more than 60% of the compressions during 30-second epochs within the first 5 minutes was associated with improved 24-hour survival. Compression-only (Hands-Only) CPR - Adult BLS protocols advise for CPR-Only resuscitation to achieve more compressions. - Pediatric cardiac arrest are majority due to asphyxia. Hence for children, it is advised to continue with CPR with rescue breaths. - If the rescuer is not trained or is not able to give rescue breaths then CPR-Only resuscitation is advised. # General Consideration - Performing a high-quality CPR based on the above guidelines can save a child's life and improve neurological outcomes. - Every community should be encouraged to get BLS- trained to ensure any person is able to deliver high-quality CPR until the EMS arrives. Limitations - C-A-B sequence change from A-B-C In order to accurately predict prognostic outcomes ROSC, survival to hospital admission, or survival to 180 days with the good neurologic outcome with respect to the C-A-B protocol there is a need for more pediatric clinical (human) studies in children as opposed to pediatric manikin studies. - In order to accurately predict prognostic outcomes ROSC, survival to hospital admission, or survival to 180 days with the good neurologic outcome with respect to the C-A-B protocol there is a need for more pediatric clinical (human) studies in children as opposed to pediatric manikin studies. - Chest compression depth Pediatric studies for the chest compression depth has a small sample size and the age of children is above 14 years in the adolescent phase which does not provide data for children less than 14 years and infants. The hospital data for OHCA is not available for the depth of compression on different surfaces. - Pediatric studies for the chest compression depth has a small sample size and the age of children is above 14 years in the adolescent phase which does not provide data for children less than 14 years and infants. - The hospital data for OHCA is not available for the depth of compression on different surfaces. AED (Automated external defibrillator) - AED is a device that is useful in as it delivers shock and does not require the bystander or lay rescuer to recognize different types of heart rhythm. - If you want to be trained in AED access this website by REDCROSS - If a manual defibrillator is not available an AED automated external defibrillator is used. - A study published by Ecker R et al concluded that older bystanders previously trained in AED are successfully able to deliver a shock for ventricular fibrillation with dispatcher assistance. - 2 minutes compression and ventilation cycle should be done before using the AED. - If there are 2 bystanders send one person to get the AED and one person should start CPR immediately. - A study by Dianne L.Atkinsa et all found the AED used in children less than 8 years of age is able to find both shockable rhythm with high sensitivity and high specificity. Steps to use AED: - Follow the AED Prompt. - Stop CPR when the AED is analyzing the rhythm and giving a shock. - Resume compressions immediately after giving shock and minimize interruptions during compressions. - Place the right pad of the AED on right below the clavicle. - Place the left pad of the AED on the left chest lateral to the left breast. - Other positions - Left pad is placed at the apex 5th Intercoastal space and the right pad placed on the left upper back. - Keep the one-inch distance between the pads and the implantable device. - Don't put the pads on a transdermal patch as it can burn the skin where the patch is placed. Foreign Body Airway Obstruction(FBAO) - Foreign Body Airway Obstruction(FBAO) also known as choking is blocking the airway which comprises of the pharynx and trachea. Children less than 3 years are at risk of choking due to the still-developing phase for swallowing and chewing. Parents, teachers should keep an eye for objects like coins, toys, balloons, and other food. - A study by C S Harris et al concluded that one death due to choking occurred every 5 days the data was analyzed for infants and children from 0-9 years for a period of 3 years. - The choking was associated with high risk in children less than 5 years of age due to meat products. - Hot dog was the most common food identified along with hard candy, nuts. - Airway obstruction - Steps to follow If the airway obstruction is mild, where the child is able to respond wait for the child to clear it and monitor for signs of severe obstruction. If the airway obstruction is severe, where the child will be silent quickly start the Heimlich maneuver or subdiaphragmatic abdominal thrust for children. For infants do 5 back blows followed by 5 compressions as abdominal thrust can damage the liver. If the child/infant becomes unresponsive start CPR immediately. After 1 cycle which will be 30 compressions check the airway if the foreign body is visible remove it but if it's not visible or accessible do not probe blindly as the foreign body can be displaced which will further damage the oropharynx. Give 2 rescue breaths after compressions and continue with compressions and ventilation cycle until the foreign body is out. - If the airway obstruction is mild, where the child is able to respond wait for the child to clear it and monitor for signs of severe obstruction. - If the airway obstruction is severe, where the child will be silent quickly start the Heimlich maneuver or subdiaphragmatic abdominal thrust for children. - For infants do 5 back blows followed by 5 compressions as abdominal thrust can damage the liver. - If the child/infant becomes unresponsive start CPR immediately. After 1 cycle which will be 30 compressions check the airway if the foreign body is visible remove it but if it's not visible or accessible do not probe blindly as the foreign body can be displaced which will further damage the oropharynx. Give 2 rescue breaths after compressions and continue with compressions and ventilation cycle until the foreign body is out. - After 1 cycle which will be 30 compressions check the airway if the foreign body is visible remove it but if it's not visible or accessible do not probe blindly as the foreign body can be displaced which will further damage the oropharynx. - Give 2 rescue breaths after compressions and continue with compressions and ventilation cycle until the foreign body is out. Resuscitation in special circumstances Child with a tracheostomy tube or stoma - The caregiver (Parents, nurse, or teacher) should be trained in how to use the tracheostomy tube. - If there is a cardiac arrest in a child with a tracheostomy start immediately CPR with compressions followed by ventilation of 2 rescue breaths. - Ventilation Give rescue breaths from mouth to a tracheostomy tube, if the chest does not rise to suction the tube, if still there is no chest rise then can give mouth to stoma ventilation or bag - mask ventilation if available. - Give rescue breaths from mouth to a tracheostomy tube, if the chest does not rise to suction the tube, if still there is no chest rise then can give mouth to stoma ventilation or bag - mask ventilation if available. Child with spinal trauma - Steps to follow in a pediatric trauma case with cardiac arrest. - Look for airway obstruction. - If there is bleeding try to tie a tourniquet and apply external pressure. - If spinal cord trauma is suspected try to avoid cervical spine movement. In spinal cord trauma, ventilation should be done with caution apply jaw thrust and do not tilt head. If the jaw thrust is not successful then one rescuer would minimize the motion of the cervical spine and the other rescuer should attempt to give rescue breadth by head still and chin lift method. To achieve a neutral position for a child while in supine posture a study by Nypaver M et all mentions that the back needs to be elevated in children less than 7 years. In children less than 7 years its found that they have a disproportionately large head compared to their full bodies and when in a supine position the neck gets flexed. To prevent cervical motion changes should be made to the backboard. Changes like Raise the chest by putting a double mattress pad or use a recess for the occiput to lower the head. - In spinal cord trauma, ventilation should be done with caution apply jaw thrust and do not tilt head. - If the jaw thrust is not successful then one rescuer would minimize the motion of the cervical spine and the other rescuer should attempt to give rescue breadth by head still and chin lift method. - To achieve a neutral position for a child while in supine posture a study by Nypaver M et all mentions that the back needs to be elevated in children less than 7 years. - In children less than 7 years its found that they have a disproportionately large head compared to their full bodies and when in a supine position the neck gets flexed. To prevent cervical motion changes should be made to the backboard. Changes like Raise the chest by putting a double mattress pad or use a recess for the occiput to lower the head. - To prevent cervical motion changes should be made to the backboard. - Changes like Raise the chest by putting a double mattress pad or use a recess for the occiput to lower the head. Child drowning - The rescuer should try to get the drowning child as soon as possible out of the water and start CPR after checking pulse and ventilation. - If the rescuer has training in In water resuscitation start ventilation in water Below is the IWR (In Water Resuscitation) guidelines: - Check if the child is breathing or conscious in the water. If the child is breathing quickly swim back and get the child out of the water. If the child is not breathing then give rescue breaths if spinal trauma is suspected then try to immobilize the spine while opening the airway and try to reach the shore as soon as possible. If the distance to reach the shore is more than 5 minutes, try to give one more rescue breath 12-16 breaths/minute. - If the child is breathing quickly swim back and get the child out of the water. - If the child is not breathing then give rescue breaths if spinal trauma is suspected then try to immobilize the spine while opening the airway and try to reach the shore as soon as possible. - If the distance to reach the shore is more than 5 minutes, try to give one more rescue breath 12-16 breaths/minute.	Pediatric BLS Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Neepa Shah, M.D. Synonyms and keywords: BLS, Basic life support in children, Pediatric BLS. # Overview Pediatric Basic Life Support is a life-saving skill comprising of high quality CPR (Cardiopulmonary Resuscitation) and Rescue Breadths with Artificial External Defibrillator (AED). Bystander CPR - Bystander resuscitation plays a key role in out of hospital CPR. A study done by Maryam Y Naim et al on communities practicing bystander CPR showed better survival outcomes in children less than 18 years from out of hospital cardiac arrest(CA). According to two studies done on a total of 781 children, about half of the Cardio-Respiratory arrests occur outside the hospital in children under 12 months. Good Prognostic Factor upon arrival at the emergency department include short interval between arrest and arrival at the hospital, less than 20 minutes of resuscitation in the emergency department, and less than 2 doses of epinephrine. # Classification - Pediatric Basic Life Support is classified according to age:[1][2][3] Age - Less than 1 year - Infant Basic Life Support Age - 1 year to Puberty - Child Basic Life Support Age - After Puberty - Adult Basic Life Support - Age - Less than 1 year - Infant Basic Life Support - Age - 1 year to Puberty - Child Basic Life Support - Age - After Puberty - Adult Basic Life Support - BLS can be classified as: BLS in Out of hospital cardiac arrest (OHCA) BLS inpatient cardiac arrest (IHCA) - BLS in Out of hospital cardiac arrest (OHCA) - BLS inpatient cardiac arrest (IHCA) # Causes of Cardiac Arrest in Children - Following is a list of common causes of cardiac arrest (CA) in children: Ventricular Fibrillation Pulseless Ventricular tachycardia Children with preexisting cardiac disorders such as: Hypertrophic cardiomyopathy Anomalous coronary artery (from the pulmonary artery) Long QT syndrome Myocarditis Drug intoxication including the following drugs: Tricyclic antidepressants Digoxin Cocaine Commotio cordis - Ventricular Fibrillation - Pulseless Ventricular tachycardia - Children with preexisting cardiac disorders such as: Hypertrophic cardiomyopathy Anomalous coronary artery (from the pulmonary artery) Long QT syndrome Myocarditis - Hypertrophic cardiomyopathy - Anomalous coronary artery (from the pulmonary artery) - Long QT syndrome - Myocarditis - Drug intoxication including the following drugs: Tricyclic antidepressants Digoxin Cocaine - Tricyclic antidepressants - Digoxin - Cocaine - Commotio cordis # Goals of Resuscitation - The goal of resuscitation is to perform high quality CPR and have a better neurological outcome post-discharge.[3] High quality CPR - Cardiopulmonary resuscitation comprises of effective chest compression and ventilation by rescue breath. According to the AHA guidelines 2015,2017,2010, the following are the steps for high-quality CPR. Rate - Rate of CPR is the frequency of the chest compressions in a minute the AHA guidelines recommend 100 compressions per minute. Depth- For high-quality CPR, the depth of the compressions should be 4 cm for infants and 5 cm for children more than 1 year of age. Chest recoil- Allow the chest to recoil during chest compression which allows blood to flow back to the heart and hence the to the other vital organs. CPR with rescue breaths- The above guidelines suggest better neurological complications in children more than 1 year of age who were given CPR with the rescue breaths as compared to children who received Compression- only CPR for cardiac arrest - According to the AHA guidelines 2015,2017,2010, the following are the steps for high-quality CPR. Rate - Rate of CPR is the frequency of the chest compressions in a minute the AHA guidelines recommend 100 compressions per minute. Depth- For high-quality CPR, the depth of the compressions should be 4 cm for infants and 5 cm for children more than 1 year of age. Chest recoil- Allow the chest to recoil during chest compression which allows blood to flow back to the heart and hence the to the other vital organs. CPR with rescue breaths- The above guidelines suggest better neurological complications in children more than 1 year of age who were given CPR with the rescue breaths as compared to children who received Compression- only CPR for cardiac arrest - Rate - Rate of CPR is the frequency of the chest compressions in a minute the AHA guidelines recommend 100 compressions per minute. - Depth- For high-quality CPR, the depth of the compressions should be 4 cm for infants and 5 cm for children more than 1 year of age. - Chest recoil- Allow the chest to recoil during chest compression which allows blood to flow back to the heart and hence the to the other vital organs. - CPR with rescue breaths- The above guidelines suggest better neurological complications in children more than 1 year of age who were given CPR with the rescue breaths as compared to children who received Compression- only CPR for cardiac arrest ## Variables with the good prognostic outcome Variables: - Age >1 year - Shockable rhythm like ventricular fibrillation - Less duration of CPR - Reactive pupil at 24 hours after ROSC - Lower serum lactate levels at 0 to 12 hours after ROSC is associated with improved outcomes. The following tables provide the details of the different studies done to determine which factors during pediatric cardiac arrest resuscitation have a superior prognosis.[4] OHCA - Out of hospital cardiac arrest. ROSC- Return of spontaneous circulation. # Approach to a Suspected Patient of Cardiac or Respiratory Arrest Following is the list of AHA guidelines for a suspected patient of cardiac or respiratory arrest:[8] - Look out for the safety of yourself as a bystander and the child/infant. - Call for help if alone and if 2 rescuers are present send one person to call the EMS (Emergency medical service) and get the AED (Automated external defibrillator). - Check for response ask "What is your name?" ''Can you hear me?" - Check if the child is breathing: If the child is breathing normally, don't do CPR. If the child is not breathing or is gasping for air, start CPR. - If the child is breathing normally, don't do CPR. - If the child is not breathing or is gasping for air, start CPR. - Check for a pulse in an infant, it is the Brachial pulse. For children above 1 year of age, check the femoral artery pulse or the Brachial pulse, for not more than 10 seconds. - The new 2010 and 2015 AHA guidelines have changed the order from "ABC" Airway, Breathing/ventilation, and Chest compressions (or Circulation) to "CAB" Compression (Circulation), Airway and Breathing/Ventilation. - High-quality chest compressions: For infants - Place 2 fingers below the intermammary line not compressing any rib or xiphoid process and start compressions 100/minute and up to 4 cm or 1.5-inch depth in infants and 5 cm or 2-inch depth in children above 1 year. Use two hands wrapped around the thorax for better grip depending on the size of the child to avoid exhaustion especially if its a lone rescuer. If 2 people are there give 15 chest compressions followed by 2 rescue breaths. Interchange the position every 2 minutes if 2 people are present to avoid exhaustion and ensure high-quality CPR. If there is a single person for CPR give 30 chest compressions followed by 2 rescue breaths. CPR with rescue breaths has more survival benefit in children vs CPR- Only Compressions. In children the majority of the cause for cardiac arrest is Asphyxia . If the lone rescuer is not trained in ventilation then Compression only CPR can be done. - For infants - Place 2 fingers below the intermammary line not compressing any rib or xiphoid process and start compressions 100/minute and up to 4 cm or 1.5-inch depth in infants and 5 cm or 2-inch depth in children above 1 year. - Use two hands wrapped around the thorax for better grip depending on the size of the child to avoid exhaustion especially if its a lone rescuer. - If 2 people are there give 15 chest compressions followed by 2 rescue breaths. Interchange the position every 2 minutes if 2 people are present to avoid exhaustion and ensure high-quality CPR. - If there is a single person for CPR give 30 chest compressions followed by 2 rescue breaths. - CPR with rescue breaths has more survival benefit in children vs CPR- Only Compressions. - In children the majority of the cause for cardiac arrest is Asphyxia . - If the lone rescuer is not trained in ventilation then Compression only CPR can be done. - Ventilation: If you are a lone rescuer, follow 30 x 2 cycle which is 30 compressions with 2 breaths. Observe for a chest rise as you are giving ventilation. Use the head tilt and chin lift method to open the airway for injured and non-injured children. If there is no chest rise after mouth to mouth ventilation adjust the neck. Infants- Follow mouth to mouth ventilation, pinch the nose to prevent air movement out of the nose. Mouth to nose ventilation can also be administered, close the mouth to prevent air being lost in the mouth. Children- Follow Mouth to Mouth ventilation with pinching the nose. In each of the rescue breaths make sure the chest rises and quickly resume immediately compressions in 30 x 2 cycle if you are a lone rescuer for improving the survival. - If you are a lone rescuer, follow 30 x 2 cycle which is 30 compressions with 2 breaths. Observe for a chest rise as you are giving ventilation. - Use the head tilt and chin lift method to open the airway for injured and non-injured children. - If there is no chest rise after mouth to mouth ventilation adjust the neck. - Infants- Follow mouth to mouth ventilation, pinch the nose to prevent air movement out of the nose. Mouth to nose ventilation can also be administered, close the mouth to prevent air being lost in the mouth. - Mouth to nose ventilation can also be administered, close the mouth to prevent air being lost in the mouth. - Children- Follow Mouth to Mouth ventilation with pinching the nose. - In each of the rescue breaths make sure the chest rises and quickly resume immediately compressions in 30 x 2 cycle if you are a lone rescuer for improving the survival. # Basic Life Support Guidelines (Revised American Heart Association 2010 Guidelines) Changes made in the new AHA guidelines 2010, 2015, 2017, 2019 According to the 2010,2015,2017,2019 Pediatric BLS Guidelines, the following changes were made and are followed:[9][8][4][3] Pediatric BLS algorithm for single and 2 or more rescuers - For single rescuers start with 30 compressions followed by 2 rescue breaths. - For 2 or more rescuers start with 15 compressions followed by 2 rescue breaths and then both rescuers should change the positions alternating between compressions and breathing every 2 minutes. Change of order of A-B-C TO C-A-B - A-B-C is airway, breathing, and compressions in that order. C-A-B is compression, airway, and breathing.[4] - This change was advised by the 2010 guidelines but in 2015 there is more evidence supporting this sequence of CPR. - Evidence: Manikin studies in both adults and children show a decrease in time to achieve the first chest compressions by following C-A-B compared to A-B-C. The delay in getting to ventilation was of 6 seconds compared with the new C-A-B compared to A-B-C. - Manikin studies in both adults and children show a decrease in time to achieve the first chest compressions by following C-A-B compared to A-B-C. - The delay in getting to ventilation was of 6 seconds compared with the new C-A-B compared to A-B-C. Chest compression rate and the depth - Adult model for compression rate and depth is to be followed for pediatrics cases due to lack of evidence. - More studies need to be found for the pediatric rate of compressions. - A study by Sutton RM et al reported among 87 pediatric CPR of more than 8 years of age, found that compression depth greater than 51 mm for more than 60% of the compressions during 30-second epochs within the first 5 minutes was associated with improved 24-hour survival. Compression-only (Hands-Only) CPR - Adult BLS protocols advise for CPR-Only resuscitation to achieve more compressions. - Pediatric cardiac arrest are majority due to asphyxia. Hence for children, it is advised to continue with CPR with rescue breaths. - If the rescuer is not trained or is not able to give rescue breaths then CPR-Only resuscitation is advised. # General Consideration - Performing a high-quality CPR based on the above guidelines can save a child's life and improve neurological outcomes. - Every community should be encouraged to get BLS- trained to ensure any person is able to deliver high-quality CPR until the EMS arrives. Limitations - C-A-B sequence change from A-B-C In order to accurately predict prognostic outcomes ROSC, survival to hospital admission, or survival to 180 days with the good neurologic outcome with respect to the C-A-B protocol there is a need for more pediatric clinical (human) studies in children as opposed to pediatric manikin studies.[4] - In order to accurately predict prognostic outcomes ROSC, survival to hospital admission, or survival to 180 days with the good neurologic outcome with respect to the C-A-B protocol there is a need for more pediatric clinical (human) studies in children as opposed to pediatric manikin studies.[4] - Chest compression depth[4] Pediatric studies for the chest compression depth has a small sample size and the age of children is above 14 years in the adolescent phase which does not provide data for children less than 14 years and infants. The hospital data for OHCA is not available for the depth of compression on different surfaces. - Pediatric studies for the chest compression depth has a small sample size and the age of children is above 14 years in the adolescent phase which does not provide data for children less than 14 years and infants. - The hospital data for OHCA is not available for the depth of compression on different surfaces. AED (Automated external defibrillator) - AED is a device that is useful in as it delivers shock and does not require the bystander or lay rescuer to recognize different types of heart rhythm. - If you want to be trained in AED access this website by REDCROSS https://www.redcross.org/take-a-class/aed - If a manual defibrillator is not available an AED automated external defibrillator is used. - A study published by Ecker R et al concluded that older bystanders previously trained in AED are successfully able to deliver a shock for ventricular fibrillation with dispatcher assistance.[8] - 2 minutes compression and ventilation cycle should be done before using the AED. - If there are 2 bystanders send one person to get the AED and one person should start CPR immediately. - A study by Dianne L.Atkinsa et all found the AED used in children less than 8 years of age is able to find both shockable rhythm with high sensitivity and high specificity. Steps to use AED: - Follow the AED Prompt. - Stop CPR when the AED is analyzing the rhythm and giving a shock. - Resume compressions immediately after giving shock and minimize interruptions during compressions. - Place the right pad of the AED on right below the clavicle. - Place the left pad of the AED on the left chest lateral to the left breast. - Other positions - Left pad is placed at the apex 5th Intercoastal space and the right pad placed on the left upper back. - Keep the one-inch distance between the pads and the implantable device. - Don't put the pads on a transdermal patch as it can burn the skin where the patch is placed. Foreign Body Airway Obstruction(FBAO) - Foreign Body Airway Obstruction(FBAO) also known as choking is blocking the airway which comprises of the pharynx and trachea. Children less than 3 years are at risk of choking due to the still-developing phase for swallowing and chewing. Parents, teachers should keep an eye for objects like coins, toys, balloons, and other food. - A study by C S Harris et al concluded that one death due to choking occurred every 5 days the data was analyzed for infants and children from 0-9 years for a period of 3 years. - The choking was associated with high risk in children less than 5 years of age due to meat products. - Hot dog was the most common food identified along with hard candy, nuts. - Airway obstruction - Steps to follow If the airway obstruction is mild, where the child is able to respond wait for the child to clear it and monitor for signs of severe obstruction. If the airway obstruction is severe, where the child will be silent quickly start the Heimlich maneuver or subdiaphragmatic abdominal thrust for children. For infants do 5 back blows followed by 5 compressions as abdominal thrust can damage the liver. If the child/infant becomes unresponsive start CPR immediately. After 1 cycle which will be 30 compressions check the airway if the foreign body is visible remove it but if it's not visible or accessible do not probe blindly as the foreign body can be displaced which will further damage the oropharynx. Give 2 rescue breaths after compressions and continue with compressions and ventilation cycle until the foreign body is out. - If the airway obstruction is mild, where the child is able to respond wait for the child to clear it and monitor for signs of severe obstruction. - If the airway obstruction is severe, where the child will be silent quickly start the Heimlich maneuver or subdiaphragmatic abdominal thrust for children. - For infants do 5 back blows followed by 5 compressions as abdominal thrust can damage the liver. - If the child/infant becomes unresponsive start CPR immediately. After 1 cycle which will be 30 compressions check the airway if the foreign body is visible remove it but if it's not visible or accessible do not probe blindly as the foreign body can be displaced which will further damage the oropharynx. Give 2 rescue breaths after compressions and continue with compressions and ventilation cycle until the foreign body is out. - After 1 cycle which will be 30 compressions check the airway if the foreign body is visible remove it but if it's not visible or accessible do not probe blindly as the foreign body can be displaced which will further damage the oropharynx. - Give 2 rescue breaths after compressions and continue with compressions and ventilation cycle until the foreign body is out. Resuscitation in special circumstances Child with a tracheostomy tube or stoma - The caregiver (Parents, nurse, or teacher) should be trained in how to use the tracheostomy tube. - If there is a cardiac arrest in a child with a tracheostomy start immediately CPR with compressions followed by ventilation of 2 rescue breaths. - Ventilation Give rescue breaths from mouth to a tracheostomy tube, if the chest does not rise to suction the tube, if still there is no chest rise then can give mouth to stoma ventilation or bag - mask ventilation if available. - Give rescue breaths from mouth to a tracheostomy tube, if the chest does not rise to suction the tube, if still there is no chest rise then can give mouth to stoma ventilation or bag - mask ventilation if available. Child with spinal trauma - Steps to follow in a pediatric trauma case with cardiac arrest. - Look for airway obstruction. - If there is bleeding try to tie a tourniquet and apply external pressure. - If spinal cord trauma is suspected try to avoid cervical spine movement. In spinal cord trauma, ventilation should be done with caution apply jaw thrust and do not tilt head. If the jaw thrust is not successful then one rescuer would minimize the motion of the cervical spine and the other rescuer should attempt to give rescue breadth by head still and chin lift method. To achieve a neutral position for a child while in supine posture a study by Nypaver M et all mentions that the back needs to be elevated in children less than 7 years. In children less than 7 years its found that they have a disproportionately large head compared to their full bodies and when in a supine position the neck gets flexed. To prevent cervical motion changes should be made to the backboard. Changes like Raise the chest by putting a double mattress pad or use a recess for the occiput to lower the head.[8] - In spinal cord trauma, ventilation should be done with caution apply jaw thrust and do not tilt head. - If the jaw thrust is not successful then one rescuer would minimize the motion of the cervical spine and the other rescuer should attempt to give rescue breadth by head still and chin lift method. - To achieve a neutral position for a child while in supine posture a study by Nypaver M et all mentions that the back needs to be elevated in children less than 7 years. - In children less than 7 years its found that they have a disproportionately large head compared to their full bodies and when in a supine position the neck gets flexed. To prevent cervical motion changes should be made to the backboard. Changes like Raise the chest by putting a double mattress pad or use a recess for the occiput to lower the head.[8] - To prevent cervical motion changes should be made to the backboard. - Changes like Raise the chest by putting a double mattress pad or use a recess for the occiput to lower the head.[8] Child drowning - The rescuer should try to get the drowning child as soon as possible out of the water and start CPR after checking pulse and ventilation.[8] - If the rescuer has training in In water resuscitation start ventilation in water Below is the IWR (In Water Resuscitation) guidelines: - Check if the child is breathing or conscious in the water. If the child is breathing quickly swim back and get the child out of the water. If the child is not breathing then give rescue breaths if spinal trauma is suspected then try to immobilize the spine while opening the airway and try to reach the shore as soon as possible. If the distance to reach the shore is more than 5 minutes, try to give one more rescue breath 12-16 breaths/minute.[8] - If the child is breathing quickly swim back and get the child out of the water. - If the child is not breathing then give rescue breaths if spinal trauma is suspected then try to immobilize the spine while opening the airway and try to reach the shore as soon as possible. - If the distance to reach the shore is more than 5 minutes, try to give one more rescue breath 12-16 breaths/minute.[8]	https://www.wikidoc.org/index.php/Pediatric_BLS
3ba64e5e0d367000e5b913e6216e4fe25fa7b546	wikidoc	Sucking louse	Sucking louse Sucking lice (Anoplura) have around 500 species and represent the smaller of the two traditional suborders of lice. The Anoplura are all blood-feeding ectoparasites of mammals. They can cause localised skin irritations and are vectors of several blood-borne diseases. Children appear particularly susceptible to attracting lice, possibly due to their fine hair. At least three species of Anoplura are parasites of humans; the human condition of being infested with sucking lice is called pediculosis. Pediculus humanus is divided into two subspecies, Pediculus humanus humanus, or the body louse, sometimes nicknamed "the seam squirrel" for its habit of laying of eggs in the seams of clothing, and Pediculus humanus capitis, or the head louse. Phthirus pubis (the pubic louse) is the cause of the condition known as crabs. de:Tierläuse eo:Anopluroj lt:Utėlės sv:Blodsugande löss	Sucking louse Sucking lice (Anoplura) have around 500 species and represent the smaller of the two traditional suborders of lice. The Anoplura are all blood-feeding ectoparasites of mammals. They can cause localised skin irritations and are vectors of several blood-borne diseases. Children appear particularly susceptible to attracting lice, possibly due to their fine hair. At least three species of Anoplura are parasites of humans; the human condition of being infested with sucking lice is called pediculosis. Pediculus humanus is divided into two subspecies, Pediculus humanus humanus, or the body louse, sometimes nicknamed "the seam squirrel" for its habit of laying of eggs in the seams of clothing, and Pediculus humanus capitis, or the head louse. Phthirus pubis (the pubic louse) is the cause of the condition known as crabs. de:Tierläuse eo:Anopluroj lt:Utėlės sv:Blodsugande löss Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Pediculus_humanus

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