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1e778e1aa9479460dc800f27c97f950b49331a90 | wikidoc | Appetite | Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher lifeforms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is termed anorexia, while polyphagia (or "hyperphagia") is increased eating. Disregulation of appetite contributes to anorexia nervosa, bulimia nervosa, cachexia, overeating, and binge eating disorder.
# Regulation
The regulation of appetite has been the subject of much research in the last decade. Breakthroughs included the discovery, in 1994, of leptin, a hormone that appeared to provide negative feedback. Later studies showed that appetite regulation is an immensely complex process involving the gastrointestinal tract, many hormones, and both the central and autonomic nervous systems.
## Effector
The hypothalamus, a part of the brain, is the main regulatory organ for human appetite. The neurons that regulate appetite appear to be mainly serotonergic, although neuropeptide Y (NPY) and Agouti-related peptide (AGRP) also play a vital role. Hypothalamocortical and hypothalamolimbic projections contribute to the awareness of hunger, and the somatic processes controlled by the hypothalamus include vagal tone (the activity of the parasympathetic autonomic nervous system), stimulation of the thyroid (thyroxine regulates the metabolic rate), the hypothalamic-pituitary-adrenal axis and a large number of other mechanisms.
## Sensor
The hypothalamus senses external stimuli mainly through a number of hormones such as leptin, ghrelin, PYY 3-36, orexin and cholecystokinin; all modify the hypothalamic response. They are produced by the digestive tract and by adipose tissue (leptin). Systemic mediators, such as tumor necrosis factor-alpha (TNFα), interleukins 1 and 6 and corticotropin-releasing hormone (CRH) influence appetite negatively; this mechanism explains why ill people often eat less.
In addition, the biological clock (which is regulated by the hypothalamus) modifies hunger. Processes from other cerebral loci, such as from the limbic system and the cerebral cortex, project on the hypothalamus and modify appetite. This explains why in clinical depression and stress, energy intake can change quite drastically.
# Role in disease
A limited or excessive appetite is not necessarily pathological. Abnormal appetite could be defined as eating habits causing malnutrition on the one side or obesity and its related problems on the other.
Both genetic and environmental factors may regulate appetite, and abnormalities in either may lead to abnormal appetite. Poor appetite (anorexia) may have numerous causes, but may be a result of physical (infectious, autoimmune or malignant disease) or psychological (stress, mental disorders) factors. Likewise, hyperphagia (excessive eating) may be a result of hormonal imbalances, mental disorders (e.g. depression) and others.
Dysregulation of appetite lies at the root of anorexia nervosa, bulimia nervosa and binge eating disorder. In addition, decreased response to satiety may promote development of obesity.
Various hereditary forms of obesity have been traced to defects in hypothalamic signalling (such as the leptin receptor and the MC-4 receptor), or are still awaiting characterisation (Prader-Willi syndrome).
# Pharmacology
Mechanisms controlling appetite are a potential target for weight loss drugs. Early anorectics were fenfluramine and phentermine. A more recent addition is sibutramine (Reductil®, Meridia®), which increases serotonin and noradrenaline levels in the central nervous system. In addition, recent reports on recombinant PYY 3-36 suggest that this agent may contribute to weight loss by suppressing appetite.
Given the epidemic proportions of obesity in the Western world, developments in this area are expected to snowball in the near future, as dieting alone is ineffective in most obese adults.
# Further reading
- Neary NM, Goldstone AP, Bloom SR. Appetite regulation: from the gut to the hypothalamus. Clin Endocrinol (Oxford) 2004;60:153-60. PMID 14725674.
- Wynne K, Stanley S, Bloom S. The gut and regulation of body weight. J Clin Endocrinol Metab 2004;89:2576–82. PMID 15181026.
ar:شهية
de:Appetit
he:תיאבון
lt:Apetitas
uk:Апетит | Appetite
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher lifeforms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is termed anorexia, while polyphagia (or "hyperphagia") is increased eating. Disregulation of appetite contributes to anorexia nervosa, bulimia nervosa, cachexia, overeating, and binge eating disorder.
# Regulation
The regulation of appetite has been the subject of much research in the last decade. Breakthroughs included the discovery, in 1994, of leptin, a hormone that appeared to provide negative feedback. Later studies showed that appetite regulation is an immensely complex process involving the gastrointestinal tract, many hormones, and both the central and autonomic nervous systems.
## Effector
The hypothalamus, a part of the brain, is the main regulatory organ for human appetite. The neurons that regulate appetite appear to be mainly serotonergic, although neuropeptide Y (NPY) and Agouti-related peptide (AGRP) also play a vital role. Hypothalamocortical and hypothalamolimbic projections contribute to the awareness of hunger, and the somatic processes controlled by the hypothalamus include vagal tone (the activity of the parasympathetic autonomic nervous system), stimulation of the thyroid (thyroxine regulates the metabolic rate), the hypothalamic-pituitary-adrenal axis and a large number of other mechanisms.
## Sensor
The hypothalamus senses external stimuli mainly through a number of hormones such as leptin, ghrelin, PYY 3-36, orexin and cholecystokinin; all modify the hypothalamic response. They are produced by the digestive tract and by adipose tissue (leptin). Systemic mediators, such as tumor necrosis factor-alpha (TNFα), interleukins 1 and 6 and corticotropin-releasing hormone (CRH) influence appetite negatively; this mechanism explains why ill people often eat less.
In addition, the biological clock (which is regulated by the hypothalamus) modifies hunger. Processes from other cerebral loci, such as from the limbic system and the cerebral cortex, project on the hypothalamus and modify appetite. This explains why in clinical depression and stress, energy intake can change quite drastically.
# Role in disease
A limited or excessive appetite is not necessarily pathological. Abnormal appetite could be defined as eating habits causing malnutrition on the one side or obesity and its related problems on the other.
Both genetic and environmental factors may regulate appetite, and abnormalities in either may lead to abnormal appetite. Poor appetite (anorexia) may have numerous causes, but may be a result of physical (infectious, autoimmune or malignant disease) or psychological (stress, mental disorders) factors. Likewise, hyperphagia (excessive eating) may be a result of hormonal imbalances, mental disorders (e.g. depression) and others.
Dysregulation of appetite lies at the root of anorexia nervosa, bulimia nervosa and binge eating disorder. In addition, decreased response to satiety may promote development of obesity.
Various hereditary forms of obesity have been traced to defects in hypothalamic signalling (such as the leptin receptor and the MC-4 receptor), or are still awaiting characterisation (Prader-Willi syndrome).
# Pharmacology
Mechanisms controlling appetite are a potential target for weight loss drugs. Early anorectics were fenfluramine and phentermine. A more recent addition is sibutramine (Reductil®, Meridia®), which increases serotonin and noradrenaline levels in the central nervous system. In addition, recent reports on recombinant PYY 3-36 suggest that this agent may contribute to weight loss by suppressing appetite.
Given the epidemic proportions of obesity in the Western world, developments in this area are expected to snowball in the near future, as dieting alone is ineffective in most obese adults.
# Further reading
- Neary NM, Goldstone AP, Bloom SR. Appetite regulation: from the gut to the hypothalamus. Clin Endocrinol (Oxford) 2004;60:153-60. PMID 14725674.
- Wynne K, Stanley S, Bloom S. The gut and regulation of body weight. J Clin Endocrinol Metab 2004;89:2576–82. PMID 15181026.
ar:شهية
de:Appetit
he:תיאבון
lt:Apetitas
uk:Апетит
Template:WS | https://www.wikidoc.org/index.php/Appetite | |
32569dce357de10a217385917551a76a1b3544e0 | wikidoc | Pamabrom | Pamabrom
Pamabrom is a diuretic product included in retail drugs available in over-the-counter medications. The active diuretic ingredient is 8-bromotheophylline.
It is also available in combination with acetaminophen (paracetamol) for menstrual relief. The acetaminophen helps reduce menstrual pains and the pamabrom reduces associated bloating. It's available in a number of products from various larger brands under different names, such as Midol Maximum Strength Teen Formula, Women's Tylenol Menstrual Relief and Pamprin Maximum Strength Menstrual Pain Relief Multi-Symptom. The dosages are essentially the same for each brand, including generic drug store varieties.
The acetaminophen/pamabrom combination is also marketed as a pain reliever for pain associated with back ache, headache, and muscle ache and can be used as a mild muscle relaxant. | Pamabrom
Pamabrom is a diuretic product included in retail drugs available in over-the-counter medications.[1] The active diuretic ingredient is 8-bromotheophylline.
It is also available in combination with acetaminophen (paracetamol) for menstrual relief. The acetaminophen helps reduce menstrual pains and the pamabrom reduces associated bloating. It's available in a number of products from various larger brands under different names, such as Midol Maximum Strength Teen Formula, Women's Tylenol Menstrual Relief and Pamprin Maximum Strength Menstrual Pain Relief Multi-Symptom. The dosages are essentially the same for each brand, including generic drug store varieties.
The acetaminophen/pamabrom combination is also marketed as a pain reliever for pain associated with back ache, headache, and muscle ache and can be used as a mild muscle relaxant.
# External links
- New Tylenol (Acetaminophen/Pamabrom), For Menstrual Pain And Bloating, Available In US
- Are 'For-Women' Products for Real?
Template:Pharma-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Aqua-Ban | |
ea89d3a38b0c74ed4f976077cbb2385b07bd686f | wikidoc | Arginase | Arginase
Arginase (EC 3.5.3.1, arginine amidinase, canavanase, L-arginase, arginine transamidinase) is a manganese-containing enzyme. The reaction catalyzed by this enzyme is: arginine + H2O → ornithine + urea. It is the final enzyme of the urea cycle. It is ubiquitous to all domains of life.
# Structure and function
Arginase belong to the ureohydrolase family of enzymes.
Arginase catalyzes the fifth and final step in the urea cycle, a series of biochemical reactions in mammals during which the body disposes of harmful ammonia. Specifically, arginase converts L-arginine into L-ornithine and urea. Mammalian arginase is active as a trimer, but some bacterial arginases are hexameric. The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. These Mn2+ ions coordinate with water, orienting and stabilizing the molecule and allowing water to act as a nucleophile and attack L-arginine, hydrolyzing it into ornithine and urea.
In most mammals, two isozymes of this enzyme exist; the first, Arginase I, functions in the urea cycle, and is located primarily in the cytoplasm of hepatocytes (liver cells). The second isozyme, Arginase II, has been implicated in the regulation of intracellular arginine/ornithine levels. It is located in mitochondria of several tissues in the body, with most abundance in the kidney and prostate. It may be found at lower levels in macrophages, lactating mammary glands, and brain. The second isozyme may be found in the absence of other urea cycle enzymes.
# Mechanism
The active site holds L-arginine in place via hydrogen bonding between the guanidine chloride group with Glu227. This bonding orients L-arginine for nucleophilic attack by the metal-associated hydroxide ion at the guanidine chloride group. This results in a tetrahedral intermediate. The manganese ions act to stabilize both the hydroxyl group in the tetrahedral intermediate, as well as the developing sp3 lone electron pair on the NH2 group as the tetrahedral intermediate is formed.
Arginase's active site is extraordinarily specific. Modifying the substrate structure and/or stereochemistry severely lowers the kinetic activity of the enzyme. This specificity occurs due to the high number of hydrogen bonds between substrate and enzyme; direct or water-facilitated hydrogen bonds exist, saturating both the four acceptor positions on the alpha carboxylate group and all three positions on the alpha amino group. N-hydroxy-L-arginine (NOHA), an intermediate of NO biosynthesis, is a moderate inhibitor of arginase. Crystal structure of its complex with the enzyme reveals that it displaces the metal-bridging hydroxide ion and bridges the binuclear manganese cluster.
Additionally, 2(S)-amino-6-boronohexonic acid (ABH) is an L-arginine analogue that also creates a tetrahedral intermediate similar to that formed in the catalysis of the natural substrate, and is a potent inhibitor of human arginase I.
# Role in sexual response
Arginase II is coexpressed with nitric oxide (NO) synthase in smooth muscle tissue, such as the muscle in the genitals of both men and women. The contraction and relaxation of these muscles has been attributed to NO synthase, which causes rapid relaxation of smooth muscle tissue and facilitates engorgement of tissue necessary for normal sexual response. However, since NO synthase and arginase compete for the same substrate (L-arginine), over-expressed arginase can affect NO synthase activity and NO-dependent smooth muscle relaxation by depleting the substrate pool of L-arginine that would otherwise be available to NO synthase. In contrast, inhibiting arginase with ABH or other boronic acid inhibitors will maintain normal cellular levels of arginine, thus allowing for normal muscle relaxation and sexual response.
Arginase is a controlling factor in both male erectile function and female sexual arousal, and is therefore a potential target for treatment of sexual dysfunction in both sexes. Additionally, supplementing the diet with additional L-arginine will decrease the amount of competition between arginase and NO synthase by providing extra substrate for each enzyme.
# Pathology
Arginase deficiency typically refers to decreased function of arginase I, the liver isoform of arginase. This deficiency is commonly referred to as hyperargininemia or arginemia. The disorder is hereditary and autosomal recessive. It is characterized by lowered activity of arginase in hepatic cells. It is considered to be the rarest of the heritable defects in ureagenesis. Arginase deficiency, unlike other urea cycle disorders, does not entirely prevent ureagenesis. A proposed reason for the continuation of arginase function is suggested by increased activity of arginase II in the kidneys of subjects with arginase I deficiency. Researchers believe that buildup of arginine triggers increased expression of arginase II. The enzymes in the kidney will then catalyze ureagenesis, compensating somewhat for a decrease in arginase I activity in the liver. Due to this alternate method of removing excess arginine and ammonia from the bloodstream, subjects with arginase deficiency tend to have longer lifespans than those who have other urea cycle defects.
Symptoms of the disorder include neurological impairment, dementia, retardation of growth, and hyperammonemia. While some symptoms of the disease can be controlled via dietary restrictions and pharmaceutical developments, no cure or completely effective therapy currently exists.
# Animal studies
Arginase I is activated by lactic acid in tumors to stimulate macrophages to help a tumor grow. When Arginase I was inhibited in a mouse model tumor size was greatly reduced.
Arginase has been studied in vitro to treat several types of cancer, such as: breast, rectal, and colon. Arginase is used to decrease the arginine levels in blood serum in order to starve the cancer cells that are auxotrophic to arginine. The in vivo approach revealed some problems that were overcame through some modifications that are described in several patent process, namely pegylation. | Arginase
Arginase (EC 3.5.3.1, arginine amidinase, canavanase, L-arginase, arginine transamidinase) is a manganese-containing enzyme. The reaction catalyzed by this enzyme is: arginine + H2O → ornithine + urea. It is the final enzyme of the urea cycle. It is ubiquitous to all domains of life.
# Structure and function
Arginase belong to the ureohydrolase family of enzymes.
Arginase catalyzes the fifth and final step in the urea cycle, a series of biochemical reactions in mammals during which the body disposes of harmful ammonia. Specifically, arginase converts L-arginine into L-ornithine and urea.[2] Mammalian arginase is active as a trimer, but some bacterial arginases are hexameric.[3] The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. These Mn2+ ions coordinate with water, orienting and stabilizing the molecule and allowing water to act as a nucleophile and attack L-arginine, hydrolyzing it into ornithine and urea.[4]
In most mammals, two isozymes of this enzyme exist; the first, Arginase I, functions in the urea cycle, and is located primarily in the cytoplasm of hepatocytes (liver cells). The second isozyme, Arginase II, has been implicated in the regulation of intracellular arginine/ornithine levels. It is located in mitochondria of several tissues in the body, with most abundance in the kidney and prostate. It may be found at lower levels in macrophages, lactating mammary glands, and brain.[5] The second isozyme may be found in the absence of other urea cycle enzymes.[4]
# Mechanism
The active site holds L-arginine in place via hydrogen bonding between the guanidine chloride group with Glu227. This bonding orients L-arginine for nucleophilic attack by the metal-associated hydroxide ion at the guanidine chloride group. This results in a tetrahedral intermediate. The manganese ions act to stabilize both the hydroxyl group in the tetrahedral intermediate, as well as the developing sp3 lone electron pair on the NH2 group as the tetrahedral intermediate is formed.[6]
Arginase's active site is extraordinarily specific.[citation needed] Modifying the substrate structure and/or stereochemistry severely lowers the kinetic activity of the enzyme. This specificity occurs due to the high number of hydrogen bonds between substrate and enzyme; direct or water-facilitated hydrogen bonds exist, saturating both the four acceptor positions on the alpha carboxylate group and all three positions on the alpha amino group. N-hydroxy-L-arginine (NOHA), an intermediate of NO biosynthesis, is a moderate inhibitor of arginase. Crystal structure of its complex with the enzyme reveals that it displaces the metal-bridging hydroxide ion and bridges the binuclear manganese cluster.[6]
Additionally, 2(S)-amino-6-boronohexonic acid (ABH) is an L-arginine analogue that also creates a tetrahedral intermediate similar to that formed in the catalysis of the natural substrate, and is a potent inhibitor of human arginase I.[7]
# Role in sexual response
Arginase II is coexpressed with nitric oxide (NO) synthase in smooth muscle tissue, such as the muscle in the genitals of both men and women. The contraction and relaxation of these muscles has been attributed to NO synthase, which causes rapid relaxation of smooth muscle tissue and facilitates engorgement of tissue necessary for normal sexual response. However, since NO synthase and arginase compete for the same substrate (L-arginine), over-expressed arginase can affect NO synthase activity and NO-dependent smooth muscle relaxation by depleting the substrate pool of L-arginine that would otherwise be available to NO synthase. In contrast, inhibiting arginase with ABH or other boronic acid inhibitors will maintain normal cellular levels of arginine, thus allowing for normal muscle relaxation and sexual response.[8]
Arginase is a controlling factor in both male erectile function and female sexual arousal, and is therefore a potential target for treatment of sexual dysfunction in both sexes. Additionally, supplementing the diet with additional L-arginine will decrease the amount of competition between arginase and NO synthase by providing extra substrate for each enzyme.[9]
# Pathology
Arginase deficiency typically refers to decreased function of arginase I, the liver isoform of arginase. This deficiency is commonly referred to as hyperargininemia or arginemia. The disorder is hereditary and autosomal recessive. It is characterized by lowered activity of arginase in hepatic cells. It is considered to be the rarest of the heritable defects in ureagenesis. Arginase deficiency, unlike other urea cycle disorders, does not entirely prevent ureagenesis. A proposed reason for the continuation of arginase function is suggested by increased activity of arginase II in the kidneys of subjects with arginase I deficiency. Researchers believe that buildup of arginine triggers increased expression of arginase II. The enzymes in the kidney will then catalyze ureagenesis, compensating somewhat for a decrease in arginase I activity in the liver. Due to this alternate method of removing excess arginine and ammonia from the bloodstream, subjects with arginase deficiency tend to have longer lifespans than those who have other urea cycle defects.[10]
Symptoms of the disorder include neurological impairment, dementia, retardation of growth, and hyperammonemia. While some symptoms of the disease can be controlled via dietary restrictions and pharmaceutical developments, no cure or completely effective therapy currently exists.[10]
# Animal studies
Arginase I is activated by lactic acid in tumors to stimulate macrophages to help a tumor grow. When Arginase I was inhibited in a mouse model tumor size was greatly reduced.[11]
Arginase has been studied in vitro to treat several types of cancer, such as: breast, rectal, and colon. Arginase is used to decrease the arginine levels in blood serum in order to starve the cancer cells that are auxotrophic to arginine. The in vivo approach revealed some problems that were overcame through some modifications that are described in several patent process, namely pegylation.[12] | https://www.wikidoc.org/index.php/Arginase | |
1055f59682e4c68ebe54e059f2c091e025e5db94 | wikidoc | Arginine | Arginine
# Overview
Arginine (abbreviated as Arg or R) is an α-amino acid. The L-form is one of the 20 most common natural amino acids. Its codons are CGU, CGC, CGA, CGG, AGA, and AGG. In mammals, arginine is classified as a semiessential or conditionally essential amino acid, depending on the developmental stage and health status of the individual. Infants are unable to effectively synthesize arginine, making it nutritionally essential for infants. Adults, however, are able to synthesize arginine in the urea cycle.
Arginine was first isolated from a lupin seedling extract in 1886 by the Swiss chemist Ernst Schulze.
# Structure
Arginine consists of a 4-carbon aliphatic straight chain, the distal end of which is capped by a complex guanidinium group. With a pKa of 12.48, the guanidinium group is positively charged in neutral, acidic and even most basic environments, and thus imparts basic chemical properties to arginine. Because of the conjugation between the double bond and the nitrogen lone pairs, the positive charge is de-localized, enabling the formation of multiple H-bonds.
# Sources
## Dietary Sources
Arginine is a nonessential amino acid, meaning it can be manufactured by the human body, and does not need to be obtained directly through the diet. Arginine is found in a wide variety of foods, including:
- Animal sources: dairy products (e.g. cottage cheese, ricotta, nonfat dry milk, skim yogurt), beef, pork (e.g. bacon, ham), poultry (e.g. chicken and turkey light meat), wild game (e.g. pheasant, quail), seafood (e.g. halibut, lobster, salmon, shrimp, snails, tuna in water)
- Vegetarian sources: wheat germ and flour, buckwheat, granola, oatmeal, nuts (coconut, pecans, cashews, walnuts, almonds, Brazil nuts, hazel nuts, peanuts), seeds (pumpkin, sesame, sunflower), chick peas, cooked soybeans, chocolate
- Other: some energy drinks
## Biosynthesis
Arginine is synthesized from citrulline by the sequential action of the cytosolic enzymes argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). This is energetically costly, as the synthesis of each molecule of argininosuccinate requires hydrolysis of adenosine triphosphate (ATP) to adenosine monophosphate (AMP); i.e., two ATP equivalents.
Citrulline can be derived from multiple sources:
- from arginine via nitric oxide synthase (NOS);
- from ornithine via catabolism of proline or glutamine/glutamate;
- from asymmetric dimethylarginine (ADMA) via DDAH.
The pathways linking arginine, glutamine, and proline are bidirectional. Thus, the net utilization or production of these amino acids is highly dependent on cell type and developmental stage.
On a whole-body basis, synthesis of arginine occurs principally via the intestinal–renal axis, wherein epithelial cells of the small intestine, which produce citrulline primarily from glutamine and glutamate, collaborate with the proximal tubule cells of the kidney, which extract citrulline from the circulation and convert it to arginine, which is returned to the circulation. Consequently, impairment of small bowel or renal function can reduce endogenous arginine synthesis, thereby increasing the dietary requirement.
Synthesis of arginine from citrulline also occurs at a low level in many other cells, and cellular capacity for arginine synthesis can be markedly increased under circumstances that also induce iNOS. Thus, citrulline, a coproduct of the NOS-catalyzed reaction, can be recycled to arginine in a pathway known as the citrulline-NO or arginine-citrulline pathway. This is demonstrated by the fact that in many cell types, citrulline can substitute for arginine to some degree in supporting NO synthesis. However, recycling is not quantitative because citrulline accumulates along with nitrate and nitrite, the stable end-products of NO, in NO-producing cells.
# Function
Arginine plays an important role in cell division, the healing of wounds, removing ammonia from the body, immune function, and the release of hormones. Arginine, taken in combination with proanthocyanidins or yohimbine, has also been used as a treatment for erectile dysfunction.
## In proteins
The geometry, charge distribution and ability to form multiple H-bonds make arginine ideal for binding negatively charged groups. For this reason arginine prefers to be on the outside of the proteins where it can interact with the polar environment.
Incorporated in proteins, arginine can also be converted to citrulline by PAD enzymes. In addition, arginine can be methylated by protein methyltransferases.
## As a precursor
Arginine is the immediate precursor of NO, urea, ornithine and agmatine; is necessary for the synthesis of creatine; and can also be used for the synthesis of polyamines (mainly through ornithine and to a lesser degree through agmatine), citrulline, and glutamate. For being a precursor of NO, (relaxes blood vessels), arginine is used in many conditions where vasodilation is required. The presence of asymmetric dimethylarginine (ADMA), a close relative, inhibits the nitric oxide reaction; therefore, ADMA is considered a marker for vascular disease, just as L-arginine is considered a sign of a healthy endothelium.
## Implication in herpes simplex viral replication
Tissues culture studies have shown the suppression of viral replication when the lysine to arginine ratio in vitro favors lysine. The therapeutic consequence of this finding is unclear, but dietary arginine may affect the effectiveness of lysine supplementation.
## Implication in contributing to risk of death from heart disease
A recent Johns Hopkins study testing the addition of L-arginine to standard postinfarction treatment has implicated L-arginine supplementation with an increased risk of death in patients recovering from heart attack. This study has been discussed in some detail in : "Reverse Heart Disease Now" by Stephen T Sinatra MD and James C Roberts MD, publ. Wiley 2006 ISBN 0-471-74704-1 at pp 111 -113.
## Growth hormone
Arginine increases the production of growth hormone.
Reports of its effects on male muscular development are not clearly proven.
## Prolactin
Although there haven't been thorough studies, some sources claim that arginine helps release prolactin, an estrogenic compound which is associated with lactation, and like all estrogenic compounds may curb the secretion of testosterone. Thus some bodybuilders stay away from pure arginine, intaking only amounts naturally found in protein. | Arginine
Template:NatOrganicBox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Arginine (abbreviated as Arg or R)[1] is an α-amino acid. The L-form is one of the 20 most common natural amino acids. Its codons are CGU, CGC, CGA, CGG, AGA, and AGG. In mammals, arginine is classified as a semiessential or conditionally essential amino acid, depending on the developmental stage and health status of the individual. Infants are unable to effectively synthesize arginine, making it nutritionally essential for infants. Adults, however, are able to synthesize arginine in the urea cycle.
Arginine was first isolated from a lupin seedling extract in 1886 by the Swiss chemist Ernst Schulze.
# Structure
Arginine consists of a 4-carbon aliphatic straight chain, the distal end of which is capped by a complex guanidinium group. With a pKa of 12.48, the guanidinium group is positively charged in neutral, acidic and even most basic environments, and thus imparts basic chemical properties to arginine. Because of the conjugation between the double bond and the nitrogen lone pairs, the positive charge is de-localized, enabling the formation of multiple H-bonds.
# Sources
## Dietary Sources
Arginine is a nonessential amino acid, meaning it can be manufactured by the human body, and does not need to be obtained directly through the diet. Arginine is found in a wide variety of foods, including[2]:
- Animal sources: dairy products (e.g. cottage cheese, ricotta, nonfat dry milk, skim yogurt), beef, pork (e.g. bacon, ham), poultry (e.g. chicken and turkey light meat), wild game (e.g. pheasant, quail), seafood (e.g. halibut, lobster, salmon, shrimp, snails, tuna in water)
- Vegetarian sources: wheat germ and flour, buckwheat, granola, oatmeal, nuts (coconut, pecans, cashews, walnuts, almonds, Brazil nuts, hazel nuts, peanuts), seeds (pumpkin, sesame, sunflower), chick peas, cooked soybeans, chocolate
- Other: some energy drinks
## Biosynthesis
Arginine is synthesized from citrulline by the sequential action of the cytosolic enzymes argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). This is energetically costly, as the synthesis of each molecule of argininosuccinate requires hydrolysis of adenosine triphosphate (ATP) to adenosine monophosphate (AMP); i.e., two ATP equivalents.
Citrulline can be derived from multiple sources:
- from arginine via nitric oxide synthase (NOS);
- from ornithine via catabolism of proline or glutamine/glutamate;
- from asymmetric dimethylarginine (ADMA) via DDAH.
The pathways linking arginine, glutamine, and proline are bidirectional. Thus, the net utilization or production of these amino acids is highly dependent on cell type and developmental stage.
On a whole-body basis, synthesis of arginine occurs principally via the intestinal–renal axis, wherein epithelial cells of the small intestine, which produce citrulline primarily from glutamine and glutamate, collaborate with the proximal tubule cells of the kidney, which extract citrulline from the circulation and convert it to arginine, which is returned to the circulation. Consequently, impairment of small bowel or renal function can reduce endogenous arginine synthesis, thereby increasing the dietary requirement.
Synthesis of arginine from citrulline also occurs at a low level in many other cells, and cellular capacity for arginine synthesis can be markedly increased under circumstances that also induce iNOS. Thus, citrulline, a coproduct of the NOS-catalyzed reaction, can be recycled to arginine in a pathway known as the citrulline-NO or arginine-citrulline pathway. This is demonstrated by the fact that in many cell types, citrulline can substitute for arginine to some degree in supporting NO synthesis. However, recycling is not quantitative because citrulline accumulates along with nitrate and nitrite, the stable end-products of NO, in NO-producing cells.[3]
# Function
Arginine plays an important role in cell division, the healing of wounds, removing ammonia from the body, immune function, and the release of hormones. Arginine, taken in combination with proanthocyanidins[4] or yohimbine[5], has also been used as a treatment for erectile dysfunction.
## In proteins
The geometry, charge distribution and ability to form multiple H-bonds make arginine ideal for binding negatively charged groups. For this reason arginine prefers to be on the outside of the proteins where it can interact with the polar environment.
Incorporated in proteins, arginine can also be converted to citrulline by PAD enzymes. In addition, arginine can be methylated by protein methyltransferases.
## As a precursor
Arginine is the immediate precursor of NO, urea, ornithine and agmatine; is necessary for the synthesis of creatine; and can also be used for the synthesis of polyamines (mainly through ornithine and to a lesser degree through agmatine), citrulline, and glutamate. For being a precursor of NO, (relaxes blood vessels), arginine is used in many conditions where vasodilation is required. The presence of asymmetric dimethylarginine (ADMA), a close relative, inhibits the nitric oxide reaction; therefore, ADMA is considered a marker for vascular disease, just as L-arginine is considered a sign of a healthy endothelium.
## Implication in herpes simplex viral replication
Tissues culture studies have shown the suppression of viral replication when the lysine to arginine ratio in vitro favors lysine. The therapeutic consequence of this finding is unclear, but dietary arginine may affect the effectiveness of lysine supplementation.[6]
## Implication in contributing to risk of death from heart disease
A recent Johns Hopkins study testing the addition of L-arginine to standard postinfarction treatment has implicated L-arginine supplementation with an increased risk of death in patients recovering from heart attack.[7] This study has been discussed in some detail in : "Reverse Heart Disease Now" by Stephen T Sinatra MD and James C Roberts MD, publ. Wiley 2006 ISBN 0-471-74704-1 at pp 111 -113.
## Growth hormone
Arginine increases the production of growth hormone.[8]
Reports of its effects on male muscular development are not clearly proven.
## Prolactin
Although there haven't been thorough studies, some sources claim that arginine helps release prolactin, an estrogenic compound which is associated with lactation, and like all estrogenic compounds may curb the secretion of testosterone. Thus some bodybuilders stay away from pure arginine, intaking only amounts naturally found in protein. | https://www.wikidoc.org/index.php/Arginine | |
6e139b37bf7f18465a3def611c6c05c3c9fbf68a | wikidoc | Arrestin | Arrestin
Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors.
Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors (GPCRs) in the visual rhodopsin system by Hermann Kühn, Scott Hall, and Ursula Wilden and in the β-adrenergic system by Martin J. Lohse and co-workers.
# Function
In response to a stimulus, GPCRs activate heterotrimeric G proteins. In order to turn off this response, or adapt to a persistent stimulus, active receptors need to be desensitized. The first step in desensitization is phosphorylation by a class of serine/threonine kinases called G protein coupled receptor kinases (GRKs). GRK phosphorylation specifically prepares the activated receptor for arrestin binding. Arrestin binding to the receptor blocks further G protein-mediated signaling and targets receptors for internalization, and redirects signaling to alternative G protein-independent pathways, such as β-arrestin signaling. In addition to GPCRs, arrestins bind to other classes of cell surface receptors and a variety of other signaling proteins.
# Subtypes
Mammals express four arrestin subtypes and each arrestin subtype is known by multiple aliases. The systematic arrestin name (1-4) plus the most widely used aliases for each arrestin subtype are listed in bold below:
- Arrestin-1 was originally identified as the S-antigen (SAG) causing uveitis (autoimmune eye disease), then independently described as a 48 kDa protein that binds light-activated phosphorylated rhodopsin before it became clear that both are one and the same. It was later renamed visual arrestin, but when another cone-specific visual subtype was cloned the term rod arrestin was coined. This also turned out to be a misnomer: arrestin-1 expresses at comparable very high levels in both rod and cone photoreceptor cells.
- Arrestin-2 was the first non-visual arrestin cloned. It was first named β-arrestin simply because between two GPCRs available in purified form at the time, rhodopsin and β2-adrenergic receptor, it showed preference for the latter.
- Arrestin-3. The second non-visual arrestin cloned was first termed β-arrestin-2 (retroactively changing the name of β-arrestin into β-arrestin-1), even though by that time it was clear that non-visual arrestins interact with hundreds of different GPCRs, not just with β2-adrenergic receptor. Systematic names, arrestin-2 and arrestin-3, respectively, were proposed soon after that.
- Arrestin-4 was cloned by two groups and termed cone arrestin, after photoreceptor type that expresses it, and X-arrestin, after the chromosome where its gene resides. In the HUGO database its gene is called arrestin-3.
Fish and other vertebrates appear to have only three arrestins: no equivalent of arrestin-2, which is the most abundant non-visual subtype in mammals, was cloned so far. The proto-chordate C. intestinalis (sea squirt) has only one arrestin, which serves as visual in its mobile larva with highly developed eyes, and becomes generic non-visual in the blind sessile adult. Conserved positions of multiple introns in its gene and those of our arrestin subtypes suggest that they all evolved from this ancestral arrestin. Lower invertebrates, such as roundworm C. elegans, also have only one arrestin. Insects have arr1 and arr2, originally termed “visual arrestins” because they are expressed in photoreceptors, and one non-visual subtype (kurtz in Drosophila). Later arr1 and arr2 were found to play an important role in olfactory neurons and renamed “sensory”. Fungi have distant arrestin relatives involved in pH sensing.
# Tissue distribution
One or more arrestin is expressed in virtually every eukaryotic cell. In mammals, arrestin-1 and arrestin-4 are largely confined to photoreceptors, whereas arrestin-2 and arrestin-3 are ubiquitous. Neurons have the highest expression level of both non-visual subtypes. In neuronal precursors both are expressed at comparable levels, whereas in mature neurons arrestin-2 is present at 10-20 fold higher levels than arrestin-3.
# Mechanism
Arrestins block GPCR coupling to G proteins in two ways. First, arrestin binding to the cytoplasmic face of the receptor occludes the binding site for heterotrimeric G-protein, preventing its activation (desensitization). Second, arrestin links the receptor to elements of the internalization machinery, clathrin and clathrin adaptor AP2, which promotes receptor internalization via coated pits and subsequent transport to internal compartments, called endosomes. Subsequently, the receptor could be either directed to degradation compartments (lysosomes) or recycled back to the plasma membrane where it can again signal. The strength of arrestin-receptor interaction plays a role in this choice: tighter complexes tend to increase the probability of receptor degradation (Class B), whereas more transient complexes favor recycling (Class A), although this “rule” is far from absolute.
# Structure
Arrestins are elongated molecules, in which several intra-molecular interactions hold the relative orientation of the two domains. In unstimulated cell arrestins are localized in the cytoplasm in this basal “inactive” conformation. Active phosphorylated GPCRs recruit arrestin to the plasma membrane. Receptor binding induces a global conformational change that involves the movement of the two arrestin domains and the release of its C-terminal tail that contains clathrin and AP2 binding sites. Increased accessibility of these sites in receptor-bound arrestin targets the arrestin-receptor complex to the coated pit. Arrestins also bind microtubules (part of the cellular “skeleton”), where they assume yet another conformation, different from both free and receptor-bound form. Microtubule-bound arrestins recruit certain proteins to the cytoskeleton, which affects their activity and/or redirects it to microtubule-associated proteins.
Arrestins shuttle between cell nucleus and cytoplasm. Their nuclear functions are not fully understood, but it was shown that all four mammalian arrestin subtypes remove some of their partners, such as protein kinase JNK3 or the ubiquitin ligase Mdm2, from the nucleus. Arrestins also modify gene expression by enhancing transcription of certain genes. | Arrestin
Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors.[2][3]
Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors (GPCRs) in the visual rhodopsin system by Hermann Kühn, Scott Hall, and Ursula Wilden[4] and in the β-adrenergic system by Martin J. Lohse and co-workers.[5][6]
# Function
In response to a stimulus, GPCRs activate heterotrimeric G proteins. In order to turn off this response, or adapt to a persistent stimulus, active receptors need to be desensitized. The first step in desensitization is phosphorylation by a class of serine/threonine kinases called G protein coupled receptor kinases (GRKs). GRK phosphorylation specifically prepares the activated receptor for arrestin binding. Arrestin binding to the receptor blocks further G protein-mediated signaling and targets receptors for internalization, and redirects signaling to alternative G protein-independent pathways, such as β-arrestin signaling.[7][8][9][10][6] In addition to GPCRs, arrestins bind to other classes of cell surface receptors and a variety of other signaling proteins.[11]
# Subtypes
Mammals express four arrestin subtypes and each arrestin subtype is known by multiple aliases. The systematic arrestin name (1-4) plus the most widely used aliases for each arrestin subtype are listed in bold below:
- Arrestin-1 was originally identified as the S-antigen (SAG) causing uveitis (autoimmune eye disease), then independently described as a 48 kDa protein that binds light-activated phosphorylated rhodopsin before it became clear that both are one and the same. It was later renamed visual arrestin, but when another cone-specific visual subtype was cloned the term rod arrestin was coined. This also turned out to be a misnomer: arrestin-1 expresses at comparable very high levels in both rod and cone photoreceptor cells.
- Arrestin-2 was the first non-visual arrestin cloned. It was first named β-arrestin simply because between two GPCRs available in purified form at the time, rhodopsin and β2-adrenergic receptor, it showed preference for the latter.
- Arrestin-3. The second non-visual arrestin cloned was first termed β-arrestin-2 (retroactively changing the name of β-arrestin into β-arrestin-1), even though by that time it was clear that non-visual arrestins interact with hundreds of different GPCRs, not just with β2-adrenergic receptor. Systematic names, arrestin-2 and arrestin-3, respectively, were proposed soon after that.
- Arrestin-4 was cloned by two groups and termed cone arrestin, after photoreceptor type that expresses it, and X-arrestin, after the chromosome where its gene resides. In the HUGO database its gene is called arrestin-3.
Fish and other vertebrates appear to have only three arrestins: no equivalent of arrestin-2, which is the most abundant non-visual subtype in mammals, was cloned so far. The proto-chordate C. intestinalis (sea squirt) has only one arrestin, which serves as visual in its mobile larva with highly developed eyes, and becomes generic non-visual in the blind sessile adult. Conserved positions of multiple introns in its gene and those of our arrestin subtypes suggest that they all evolved from this ancestral arrestin.[12] Lower invertebrates, such as roundworm C. elegans, also have only one arrestin. Insects have arr1 and arr2, originally termed “visual arrestins” because they are expressed in photoreceptors, and one non-visual subtype (kurtz in Drosophila). Later arr1 and arr2 were found to play an important role in olfactory neurons and renamed “sensory”. Fungi have distant arrestin relatives involved in pH sensing.
# Tissue distribution
One or more arrestin is expressed in virtually every eukaryotic cell. In mammals, arrestin-1 and arrestin-4 are largely confined to photoreceptors, whereas arrestin-2 and arrestin-3 are ubiquitous. Neurons have the highest expression level of both non-visual subtypes. In neuronal precursors both are expressed at comparable levels, whereas in mature neurons arrestin-2 is present at 10-20 fold higher levels than arrestin-3.
# Mechanism
Arrestins block GPCR coupling to G proteins in two ways. First, arrestin binding to the cytoplasmic face of the receptor occludes the binding site for heterotrimeric G-protein, preventing its activation (desensitization).[13] Second, arrestin links the receptor to elements of the internalization machinery, clathrin and clathrin adaptor AP2, which promotes receptor internalization via coated pits and subsequent transport to internal compartments, called endosomes. Subsequently, the receptor could be either directed to degradation compartments (lysosomes) or recycled back to the plasma membrane where it can again signal. The strength of arrestin-receptor interaction plays a role in this choice: tighter complexes tend to increase the probability of receptor degradation (Class B), whereas more transient complexes favor recycling (Class A), although this “rule” is far from absolute.[2]
# Structure
Arrestins are elongated molecules, in which several intra-molecular interactions hold the relative orientation of the two domains. In unstimulated cell arrestins are localized in the cytoplasm in this basal “inactive” conformation. Active phosphorylated GPCRs recruit arrestin to the plasma membrane. Receptor binding induces a global conformational change that involves the movement of the two arrestin domains and the release of its C-terminal tail that contains clathrin and AP2 binding sites. Increased accessibility of these sites in receptor-bound arrestin targets the arrestin-receptor complex to the coated pit. Arrestins also bind microtubules (part of the cellular “skeleton”), where they assume yet another conformation, different from both free and receptor-bound form. Microtubule-bound arrestins recruit certain proteins to the cytoskeleton, which affects their activity and/or redirects it to microtubule-associated proteins.
Arrestins shuttle between cell nucleus and cytoplasm. Their nuclear functions are not fully understood, but it was shown that all four mammalian arrestin subtypes remove some of their partners, such as protein kinase JNK3 or the ubiquitin ligase Mdm2, from the nucleus. Arrestins also modify gene expression by enhancing transcription of certain genes. | https://www.wikidoc.org/index.php/Arrestin | |
e7e98fc06c8e8d749500ddf724e6cad3329eb2c9 | wikidoc | Arsenite | Arsenite
The arsenite ion is H2AsO3−, or similar.
An arsenite (compound) is a compound that contains this ion.
The arsenite ion may be formed from arsenic trioxide by adding base. Arsenite has a valency of 3 and is also known as trivalent arsenic.
Its white odorless crystals are toxic and very soluble in water. It occurs in nature as arsenolite and claudetite and is also a by-product of metal smelting. Its main use is in producing copper chrome arsenate to treat timber. It is also used for arsenic pesticides, glass production, pharmaceuticals and non-ferrous alloys.
# Addendum
The definition above is incomplete. In fields that commonly deal with groundwater chemistry, arsenite commonly refers to As2O3 and sodium arsenite refers to NaAsO2. Sodium arsenite is used in the water gas shift reaction to remove carbon dioxide. | Arsenite
The arsenite ion is H2AsO3−, or similar.
An arsenite (compound) is a compound that contains this ion.
The arsenite ion may be formed from arsenic trioxide by adding base. Arsenite has a valency of 3 and is also known as trivalent arsenic.
Its white odorless crystals are toxic and very soluble in water. It occurs in nature as arsenolite and claudetite and is also a by-product of metal smelting. Its main use is in producing copper chrome arsenate to treat timber. It is also used for arsenic pesticides, glass production, pharmaceuticals and non-ferrous alloys.
# Addendum
The definition above is incomplete. In fields that commonly deal with groundwater chemistry, arsenite commonly refers to As2O3 and sodium arsenite refers to NaAsO2. Sodium arsenite is used in the water gas shift reaction to remove carbon dioxide.
# External links
- Case Studies in Environmental Medicine - Arsenic Toxicity
- Page at chemicalland21.com
Template:Inorganic-compound-stub
ar:زرنيخيت
fi:Arseniitti
Template:WS | https://www.wikidoc.org/index.php/Arsenite | |
a2068b8e0dde3e3bd9da84c750e169caf494620c | wikidoc | Embolism | Embolism
# Overview
In medicine, an embolism occurs when an object (the embolus, plural emboli) migrates from one part of the body (through circulation) and cause(s) a blockage (occlusion) of a blood vessel in another part of the body. The term was coined in 1848 by Rudolph Carl Virchow.
This can be contrasted with a "thrombus" which is the formation of a clot within a blood vessel, rather than being carried from somewhere else. Thrombus mainly form in the Arteries whereas Emboli form in the Veins.
Blood clots form the most common embolic material by far: other possible embolic materials include fat globules (a fat embolism), air bubbles (an air embolism), talc embolism (often following drug abuse), septic emboli (containing pus and bacteria), or amniotic fluid.
Emboli often have more serious consequences when they occur in the so-called "end-circulation": areas of the body that have no redundant blood supply, such as the brain, heart, and lungs.
Assuming a normal circulation, a thrombus or other embolus formed in a systemic vein will always impact in the lungs, after passing through the right side of the heart. This forms a pulmonary embolism that can be a complication of deep-vein thrombosis. Note that, contrary to popular belief, the most common site of origin of pulmonary emboli are the femoral veins, not the deep veins of the calf. Deep veins of the calf are the most common site of thrombi, not emboli origin.
Some congenital abnormalities of the circulation, especially septal defects (holes in the cardiac septum), allow an embolus from a systemic vein to cross into the arterial system and land anywhere in the body. The most common such abnormality is patent foramen ovale, occurring in about 25 % of the adult population, but here the defect functions as a valve which is normally closed, because pressure is slightly higher in the left side of the heart. In certain circumstances, e.g. if patient is coughing just when an embolus is passing, passage to the arterial system may occur.
Emboli starting in the heart (from a thrombus in the left atrium secondary to atrial fibrillation or septic emboli from endocarditis) can cause emboli in any part of the body.
An embolus landing in the brain from either the heart or a carotid artery will likely cause an ischemic stroke.
Emboli of cardiac origin are also frequently encountered in clinical practice. Thrombus formation within the atrium in valvular disease occurs mainly in patients with mitral valve disease, and especially in those with mitral valve stenosis with atrial fibrillation (AF). In the absence of AF, pure mitral regurgitation has low incidence of thromboembolism.
Absolute risk of emboli in idiopathic AF depends on other risk factors such as increasing age, hypertension, diabetes, recent heart failure, or previous stroke.
Thrombus formation can also take place within the ventricles, and it occurs in approximately 30% of anterior wall myocardial infarctions, compared to only 5% of inferior ones. Other risk factors include poor ejection fraction (<35%), size of infarct, as well as presence of AF. In the first three months after infarction, left ventricle aneurysms have 10% risk of embolization.
Patients with prosthetic valves also carry a significant increase in risk of thromboembolism. Risk varies on the valve type (bioprosthetic or mechanical), the positon (mitral or aortic), and presence of other factors such as AF, left ventricular dysfunction, previous emboli, etc. | Embolism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In medicine, an embolism occurs when an object (the embolus, plural emboli) migrates from one part of the body (through circulation) and cause(s) a blockage (occlusion) of a blood vessel in another part of the body. The term was coined in 1848 by Rudolph Carl Virchow.[1]
This can be contrasted with a "thrombus" which is the formation of a clot within a blood vessel, rather than being carried from somewhere else. Thrombus mainly form in the Arteries whereas Emboli form in the Veins.
Blood clots form the most common embolic material by far: other possible embolic materials include fat globules (a fat embolism), air bubbles (an air embolism), talc embolism (often following drug abuse), septic emboli (containing pus and bacteria), or amniotic fluid.
Emboli often have more serious consequences when they occur in the so-called "end-circulation": areas of the body that have no redundant blood supply, such as the brain, heart, and lungs.
Assuming a normal circulation, a thrombus or other embolus formed in a systemic vein will always impact in the lungs, after passing through the right side of the heart. This forms a pulmonary embolism that can be a complication of deep-vein thrombosis. Note that, contrary to popular belief, the most common site of origin of pulmonary emboli are the femoral veins, not the deep veins of the calf. Deep veins of the calf are the most common site of thrombi, not emboli origin.
Some congenital abnormalities of the circulation, especially septal defects (holes in the cardiac septum), allow an embolus from a systemic vein to cross into the arterial system and land anywhere in the body. The most common such abnormality is patent foramen ovale, occurring in about 25 % of the adult population, but here the defect functions as a valve which is normally closed, because pressure is slightly higher in the left side of the heart. In certain circumstances, e.g. if patient is coughing just when an embolus is passing, passage to the arterial system may occur.
Emboli starting in the heart (from a thrombus in the left atrium secondary to atrial fibrillation or septic emboli from endocarditis) can cause emboli in any part of the body.
An embolus landing in the brain from either the heart or a carotid artery will likely cause an ischemic stroke.
Emboli of cardiac origin are also frequently encountered in clinical practice. Thrombus formation within the atrium in valvular disease occurs mainly in patients with mitral valve disease, and especially in those with mitral valve stenosis with atrial fibrillation (AF). In the absence of AF, pure mitral regurgitation has low incidence of thromboembolism.
Absolute risk of emboli in idiopathic AF depends on other risk factors such as increasing age, hypertension, diabetes, recent heart failure, or previous stroke.
Thrombus formation can also take place within the ventricles, and it occurs in approximately 30% of anterior wall myocardial infarctions, compared to only 5% of inferior ones. Other risk factors include poor ejection fraction (<35%), size of infarct, as well as presence of AF. In the first three months after infarction, left ventricle aneurysms have 10% risk of embolization.
Patients with prosthetic valves also carry a significant increase in risk of thromboembolism. Risk varies on the valve type (bioprosthetic or mechanical), the positon (mitral or aortic), and presence of other factors such as AF, left ventricular dysfunction, previous emboli, etc. | https://www.wikidoc.org/index.php/Arterial_embolism | |
d9322b187861b9c4321382178bbc5c4982bbf97e | wikidoc | Ischemia | Ischemia
# Overview
In medicine, ischemia (Greek ισχαιμία, isch- is restriction, hema or haema is blood) is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia.
# Mechanism
Rather than in hypoxia, a more general term denoting a shortage of oxygen (usually a result of lack of oxygen in the air being breathed), ischemia is an absolute or relative shortage of the blood supply to an organ. Relative shortage means the mismatch of blood supply (oxygen delivery) and blood request for adequate oxygenation of tissue.
Ischemia can also be described as an inadequate flow of blood to a part of the body, caused by constriction or blockage of the blood vessels supplying it. Ischemia of heart muscle produces angina pectoris.
This can be due to:
- Tachycardia (abnormally rapid beating of the heart)
- Atherosclerosis (lipid-laden plaques obstructing the lumen of arteries)
- Hypotension (low blood pressure, e.g. in septic shock, heart failure)
- Thromboembolism (blood clots)
- Outside compression of a blood vessel, e.g. by a tumor
- Foreign bodies in the circulation (e.g. amniotic fluid in amniotic fluid embolism)
- Sickle cell disease (abnormally shaped hemoglobin)
- Induced g-forces which restrict the blood flow and force the blood to the extremities of the body, as in aerobatics and military flying
# Consequences
Since oxygen is mainly bound to hemoglobin in red blood cells, insufficient blood supply causes tissue to become hypoxic, or, if no oxygen is supplied at all, anoxic. This can cause necrosis (i.e. cell death). In very aerobic tissues such as heart and brain, at body temperature Necrosis due to ischemia usually takes about 3-4 hours before becoming irreversible. This and typically some collateral circulation to the ischemic area accounts for the efficacy of "clot-buster" drugs such as Alteplase, given for stroke and heart-attack within this time period. However, complete cessation of oxygenation of such organs for more than 20 minutes typically results in irreversible damage.
Ischemia is a feature of heart diseases, transient ischemic attacks, cerebrovascular accidents, ruptured arteriovenous malformations, and peripheral artery occlusive disease.
The heart, the kidneys, and the brain are among the organs that are the most sensitive to inadequate blood supply. Ischemia in brain tissue, for example due to stroke or head injury, causes a process called the ischemic cascade to be unleashed, in which proteolytic enzymes, reactive oxygen species, and other harmful chemicals damage and may ultimately kill brain tissue.
Restoration of blood flow after a period of ischemia can actually be more damaging than the ischemia. Reintroduction of oxygen causes a greater production of damaging free radicals, resulting in reperfusion injury. With reperfusion injury, necrosis can be greatly accelerated.
# Detection of cardiac ischemia
- Initial evaluation of chest-pain patients involves a 12 lead electrocardiogram (ECG) and cardiac markers such as troponins. These tests are highly specific but very insensitive and often leave the requirement for further testing to achieve an accurate diagnosis.
- Magnetocardiography (MCG) imaging utilises superconducting quantum interference devices (SQUIDs) to detect the weak magnetic fields generated by the heart's electrical fields. There might be a direct correlation between abnormal cardiac depolarization or repolarisation and abnormality in the magnetic field map. In July 2004, the Food and Drug Administration (FDA) approved the CardioMag Imaging MCG as a safe device for the non-invasive detection of ischemia. | Ischemia
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In medicine, ischemia (Greek ισχαιμία, isch- is restriction, hema or haema is blood) is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia.
# Mechanism
Rather than in hypoxia, a more general term denoting a shortage of oxygen (usually a result of lack of oxygen in the air being breathed), ischemia is an absolute or relative shortage of the blood supply to an organ. Relative shortage means the mismatch of blood supply (oxygen delivery) and blood request for adequate oxygenation of tissue.
Ischemia can also be described as an inadequate flow of blood to a part of the body, caused by constriction or blockage of the blood vessels supplying it. Ischemia of heart muscle produces angina pectoris.
This can be due to:
- Tachycardia (abnormally rapid beating of the heart)
- Atherosclerosis (lipid-laden plaques obstructing the lumen of arteries)
- Hypotension (low blood pressure, e.g. in septic shock, heart failure)
- Thromboembolism (blood clots)
- Outside compression of a blood vessel, e.g. by a tumor
- Foreign bodies in the circulation (e.g. amniotic fluid in amniotic fluid embolism)
- Sickle cell disease (abnormally shaped hemoglobin)
- Induced g-forces which restrict the blood flow and force the blood to the extremities of the body, as in aerobatics and military flying
# Consequences
Since oxygen is mainly bound to hemoglobin in red blood cells, insufficient blood supply causes tissue to become hypoxic, or, if no oxygen is supplied at all, anoxic. This can cause necrosis (i.e. cell death). In very aerobic tissues such as heart and brain, at body temperature Necrosis due to ischemia usually takes about 3-4 hours before becoming irreversible. This and typically some collateral circulation to the ischemic area accounts for the efficacy of "clot-buster" drugs such as Alteplase, given for stroke and heart-attack within this time period. However, complete cessation of oxygenation of such organs for more than 20 minutes typically results in irreversible damage.
Ischemia is a feature of heart diseases, transient ischemic attacks, cerebrovascular accidents, ruptured arteriovenous malformations, and peripheral artery occlusive disease.
The heart, the kidneys, and the brain are among the organs that are the most sensitive to inadequate blood supply. Ischemia in brain tissue, for example due to stroke or head injury, causes a process called the ischemic cascade to be unleashed, in which proteolytic enzymes, reactive oxygen species, and other harmful chemicals damage and may ultimately kill brain tissue.
Restoration of blood flow after a period of ischemia can actually be more damaging than the ischemia. Reintroduction of oxygen causes a greater production of damaging free radicals, resulting in reperfusion injury. With reperfusion injury, necrosis can be greatly accelerated.
# Detection of cardiac ischemia
- Initial evaluation of chest-pain patients involves a 12 lead electrocardiogram (ECG) and cardiac markers such as troponins. These tests are highly specific but very insensitive and often leave the requirement for further testing to achieve an accurate diagnosis.
- Magnetocardiography (MCG) imaging utilises superconducting quantum interference devices (SQUIDs) to detect the weak magnetic fields generated by the heart's electrical fields. There might be a direct correlation between abnormal cardiac depolarization or repolarisation and abnormality in the magnetic field map. In July 2004, the Food and Drug Administration (FDA) approved the CardioMag Imaging MCG as a safe device for the non-invasive detection of ischemia. | https://www.wikidoc.org/index.php/Arterial_insufficiency | |
4edb8818be23970cb3730d352c0b4e3ca0920ffd | wikidoc | Atheroma | Atheroma
# Overview
In pathology, an atheroma (plural: atheromata) is an accumulation and swelling (-oma) in artery walls that is made up of cells, or cell debris, that contain lipids (cholesterol and fatty acids), calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous plaques. It is an unhealthy condition, but is found in most humans.
These anatomic lesions usually begin in later childhood, well before age 10, and progress over time. Veins do not develop atheromata, unless surgically moved to function as an artery, as in bypass surgery. The accumulation (swelling) is always between the endothelium lining and the smooth muscle wall central region (media) of the arterial tube, see IMT. While the early stages, based on gross appearance, have traditionally been termed fatty streaks by pathologists, they are not composed of fat cells, i.e. adipose cells, but of accumulations of white blood cells, especially macrophages that have taken up oxidized low-density lipoprotein (LDL). After they accumulate large amounts of cytoplasmic membranes (with associated high cholesterol content) they are called foam cells. When foam cells die, their contents are released, which attracts more macrophages and creates an extracellular lipid core near the center to inner surface of each atherosclerotic plaque. Conversely, the outer, older portions of the plaque become more calcific, less metabolically active and more physically stiff over time.
Collectively, the process of atheroma development within an individual is called atherogenesis and the overall result of the disease process is termed atherosclerosis.
# Difficulty of Tracking, Researching and Better Understanding Atheroma
For most people the first clinical symptoms result from atheroma progression within the heart arteries, most commonly resulting in a heart attack and ensuing debility. However, the heart arteries, because (a) they are small (from about 5 mm down to invisible), (b) they are hidden deep within the chest and (c) they never stop moving, have been a difficult target organ to track, especially clinically in individuals who are still asymptomatic. Additionally all mass applied clinical strategies focus on both (a) minimal cost and (b) the overall safety of the procedure. Therefore existing diagnostic strategies for detecting atheroma and tracking response to treatment have been extremely limited. The methods most commonly relied upon, patient symptoms and cardiac stress testing, do not detect any symptoms of the problem until atheromatous disease is very advanced.
# Evolving Concepts and Understanding
In First World countries, with improved public health, infection control and increasing life spans, atheroma processes have become an increasingly important problem and burden for society.
Atheroma continue to be the number one underlying basis for disability and death, despite a trend for gradual improvement since the early 1960s (adjusted for patient age). Thus, increasing efforts towards better understanding, treating and preventing the problem are continuing to evolve.
In the mid-twentieth century, it was assumed (incorrectly) that atheromata simply expanded into the lumen and produced stenoses as they grew, since the disease always developed between the inner endothelial lining and the muscular wall. This belief was based on angiographic views of the blood column within arteries and a belief that the smooth muscle wall of an artery (the thickest and strongest portion of the artery wall in a healthy artery) would not change in size and structure over time. This belief continued despite increasing contradicting evidence that this was an overly simplistic theory and did not explain many empirical observations. Most artists' illustrations of atheromata and the atherosclerosis process in 2004 still portray this concept, even though quite incorrect. By the late 1980s and early 1990s, careful pathology work and research using intravascular ultrasound (IVUS) showed clearly that this angiographic assumption was incorrect.
Since the early to mid 1990s, better research has led to a somewhat wider recognition that one of two changes typically occur in the artery wall structure as an atheroma develops and progresses:
(a) wall thickening and external enlargement with associated lumen (blood flow opening) preservation until late in the process; or
(b) wall thickening with both external and lumen enlargement.
These processes both have survival value, as they reduce and hide some of the effects of the atheroma process and help prevent symptoms, for a time. However they also prevent detection of the disease process by most conventional diagnostic tests, (e.g. cardiac stress tests and angiography), until advanced stages.
According to United States data, 2004, for about 65% of men and 47% of women, the first symptom of cardiovascular disease is heart attack or sudden death (death within one hour of symptom onset.)
Most artery flow disrupting events occur at locations with less than 50% lumen narrowing. From clinical studies published in the late 1990s to IVUS (in-the-artery-ultrasound) to visualize disease status, the typical heart attack occurs at locations with about 20% stenosis (narrowing), prior to sudden lumen closure and resulting heart attack. Cardiac stress testing, traditionally the most commonly performed non-invasive testing method for blood flow limitations generally only detects lumen narrowing of ~75% or greater, although some physicians advocate that nuclear stress methods can sometimes detect as little as 50%.
# Actual Artery/Atheroma Behavior
## External Artery Enlargement; Eventual Possible Stenosis and/or Closure
Over time, atheroma usually progress in size and thickness and induce the surrounding muscular central region (the media) of the artery to stretch out, termed remodeling, typically just enough to compensate for their size such that the caliber of the artery remains unchanged until typically over 40-50% of the artery wall cross sectional area consists of atheromatous tissue (see: Glagov, below).
If the muscular wall enlargement eventually fails to keep up with the enlargement of the atheroma volume, then the lumen of the artery begins to narrow, commonly as a result of repeated ruptures of the covering tissues separating the atheroma from the blood stream. This becomes a more common event after decades of living, increasingly more common after people are over 40 years old.
The endothelium (the cell monolayer on the inside of the vessel) and covering tissue, termed fibrous cap, separate atheroma from the blood in the lumen. If a rupture occurs of the endothelium and fibrous cap, then a platelet and clotting response over the rupture rapidly develops. Additionally, the rupture may result in a shower of debris. Platelet and clot accumulation over the rupture may produce narrowing/closure of the lumen and tissue damage may occur due to either closure of the lumen and loss of blood flow beyond the ruptured atheroma and/or by occlusion of smaller downstream vessels by debris. See vulnerable plaque.
This is the principal mechanism of heart attack, stroke or other related cardiovascular disease problems. As research has shown, this process is not a result of stenosis. Prior to the rupture, there may have been no lumen narrowing, even aneurysmal enlargement, at the atheroma. On average, by clinical research using IVUS, there is a minor stenosis, about 20%, present over those unstable atheroma which rupture and result in major disability or death. Comparatively, stenoses of about 75% are required to produce detectable abnormalities during cardiac stress tests.
## External Artery Enlargement and Lumen Enlargement
If the muscular wall enlargement is overdone over time, then a gross enlargement of the artery results, usually over decades of living. This is a less common outcome. Atheroma within aneurysmal enlargement (vessel bulging) can also rupture and shower debris of atheroma and clot downstream. If the arterial enlargement continues to 2 to 3 times the usual diameter, the walls often become weak enough that with just the stress of the pulse, a loss of wall integrity may occur leading to sudden hemorrhage (bleeding), major symptoms and debility; often rapid death. The main stimulus for aneurysm formation is pressure atrophy of the structural support of the muscle layers. The main structural proteins are collagen and elastin. This causes thinning and the wall balloons allowing gross enlargement to occur, as is common in the abdominal region of the aorta.
# Evolution of Strategies and Changing Focus
The sudden nature of the complications of pre-existing atheroma, vulnerable plaque, have led, since the 1950s, to the development of intensive care units and complex medical and surgical interventions. Angiography and later cardiac stress testing was begun to either visualize or indirectly detect stenosis. Next came bypass surgery, to plumb transplanted veins, sometimes arteries, around the stenoses and more recently angioplasty, now including stents, most recently drug coated stents, to stretch the stenoses more open.
Yet despite these medical advances, with success in reducing the symptoms of angina and reduced blood flow, atheroma rupture events remain the major problem and still sometimes result in sudden disability and death despite even the most rapid, massive and skilled medical and surgical intervention available anywhere today. According to some clinical trials, bypass surgery and angioplasty procedures have had at best a minimal effect, if any, on improving overall survival. Typically mortality of by-pass operations is from 1-4%, of angioplasty about 1-1.5%.
Additionally, these vascular interventions are often done only after an individual is symptomatic, often already partially disabled, as a result of the disease. It is also clear that both angioplasty and by-pass interventions do not prevent future heart attack.
The older methods for understanding atheroma, dating to before World War II, relied on autopsy data. Autopsy data has long shown initiation of fatty streaks in later childhood with slow asymptomatic progression over decades.
One way to see atheroma is the very invasive and costly IVUS ultrasound technology; it gives us the precise volume of the inside intima plus the central media layers of about 2.5 cm of artery length. Unfortunately, it gives no information about the structural strength of the artery. Angiography does not visualize atheroma; it only makes the blood flow within blood vessels visible. Alternative methods that are non or less physically invasive and less expensive per individual test have been used and are continuing to be developed, such as those using computed tomography (CT; lead by the Electron Beam Tomography form, given its greater speed) and magnetic resonance imaging (MRI). The most promising since the early 1990s has been EBT, detecting calcification within the atheroma before most individuals start having clinically recognized symptoms and debility. Interestingly, statin therapy (to lower cholesterol) does not slow the speed of calcification as determined by CT scan. Most visualization techniques are used in research, they are not widely available to most patients, have significant technical limitations, have not been widely accepted and generally are not covered by medical insurance carriers.
From human clinical trials, it has become increasingly evident that a more effective focus of treatment is slowing, stopping and even partially reversing the atheroma growth process. However, this effort has been slow, partly because the asymptomatic nature of atheromata make them especially difficult to study. Promising results are found using B-vitamins that reduce a protein corrosive, homocysteine and that reduce neck carotid artery plaque volume and thickness, and stroke, even in late-stage disease.
Additionally, understanding what drives atheroma development is complex with multiple factors involved, only some of which, such as lipoproteins, more importantly lipoprotein subclass analysis, blood sugar levels and hypertension are best known and researched. More recently, some of the complex immune system patterns that promote, or inhibit, the inherent inflammatory macrophage triggering processes involved in atheroma progression are slowly being better elucidated in animal models of atherosclerosis.
# Detection and Diagnosis Options
Arterial wall fixation, staining and thin section: historically this has been the gold standard for detection and description of atheroma, though only done after autopsy. With special stains and examination, micro calcifications can be detected, typically with smooth muscle cells of the arterial media near the fatty streaks within a year or two of fatty streaks forming.
IVUS is the current most sensitive method detecting and measuring more advanced atheroma within living individuals, though it is typically not used until decades after atheroma begin forming due to cost and body invasiveness.
CT Scans using state of the art higher resolution spiral, or the higher speed EBT, machines have been the most effective method for detecting calcification present in plaque. However, the atheroma have to be advanced enough to have relatively large areas of calcification within them to create large enough regions of ~130 hounsfield units which the CT scanner software can recognize as distinct from the other surrounding tissues. Typically, such regions start occurring within the heart arteries about 2-3 decades after atheroma start developing.
Arterial ultrasound, especially of the carotid arteries, with measurement of the thickness of the artery wall, offers a way to partially track the disease progression. As of 2006, the thickness, commonly referred to as IMT for intimal-medial thickness, is not measured clinically though it has used by some researchers since the mid 1990's to track changes in arterial walls. Traditionally, clinical carotid ultrasounds have only estimated the degree of blood lumen restriction, stenosis, a result of very advanced disease. More progression clinicians have begun using IMT measurement as a way to quantify and track disease progression or stability within individual patients.
Angiography, since the 1960s, has been the traditional way of evaluating for atheroma. However, angiography is only motion or still images of dye mixed with the blood with the arterial lumen and never show atheroma; the wall of arteries, including atheroma with the arterial wall remain invisible. The limited exception to this rule is that with very advance atheroma, with extensive calcification within the wall, a halo-like ring of radiodensity can be seen in most older humans, especially when arterial lumens are visualized end-on. On cine-floro, cardiologists and radiologists typically look for these calcification shadows to recognize arteries before they inject any contrast agent during angiograms.
# Treatment Options
Many approaches, including food choices, staying slender (especially in the abdominal area), aerobic exercise and many different supplements have been promoted as methods to reduce atheroma progression. For most people, changing their internal physiologic behaviors, mostly hidden within, from the usual ones which promote atheroma progression (i.e. high risk, meaning high event rates for symptomatic cardiovascular disease) to reduced risk, requires a combination of strategies, including taking several compounds, on a daily basis and indefinitely. More and more human treatment trials have been done and are ongoing which demonstrate improved outcome for those people using more complex and effective treatment regimens which change physiologic behavior patterns to more closely resemble those which humans more commonly exhibit in childhood at a time before fatty streaks begin forming. Calculated LDLipoprotein cholesterol levels at this time of life are usually in the 20 to 40 mg/dL range, far below what are usually considered "normal" adult concentrations.
The group of medications referred to as statins, originally discovered in 1972 by a Japanese researcher as a compound produced by certain strains of fungi, e.g. Aspergillus terreus, Monascus ruber and Monascus purpureus, have been the most successful single approach, with the lowest rates of undesirable side-effects, to reducing atherosclerotic disease events. However, current research evidence continues to support using a combination of several approaches, including: (a) food choices (such as consuming omega-3 containing fats), (b) abdominal fat reduction, (c) low normal blood glucose levels (glycosylated hemoglobin, also called HbA1c, values < 5.0), (d) aerobic exercise and (e) micronutrient (multivitamin and magnesium) supplements to improve the odds of maintaining better health with absence of either symptoms or worse, catastrophic disease events.
The latest statin approved in the United States but not in some other countries, rosuvastatin, showed regression of atherosclerotic plaque (in fact, a decrease in intima + media volume) in the coronary arteries by IVUS evaluation in the prospective treatment ASTEROID study which utilized IVUS to directly visualize volume plaque changes with treatment. Page 8, shows an artery before and after about 2 years of 40 mg/day treatment; the relevant wall volume is reduced to about half by a decrease in the volume of atheroma. However, keep in mind that the IVUS images on page 8 are only for illustration and are not presented as typical for the group. A careful ready on the article provides a clearer, though still favorable than other trial view of the outcomes. This is the first human clinical trial, with any treatment agent available within the USA, that has produced some plaque regression (as opposed to only slowed rates of increase in quantified volume).
Also be aware that controversy over treatments continue and reportedly Health Canada issued a "Dear doctor" warning concerning the dose used in the ASTEROID study. As another instance, someone editing this page claimed that the PROSPER trial, which used a much less potent statin, showed no evidence of mortality reduction; actual reading of the trial results and interpretation by the investigators demonstrates another conclusion.
A key issue is that there is no magic pill. The important issues are multiple internal physiologic behaviors within each of us; supplements, including the far more rigorously researched precription agents, are simply tools, which if used with wisdom, in careful combinations with a goal of dramatically changing physiologic behaviors to emulate patterns known to much healthier, often work very well. All always, no single approach is perfect or applicable to everyone, at least not without careful attention to detail and individual adjustments. | Atheroma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In pathology, an atheroma (plural: atheromata) is an accumulation and swelling (-oma) in artery walls that is made up of cells, or cell debris, that contain lipids (cholesterol and fatty acids), calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous plaques. It is an unhealthy condition, but is found in most humans.
These anatomic lesions usually begin in later childhood, well before age 10, and progress over time. Veins do not develop atheromata, unless surgically moved to function as an artery, as in bypass surgery. The accumulation (swelling) is always between the endothelium lining and the smooth muscle wall central region (media) of the arterial tube, see IMT. While the early stages, based on gross appearance, have traditionally been termed fatty streaks by pathologists, they are not composed of fat cells, i.e. adipose cells, but of accumulations of white blood cells, especially macrophages that have taken up oxidized low-density lipoprotein (LDL). After they accumulate large amounts of cytoplasmic membranes (with associated high cholesterol content) they are called foam cells. When foam cells die, their contents are released, which attracts more macrophages and creates an extracellular lipid core near the center to inner surface of each atherosclerotic plaque. Conversely, the outer, older portions of the plaque become more calcific, less metabolically active and more physically stiff over time.
Collectively, the process of atheroma development within an individual is called atherogenesis and the overall result of the disease process is termed atherosclerosis.
# Difficulty of Tracking, Researching and Better Understanding Atheroma
For most people the first clinical symptoms result from atheroma progression within the heart arteries, most commonly resulting in a heart attack and ensuing debility. However, the heart arteries, because (a) they are small (from about 5 mm down to invisible), (b) they are hidden deep within the chest and (c) they never stop moving, have been a difficult target organ to track, especially clinically in individuals who are still asymptomatic. Additionally all mass applied clinical strategies focus on both (a) minimal cost and (b) the overall safety of the procedure. Therefore existing diagnostic strategies for detecting atheroma and tracking response to treatment have been extremely limited. The methods most commonly relied upon, patient symptoms and cardiac stress testing, do not detect any symptoms of the problem until atheromatous disease is very advanced.
# Evolving Concepts and Understanding
In First World countries, with improved public health, infection control and increasing life spans, atheroma processes have become an increasingly important problem and burden for society.
Atheroma continue to be the number one underlying basis for disability and death, despite a trend for gradual improvement since the early 1960s (adjusted for patient age). Thus, increasing efforts towards better understanding, treating and preventing the problem are continuing to evolve.
In the mid-twentieth century, it was assumed (incorrectly) that atheromata simply expanded into the lumen and produced stenoses as they grew, since the disease always developed between the inner endothelial lining and the muscular wall. This belief was based on angiographic views of the blood column within arteries and a belief that the smooth muscle wall of an artery (the thickest and strongest portion of the artery wall in a healthy artery) would not change in size and structure over time. This belief continued despite increasing contradicting evidence that this was an overly simplistic theory and did not explain many empirical observations. Most artists' illustrations of atheromata and the atherosclerosis process in 2004 still portray this concept, even though quite incorrect. By the late 1980s and early 1990s, careful pathology work and research using intravascular ultrasound (IVUS) showed clearly that this angiographic assumption was incorrect.
Since the early to mid 1990s, better research has led to a somewhat wider recognition that one of two changes typically occur in the artery wall structure as an atheroma develops and progresses:
(a) wall thickening and external enlargement with associated lumen (blood flow opening) preservation until late in the process; or
(b) wall thickening with both external and lumen enlargement.
These processes both have survival value, as they reduce and hide some of the effects of the atheroma process and help prevent symptoms, for a time. However they also prevent detection of the disease process by most conventional diagnostic tests, (e.g. cardiac stress tests and angiography), until advanced stages.
According to United States data, 2004, for about 65% of men and 47% of women, the first symptom of cardiovascular disease is heart attack or sudden death (death within one hour of symptom onset.)
Most artery flow disrupting events occur at locations with less than 50% lumen narrowing. From clinical studies published in the late 1990s to IVUS (in-the-artery-ultrasound) to visualize disease status, the typical heart attack occurs at locations with about 20% stenosis (narrowing), prior to sudden lumen closure and resulting heart attack. Cardiac stress testing, traditionally the most commonly performed non-invasive testing method for blood flow limitations generally only detects lumen narrowing of ~75% or greater, although some physicians advocate that nuclear stress methods can sometimes detect as little as 50%.
# Actual Artery/Atheroma Behavior
## External Artery Enlargement; Eventual Possible Stenosis and/or Closure
Over time, atheroma usually progress in size and thickness and induce the surrounding muscular central region (the media) of the artery to stretch out, termed remodeling, typically just enough to compensate for their size such that the caliber of the artery remains unchanged until typically over 40-50% of the artery wall cross sectional area consists of atheromatous tissue (see: Glagov, below).
If the muscular wall enlargement eventually fails to keep up with the enlargement of the atheroma volume, then the lumen of the artery begins to narrow, commonly as a result of repeated ruptures of the covering tissues separating the atheroma from the blood stream. This becomes a more common event after decades of living, increasingly more common after people are over 40 years old.
The endothelium (the cell monolayer on the inside of the vessel) and covering tissue, termed fibrous cap, separate atheroma from the blood in the lumen. If a rupture occurs of the endothelium and fibrous cap, then a platelet and clotting response over the rupture rapidly develops. Additionally, the rupture may result in a shower of debris. Platelet and clot accumulation over the rupture may produce narrowing/closure of the lumen and tissue damage may occur due to either closure of the lumen and loss of blood flow beyond the ruptured atheroma and/or by occlusion of smaller downstream vessels by debris. See vulnerable plaque.
This is the principal mechanism of heart attack, stroke or other related cardiovascular disease problems. As research has shown, this process is not a result of stenosis. Prior to the rupture, there may have been no lumen narrowing, even aneurysmal enlargement, at the atheroma. On average, by clinical research using IVUS, there is a minor stenosis, about 20%, present over those unstable atheroma which rupture and result in major disability or death. Comparatively, stenoses of about 75% are required to produce detectable abnormalities during cardiac stress tests.
## External Artery Enlargement and Lumen Enlargement
If the muscular wall enlargement is overdone over time, then a gross enlargement of the artery results, usually over decades of living. This is a less common outcome. Atheroma within aneurysmal enlargement (vessel bulging) can also rupture and shower debris of atheroma and clot downstream. If the arterial enlargement continues to 2 to 3 times the usual diameter, the walls often become weak enough that with just the stress of the pulse, a loss of wall integrity may occur leading to sudden hemorrhage (bleeding), major symptoms and debility; often rapid death. The main stimulus for aneurysm formation is pressure atrophy of the structural support of the muscle layers. The main structural proteins are collagen and elastin. This causes thinning and the wall balloons allowing gross enlargement to occur, as is common in the abdominal region of the aorta.
# Evolution of Strategies and Changing Focus
The sudden nature of the complications of pre-existing atheroma, vulnerable plaque, have led, since the 1950s, to the development of intensive care units and complex medical and surgical interventions. Angiography and later cardiac stress testing was begun to either visualize or indirectly detect stenosis. Next came bypass surgery, to plumb transplanted veins, sometimes arteries, around the stenoses and more recently angioplasty, now including stents, most recently drug coated stents, to stretch the stenoses more open.
Yet despite these medical advances, with success in reducing the symptoms of angina and reduced blood flow, atheroma rupture events remain the major problem and still sometimes result in sudden disability and death despite even the most rapid, massive and skilled medical and surgical intervention available anywhere today. According to some clinical trials, bypass surgery and angioplasty procedures have had at best a minimal effect, if any, on improving overall survival. Typically mortality of by-pass operations is from 1-4%, of angioplasty about 1-1.5%.
Additionally, these vascular interventions are often done only after an individual is symptomatic, often already partially disabled, as a result of the disease. It is also clear that both angioplasty and by-pass interventions do not prevent future heart attack.
The older methods for understanding atheroma, dating to before World War II, relied on autopsy data. Autopsy data has long shown initiation of fatty streaks in later childhood with slow asymptomatic progression over decades.
One way to see atheroma is the very invasive and costly IVUS ultrasound technology; it gives us the precise volume of the inside intima plus the central media layers of about 2.5 cm of artery length. Unfortunately, it gives no information about the structural strength of the artery. Angiography does not visualize atheroma; it only makes the blood flow within blood vessels visible. Alternative methods that are non or less physically invasive and less expensive per individual test have been used and are continuing to be developed, such as those using computed tomography (CT; lead by the Electron Beam Tomography form, given its greater speed) and magnetic resonance imaging (MRI). The most promising since the early 1990s has been EBT, detecting calcification within the atheroma before most individuals start having clinically recognized symptoms and debility. Interestingly, statin therapy (to lower cholesterol) does not slow the speed of calcification as determined by CT scan. Most visualization techniques are used in research, they are not widely available to most patients, have significant technical limitations, have not been widely accepted and generally are not covered by medical insurance carriers.
From human clinical trials, it has become increasingly evident that a more effective focus of treatment is slowing, stopping and even partially reversing the atheroma growth process. However, this effort has been slow, partly because the asymptomatic nature of atheromata make them especially difficult to study. Promising results are found using B-vitamins that reduce a protein corrosive, homocysteine and that reduce neck carotid artery plaque volume and thickness, and stroke, even in late-stage disease.
Additionally, understanding what drives atheroma development is complex with multiple factors involved, only some of which, such as lipoproteins, more importantly lipoprotein subclass analysis, blood sugar levels and hypertension are best known and researched. More recently, some of the complex immune system patterns that promote, or inhibit, the inherent inflammatory macrophage triggering processes involved in atheroma progression are slowly being better elucidated in animal models of atherosclerosis.
# Detection and Diagnosis Options
Arterial wall fixation, staining and thin section: historically this has been the gold standard for detection and description of atheroma, though only done after autopsy. With special stains and examination, micro calcifications can be detected, typically with smooth muscle cells of the arterial media near the fatty streaks within a year or two of fatty streaks forming.
IVUS is the current most sensitive method detecting and measuring more advanced atheroma within living individuals, though it is typically not used until decades after atheroma begin forming due to cost and body invasiveness.
CT Scans using state of the art higher resolution spiral, or the higher speed EBT, machines have been the most effective method for detecting calcification present in plaque. However, the atheroma have to be advanced enough to have relatively large areas of calcification within them to create large enough regions of ~130 hounsfield units which the CT scanner software can recognize as distinct from the other surrounding tissues. Typically, such regions start occurring within the heart arteries about 2-3 decades after atheroma start developing.
Arterial ultrasound, especially of the carotid arteries, with measurement of the thickness of the artery wall, offers a way to partially track the disease progression. As of 2006, the thickness, commonly referred to as IMT for intimal-medial thickness, is not measured clinically though it has used by some researchers since the mid 1990's to track changes in arterial walls. Traditionally, clinical carotid ultrasounds have only estimated the degree of blood lumen restriction, stenosis, a result of very advanced disease. More progression clinicians have begun using IMT measurement as a way to quantify and track disease progression or stability within individual patients.
Angiography, since the 1960s, has been the traditional way of evaluating for atheroma. However, angiography is only motion or still images of dye mixed with the blood with the arterial lumen and never show atheroma; the wall of arteries, including atheroma with the arterial wall remain invisible. The limited exception to this rule is that with very advance atheroma, with extensive calcification within the wall, a halo-like ring of radiodensity can be seen in most older humans, especially when arterial lumens are visualized end-on. On cine-floro, cardiologists and radiologists typically look for these calcification shadows to recognize arteries before they inject any contrast agent during angiograms.
# Treatment Options
Many approaches, including food choices, staying slender (especially in the abdominal area), aerobic exercise and many different supplements have been promoted as methods to reduce atheroma progression. For most people, changing their internal physiologic behaviors, mostly hidden within, from the usual ones which promote atheroma progression (i.e. high risk, meaning high event rates for symptomatic cardiovascular disease) to reduced risk, requires a combination of strategies, including taking several compounds, on a daily basis and indefinitely. More and more human treatment trials have been done and are ongoing which demonstrate improved outcome for those people using more complex and effective treatment regimens which change physiologic behavior patterns to more closely resemble those which humans more commonly exhibit in childhood at a time before fatty streaks begin forming. Calculated LDLipoprotein cholesterol levels at this time of life are usually in the 20 to 40 mg/dL range, far below what are usually considered "normal" adult concentrations.
The group of medications referred to as statins, originally discovered in 1972 by a Japanese researcher as a compound produced by certain strains of fungi, e.g. Aspergillus terreus, Monascus ruber and Monascus purpureus, have been the most successful single approach, with the lowest rates of undesirable side-effects, to reducing atherosclerotic disease events. However, current research evidence continues to support using a combination of several approaches, including: (a) food choices (such as consuming omega-3 containing fats), (b) abdominal fat reduction, (c) low normal blood glucose levels (glycosylated hemoglobin, also called HbA1c, values < 5.0), (d) aerobic exercise and (e) micronutrient (multivitamin and magnesium) supplements to improve the odds of maintaining better health with absence of either symptoms or worse, catastrophic disease events.
The latest statin approved in the United States but not in some other countries, rosuvastatin, showed regression of atherosclerotic plaque (in fact, a decrease in intima + media volume) in the coronary arteries by IVUS evaluation[1] in the prospective treatment ASTEROID study which utilized IVUS to directly visualize volume plaque changes with treatment. Page 8, shows an artery before and after about 2 years of 40 mg/day treatment; the relevant wall volume is reduced to about half by a decrease in the volume of atheroma. However, keep in mind that the IVUS images on page 8 are only for illustration and are not presented as typical for the group. A careful ready on the article provides a clearer, though still favorable than other trial view of the outcomes. This is the first human clinical trial, with any treatment agent available within the USA, that has produced some plaque regression (as opposed to only slowed rates of increase in quantified volume).
Also be aware that controversy over treatments continue and reportedly Health Canada issued a "Dear doctor" warning concerning the dose used in the ASTEROID study. As another instance, someone editing this page claimed that the PROSPER trial,[2] which used a much less potent statin, showed no evidence of mortality reduction; actual reading of the trial results and interpretation by the investigators demonstrates another conclusion.
A key issue is that there is no magic pill. The important issues are multiple internal physiologic behaviors within each of us; supplements, including the far more rigorously researched precription agents, are simply tools, which if used with wisdom, in careful combinations with a goal of dramatically changing physiologic behaviors to emulate patterns known to much healthier, often work very well. All always, no single approach is perfect or applicable to everyone, at least not without careful attention to detail and individual adjustments. | https://www.wikidoc.org/index.php/Arterial_plaque | |
d9d26eaeb41174f7f2e2f9785fed794ed86c1f87 | wikidoc | Artifact | Artifact
Artifact or artefact may refer to:
- Artifact (archaeology), any object made or modified by a human culture, and later recovered by an archaeological endeavor
- Artefact (band) black metal band from France
- Artifact (band), a band from Norway
- Artifact (error), an error or misrepresentation introduced by a technique and/or technology
- Artifact (fantasy), in the fantasy genre, is usually a magical object so powerful that it cannot be duplicated or destroyed by ordinary means
- Artifact (medical imaging), misrepresentations of tissue structures seen in medical images
- Artifact (observational), any perceived distortion or other data error caused by the instrument of observation
- Artifact (software development), one of many kinds of tangible byproduct produced during the development of software
- The Artifact (Eureka), a fictional object appearing in the TV series Eureka
- Compression artifact, data compression artifact in computer science, resulting from lossy data compression
- Cultural artifact, a human-made object which gives information about the culture of its creator and users
- Digital artifact, a visible defect in a digital photo or video picture
- Iatrogenic artifact, a disease made up by doctors
- Social artifact, a product of individuals or groups (social beings) or of their social behavior
- Sonic artifact, in sound and music production, sonic material that is accidental or unwanted, resulting from the editing of another sound
- Virtual artifact, objects in the digital environment | Artifact
Template:Wiktionarypar
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Artifact or artefact may refer to:
- Artifact (archaeology), any object made or modified by a human culture, and later recovered by an archaeological endeavor
- Artefact (band) black metal band from France
- Artifact (band), a band from Norway
- Artifact (error), an error or misrepresentation introduced by a technique and/or technology
- Artifact (fantasy), in the fantasy genre, is usually a magical object so powerful that it cannot be duplicated or destroyed by ordinary means
- Artifact (medical imaging), misrepresentations of tissue structures seen in medical images
- Artifact (observational), any perceived distortion or other data error caused by the instrument of observation
- Artifact (software development), one of many kinds of tangible byproduct produced during the development of software
- The Artifact (Eureka), a fictional object appearing in the TV series Eureka
- Compression artifact, data compression artifact in computer science, resulting from lossy data compression
- Cultural artifact, a human-made object which gives information about the culture of its creator and users
- Digital artifact, a visible defect in a digital photo or video picture
- Iatrogenic artifact, a disease made up by doctors
- Social artifact, a product of individuals or groups (social beings) or of their social behavior
- Sonic artifact, in sound and music production, sonic material that is accidental or unwanted, resulting from the editing of another sound
- Virtual artifact, objects in the digital environment | https://www.wikidoc.org/index.php/Artifact | |
f67b6b343f82d9f1f8d3af4fdab12c7612da809d | wikidoc | Fraxinus | Fraxinus
# Overview
Fraxinus is a genus of flowering plants in the olive and lilac family, Oleaceae. It contains 45-65 species of usually medium to large trees, mostly deciduous though a few subtropical species are evergreen. The tree's common English name, ash, goes back to the Old English æsc, while the generic name originated in Latin. Both words also meant "spear" in their respective languages. The leaves are opposite (rarely in whorls of three), and mostly pinnately compound, simple in a few species. The seeds, popularly known as keys or helicopter seeds, are a type of fruit known as a samara. Rowans or Mountain Ashes are unrelated to true ashes and belong to the Genus Sorbus though the leaves and buds are superficially similar.
# Selected species
- Fraxinus americana L. – White Ash or Autumn Purple Ash
- Fraxinus caroliniana Mill. – Carolina Ash
- Fraxinus nigra Marshall – Black Ash
- Fraxinus pennsylvanica Marshall Green Ash
- Fraxinus profunda (Bush) Bush – Pumpkin Ash
- Fraxinus quadrangulata Michx. – Blue Ash
- Fraxinus anomala Torr. ex S.Watson – Singleleaf Ash
- Fraxinus berlandieriana DC. – Mexican Ash
- Fraxinus cuspidata Torr. – Fragrant Ash
- Fraxinus dipetala Hook. & Arn. – California Ash or Two-petal Ash
- Fraxinus dubia
- Fraxinus gooddingii – Goodding's Ash
- Fraxinus greggii A.Gray – Gregg's Ash
- Fraxinus latifolia Benth. – Oregon Ash
- Fraxinus lowellii – Lowell Ash
- Fraxinus papillosa Lingelsh. – Chihuahua Ash
- Fraxinus purpusii
- Fraxinus rufescens
- Fraxinus texensis (A.Gray) Sarg. – Texas Ash
- Fraxinus uhdei (Wenz.) Lingelsh. – Shamel Ash or Tropical Ash
- Fraxinus velutina Torr. – Velvet Ash or Arizona Ash
- Fraxinus angustifolia Vahl – Narrow-leafed Ash
Fraxinus angustifolia subsp. oxycarpa – Caucasian Ash
- Fraxinus angustifolia subsp. oxycarpa – Caucasian Ash
- Fraxinus dimorpha
- Fraxinus excelsior L. – European Ash
- Fraxinus holotricha Koehne
- Fraxinus ornus L. – Manna Ash or Flowering Ash
- Fraxinus syriaca
- Fraxinus pallisiae Wilmott – Pallis' Ash
- Fraxinus apertisquamifera
- Fraxinus baroniana
- Fraxinus bungeana DC. – Bunge's Ash
- Fraxinus chinensis Roxb. – Chinese Ash or Korean Ash
- Fraxinus chiisanensis
- Fraxinus floribunda Wall. – Himalayan Manna Ash
- Fraxinus griffithiiC.B.Clarke – Griffith's Ash
- Fraxinus hubeiensis
- Fraxinus japonica – Japanese Ash
- Fraxinus lanuginosa
- Fraxinus longicuspis
- Fraxinus malacophylla
- Fraxinus mandschurica Rupr. – Manchurian Ash
- Fraxinus mariesii – Maries' Ash
- Fraxinus micrantha Lingelsh.
- Fraxinus paxiana Lingelsh.
- Fraxinus platypoda
- Fraxinus raibocarpa Regel
- Fraxinus sieboldiana Blume – Japanese Flowering Ash
- Fraxinus sogdiana Bge
- Fraxinus spaethiana Lingelsh. – Späth's Ash
- Fraxinus trifoliata
- Fraxinus xanthoxyloides (G.Don) Wall. ex DC. – Afghan Ash
# Ecology
Ash is used as a food plant by the larvae of some Lepidoptera species (butterflies and moths) -- see list of Lepidoptera that feed on ashes.
# Threats
The emerald ash borer (Agrilus planipennis) is a wood-boring beetle accidentally introduced to North America from eastern Asia via solid wood packing material in the late 1980's to early 1990's. It has killed tens of millions of trees in 15 states in the United States and adjacent Ontario. It threatens some 7 billion ash trees in North America. Research is being conducted to determine if three native asian wasps, who are natural predators of EAB could be used as a biological control for the management of EAB populations in the United States. The public is being cautioned not to transport unfinished wood products, such as firewood, to slow the spread of this insect pest.
# Uses
Ash is a hardwood and is hard, dense (within 20% of 670 kg/m³ for Fraxinus americana, and higher at 710 kg/m³ for Fraxinus excelsior), tough and very strong but elastic, extensively used for making bows, tool handles, baseball bats, hurleys and other uses demanding high strength and resilience.
It is also often used as material for electric guitar bodies and, less commonly, for acoustic guitar bodies, known for its bright, cutting tone and sustaining quality. They are also used for making drum shells. Interior joinery is another common user of both European Ash and White Ash. Ash veneers are extensively used in office furniture. Ash is not used extensively outdoors due to the heartwood having a low durability to ground contact, meaning it will typically perish within five years.
Woodworkers generally like the timber for its great finishing qualities. It also has good machining qualities, and is quite easy to use with nails, screws and glue. Ash was commonly used for the structural members of the bodies of cars made by carriage builders. Early cars had frames which were intended to flex as part of the suspension system in order to simplify construction The Morgan Motor Company of Great Britain still manufacture sports cars with frames made from Ash. It was also widely used by early aviation pioneers for the aircraft.
It makes excellent firewood and barbecue or smoking wood. The two most economically important species for wood production are White Ash in eastern North America, and European Ash in Europe. The Green Ash (F. pennsylvanica) is widely planted as a street tree in the United States. The inner bark of the Blue Ash (F. quadrangulata) has been used as a source for a blue dye.
# Cultural aspects
In Greek mythology, the Meliae were nymphs of the ash, perhaps specifically of the Manna Ash (Fraxinus ornus), as dryads were nymphs of the oak. They appear in Hesiod's Theogony.
The ash exudes a sugary substance that, it has been suggested, was fermented to create the Norse Mead of Inspiration. In Norse mythology, the World Tree Yggdrasil is commonly held to be an ash tree, and the first man, Ask, was formed from an ash tree. Elsewhere in Europe, snakes were said to be repelled by ash leaves or a circle drawn by an ash branch. Irish folklore claims that shadows from an ash tree would damage crops. In Cheshire, it was said that ash could be used to cure warts or rickets. In Sussex the ash and elm tree were known as the Widow Maker because the large boughs would often drop without warning.
# Footnotes
- ↑ "Fraxinus L." Germplasm Resources Information Network. United States Department of Agriculture. 2006-04-03. Retrieved 2010-02-22..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}
- ↑ J. P. Mallory, Douglas Q. Adams, ed. (1997). Encyclopedia of Indo-European culture. Taylor & Francis. p. 32. ISBN 978-1-884964-98-5.
- ↑ "Species Records of Fraxinus". Germplasm Resources Information Network. United States Department of Agriculture. Retrieved 2010-02-22.
- ↑ "Fraxinus L." ITIS Standard Reports. Integrated Taxonomic Information System. Retrieved 2010-02-22.
- ↑ "The Problem". Don't Move Firewood. Retrieved 14 October 2011.
- ↑ Jump up to: 6.0 6.1 "White Ash". Niche Timbers. Retrieved 2010-02-22.
- ↑ Jump up to: 7.0 7.1 "Ash". Niche Timbers. Retrieved 2010-02-22.
- ↑ Dumont, Darl J. (1992). "The Ash Tree In Indo-European Culture". Mankind Quarterly. 32 (4): 323–336. Unknown parameter |month= ignored (help)
# Bibliography
Philips, Roger. Trees of North America and Europe, Random House, Inc., New York ISBN 0-394-50259-0, 1979. | Fraxinus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Fraxinus is a genus of flowering plants in the olive and lilac family, Oleaceae. It contains 45-65 species of usually medium to large trees, mostly deciduous though a few subtropical species are evergreen. The tree's common English name, ash, goes back to the Old English æsc, while the generic name originated in Latin. Both words also meant "spear" in their respective languages.[2] The leaves are opposite (rarely in whorls of three), and mostly pinnately compound, simple in a few species. The seeds, popularly known as keys or helicopter seeds, are a type of fruit known as a samara. Rowans or Mountain Ashes are unrelated to true ashes and belong to the Genus Sorbus though the leaves and buds are superficially similar.
# Selected species
- Fraxinus americana L. – White Ash or Autumn Purple Ash
- Fraxinus caroliniana Mill. – Carolina Ash
- Fraxinus nigra Marshall – Black Ash
- Fraxinus pennsylvanica Marshall Green Ash
- Fraxinus profunda (Bush) Bush – Pumpkin Ash
- Fraxinus quadrangulata Michx. – Blue Ash
- Fraxinus anomala Torr. ex S.Watson – Singleleaf Ash
- Fraxinus berlandieriana DC. – Mexican Ash
- Fraxinus cuspidata Torr. – Fragrant Ash
- Fraxinus dipetala Hook. & Arn. – California Ash or Two-petal Ash
- Fraxinus dubia
- Fraxinus gooddingii – Goodding's Ash
- Fraxinus greggii A.Gray – Gregg's Ash
- Fraxinus latifolia Benth. – Oregon Ash
- Fraxinus lowellii – Lowell Ash
- Fraxinus papillosa Lingelsh. – Chihuahua Ash
- Fraxinus purpusii
- Fraxinus rufescens
- Fraxinus texensis (A.Gray) Sarg. – Texas Ash
- Fraxinus uhdei (Wenz.) Lingelsh. – Shamel Ash or Tropical Ash
- Fraxinus velutina Torr. – Velvet Ash or Arizona Ash
- Fraxinus angustifolia Vahl – Narrow-leafed Ash
Fraxinus angustifolia subsp. oxycarpa – Caucasian Ash
- Fraxinus angustifolia subsp. oxycarpa – Caucasian Ash
- Fraxinus dimorpha
- Fraxinus excelsior L. – European Ash
- Fraxinus holotricha Koehne
- Fraxinus ornus L. – Manna Ash or Flowering Ash
- Fraxinus syriaca
- Fraxinus pallisiae Wilmott – Pallis' Ash
- Fraxinus apertisquamifera
- Fraxinus baroniana
- Fraxinus bungeana DC. – Bunge's Ash
- Fraxinus chinensis Roxb. – Chinese Ash or Korean Ash
- Fraxinus chiisanensis
- Fraxinus floribunda Wall. – Himalayan Manna Ash
- Fraxinus griffithiiC.B.Clarke – Griffith's Ash
- Fraxinus hubeiensis
- Fraxinus japonica – Japanese Ash
- Fraxinus lanuginosa
- Fraxinus longicuspis
- Fraxinus malacophylla
- Fraxinus mandschurica Rupr. – Manchurian Ash
- Fraxinus mariesii – Maries' Ash
- Fraxinus micrantha Lingelsh.
- Fraxinus paxiana Lingelsh.
- Fraxinus platypoda
- Fraxinus raibocarpa Regel
- Fraxinus sieboldiana Blume – Japanese Flowering Ash
- Fraxinus sogdiana Bge
- Fraxinus spaethiana Lingelsh. – Späth's Ash
- Fraxinus trifoliata
- Fraxinus xanthoxyloides (G.Don) Wall. ex DC. – Afghan Ash[3][4]
# Ecology
Ash is used as a food plant by the larvae of some Lepidoptera species (butterflies and moths) -- see list of Lepidoptera that feed on ashes.
# Threats
The emerald ash borer (Agrilus planipennis) is a wood-boring beetle accidentally introduced to North America from eastern Asia via solid wood packing material in the late 1980's to early 1990's. It has killed tens of millions of trees in 15 states in the United States and adjacent Ontario. It threatens some 7 billion ash trees in North America. Research is being conducted to determine if three native asian wasps, who are natural predators of EAB could be used as a biological control for the management of EAB populations in the United States. The public is being cautioned not to transport unfinished wood products, such as firewood, to slow the spread of this insect pest.[5]
# Uses
Ash is a hardwood and is hard, dense (within 20% of 670 kg/m³ for Fraxinus americana,[6] and higher at 710 kg/m³ for Fraxinus excelsior[7]), tough and very strong but elastic, extensively used for making bows, tool handles, baseball bats, hurleys and other uses demanding high strength and resilience.
It is also often used as material for electric guitar bodies and, less commonly, for acoustic guitar bodies, known for its bright, cutting tone and sustaining quality. They are also used for making drum shells. Interior joinery is another common user of both European Ash and White Ash. Ash veneers are extensively used in office furniture. Ash is not used extensively outdoors due to the heartwood having a low durability to ground contact,[7] meaning it will typically perish within five years.
Woodworkers generally like the timber for its great finishing qualities. It also has good machining qualities, and is quite easy to use with nails, screws and glue.[6] Ash was commonly used for the structural members of the bodies of cars made by carriage builders. Early cars had frames which were intended to flex as part of the suspension system in order to simplify construction The Morgan Motor Company of Great Britain still manufacture sports cars with frames made from Ash. It was also widely used by early aviation pioneers for the aircraft.
It makes excellent firewood and barbecue or smoking wood. The two most economically important species for wood production are White Ash in eastern North America, and European Ash in Europe. The Green Ash (F. pennsylvanica) is widely planted as a street tree in the United States. The inner bark of the Blue Ash (F. quadrangulata) has been used as a source for a blue dye.
# Cultural aspects
In Greek mythology, the Meliae were nymphs of the ash, perhaps specifically of the Manna Ash (Fraxinus ornus), as dryads were nymphs of the oak. They appear in Hesiod's Theogony.
The ash exudes a sugary substance that, it has been suggested, was fermented to create the Norse Mead of Inspiration.[8] In Norse mythology, the World Tree Yggdrasil is commonly held to be an ash tree, and the first man, Ask, was formed from an ash tree. Elsewhere in Europe, snakes were said to be repelled by ash leaves or a circle drawn by an ash branch. Irish folklore claims that shadows from an ash tree would damage crops. In Cheshire, it was said that ash could be used to cure warts or rickets. In Sussex the ash and elm tree were known as the Widow Maker because the large boughs would often drop without warning.
# Footnotes
- ↑ "Fraxinus L." Germplasm Resources Information Network. United States Department of Agriculture. 2006-04-03. Retrieved 2010-02-22..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}
- ↑ J. P. Mallory, Douglas Q. Adams, ed. (1997). Encyclopedia of Indo-European culture. Taylor & Francis. p. 32. ISBN 978-1-884964-98-5.
- ↑ "Species Records of Fraxinus". Germplasm Resources Information Network. United States Department of Agriculture. Retrieved 2010-02-22.
- ↑ "Fraxinus L." ITIS Standard Reports. Integrated Taxonomic Information System. Retrieved 2010-02-22.
- ↑ "The Problem". Don't Move Firewood. Retrieved 14 October 2011.
- ↑ Jump up to: 6.0 6.1 "White Ash". Niche Timbers. Retrieved 2010-02-22.
- ↑ Jump up to: 7.0 7.1 "Ash". Niche Timbers. Retrieved 2010-02-22.
- ↑ Dumont, Darl J. (1992). "The Ash Tree In Indo-European Culture". Mankind Quarterly. 32 (4): 323–336. Unknown parameter |month= ignored (help)
# Bibliography
Philips, Roger. Trees of North America and Europe, Random House, Inc., New York ISBN 0-394-50259-0, 1979. | https://www.wikidoc.org/index.php/Ash_tree | |
811e092aac56ce0acf2c6e4894f7f30052b6e86f | wikidoc | Aspergum | Aspergum
Aspergum (generic name Aspirin Gum-Oral) is the United States trademark name for an analgesic chewing gum, whose active ingredient is aspirin.
Such acetylsalicylic-acid chewing gum typically contains a dose of 227 mg (3½ grains) of aspirin, and is available in cherry and orange flavors. The aspirin in the gum delivers qualities that may assist in areas such as analgesic, salicylate, anti-inflammatory, pain, arthritis, and fever. The Aspergum trademark is currently owned by Insight Pharmaceuticals, the same company that produces the aspirin and caffeine based Anacin.
# History
Medicated chewing gum containing aspirin was first sold in the United States in 1924. In December 1927, Frank M. Dillard (inventor of Feenamint) and William C. Nalle formed the Dillard-Nalle company and sought U.S. trademark protection for Aspergum. Dillard-Nalle then began selling their Dellard's Aspergum in the United States in 1928. it was an early example of a functional gum - chewing gum as a drug delivery system.
It was significant in the recognition of aspirin's antithrombotic effect, when general practitioner Lawrence Craven reported in 1953 that patients who chewed Aspergum as an analgesic after tonsillectomy tended to bleed more easily. As a result of Dr. Craven's discovery through Aspergum in the 1950s, physicians themselves now often take low-dose aspirin to prevent heart attacks and strokes and emergency rooms routinely give aspirin to patients who they suspect may be experiencing a heart attack.
In June 1993, Farmades spa of Rome, Italy began manufacturing Aspergum Confetti Gommosi Masticabili for sale in Italy.
People have adopted their own uses for the gum. For example, in her 1997 book Streisand, Academy Award-winning American singer Barbra Streisand relates a story of how she filled in the gap caused by the removal of two front teeth with Aspergum when she began her career.
In 1998, Gumtech announced that it was to produce Aspergum for Schering-Plough HealthCare Products. | Aspergum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Aspergum (generic name Aspirin Gum-Oral)[1] is the United States trademark name for an analgesic chewing gum, whose active ingredient is aspirin.
Such acetylsalicylic-acid chewing gum typically contains a dose of 227 mg (3½ grains) of aspirin, and is available in cherry and orange flavors.[2] The aspirin in the gum delivers qualities that may assist in areas such as analgesic, salicylate, anti-inflammatory, pain, arthritis, and fever. The Aspergum trademark is currently owned by Insight Pharmaceuticals,[3] the same company that produces the aspirin and caffeine based Anacin.
# History
Medicated chewing gum containing aspirin was first sold in the United States in 1924.[4] In December 1927, Frank M. Dillard (inventor of Feenamint)[5] and William C. Nalle formed the Dillard-Nalle company and sought U.S. trademark protection for Aspergum.[6] Dillard-Nalle then began selling their Dellard's Aspergum in the United States in 1928.[7][8] it was an early example of a functional gum - chewing gum as a drug delivery system.
It was significant in the recognition of aspirin's antithrombotic effect, when general practitioner Lawrence Craven reported in 1953 that patients who chewed Aspergum as an analgesic after tonsillectomy tended to bleed more easily.[9][10] As a result of Dr. Craven's discovery through Aspergum in the 1950s, physicians themselves now often take low-dose aspirin to prevent heart attacks and strokes and emergency rooms routinely give aspirin to patients who they suspect may be experiencing a heart attack.[11]
In June 1993, Farmades spa of Rome, Italy began manufacturing Aspergum Confetti Gommosi Masticabili for sale in Italy.[12]
People have adopted their own uses for the gum. For example, in her 1997 book Streisand, Academy Award-winning American singer Barbra Streisand relates a story of how she filled in the gap caused by the removal of two front teeth with Aspergum when she began her career.[13]
In 1998, Gumtech announced that it was to produce Aspergum for Schering-Plough HealthCare Products.[14] | https://www.wikidoc.org/index.php/Aspergum | |
0825aa7fb7108993baf471b6303fcf41a9b0f8a9 | wikidoc | Asphyxia | Asphyxia
# Overview
Asphyxia (from Greek a-, "without" and σφυγμός (sphygmos), "pulse, heartbeat") is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs most sensitive to hypoxia first, such as the brain, hence resulting in cerebral hypoxia. Asphyxia is usually characterized by air hunger but this is not always the case; the urge to breathe is triggered by rising carbon dioxide levels in the blood rather than diminishing oxygen levels. Sometimes there is not enough carbon dioxide to cause air hunger, and victims become hypoxic without knowing it. In any case, the absence of effective remedial action will very rapidly lead to unconsciousness, brain damage and death. The time to death is dependent on the particular mechanism of asphyxia.
# Classification
## Smothering
Smothering refers to the mechanical obstruction of the flow of air from the environment into the mouth and/or nostrils, for instance by covering the mouth and nose with a hand, pillow, or a plastic bag. Smothering can be either partial or complete, where partial indicates that the person being smothered is able to inhale some air, although less than required. Normally, smothering requires at least partial obstruction of both the nasal cavities and the mouth to lead to asphyxia. Smothering with the hands or chest is used in some combat sports to distract the opponent, and create openings for transitions, as the opponent is forced to react to the smothering. It is also used in BDSM as a type of facesitting.
In some cases, smothering is combined with simultaneous compressive asphyxia. One example is overlay, in which an adult accidentally rolls over an infant during co-sleeping; an accident that often goes unnoticed and is mistakenly thought to be sudden infant death syndrome. Other accidents involving a similar mechanism are cave-ins or when an individual is buried in sand or grain. In homicidal cases, the term burking is often ascribed to a killing method that involves simultaneous smothering and compression of the torso.
## Compressive Asphyxia
Compressive asphyxia (also called chest compression) refers to the mechanical limitation of the expansion of the lungs by compressing the torso, hence interfering with breathing. Compressive asphyxia occurs when the chest or abdomen is compressed posteriorly.
In accidents, the term traumatic asphyxia or crush asphyxia is usually used to describe compressive asphyxia resulting from being crushed or pinned under a large weight or force. An example of traumatic asphyxia include cases where an individual has been using a car-jack to repair a car from below only to be crushed under the weight of the vehicle when the car-jack slips.
In fatal crowd disasters, contrary to popular belief, it is not the blunt trauma from trampling that causes the large part of the deaths, but rather the compressive asphyxia from being crushed against the crowd. In confined spaces, people push and lean against each other; evidence from bent steel railings in several fatal crowd accidents have shown horizontal forces over 4500 N (comparative weight approximately 460kg). In cases where people have stacked up on each other forming a human pile, estimations have been made of around 380kg of compressive weight in the lowest layer.
Chest compression is also featured in various grappling combat sports, where it is sometimes called wringing. Such techniques are either used to tire the opponent, or as complementary or distractive moves in combination with pinning holds, or sometimes even as submission holds.
Examples of chest compression include the knee-on-stomach position, or techniques such as leg scissors (also referred to as body scissors and in budo referred to as do-jime, 胴絞, "trunk strangle") where you wrap the legs around the opponent's midsection and squeeze them together.
Pressing is a form of torture or execution which works through asphyxia.
# Causes
Asphyxia is used to maim or kill in capital punishment, suicide, torture, and warfare. It is also used non-fatally in martial arts, combat sports, BDSM and during sex as erotic asphyxia. Because the need to breathe is triggered by the level of carbon dioxide in the blood, some victims may not experience an urgent need to breathe and may remain unaware of the onset of hypoxia.
Various chemical and physiological situations can interfere with the body's ability to absorb and use oxygen or regulate blood oxygen levels:
- Carbon monoxide inhalation, such as from a car exhaust, carbon monoxide has a higher affinity than oxygen to the hemoglobin in the blood's red blood corpuscles bonding with it tenaciously, displacing oxygen and preventing the blood from transporting it around the body.
- Contact with certain chemicals, including pulmonary agents (such as phosgene) and blood agents (such as hydrogen cyanide).
- Self-induced hypocapnia by hyperventilation, as in shallow water or deep water blackout and the choking game.
- A seizure which stops breathing activity.
- Sleep apnea.
- Drug overdose.
- Ondine's curse, central alveolar hypoventilation syndrome, or primary alveolar hypoventilation, a disorder of the autonomic nervous system in which a patient must consciously breathe. Although it is often said that persons with this disease will die if they fall asleep, this is not usuall the case.
- Acute respiratory distress syndrome | Asphyxia
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Asphyxia (from Greek a-, "without" and σφυγμός (sphygmos), "pulse, heartbeat") is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs most sensitive to hypoxia first, such as the brain, hence resulting in cerebral hypoxia. Asphyxia is usually characterized by air hunger but this is not always the case; the urge to breathe is triggered by rising carbon dioxide levels in the blood rather than diminishing oxygen levels. Sometimes there is not enough carbon dioxide to cause air hunger, and victims become hypoxic without knowing it. In any case, the absence of effective remedial action will very rapidly lead to unconsciousness, brain damage and death. The time to death is dependent on the particular mechanism of asphyxia.
# Classification
## Smothering
Smothering refers to the mechanical obstruction of the flow of air from the environment into the mouth and/or nostrils, for instance by covering the mouth and nose with a hand, pillow, or a plastic bag. Smothering can be either partial or complete, where partial indicates that the person being smothered is able to inhale some air, although less than required. Normally, smothering requires at least partial obstruction of both the nasal cavities and the mouth to lead to asphyxia. Smothering with the hands or chest is used in some combat sports to distract the opponent, and create openings for transitions, as the opponent is forced to react to the smothering. It is also used in BDSM as a type of facesitting.
In some cases, smothering is combined with simultaneous compressive asphyxia. One example is overlay, in which an adult accidentally rolls over an infant during co-sleeping; an accident that often goes unnoticed and is mistakenly thought to be sudden infant death syndrome. Other accidents involving a similar mechanism are cave-ins or when an individual is buried in sand or grain. In homicidal cases, the term burking is often ascribed to a killing method that involves simultaneous smothering and compression of the torso.
## Compressive Asphyxia
Compressive asphyxia (also called chest compression) refers to the mechanical limitation of the expansion of the lungs by compressing the torso, hence interfering with breathing. Compressive asphyxia occurs when the chest or abdomen is compressed posteriorly.
In accidents, the term traumatic asphyxia or crush asphyxia is usually used to describe compressive asphyxia resulting from being crushed or pinned under a large weight or force. An example of traumatic asphyxia include cases where an individual has been using a car-jack to repair a car from below only to be crushed under the weight of the vehicle when the car-jack slips.
In fatal crowd disasters, contrary to popular belief, it is not the blunt trauma from trampling that causes the large part of the deaths, but rather the compressive asphyxia from being crushed against the crowd. In confined spaces, people push and lean against each other; evidence from bent steel railings in several fatal crowd accidents have shown horizontal forces over 4500 N (comparative weight approximately 460kg). In cases where people have stacked up on each other forming a human pile, estimations have been made of around 380kg of compressive weight in the lowest layer.
Chest compression is also featured in various grappling combat sports, where it is sometimes called wringing. Such techniques are either used to tire the opponent, or as complementary or distractive moves in combination with pinning holds, or sometimes even as submission holds.
Examples of chest compression include the knee-on-stomach position, or techniques such as leg scissors (also referred to as body scissors and in budo referred to as do-jime, 胴絞, "trunk strangle") where you wrap the legs around the opponent's midsection and squeeze them together.
Pressing is a form of torture or execution which works through asphyxia.
# Causes
Asphyxia is used to maim or kill in capital punishment, suicide, torture, and warfare. It is also used non-fatally in martial arts, combat sports, BDSM and during sex as erotic asphyxia. Because the need to breathe is triggered by the level of carbon dioxide in the blood, some victims may not experience an urgent need to breathe and may remain unaware of the onset of hypoxia.
Various chemical and physiological situations can interfere with the body's ability to absorb and use oxygen or regulate blood oxygen levels:
- Carbon monoxide inhalation, such as from a car exhaust, carbon monoxide has a higher affinity than oxygen to the hemoglobin in the blood's red blood corpuscles bonding with it tenaciously, displacing oxygen and preventing the blood from transporting it around the body.
- Contact with certain chemicals, including pulmonary agents (such as phosgene) and blood agents (such as hydrogen cyanide).
- Self-induced hypocapnia by hyperventilation, as in shallow water or deep water blackout and the choking game.
- A seizure which stops breathing activity.
- Sleep apnea.
- Drug overdose.
- Ondine's curse, central alveolar hypoventilation syndrome, or primary alveolar hypoventilation, a disorder of the autonomic nervous system in which a patient must consciously breathe. Although it is often said that persons with this disease will die if they fall asleep, this is not usuall the case.
- Acute respiratory distress syndrome | https://www.wikidoc.org/index.php/Asphyxia | |
4f7fcf70df8bd735811c298ad91570b370616f17 | wikidoc | Asprosin | Asprosin
Asprosin is a protein hormone produced by mammals in their fatty (white adipose) tissues that stimulates the liver to release glucose into the blood stream. In these tissues, asprosin is encoded by the gene FBN1, which also encodes the protein fibrillin. In the liver, asprosin activates rapid glucose release via a cyclic adenosine monophosphate (cAMP) dependent pathway.
# Background
Asprosin is a protein hormone that has been found to be produced by white adipose tissue in mammals; it is transported to the liver, where it stimulates the release of glucose into the blood stream, via a cAMP-dependent pathway.
Glucose released by the liver into the blood stream is required for the normal function of the brain and other organs, as well as for survival during fasting and other aspects of mammalian function. Individuals with Marfanoid–progeroid–lipodystrophy syndrome (MPL) are deficient in asprosin, while people presenting the condition of insulin resistance and obesity produce it in abundance.
# Discovery and function
Asprosin was first identified by Dr. Atul Chopra and coworkers at Baylor College of Medicine as a C-terminal cleavage product of the FBN1 gene product profibrillin. They found mutations in the FBN1 gene in two patients with congenital partial lipodystrophy and a progeroid appearance. The two patients were Lizzie Velasquez and Abby Solomon. Truncations of the FBN1 protein in these patients were seen to have two consequences for protein production: a mutant/truncated fibrillin protein and very low plasma asprosin levels (from a postulated dominant negative effect). The condition has since been named Marfanoid–progeroid–lipodystrophy syndrome.
# Therapeutic potential
In a test of pharmacologic asprosin depletion in animals, preliminary results raised the possibility of its use, therapeutically, in treating type 2 diabetes and obesity. For instance, Chopra and coworkers observed that when antibodies targeting asprosin were injected into diabetic mice, blood glucose and insulin levels improved.
# Notes
- ↑ Jump up to: 1.0 1.1 1.2 1.3 Romere et al., 2016.
- ↑ Levine R (1986). "Monosaccharides in Health and Disease". Annu. Rev. Nutr. 6: 211–224. doi:10.1146/annurev.nu.06.070186.001235. Retrieved 25 November 2016..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}
- ↑ Röder PV, Wu B, Liu Y, Han W (March 2016). "Pancreatic regulation of glucose homeostasis". Experimental & Molecular Medicine. 48 (3, March): e219. doi:10.1038/emm.2016.6. PMC 4892884. PMID 26964835.
- ↑ Grens K (April 15, 2016). "Newly Discovered Hormone Explains Disease". The Scientist. Retrieved 18 April 2016.
- ↑ Romere et al., 2016, describe two patients, whom they characterize as having "neonatal progeroid syndrome (NPS)", citing O'Neil et al., 2007. No additional clinical information was provided (see also the description of Romere et al. in OMIM entry *134797 FIBRILLIN 1 ). However, in a later paper (Garg & Xing 2013; not cited by Romere et al.) the two patients described by O'Neil et al. in 2007 as having NPS were re-examined and found to exhibit several features associated with Marfan syndrome, and were re-characterized as having "progeroid fibrillinopathy" based on the presence of mutations in the FBN1 gene. See also the description of Romere et al in OMIM entry #616914 - MARFAN LIPODYSTROPHY SYNDROME; MFLS; accessed 9 December 2016.
- ↑ Kennedy, Pagan (25 Nov 2016). "The Thin Gene". The New York Times. Retrieved 22 May 2017.
- ↑ Bordo, Sara (Director); Campo, Michael (Writer); Velasquez, Lizzie (Star) (2015). A Brave Heart: The Lizzie Velasquez Story. Event occurs at 45:50 to 50:36.
- ↑ Jump up to: 8.0 8.1 Pathak 2016.
- ↑ Coghlan A (14 April 2016). "Newly discovered hormone could fight type 2 diabetes and obesity". New Scientist. Retrieved 20 April 2016.
- ↑ Greenhill C (2016). "Liver: Asprosin - new hormone involved in hepatic glucose release". Nat Rev Endocrinol. 12 (6): 312. doi:10.1038/nrendo.2016.66. PMID 27125501. | Asprosin
Asprosin is a protein hormone produced by mammals in their fatty (white adipose) tissues that stimulates the liver to release glucose into the blood stream. In these tissues, asprosin is encoded by the gene FBN1, which also encodes the protein fibrillin. In the liver, asprosin activates rapid glucose release via a cyclic adenosine monophosphate (cAMP) dependent pathway.
# Background
Asprosin is a protein hormone that has been found to be produced by white adipose tissue in mammals; it is transported to the liver, where it stimulates the release of glucose into the blood stream, via a cAMP-dependent pathway.[1]
Glucose released by the liver into the blood stream is required for the normal function of the brain and other organs, as well as for survival during fasting and other aspects of mammalian function.[2][3] Individuals with Marfanoid–progeroid–lipodystrophy syndrome (MPL) are deficient in asprosin, while people presenting the condition of insulin resistance and obesity produce it in abundance.[1][4]
# Discovery and function
Asprosin was first identified by Dr. Atul Chopra and coworkers at Baylor College of Medicine as a C-terminal cleavage product of the FBN1 gene product profibrillin. They found mutations in the FBN1 gene in two patients with congenital partial lipodystrophy and a progeroid appearance.[5] The two patients were Lizzie Velasquez and Abby Solomon.[6][7] Truncations of the FBN1 protein in these patients were seen to have two consequences for protein production: a mutant/truncated fibrillin protein and very low plasma asprosin levels (from a postulated dominant negative effect).[1][8][9] The condition has since been named Marfanoid–progeroid–lipodystrophy syndrome.
# Therapeutic potential
In a test of pharmacologic asprosin depletion in animals, preliminary results raised the possibility of its use, therapeutically, in treating type 2 diabetes and obesity.[10] For instance, Chopra and coworkers observed that when antibodies targeting asprosin were injected into diabetic mice, blood glucose and insulin levels improved.[1][8]
# Notes
- ↑ Jump up to: 1.0 1.1 1.2 1.3 Romere et al., 2016.
- ↑ Levine R (1986). "Monosaccharides in Health and Disease". Annu. Rev. Nutr. 6: 211–224. doi:10.1146/annurev.nu.06.070186.001235. Retrieved 25 November 2016..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}
- ↑ Röder PV, Wu B, Liu Y, Han W (March 2016). "Pancreatic regulation of glucose homeostasis". Experimental & Molecular Medicine. 48 (3, March): e219. doi:10.1038/emm.2016.6. PMC 4892884. PMID 26964835.
- ↑ Grens K (April 15, 2016). "Newly Discovered Hormone Explains Disease". The Scientist. Retrieved 18 April 2016.
- ↑ Romere et al., 2016, describe two patients, whom they characterize as having "neonatal progeroid syndrome (NPS)", citing O'Neil et al., 2007. No additional clinical information was provided (see also the description of Romere et al. in OMIM entry *134797 FIBRILLIN 1 ). However, in a later paper (Garg & Xing 2013; not cited by Romere et al.) the two patients described by O'Neil et al. in 2007 as having NPS were re-examined and found to exhibit several features associated with Marfan syndrome, and were re-characterized as having "progeroid fibrillinopathy" based on the presence of mutations in the FBN1 gene. See also the description of Romere et al in OMIM entry #616914 - MARFAN LIPODYSTROPHY SYNDROME; MFLS; accessed 9 December 2016.
- ↑ Kennedy, Pagan (25 Nov 2016). "The Thin Gene". The New York Times. Retrieved 22 May 2017.
- ↑ Bordo, Sara (Director); Campo, Michael (Writer); Velasquez, Lizzie (Star) (2015). A Brave Heart: The Lizzie Velasquez Story. Event occurs at 45:50 to 50:36.
- ↑ Jump up to: 8.0 8.1 Pathak 2016.
- ↑ Coghlan A (14 April 2016). "Newly discovered hormone could fight type 2 diabetes and obesity". New Scientist. Retrieved 20 April 2016.
- ↑ Greenhill C (2016). "Liver: Asprosin - new hormone involved in hepatic glucose release". Nat Rev Endocrinol. 12 (6): 312. doi:10.1038/nrendo.2016.66. PMID 27125501. | https://www.wikidoc.org/index.php/Asprosin | |
66f2cf235fc72e2bc3b6bf39111a5b8bccaded97 | wikidoc | Asystole | Asystole
# Overview
Asystole is a state of no cardiac electrical activity, hence no contractions of the myocardium and no cardiac output or blood flow. Asystole is one of the conditions required for a medical practitioner to certify death.
In asystole, the heart will not respond to defibrillation because it is already depolarized, however some emergency physicians advocate a trial of defibrillation in case the rhythm is actually fine ventricular fibrillation, although little evidence exists to support the practice. Asystole is usually a confirmation of death as opposed to a heart rhythm to be treated, although a small minority of patients are successfully resuscitated, if the underlying cause is identified and treated immediately.
# Causes
## Common Causes
Possible underlying causes include the Hs and Ts.
- Hypovolemia
- Hypoxia
- Acidosis
- Hypothermia
- Hyperkalemia or Hypokalemia
- Hypoglycemia
- Cardiac Tamponade
- Tension pneumothorax
- Thrombosis
- Myocardial infarction
- Thrombosis
- Pulmonary embolism
- Cardiogenic shock
- Degeneration of the sinoatrial or atrioventricular nodes
- Ischemic stroke
## Causes by Organ System
## Causes in Alphabetical Order
- Acidosis
- Beta blockers
- Cardiac tamponade
- Cardiogenic shock
- Degeneration of the sinoatrial or atrioventricular nodes
- Drowning
- Drug overdose
- Hyperkalemia
- Hypokalemia
- Hypoglycemia
- Hypothermia
- Hypovolemia
- Hypoxia
- Ischemic stroke
- Lightning strike
- Myocardial infarction
- Pacemaker failure
- Pulmonary embolism
- Tension pneumothorax
- Thrombosis
- Trauma
# Diagnosis
## Electrocardigram
Shown below are EKGs depicting asystole.
# Treatment
## Medical Therapy
It is important to exclude fine ventricular fibrillation in the patient presumed to have asystole. If VF is present, then cardioversion should be performed.
While the heart is asystolic, there is no blood flow to the brain unless CPR or internal cardiac massage (when the chest is opened and the heart is manually compressed) is performed, and even then, it is still a small amount. After many emergency treatments have been applied but the heart is still unresponsive, it is time to consider pronouncing the patient dead. Even in the rare case that a rhythm should reappear, if asystole has persisted for fifteen minutes or more the brain will have been deprived of oxygen long enough to cause brain death.
# Related Chapters
- Cardiac arrest
- Myocardial infarction
- Ventricular fibrillation | Asystole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Asystole is a state of no cardiac electrical activity, hence no contractions of the myocardium and no cardiac output or blood flow. Asystole is one of the conditions required for a medical practitioner to certify death.
In asystole, the heart will not respond to defibrillation because it is already depolarized, however some emergency physicians advocate a trial of defibrillation in case the rhythm is actually fine ventricular fibrillation, although little evidence exists to support the practice. Asystole is usually a confirmation of death as opposed to a heart rhythm to be treated, although a small minority of patients are successfully resuscitated, if the underlying cause is identified and treated immediately.
# Causes
## Common Causes
Possible underlying causes include the Hs and Ts.[1][2][3]
- Hypovolemia
- Hypoxia
- Acidosis
- Hypothermia
- Hyperkalemia or Hypokalemia
- Hypoglycemia
- Cardiac Tamponade
- Tension pneumothorax
- Thrombosis
- Myocardial infarction
- Thrombosis
- Pulmonary embolism
- Cardiogenic shock
- Degeneration of the sinoatrial or atrioventricular nodes
- Ischemic stroke
## Causes by Organ System
## Causes in Alphabetical Order
- Acidosis
- Beta blockers
- Cardiac tamponade
- Cardiogenic shock
- Degeneration of the sinoatrial or atrioventricular nodes
- Drowning
- Drug overdose
- Hyperkalemia
- Hypokalemia
- Hypoglycemia
- Hypothermia
- Hypovolemia
- Hypoxia
- Ischemic stroke
- Lightning strike
- Myocardial infarction
- Pacemaker failure
- Pulmonary embolism
- Tension pneumothorax
- Thrombosis
- Trauma
# Diagnosis
## Electrocardigram
Shown below are EKGs depicting asystole.
# Treatment
## Medical Therapy
It is important to exclude fine ventricular fibrillation in the patient presumed to have asystole. If VF is present, then cardioversion should be performed.
While the heart is asystolic, there is no blood flow to the brain unless CPR or internal cardiac massage (when the chest is opened and the heart is manually compressed) is performed, and even then, it is still a small amount. After many emergency treatments have been applied but the heart is still unresponsive, it is time to consider pronouncing the patient dead. Even in the rare case that a rhythm should reappear, if asystole has persisted for fifteen minutes or more the brain will have been deprived of oxygen long enough to cause brain death.
# Related Chapters
- Cardiac arrest
- Myocardial infarction
- Ventricular fibrillation | https://www.wikidoc.org/index.php/Asystole | |
2cf32b9690d55d8c2378a8d5fa3d39739cd76cb3 | wikidoc | Ataxin-2 | Ataxin-2
Ataxin-2 is a protein that in humans is encoded by the ATXN2 gene. Mutations in ATXN2 cause spinocerebellar ataxia type 2 (SCA2).
# Protein structure
Ataxin-2 contains the following protein domains:
- Two LSm domains, which likely allow it to bind RNA
- A PAM2 motif, predicted to associate with the poly(A)-binding protein
- A polyglutamine tract in some species (located near the amino terminal in primates and between the LSm domains in insects)
A potential transcript variant, missing an internal coding exon, has been described; however, its full-length nature is not certain.
# Species, tissue, and subcellular distribution
ATXN2 is conserved across eukaryotes. Most vertebrates have two orthologs of the gene (called ATXN2 and ATXN2L in humans), with the exception of birds which only have one. Plant species have two to six ATXN2 orthologs.
ATXN2 is ubiquitously expressed in different tissues. Within individual cells, it localizes to the Golgi apparatus and stress granules.
# Function
Ataxin-2 is involved in regulating mRNA translation through its interactions with the poly(A)-binding protein. It is also involved in the formation of stress granules and P-bodies, which also play roles in RNA regulation.
# Clinical significance
## Spinocerebellar ataxia type 2 (SCA2)
The polyglutamine tract in human ataxin-2 is unstable and can expand as it is transmitted across generations. Normal alleles usually have 22 or 23 repeats, but can contain up to 31 repeats. Longer expansions can cause spinocerebellar ataxia type 2 (SCA2), a fatal progressive genetic disorder in which neurons degenerate in the cerebellum, inferior olive, pons, and other areas. Symptoms of SCA2 include ataxia (a loss of coordinated movements), parkinsonism, and dementia in some cases. The disease allele usually contains 34-52 CAG repeats, but can contain as few as 32 or more than 100, and can expand in size when transmitted to successive generations. How the polyglutamine expansion in ataxin-2 leads to these symptoms is unknown.
## Amyotrophic lateral sclerosis (ALS)
In 2010, work from Aaron Gitler and Nancy Bonini at the University of Pennsylvania discovered that intermediate-size CAG repeat expansions are significantly associated with risk for developing amyotrophic lateral sclerosis (Lou Gehrig's disease). | Ataxin-2
Ataxin-2 is a protein that in humans is encoded by the ATXN2 gene.[1][2] Mutations in ATXN2 cause spinocerebellar ataxia type 2 (SCA2).
# Protein structure
Ataxin-2 contains the following protein domains:[3]
- Two LSm domains, which likely allow it to bind RNA
- A PAM2 motif, predicted to associate with the poly(A)-binding protein
- A polyglutamine tract in some species (located near the amino terminal in primates and between the LSm domains in insects)[4]
A potential transcript variant, missing an internal coding exon, has been described; however, its full-length nature is not certain.[5]
# Species, tissue, and subcellular distribution
ATXN2 is conserved across eukaryotes. Most vertebrates have two orthologs of the gene (called ATXN2 and ATXN2L in humans), with the exception of birds which only have one. Plant species have two to six ATXN2 orthologs.[4]
ATXN2 is ubiquitously expressed in different tissues. Within individual cells, it localizes to the Golgi apparatus and stress granules.[6]
# Function
Ataxin-2 is involved in regulating mRNA translation through its interactions with the poly(A)-binding protein. It is also involved in the formation of stress granules and P-bodies, which also play roles in RNA regulation.[6]
# Clinical significance
## Spinocerebellar ataxia type 2 (SCA2)
The polyglutamine tract in human ataxin-2 is unstable and can expand as it is transmitted across generations. Normal alleles usually have 22 or 23 repeats, but can contain up to 31 repeats. Longer expansions can cause spinocerebellar ataxia type 2 (SCA2), a fatal progressive genetic disorder in which neurons degenerate in the cerebellum, inferior olive, pons, and other areas. Symptoms of SCA2 include ataxia (a loss of coordinated movements), parkinsonism, and dementia in some cases.[7] The disease allele usually contains 34-52 CAG repeats, but can contain as few as 32 or more than 100, and can expand in size when transmitted to successive generations. How the polyglutamine expansion in ataxin-2 leads to these symptoms is unknown.
## Amyotrophic lateral sclerosis (ALS)
In 2010, work from Aaron Gitler and Nancy Bonini at the University of Pennsylvania discovered that intermediate-size CAG repeat expansions are significantly associated with risk for developing amyotrophic lateral sclerosis (Lou Gehrig's disease).[8] | https://www.wikidoc.org/index.php/Ataxin-2 | |
4d20ca781ac212465a8e312d565dead55fe3ec6c | wikidoc | Atopaxar | Atopaxar
# Overview
Atopaxar (previously known as E5555) is a potent and orally-active PAR-1 inhibitor that was developed by Eisai. Compared with vorapaxar, atopaxar is a synthetic agent with a shorter elimination half-life and a primary gastrointestinal metabolism. This small molecule inhibits the binding of thrombin either at or very close to the tethered ligand-binding site and available evidence indicates that atopaxar may have potential anti-inflammatory properties. The drug is currently not commercially available.
# Phase II of Atopaxar: the LANCELOT studies
The phase II of atopaxar included 4 clinical trials conducted in patients with atherothrombosis, 2 studies in Japanese subjects and 2 in subjects of non-Japanese ethnicity.
The J-LANCELOT studies were conducted in Japanese patients with NSTEACS (n = 241) and high-risk CAD (n = 263) respectively. All patients were treated with aspirin. Patients were assigned to 1 of 4 groups: atopaxar 50, 100, or 200 mg or matching placebo for a 12- (ACS patients) or 24-weeks (CAD patients) duration. The primary end-point was the occurrence of bleeding classified against the CURE scale and the TIMI scale. The incidence of major bleeding with either scales was very low and similar between atopaxar and placebo while the occurrence of any TIMI bleeding was numerically higher with the highest atopaxar doses. The incidence of major adverse cardiovascular events (MACEs) was low overall and no cardiovascular death was reported. Overall, 13 MACEs were observed in the ACS study and 5 in the CAD study with a numerical reduction in atopaxar treated patients observed in both studies. The platelet substudy showed that, after stimulation with 15 µM of TRA peptide, platelet aggregation inhibition reached > 90% with 100 mg and 200 mg of atopaxar while the inhibition provided by the 50 mg dose was 50-60% in CAD patients and only 20-50% in ACS patients. A dose-dependent increase in liver function abnormalities was observed in both studies in atopaxar treated patients (especially in patients on dual antiplatelet therapy), and also, a prolongation of the QTc interval.
Recently, it was presented the LANCELOT ACS trial, where atopaxar was tested in 603 patients with NSTEACS of non-Japanese ethnicity as a 400-mg loading dose followed by a daily dose of 50 mg, 100 mg, or 200 mg for 12 weeks or matching placebo in addition to aspirin and, in > 75% of patients, dual antiplatelet therapy with aspirin and a thienopyridine. The study showed a similar incidence of bleeding between the 3 doses of atopaxar and placebo and a favorable trends for efficacy indicated by a reduction in Holter-detected ischemia. The study however, like the Japanese studies, showed a dose-dependent increase in liver-function enzymes and a prolongation of the QTc interval at the highest doses. | Atopaxar
Editors-in-Chief: Sergio Leonardi, M.D., Duke Clinical Research Institute and C. Michael Gibson, M.S., M.D.
# Overview
Atopaxar (previously known as E5555) is a potent and orally-active PAR-1 inhibitor that was developed by Eisai. Compared with vorapaxar, atopaxar is a synthetic agent with a shorter elimination half-life and a primary gastrointestinal metabolism. This small molecule inhibits the binding of thrombin either at or very close to the tethered ligand-binding site and available evidence indicates that atopaxar may have potential anti-inflammatory properties. The drug is currently not commercially available.
# Phase II of Atopaxar: the LANCELOT studies
The phase II of atopaxar included 4 clinical trials conducted in patients with atherothrombosis, 2 studies in Japanese subjects and 2 in subjects of non-Japanese ethnicity.
The J-LANCELOT studies were conducted in Japanese patients with NSTEACS (n = 241) and high-risk CAD (n = 263) respectively. All patients were treated with aspirin. Patients were assigned to 1 of 4 groups: atopaxar 50, 100, or 200 mg or matching placebo for a 12- (ACS patients) or 24-weeks (CAD patients) duration. The primary end-point was the occurrence of bleeding classified against the CURE scale and the TIMI scale. The incidence of major bleeding with either scales was very low and similar between atopaxar and placebo while the occurrence of any TIMI bleeding was numerically higher with the highest atopaxar doses. The incidence of major adverse cardiovascular events (MACEs) was low overall and no cardiovascular death was reported. Overall, 13 MACEs were observed in the ACS study and 5 in the CAD study with a numerical reduction in atopaxar treated patients observed in both studies. The platelet substudy showed that, after stimulation with 15 µM of TRA peptide, platelet aggregation inhibition reached > 90% with 100 mg and 200 mg of atopaxar while the inhibition provided by the 50 mg dose was 50-60% in CAD patients and only 20-50% in ACS patients. A dose-dependent increase in liver function abnormalities was observed in both studies in atopaxar treated patients (especially in patients on dual antiplatelet therapy), and also, a prolongation of the QTc interval.
Recently, it was presented the LANCELOT ACS trial, where atopaxar was tested in 603 patients with NSTEACS of non-Japanese ethnicity as a 400-mg loading dose followed by a daily dose of 50 mg, 100 mg, or 200 mg for 12 weeks or matching placebo in addition to aspirin and, in > 75% of patients, dual antiplatelet therapy with aspirin and a thienopyridine. The study showed a similar incidence of bleeding between the 3 doses of atopaxar and placebo and a favorable trends for efficacy indicated by a reduction in Holter-detected ischemia. The study however, like the Japanese studies, showed a dose-dependent increase in liver-function enzymes and a prolongation of the QTc interval at the highest doses.
# External Links
- Serebruany VL, Kogushi M, Dastros-Pitei D, Flather M, Bhatt DL. (2009). "The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease". Thromb Haemost. 102 (1): 111–119. PMID 19572075.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL; on behalf of the J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigators. (2010). "Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease". Eur Heart J. PMID 20805115.CS1 maint: Multiple names: authors list (link) [Epub ahead of print] | https://www.wikidoc.org/index.php/Atopaxar | |
02499db940f09bb987d494e11f3ad713d92bf74a | wikidoc | Atosiban | Atosiban
# Overview
Atosiban (trade names Tractocile, Antocin, atosiban SUN) is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. Although initial studies suggested it could be used as a nasal spray and hence would not require hospital admission, it is not used in that form. It was developed by Ferring Pharmaceuticals in Sweden and first reported in the literature in 1985. Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent pre-term birth in pregnant adult women.
# Mechanism of action
Atosiban is a nonapeptide, desamino-oxytocin analogue, and a competitive vasopressin/oxytocin receptor antagonist (VOTra). Atosiban inhibits the oxytocin-mediated release of inositol trisphosphate from the myometrial cell membrane. As a result, there is reduced release of intracellular, stored calcium from the sarcoplasmic reticulum of myometrial cells, and reduced influx of Ca2+ from the extracellular space through voltage gated channels. In addition, atosiban suppresses oxytocin-mediated release of PGE and PGF from the decidua.
In human pre-term labour, atosiban, at the recommended dosage, antagonises uterine contractions and induces uterine quiescence. The onset of uterus relaxation following atosiban is rapid, uterine contractions being significantly reduced within 10 minutes to achieve stable uterine quiescence.
# Indications
Atosiban is indicated to delay imminent pre-term birth in pregnant adult women with:
- regular uterine contractions of at least 30 seconds duration at a rate of ≥ 4 per 30 minutes
- a cervical dilation of 1 to 3 cm (0-3 for nulliparas) and effacement of ≥ 50%
- a gestational age from 24 until 33 completed weeks
- a normal foetal heart rate
# Other uses
## Atosiban use after assisted reproduction
Atosiban is useful in improving the pregnancy outcome of in vitro fertilization-embryo transfer (IVF-ET) in patients with repeated implantation failure (RIF). The pregnancy rate improved from zero to 43.7%.
It was seen that the first- and second-trimester bleeding was more prevalent in ART than in spontaneous pregnancies.From 2004 to 2010, 33 first-trimester pregnancies with vaginal bleeding after ART with evident uterine contractions, author used atosiban and/or ritodrine, and there was no preterm delivery before 30 weeks.
In a recent meta-analysis, nifedipine is superior to β2-adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor (20–36 weeks), but it has been assigned to pregnancy category C by the Food and Drug Administration (FDA) so is not recommended before 20 weeks, or in the first trimester. Recent reports supports the use of atosiban, even at very early pregnancy, to decrease the frequency of uterine contractions to enhance success of pregnancy.
## Clinical trials
### Atosiban vs. nifedipine
Recently published a retrospective study (Saleh SS et al. 2013) comparing the efficacy and safety of atosiban and nifedipine in the suppression of pre-term labour concluded that atosiban and nifedipine are effective in delaying delivery for 7 days or more in women presenting with pre-term labour. A total of 68.3% of women in the atosiban group remained undelivered at 7 days or more, compared with 64.7% in the nifedipine group. They have the same efficacy and associated minor side-effects. However, flushing, palpitation and hypotension were significantly higher in the nifedipine group.
A clinical trial (Salim R et al. 2012) compared tocolytic efficacy and tolerability of atosiban with that of nifedipine. Forty-eight (68.6%) women allocated to atosiban and 39 (52%) to nifedipine did not deliver and did not require an alternate agent at 48 hours respectively (P=.03). Study concludes that atosiban has fewer failures within 48 hours. Nifedipine may be associated with a longer postponement of delivery.
Randomised controlled study (de Heus R et al. 2009), demonstrates for the first time, the direct effects of atosiban on fetal movement, heart rate and blood flow. Tocolysis with either atosiban or nifedipine combined with betamethasone administration have no direct fetal adverse effects.
### Atosiban vs. ritodrine
Multicentre, controlled trial of atosiban Vs. ritodrine in 128 women shows a significantly better tocolytic efficacy after 7 days in the atosiban group than in the ritodrine group (60.3 versus 34.9%), but not at 48 hours (68.3 versus 58.7%). Maternal adverse events were reported less frequently in the atosiban group (7.9 vs 70.8%), resulting in fewer early drug terminations due to adverse events (0 versus 20.0%). Therefore atosiban is superior to ritodrine in the treatment of preterm labour.
### Systematic Review
A systematic review of atosiban for tocolysis in preterm labour, six clinical studies - two compared atosiban to placebo and four atosiban to a beta-agonist showed a significant increase in the proportion of women undelivered by 48 hours in women receiving atosiban compared to placebo. When compared with beta-agonists, atosiban increased the proportion of women undelivered by 48 hours and was more safer compared to beta-agonists. Therefore oxytocin antagonists appear to be effective and safe for tocolysis in preterm labour.
A 2005 systematic review by the Cochrane Collaboration showed that while atosiban had fewer side-effects than alternative drugs (such as ritodrine,), other beta blockers, calcium channel antagonists. It was no better than placebo in the major outcomes. | Atosiban
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Atosiban (trade names Tractocile, Antocin, atosiban SUN) is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. Although initial studies suggested it could be used as a nasal spray and hence would not require hospital admission, it is not used in that form. It was developed by Ferring Pharmaceuticals in Sweden and first reported in the literature in 1985.[1] Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent pre-term birth in pregnant adult women.
# Mechanism of action
Atosiban is a nonapeptide, desamino-oxytocin analogue, and a competitive vasopressin/oxytocin receptor antagonist (VOTra). Atosiban inhibits the oxytocin-mediated release of inositol trisphosphate from the myometrial cell membrane. As a result, there is reduced release of intracellular, stored calcium from the sarcoplasmic reticulum of myometrial cells, and reduced influx of Ca2+ from the extracellular space through voltage gated channels. In addition, atosiban suppresses oxytocin-mediated release of PGE and PGF from the decidua.[2]
In human pre-term labour, atosiban, at the recommended dosage, antagonises uterine contractions and induces uterine quiescence. The onset of uterus relaxation following atosiban is rapid, uterine contractions being significantly reduced within 10 minutes to achieve stable uterine quiescence.
# Indications
Atosiban is indicated to delay imminent pre-term birth in pregnant adult women with:[3]
- regular uterine contractions of at least 30 seconds duration at a rate of ≥ 4 per 30 minutes
- a cervical dilation of 1 to 3 cm (0-3 for nulliparas) and effacement of ≥ 50%
- a gestational age from 24 until 33 completed weeks
- a normal foetal heart rate
# Other uses
## Atosiban use after assisted reproduction
Atosiban is useful in improving the pregnancy outcome of in vitro fertilization-embryo transfer (IVF-ET) in patients with repeated implantation failure (RIF).[4] The pregnancy rate improved from zero to 43.7%.[5]
It was seen that the first- and second-trimester bleeding was more prevalent in ART than in spontaneous pregnancies.From 2004 to 2010, 33 first-trimester pregnancies with vaginal bleeding after ART with evident uterine contractions, author used atosiban and/or ritodrine, and there was no preterm delivery before 30 weeks.[6]
In a recent meta-analysis,[7] nifedipine is superior to β2-adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor (20–36 weeks), but it has been assigned to pregnancy category C by the Food and Drug Administration (FDA) so is not recommended before 20 weeks, or in the first trimester.[6] Recent reports supports the use of atosiban, even at very early pregnancy, to decrease the frequency of uterine contractions to enhance success of pregnancy.[4]
## Clinical trials
### Atosiban vs. nifedipine
Recently published a retrospective study (Saleh SS et al. 2013) comparing the efficacy and safety of atosiban and nifedipine in the suppression of pre-term labour concluded that atosiban and nifedipine are effective in delaying delivery for 7 days or more in women presenting with pre-term labour. A total of 68.3% of women in the atosiban group remained undelivered at 7 days or more, compared with 64.7% in the nifedipine group. They have the same efficacy and associated minor side-effects. However, flushing, palpitation and hypotension were significantly higher in the nifedipine group.[8]
A clinical trial (Salim R et al. 2012) compared tocolytic efficacy and tolerability of atosiban with that of nifedipine. Forty-eight (68.6%) women allocated to atosiban and 39 (52%) to nifedipine did not deliver and did not require an alternate agent at 48 hours respectively (P=.03). Study concludes that atosiban has fewer failures within 48 hours. Nifedipine may be associated with a longer postponement of delivery.[9]
Randomised controlled study (de Heus R et al. 2009), demonstrates for the first time, the direct effects of atosiban on fetal movement, heart rate and blood flow. Tocolysis with either atosiban or nifedipine combined with betamethasone administration have no direct fetal adverse effects.[10]
### Atosiban vs. ritodrine
Multicentre, controlled trial of atosiban Vs. ritodrine in 128 women shows a significantly better tocolytic efficacy after 7 days in the atosiban group than in the ritodrine group (60.3 versus 34.9%), but not at 48 hours (68.3 versus 58.7%). Maternal adverse events were reported less frequently in the atosiban group (7.9 vs 70.8%), resulting in fewer early drug terminations due to adverse events (0 versus 20.0%). Therefore atosiban is superior to ritodrine in the treatment of preterm labour.[11]
### Systematic Review
A systematic review of atosiban for tocolysis in preterm labour, six clinical studies - two compared atosiban to placebo and four atosiban to a beta-agonist showed a significant increase in the proportion of women undelivered by 48 hours in women receiving atosiban compared to placebo. When compared with beta-agonists, atosiban increased the proportion of women undelivered by 48 hours and was more safer compared to beta-agonists. Therefore oxytocin antagonists appear to be effective and safe for tocolysis in preterm labour.[12]
A 2005 systematic review by the Cochrane Collaboration showed that while atosiban had fewer side-effects than alternative drugs (such as ritodrine,), other beta blockers, calcium channel antagonists. It was no better than placebo in the major outcomes.[13] | https://www.wikidoc.org/index.php/Atosiban | |
9d9eb5e9e44420b20bcb33a983781b3fe5399c5d | wikidoc | Atriplex | Atriplex
# Overview
Atriplex (/ˈætrplɛks/ Á-tri-plex) is a plant genus of 100-200 species, known by the common names of saltbush and orache (or orach). The genus is quite variable and widely distributed. It includes many desert and seashore plants and halophytes, as well as plants of moist environments. The goosefoot subfamily (Chenopodioideae) of the Amaranthaceae, in which the genus Atriplex is placed in the APG II system, was formerly considered a distinct family (Chenopodiaceae).
The generic name originated in Latin and was applied by Pliny the Elder to the edible oraches.
Saltbushes are extremely tolerant of salt content in the ground: their name derives from the fact that they retain salt in their leaves, which makes them of great use in areas affected by soil salination.
Atriplex species are used as food plants by the larvae of some Lepidoptera species; see the list of Lepidoptera which feed on Atriplex. For spiders such as Phidippus californicus and other arthropods, saltbush plants offer opportunities to hide and hunt in habitat that is otherwise often quite barren.
# Use by humans
Many species are edible. However, the favored species for human consumption is Garden Orache (A. hortensis). Use of Atriplex as food is known since at least the late Epipaleolithic (Mesolithic). The Ertebølle culture presumably used Common Orache (A. patula) as a vegetable (A. patula is attested as an archaeophyte in northern Europe). In the biblical Book of Job, mallûḥa (מַלּ֣וּחַ, probably Mediterranean Saltbush, A. halimus, the major culinary saltbush in the region) is mentioned as food eaten by social outcasts (Template:Bibleverse). Grey Saltbush (A. cinerea) is used as bushfood in Australia since prehistoric times.
Chamiso (A. canescens) and Shadscale (A. confertifolia) were eaten by Native Americans, and Spearscale (A. hastata) was a food in rural Eurasia.
The Garden Orache (A. hortensis), also called Red Orach, Mountain Spinach, or French Spinach, is an annual leaf vegetable with a salty, spinach-like taste.
The plant grows 1–2 m (3–6 ft) in height and the leaves are used cooked or in salads. It was commonly grown in Mediterranean regions from early times until spinach became the more favored leaf vegetable. The leaves can come in red, white and green varieties. The green leaves were once used to color pasta in Italy. Another common use of orach is to balance out the acidic flavor of sorrel.
Meat from sheep which have grazed on saltbush has surprisingly high levels of vitamin E, is leaner and more hydrated than regular lamb and has consumer appeal equal to grain-fed lamb. The vitamin E levels could have animal health benefits while extending the shelf-life and maintaining the fresh red colour of saltbush lamb. This effect has been demonstrated for Old Man Saltbush (A. nummularia) and River Saltbush (A. amnicola). For reasons unknown, sheep seem to prefer the more fibrous, less nutritious River Saltbush.
Saltbushes are also used as an ornamental plant in landscaping and can be used to prevent soil erosion in coastal areas. Old Man Saltbush has also been successfully used to rehabilitate old mining sites around Lightning Ridge (Australia).
# Selected species
- Atriplex acadiensis – Maritime Saltbush
- Atriplex acanthocarpa
- Atriplex acutibractea
- Atriplex acutiloba
- Atriplex alaskensis – Alaska Orache
- Atriplex amnicola – River Saltbush, Swamp Saltbush
- Atriplex angulata
- Atriplex × aptera
- Atriplex argentea – Silvery Saltbush
- Atriplex asterocarpa
- Atriplex australasica
- Atriplex barclayana
- Atriplex billardierei
- Atriplex bonnevillensis
- Atriplex bunburyana F.Muell.
- Atriplex californica
- Atriplex calotheca
- Atriplex canescens – Chamiso, Chamiza, Four-winged Saltbush, Grey Sagebrush
- Atriplex cephalantha
- Atriplex cinerea – Grey Saltbush, truganini
- Atriplex codonocarpa
- Atriplex conduplicata F.Muell.
- Atriplex confertifolia – Shadscale (Saltbush)
- Atriplex cordifolia
- Atriplex cordulata
- Atriplex cornigera
- Atriplex coronata
- Atriplex corrugata
- Atriplex coulteri
- Atriplex crassipes
- Atriplex cristata
- Atriplex cryptocarpa
- Atriplex cuneata
- Atriplex depressa
- Atriplex dioica – Thick-leaved Orache, Saline Saltbush
- Atriplex drymarioides
- Atriplex eardleyae
- Atriplex eichleri
- Atriplex elachophylla F.Muell.
- Atriplex elegans
- Atriplex erecticaulis
- Atriplex exilifolia F.Muell.
- Atriplex falcata – Sickle Saltbush
- Atriplex fissivalvis F.Muell.
- Atriplex flabelliformis
- Atriplex franktonii – Frankton's Saltbush
- Atriplex fruticulosa
- Atriplex gardneri – Gardner's Saltbush, Moundscale
- Atriplex garrettii
- Atriplex glabriuscula – Northeastern Saltbush, Babington's Orache, Smooth Orache, Scotland Orache, Glabrous Orache
- Atriplex gmelinii – Gmelin's Saltbush
- Atriplex graciliflora
- Atriplex griffithsii – Griffith's Saltbush (sometimes included in A. lentiformis or A. torreyi)
- Atriplex halimus – Mediterranean Saltbush, Sea Orache, Shrubby Orache
- Atriplex hastata – Halberd-leaved Orache, Spearscale (often included in A. patula)
- Atriplex heterosperma – Two-scaled Orache
- Atriplex holocarpa F.Muell.
- Atriplex hortensis – Garden Orache, Red Orach, Mountain Spinach, French Spinach
- Atriplex humifusa
- Atriplex humilis F.Muell.
- Atriplex hymenelytra – Desert Holly
- Atriplex hymenotheca
- Atriplex hypoleuca
- Atriplex incrassata F.Muell.
- Atriplex infrequens
- Atriplex intermedia
- Atriplex isatidea
- Atriplex joaquiniana
- Atriplex johnsonii
- Atriplex johnstonii
- Atriplex klebergorum
- Atriplex kochiana Maiden
- Atriplex laciniata – Frosted Orache
- Atriplex lampa
- Atriplex lanfrancoi
- Atriplex latifolia
- Atriplex lentiformis – Quail Bush
Atriplex lentiformis ssp. breweri – Brewer's Saltbrush
- Atriplex lentiformis ssp. breweri – Brewer's Saltbrush
- Atriplex leptocarpa F.Muell.
- Atriplex leucophylla
- Atriplex limbata
- Atriplex lindleyi
- Atriplex littoralis – Grass-leaved Orache, Tropical Saltbush
- Atriplex lobativalvis F.Muell.
- Atriplex longipes – Long-stalked Orache
- Atriplex macropterocarpa
- Atriplex matamorensis
- Atriplex maximowicziana – Maximowicz's Saltbush
- Atriplex micrantha
- Atriplex minuscula
- Atriplex minuticarpa
- Atriplex morrisii
- Atriplex muelleri
- Atriplex nana
- Atriplex navajoensis
- Atriplex nessorhina
- Atriplex nitens
- Atriplex nudicaulis – Baltic Saltbush
- Atriplex nummularia – Old Man Saltbush, Giant Saltbush
- Atriplex nuttallii – Nuttall's Saltbush
- Atriplex obconica
- Atriplex oblongifolia – Oblong-leaved Orache
- Atriplex obovata
- Atriplex pachypoda
- Atriplex pacifica
- Atriplex paludosa R.Br.
- Atriplex papillata
- Atriplex parishii
- Atriplex parryi
- Atriplex patula – Common Orache, Spreading Orache
- Atriplex persistens
- Atriplex phyllostegia
- Atriplex plebeja
- Atriplex polycarpa – Allscale (Saltbush), Desert Saltbush, Cattle Saltbush, Cattle Spinach
- Atriplex powellii – Powell's Saltbush
- Atriplex praecox – Early Orache
- Atriplex prostrata – Spear-leaved Orache, Thin-leaved Orache, Triangle Orache, "fat hen"
- Atriplex pseudocampanulata
- Atriplex pumilio R.Br.
- Atriplex pusilla
- Atriplex quadrivalvata
- Atriplex quinii F.Muell.
- Atriplex rhagodioides F.Muell.
- Atriplex rosea – Tumbling Orache
- Atriplex saccaria
- Atriplex semibaccata – Australian Saltbush, Berry Saltbush, Creeping Saltbush
- Atriplex semilunaris
- Atriplex serenana
- Atriplex sibirica
- Atriplex spinibractea
- Atriplex spinifera
- Atriplex spinulosa
- Atriplex spongiosa F.Muell.
- Atriplex stipitata
- Atriplex sturtii
- Atriplex suberecta, or Peregrine Saltbush
- Atriplex subspicata
- Atriplex subtilis
- Atriplex tatarica
- Atriplex tenuissima
- Atriplex texana
- Atriplex torreyi
- Atriplex tridentata
- Atriplex truncata – Wedge-leaved Saltbush
- Atriplex tularensis
- Atriplex turbinata
- Atriplex vallicola
- Atriplex velutinella F.Muell.
- Atriplex vesicaria – Bladder Saltbush
- Atriplex vestita
- Atriplex wardii
- Atriplex watsonii
- Atriplex welshii
- Atriplex wolfii
- Atriplex wrightii
## Formerly placed here
- Chenopodium album L. (as A. alba or A. viridis)
- Chenopodium oahuense (Meyen) Aellen (as A. oahuensis Meyen)
- Halimione pedunculata (as A. pedunculata)
- Halimione portulacoides (L.) Aellen (as A. portulacoides L.)
- Manochlamys albicans (Aiton) Aellen (as A. albicans Aiton)
# Footnotes
- ↑ "Genus: Atriplex L." Germplasm Resources Information Network. United States Department of Agriculture. 2007-10-05. Retrieved 2010-10-30..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}
- ↑ Sunset Western Garden Book, 1995:606–607
- ↑ Quattrocchi, Umberto (2000). CRC World Dictionary of Plant Names. I: A-C. CRC Press. p. 232. ISBN 978-0-8493-2675-2.
- ↑ Mistranslated as "mallows" in the King James Bible and as Nesseln (nettles) in the Luther Bible
- ↑ Davidson (1999)
- ↑ Norman et al. (2004), Pearce & Jacob (2004)
- ↑ Tasmanian name, also transcribed trucanini, trucaninny, trugannini, trugernanna, etc. The plant was the namesake for Truganini, among the last of her people.
- ↑ Gudrun Kadereit, Evgeny V. Mavrodiev, Elizabeth H. Zacharias & Alexander P. Sukhorukov: Molecular phylogeny of Atripliceae (Chenopodioideae, Chenopodiaceae): Implications for systematics, biogeography, flower and fruit evolution, and the origin of C4 Photosynthesis. - American Journal of Botany 97(10): 1664-1687, 2010.
- ↑ Jump up to: 9.0 9.1 "GRIN Species Records of Atriplex". Germplasm Resources Information Network. United States Department of Agriculture. Retrieved 2010-10-30. | Atriplex
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Atriplex (/[invalid input: 'icon']ˈætr[invalid input: 'ɨ']plɛks/[2] Á-tri-plex) is a plant genus of 100-200 species, known by the common names of saltbush and orache (or orach). The genus is quite variable and widely distributed. It includes many desert and seashore plants and halophytes, as well as plants of moist environments. The goosefoot subfamily (Chenopodioideae) of the Amaranthaceae, in which the genus Atriplex is placed in the APG II system, was formerly considered a distinct family (Chenopodiaceae).
The generic name originated in Latin and was applied by Pliny the Elder to the edible oraches.[3]
Saltbushes are extremely tolerant of salt content in the ground: their name derives from the fact that they retain salt in their leaves, which makes them of great use in areas affected by soil salination.
Atriplex species are used as food plants by the larvae of some Lepidoptera species; see the list of Lepidoptera which feed on Atriplex. For spiders such as Phidippus californicus and other arthropods, saltbush plants offer opportunities to hide and hunt in habitat that is otherwise often quite barren.
# Use by humans
Many species are edible. However, the favored species for human consumption is Garden Orache (A. hortensis). Use of Atriplex as food is known since at least the late Epipaleolithic (Mesolithic). The Ertebølle culture presumably used Common Orache (A. patula) as a vegetable (A. patula is attested as an archaeophyte in northern Europe). In the biblical Book of Job, mallûḥa (מַלּ֣וּחַ, probably Mediterranean Saltbush, A. halimus, the major culinary saltbush in the region) is mentioned as food eaten by social outcasts (Template:Bibleverse[4]). Grey Saltbush (A. cinerea) is used as bushfood in Australia since prehistoric times.
Chamiso (A. canescens) and Shadscale (A. confertifolia) were eaten by Native Americans, and Spearscale (A. hastata) was a food in rural Eurasia.
The Garden Orache (A. hortensis), also called Red Orach, Mountain Spinach, or French Spinach, is an annual leaf vegetable with a salty, spinach-like taste.
The plant grows 1–2 m (3–6 ft) in height and the leaves are used cooked or in salads. It was commonly grown in Mediterranean regions from early times until spinach became the more favored leaf vegetable. The leaves can come in red, white and green varieties. The green leaves were once used to color pasta in Italy. Another common use of orach is to balance out the acidic flavor of sorrel.[5]
Meat from sheep which have grazed on saltbush has surprisingly high levels of vitamin E, is leaner and more hydrated than regular lamb and has consumer appeal equal to grain-fed lamb.[citation needed] The vitamin E levels could have animal health benefits while extending the shelf-life and maintaining the fresh red colour of saltbush lamb. This effect has been demonstrated for Old Man Saltbush (A. nummularia) and River Saltbush (A. amnicola). For reasons unknown, sheep seem to prefer the more fibrous, less nutritious River Saltbush.[6]
Saltbushes are also used as an ornamental plant in landscaping and can be used to prevent soil erosion in coastal areas. Old Man Saltbush has also been successfully used to rehabilitate old mining sites around Lightning Ridge (Australia).
# Selected species
- Atriplex acadiensis – Maritime Saltbush
- Atriplex acanthocarpa
- Atriplex acutibractea
- Atriplex acutiloba
- Atriplex alaskensis – Alaska Orache
- Atriplex amnicola – River Saltbush, Swamp Saltbush
- Atriplex angulata
- Atriplex × aptera
- Atriplex argentea – Silvery Saltbush
- Atriplex asterocarpa
- Atriplex australasica
- Atriplex barclayana
- Atriplex billardierei
- Atriplex bonnevillensis
- Atriplex bunburyana F.Muell.
- Atriplex californica
- Atriplex calotheca
- Atriplex canescens – Chamiso, Chamiza, Four-winged Saltbush, Grey Sagebrush
- Atriplex cephalantha
- Atriplex cinerea – Grey Saltbush, truganini[7]
- Atriplex codonocarpa
- Atriplex conduplicata F.Muell.
- Atriplex confertifolia – Shadscale (Saltbush)
- Atriplex cordifolia
- Atriplex cordulata
- Atriplex cornigera
- Atriplex coronata
- Atriplex corrugata
- Atriplex coulteri
- Atriplex crassipes
- Atriplex cristata
- Atriplex cryptocarpa
- Atriplex cuneata
- Atriplex depressa
- Atriplex dioica – Thick-leaved Orache, Saline Saltbush
- Atriplex drymarioides
- Atriplex eardleyae
- Atriplex eichleri
- Atriplex elachophylla F.Muell.
- Atriplex elegans
- Atriplex erecticaulis
- Atriplex exilifolia F.Muell.
- Atriplex falcata – Sickle Saltbush
- Atriplex fissivalvis F.Muell.
- Atriplex flabelliformis
- Atriplex franktonii – Frankton's Saltbush
- Atriplex fruticulosa
- Atriplex gardneri – Gardner's Saltbush, Moundscale
- Atriplex garrettii
- Atriplex glabriuscula – Northeastern Saltbush, Babington's Orache, Smooth Orache, Scotland Orache, Glabrous Orache
- Atriplex gmelinii – Gmelin's Saltbush
- Atriplex graciliflora
- Atriplex griffithsii – Griffith's Saltbush (sometimes included in A. lentiformis or A. torreyi)
- Atriplex halimus – Mediterranean Saltbush, Sea Orache, Shrubby Orache
- Atriplex hastata – Halberd-leaved Orache, Spearscale (often included in A. patula)
- Atriplex heterosperma – Two-scaled Orache
- Atriplex holocarpa F.Muell.
- Atriplex hortensis – Garden Orache, Red Orach, Mountain Spinach, French Spinach
- Atriplex humifusa
- Atriplex humilis F.Muell.
- Atriplex hymenelytra – Desert Holly
- Atriplex hymenotheca
- Atriplex hypoleuca
- Atriplex incrassata F.Muell.
- Atriplex infrequens
- Atriplex intermedia
- Atriplex isatidea
- Atriplex joaquiniana
- Atriplex johnsonii[verification needed]
- Atriplex johnstonii[verification needed]
- Atriplex klebergorum
- Atriplex kochiana Maiden
- Atriplex laciniata – Frosted Orache
- Atriplex lampa
- Atriplex lanfrancoi [8]
- Atriplex latifolia
- Atriplex lentiformis – Quail Bush
Atriplex lentiformis ssp. breweri – Brewer's Saltbrush
- Atriplex lentiformis ssp. breweri – Brewer's Saltbrush
- Atriplex leptocarpa F.Muell.
- Atriplex leucophylla
- Atriplex limbata
- Atriplex lindleyi
- Atriplex littoralis – Grass-leaved Orache, Tropical Saltbush
- Atriplex lobativalvis F.Muell.
- Atriplex longipes – Long-stalked Orache
- Atriplex macropterocarpa
- Atriplex matamorensis
- Atriplex maximowicziana – Maximowicz's Saltbush
- Atriplex micrantha
- Atriplex minuscula
- Atriplex minuticarpa
- Atriplex morrisii
- Atriplex muelleri
- Atriplex nana
- Atriplex navajoensis
- Atriplex nessorhina
- Atriplex nitens
- Atriplex nudicaulis – Baltic Saltbush
- Atriplex nummularia – Old Man Saltbush, Giant Saltbush
- Atriplex nuttallii – Nuttall's Saltbush
- Atriplex obconica
- Atriplex oblongifolia – Oblong-leaved Orache
- Atriplex obovata
- Atriplex pachypoda
- Atriplex pacifica
- Atriplex paludosa R.Br.
- Atriplex papillata
- Atriplex parishii
- Atriplex parryi
- Atriplex patula – Common Orache, Spreading Orache
- Atriplex persistens
- Atriplex phyllostegia
- Atriplex plebeja
- Atriplex polycarpa – Allscale (Saltbush), Desert Saltbush, Cattle Saltbush, Cattle Spinach
- Atriplex powellii – Powell's Saltbush
- Atriplex praecox – Early Orache
- Atriplex prostrata – Spear-leaved Orache, Thin-leaved Orache, Triangle Orache, "fat hen"
- Atriplex pseudocampanulata
- Atriplex pumilio R.Br.
- Atriplex pusilla
- Atriplex quadrivalvata
- Atriplex quinii F.Muell.
- Atriplex rhagodioides F.Muell.
- Atriplex rosea – Tumbling Orache
- Atriplex saccaria
- Atriplex semibaccata – Australian Saltbush, Berry Saltbush, Creeping Saltbush
- Atriplex semilunaris
- Atriplex serenana
- Atriplex sibirica
- Atriplex spinibractea
- Atriplex spinifera
- Atriplex spinulosa
- Atriplex spongiosa F.Muell.
- Atriplex stipitata
- Atriplex sturtii
- Atriplex suberecta, or Peregrine Saltbush
- Atriplex subspicata
- Atriplex subtilis
- Atriplex tatarica
- Atriplex tenuissima
- Atriplex texana
- Atriplex torreyi
- Atriplex tridentata
- Atriplex truncata – Wedge-leaved Saltbush
- Atriplex tularensis
- Atriplex turbinata
- Atriplex vallicola
- Atriplex velutinella F.Muell.
- Atriplex vesicaria – Bladder Saltbush
- Atriplex vestita
- Atriplex wardii
- Atriplex watsonii
- Atriplex welshii
- Atriplex wolfii
- Atriplex wrightii
## Formerly placed here
- Chenopodium album L. (as A. alba or A. viridis)
- Chenopodium oahuense (Meyen) Aellen (as A. oahuensis Meyen)[9]
- Halimione pedunculata (as A. pedunculata)
- Halimione portulacoides (L.) Aellen (as A. portulacoides L.)
- Manochlamys albicans (Aiton) Aellen (as A. albicans Aiton)[9]
# Footnotes
- ↑ "Genus: Atriplex L." Germplasm Resources Information Network. United States Department of Agriculture. 2007-10-05. Retrieved 2010-10-30..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}
- ↑ Sunset Western Garden Book, 1995:606–607
- ↑ Quattrocchi, Umberto (2000). CRC World Dictionary of Plant Names. I: A-C. CRC Press. p. 232. ISBN 978-0-8493-2675-2.
- ↑ Mistranslated as "mallows" in the King James Bible and as Nesseln (nettles) in the Luther Bible
- ↑ Davidson (1999)
- ↑ Norman et al. (2004), Pearce & Jacob (2004)
- ↑ Tasmanian name, also transcribed trucanini, trucaninny, trugannini, trugernanna, etc. The plant was the namesake for Truganini, among the last of her people.
- ↑ Gudrun Kadereit, Evgeny V. Mavrodiev, Elizabeth H. Zacharias & Alexander P. Sukhorukov: Molecular phylogeny of Atripliceae (Chenopodioideae, Chenopodiaceae): Implications for systematics, biogeography, flower and fruit evolution, and the origin of C4 Photosynthesis. - American Journal of Botany 97(10): 1664-1687, 2010.
- ↑ Jump up to: 9.0 9.1 "GRIN Species Records of Atriplex". Germplasm Resources Information Network. United States Department of Agriculture. Retrieved 2010-10-30.
# External links and references
Template:Wikispecies
- Template:Aut (1999): Orach. In: Oxford Companion to Food: 556. ISBN 0-19-211579-0
- Everitt, J.H. (2007). Weeds in South Texas and Northern Mexico. Lubbock: Texas Tech University Press. Unknown parameter |coauthors= ignored (help) ISBN 0-89672-614-2
- Template:Aut (2004): Saltbush lifts sheep meat vitamin content. Farming Ahead 153(October): 63. PDF fulltext
- Template:Aut (2004): Variation within and between two saltbush species in plant composition and subsequent selection by sheep. Aust. J. Agr. Res. 55(9): 999–1007. doi:10.1071/AR04031 (HTML abstract)
ar:قطف
az:Sirkən
ba:Алабута
be:Лебяда
ca:Atriplex
da:Mælde
de:Melden
nv:Díkʼǫ́ǫ́zhí (chʼil)
fa:اسفناج باغی
hsb:Łoboda
it:Atriplex
he:מלוח (צמח)
ka:თათაბო
kk:Алабота (өсімдік)
ky:Алабата
lt:Balandūnė
nl:Melde
no:Melde
fi:Maltsat
uk:Лобода | https://www.wikidoc.org/index.php/Atriplex | |
05eb6779bd4c94bdae1d889a29f74b119d58fb76 | wikidoc | Thalamus | Thalamus
# Overview
The thalamus (from Greek θάλαμος = bedroom, chamber, IPA= /ˈθæləməs/) is a pair and symmetric part of the brain. It constitutes the main part of the diencephalon.
# Location and topography
In the caudal (tail) to oral (mouth) sequence of neuromeres, the diencephalon is located between the mesencephalon (cerebral peduncule, belonging to the brain stem) and the telencephalon. The diencephalon includes also the dorsally located epithalamus (essentially the habenula and annexes) and the perithalamus (prethalamus formerly described as ventral thalamus) containing the zona incerta and the "reticulate nucleus" (not the reticular, term of confusion). Due to their different ontogenetic origins, the epithalamus and the perithalamus are formally distinguished from the thalamus proper.
Phylogenetic modifications are such that this article essentially deals with the human thalamus and may differ in comparison with accounts in non-upper primate species. In normal humans, the two thalami are prominent bulb-shaped masses, about 5.7 cm in length, located obliquely (about 30°) and symmetrically on each side of the third ventricle. The two can adhere on a variable extent in 30% of humans. This adhesio interthalamica (interthalamic adhesion, or massa intermedia) does not contain interthalamic neural connection in our species.
# Anatomy
The thalamus comprises a system of lamellae (made up of myelinated fibers) separating different thalamic subparts. Other areas are defined by distinct clusters of neurons, such as the periventricular gray, the intralaminar elements, the "nucleus limitans", and others. These latter structures, different in structure from the major part of the thalamus, have been grouped together into the allothalamus as opposed to the isothalamus (Percheron, 2003). This distinction simplifies the global description of the thalamus.
Please see also List of thalamic nuclei.
# Arterial supply
The thalamus derives its blood supply from a number of arteries including polar and paramedian arteries, inferolateral (thalamogeniculate) arteries, and posterior (medial and lateral) choroidal arteries. These are all branches of the posterior cerebral artery.
# Function
The thalamus is known to have multiple functions. Deduced from the design of the isothalamus, it is generally believed to act as a translator for which various "prethalamic" inputs are processed into a form readable by the cortex. The thalamus is believed to relay information selectively to various parts of the cortex, as one thalamic point may reach one or several regions in the cortex.
The thalamus also plays an important role in regulating states of sleep and wakefulness. Thalamic nuclei have strong reciprocal connections with the cerebral cortex, forming thalamo-cortico-thalamic circuits that are believed to be involved with consciousness. The thalamus plays a major role in regulating arousal, the level of awareness and activity. Damaged thalamus can lead to permanent coma.
Many different functions are linked to the system to which thalamic parts belong. This is at first the case for sensory systems (which excepts the olfactory function) auditory, somatic, visceral, gustatory and visual systems where localised lesions provoke particular sensory deficits. A major role of the thalamus is devoted to "motor" systems. This has been and continues to be a subject of interest for investigators. VIm, the relay of cerebellar afferences, is the target of stereotactians particularly for the improvement of tremor. The role of the thalamus in the more anterior pallidal and nigral territories in the basal ganglia system disturbances is recognized but still poorly known. The contribution of the thalamus to vestibular or to tectal functions is almost ignored. The thalamus has been thought of as a "relay" that simply forwards signals to the cerebral cortex. Newer research suggests that thalamic function is more complicated.
# Pathology
Cerebrovascular accidents (strokes) can cause thalamic syndrome (Dejerine and Roussy, 1906), which results in a contralateral hemianaesthesia, burning or aching sensation on one half of a body (painful anaesthesia), often accompanied by mood swings. Ischaemia of the territory of the paramedian artery, if bilateral, causes serious troubles including akinetic mutism accompanied or not by oculomotor troubles.
Korsakoff's Syndrome, stems from mammillary bodies, mammilothalamic, or thalamic lesions.
# Development
The thalamic complex is composed of the perithalamus (or prethalamus, previously also known as ventral thalamus), the zona limitans intrathalamica (ZLI) and the thalamus (dorsal thalamus).
The ZLI is a transverse boundary located between the perithalamus and the functional distinct thalamus. Besides its morphological characteristics, it bears the hallmarks of a signalling centre. Fate mapping experiments in chick have shown that the ZLI is cell lineage restricted at its boundaries and therefore can be termed a true developmental compartment in the forebrain.
Besides morphological characteristics, the ZLI is the only structure in the alar plate of the neural tube that expresses signaling molecules.
In mouse, the function of Shh (Sonic Hedgehog) signaling at the ZLI has not been addressed directly due to a complete absence of the diencephalon in Shh mutants.
Studies in chicks have shown that Shh is both necessary and sufficient for thalamic gene induction.
In zebrafish, it was shown that the expression of two Shh genes, shh-a and shh-b (formerly described as twhh) mark the ZLI territory, and that Shh signaling is sufficient for the molecular differentiation of both the prethalamus and the thalamus but is not required for their maintenance and Shh signaling from the ZLI/alar plate is sufficient for the maturation of prethalamic and thalamic territory while ventral Shh signals are dispensable. | Thalamus
Template:Infobox Brain
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
The thalamus (from Greek θάλαμος = bedroom, chamber, IPA= /ˈθæləməs/) is a pair and symmetric part of the brain. It constitutes the main part of the diencephalon.
# Location and topography
In the caudal (tail) to oral (mouth) sequence of neuromeres, the diencephalon is located between the mesencephalon (cerebral peduncule, belonging to the brain stem) and the telencephalon. The diencephalon includes also the dorsally located epithalamus (essentially the habenula and annexes) and the perithalamus (prethalamus formerly described as ventral thalamus) containing the zona incerta and the "reticulate nucleus" (not the reticular, term of confusion). Due to their different ontogenetic origins, the epithalamus and the perithalamus are formally distinguished from the thalamus proper.
Phylogenetic modifications are such that this article essentially deals with the human thalamus and may differ in comparison with accounts in non-upper primate species. In normal humans, the two thalami are prominent bulb-shaped masses, about 5.7 cm in length, located obliquely (about 30°) and symmetrically on each side of the third ventricle. The two can adhere on a variable extent in 30% of humans. This adhesio interthalamica (interthalamic adhesion, or massa intermedia) does not contain interthalamic neural connection in our species.
# Anatomy
The thalamus comprises a system of lamellae (made up of myelinated fibers) separating different thalamic subparts. Other areas are defined by distinct clusters of neurons, such as the periventricular gray, the intralaminar elements, the "nucleus limitans", and others. These latter structures, different in structure from the major part of the thalamus, have been grouped together into the allothalamus as opposed to the isothalamus (Percheron, 2003).[1] This distinction simplifies the global description of the thalamus.
Please see also List of thalamic nuclei.
# Arterial supply
The thalamus derives its blood supply from a number of arteries including polar and paramedian arteries, inferolateral (thalamogeniculate) arteries, and posterior (medial and lateral) choroidal arteries.[2] These are all branches of the posterior cerebral artery.
# Function
The thalamus is known to have multiple functions. Deduced from the design of the isothalamus, it is generally believed to act as a translator for which various "prethalamic" inputs are processed into a form readable by the cortex. The thalamus is believed to relay information selectively to various parts of the cortex, as one thalamic point may reach one or several regions in the cortex.
The thalamus also plays an important role in regulating states of sleep and wakefulness. Thalamic nuclei have strong reciprocal connections with the cerebral cortex, forming thalamo-cortico-thalamic circuits that are believed to be involved with consciousness. The thalamus plays a major role in regulating arousal, the level of awareness and activity. Damaged thalamus can lead to permanent coma.
Many different functions are linked to the system to which thalamic parts belong. This is at first the case for sensory systems (which excepts the olfactory function) auditory, somatic, visceral, gustatory and visual systems where localised lesions provoke particular sensory deficits. A major role of the thalamus is devoted to "motor" systems. This has been and continues to be a subject of interest for investigators. VIm, the relay of cerebellar afferences, is the target of stereotactians particularly for the improvement of tremor. The role of the thalamus in the more anterior pallidal and nigral territories in the basal ganglia system disturbances is recognized but still poorly known. The contribution of the thalamus to vestibular or to tectal functions is almost ignored. The thalamus has been thought of as a "relay" that simply forwards signals to the cerebral cortex. Newer research suggests that thalamic function is more complicated.[3]
# Pathology
Cerebrovascular accidents (strokes) can cause thalamic syndrome (Dejerine and Roussy, 1906),[4] which results in a contralateral hemianaesthesia, burning or aching sensation on one half of a body (painful anaesthesia), often accompanied by mood swings. Ischaemia of the territory of the paramedian artery, if bilateral, causes serious troubles including akinetic mutism accompanied or not by oculomotor troubles.
Korsakoff's Syndrome, stems from mammillary bodies, mammilothalamic, or thalamic lesions.
# Development
The thalamic complex is composed of the perithalamus (or prethalamus, previously also known as ventral thalamus), the zona limitans intrathalamica (ZLI) and the thalamus (dorsal thalamus).[5][6]
The ZLI is a transverse boundary located between the perithalamus and the functional distinct thalamus. Besides its morphological characteristics, it bears the hallmarks of a signalling centre. Fate mapping experiments in chick have shown that the ZLI is cell lineage restricted at its boundaries and therefore can be termed a true developmental compartment in the forebrain.[7]
Besides morphological characteristics, the ZLI is the only structure in the alar plate of the neural tube that expresses signaling molecules.[8]
In mouse, the function of Shh (Sonic Hedgehog) signaling at the ZLI has not been addressed directly due to a complete absence of the diencephalon in Shh mutants.[9]
Studies in chicks have shown that Shh is both necessary and sufficient for thalamic gene induction.[10]
In zebrafish, it was shown that the expression of two Shh genes, shh-a and shh-b (formerly described as twhh) mark the ZLI territory, and that Shh signaling is sufficient for the molecular differentiation of both the prethalamus and the thalamus but is not required for their maintenance and Shh signaling from the ZLI/alar plate is sufficient for the maturation of prethalamic and thalamic territory while ventral Shh signals are dispensable.[11] | https://www.wikidoc.org/index.php/Auditory_thalamus | |
c6867d56e150fc2c2e4fce0f4d88c5fddb5d7adb | wikidoc | Auer rod | Auer rod
Auer rods can be seen in the leukemic blasts of Acute Myeloid Leukemia. Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts. They are composed of fused lysosomes and contain peroxidase, lysosomal enzymes, and large crystalline inclusions.
# Diagnosis
Auer rods are classically seen in myeloid blasts of M1, M2, M3, and M4 acute leukemias.
They are also used to distinguish the pre-leukemia Myelodysplastic Syndromes: Refractory Anemia with Excess Blasts 2 (which has Auer rods) from RAEB 1 (which does not).
## Pathology
- Bone marrow aspirate showing acute myeloid leukemia with Auer rods in several blasts
- AML - Auer Rods, DIC
- AML with Auer Rods
# Eponym
These cytoplasmic inclusions were named by John Auer, an American physiologist (1875-1948).
# Reference
- ↑ Auer J. Some hitherto undescribed structures found in the large lymphocytes of a case of acute leukaemia. Am J Med Sci 1906;131:1002-1015. | Auer rod
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Auer rods can be seen in the leukemic blasts of Acute Myeloid Leukemia. Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts. They are composed of fused lysosomes and contain peroxidase, lysosomal enzymes, and large crystalline inclusions.
# Diagnosis
Auer rods are classically seen in myeloid blasts of M1, M2, M3, and M4 acute leukemias.
They are also used to distinguish the pre-leukemia Myelodysplastic Syndromes: Refractory Anemia with Excess Blasts 2 (which has Auer rods) from RAEB 1 (which does not).
## Pathology
- Bone marrow aspirate showing acute myeloid leukemia with Auer rods in several blasts
- AML - Auer Rods, DIC
- AML with Auer Rods
# Eponym
These cytoplasmic inclusions were named by John Auer, an American physiologist (1875-1948).[1]
# Reference
- ↑ Auer J. Some hitherto undescribed structures found in the large lymphocytes of a case of acute leukaemia. Am J Med Sci 1906;131:1002-1015.
# External links
- Overview at University of Virginia
- Image at NIH/MedlinePlus
- Slides at wadsworth.org
- Image at University of Utah
Template:WikiDoc Sources
sv:Auerstav | https://www.wikidoc.org/index.php/Auer_rod | |
9d3b9893e776468174b940e119cb54e26a634e15 | wikidoc | Microtia | Microtia
# Overview
Microtia (meaning 'Small ear') is a congenital deformity of the pinna] (outer ear). It can be unilateral (one side only) or bilateral (affecting both sides). It occurs in 1 out of about 8,000-10,000 births. In unilateral microtia, the right ear is most typically affected.
# Grading
There are four grades of microtia :
- Grade I: A slightly small ear with identifiable structures and a small but present external ear canal
- Grade II: A partial or hemi-ear with a closed off or stenotic external ear canal producing a conductive hearing loss
- Grade III: Absence of the external ear with a small peanut vestige structure and an absence of the external ear canal and ear drum
- Grade IV: Absence of the total ear or anotia.
Grade III is most common, and can be corrected by surgery. Typically, testing is first done to determine if the inner ear is intact and hearing is normal. If hearing is normal, the next step (if a canal is not visible externally) will be to determine if a canal exists, by CT scan. For younger patients, this is done under sedation. Age when outer ear surgery can be attempted depends on the technique chosen (see below). The earliest age surgery can be attempted is age 3 for Medpor and 5 1/2 for Rib Graft. Less experienced surgeons may recommend waiting until a later age, such as 8-10 when the ear is full adult size.
# Options
There are two separate issues in microtia surgery:
- Auricular reconstruction to restore the visual appearance and form of the outer ear
- Repair of atresia or application of a bone-anchored hearing aid BAHA to restore hearing.
Unilateral deafness is not generally considered a serious disability, especially when the person is able to adjust to it from birth. In some areas the benefits of intervention to enable hearing in the microtic ear are not considered to outweigh the risks, except in bilateral microtia. However, children with untreated unilateral hearing loss are eight to ten times more likely to have to repeat a grade in school. If surgery or aids are not used, special steps should be taken to ensure that the child is accessing and understanding all of the verbal information presented in school settings. Age for BAHA implantation depends on whether you are in Europe (18 months) or the US (age 5). If the child is under the age for surgical implantation, the BAHA can be worn on a headband
For auricular reconstruction, there are four different options:
- Rib-Graft Reconstruction. Because the implant is the patient's own living cartilage, the ear continues to grow as the child does. The procedure is usually performed after age 6, one reason being to ensure that the rib cage is large enough to provide the donor material necessary. This is a three to five stage surgery. The number of surgeries can vary.
- Reconstruct the ear using a Medpor polyethylene plastic implant. This is a two stage surgery which can start around age 3. Note that for patients with both Microtia and Atresia, that when using Medpor for the outer ear reconstruction the atresia repair must be done FIRST (as mentioned above with the rib graft reconstruction, the atresia repair is done AFTER).
- Ear Prosthesis. A craniofacial prosthesis or auricular (ear) prosthesis is custom made by an anaplastologist to mirror the other ear. Prosthetic ears can appear very realistic yet they do require a few minutes of daily care. They are typically made of silicone which is colored to match your individual skin and can be attached using adhesive or with titanium screws inserted into the skull to which the prosthetic is attached with a magnetic or bar/clip type system. These screws are the same as the BAHA (bone anchored hearing aid) screws and can be placed simultaneously. The optimal age to begin wearing an ear prosthesis is between the age of 6 and 9. The child should be mature enough to want and help care for the prosthesis. A person with grade I & II microtia need not consider an ear prosthesis. A person with grade IV (anotia) is best suited for an ear prosthesis. A person with grade III construction has three options for reconstruction.
Leave the skin tags for future surgical reconstructive purposes and make an adhesive retained prosthesis over the top of the existing ear. The advantage is that you can keep your reconstructive options open and you get more definition in the ear than a surgical approach. This allows you to try out the prosthetic approach without burning any bridges. It is also the least expensive approach. The disadvantage is that the ear is typically placed lower and more forward and tends to appear more bulky than the other ear. It will give you a good outline though. Placement is more difficult than prosthetics option '2'. If you like the look of the prosthesis and want to make it more permanent, you can proceed with option '3'.
Remove the skin tags and use an adhesive retained ear. The advantage over prosthetic option '1' is that your prosthetic ear can be a near identical mirror image of your other ear. Placement is much easier as well because the skin is flat. The disadvantage is that you remove the skin tags which are necessary for surgical reconstruction. You always have the option of placing the implants in the future.
Remove the skin tags and simultaneously place the implants for a prosthesis. The visual results are very similar to prosthetic option '2'. The advantage is that placement of the ear becomes even easier and you eliminate the costs of adhesive and the associated daily care. The disadvantage is again that you limit your surgical reconstructive options.
- Leave the skin tags for future surgical reconstructive purposes and make an adhesive retained prosthesis over the top of the existing ear. The advantage is that you can keep your reconstructive options open and you get more definition in the ear than a surgical approach. This allows you to try out the prosthetic approach without burning any bridges. It is also the least expensive approach. The disadvantage is that the ear is typically placed lower and more forward and tends to appear more bulky than the other ear. It will give you a good outline though. Placement is more difficult than prosthetics option '2'. If you like the look of the prosthesis and want to make it more permanent, you can proceed with option '3'.
- Remove the skin tags and use an adhesive retained ear. The advantage over prosthetic option '1' is that your prosthetic ear can be a near identical mirror image of your other ear. Placement is much easier as well because the skin is flat. The disadvantage is that you remove the skin tags which are necessary for surgical reconstruction. You always have the option of placing the implants in the future.
- Remove the skin tags and simultaneously place the implants for a prosthesis. The visual results are very similar to prosthetic option '2'. The advantage is that placement of the ear becomes even easier and you eliminate the costs of adhesive and the associated daily care. The disadvantage is again that you limit your surgical reconstructive options.
- Soft tissue reconstruction: The reasoning for soft tissue reconstruction is that surgically reconstructed ears using rib-graft or implants are sensitive, though the sensation is not the same as for normal ears due to the transplant of skin from other areas of the body.
# Complications
Aural atresia is commonly associated with microtia. Atresia occurs because patients with microtia may not have an external opening to the ear canal, though the cochlea and inner ear are usually present. The grade of microtia correlates to the development of the middle ear.
Microtia is usually isolated, but may occur in conjunction with hemifacial microsoma or Treacher-Collins Syndrome.
Microtia can cause difficulties with wearing headphones and glasses. It is also occasionally associated with syndromes that can cause balance problems, kidney problems, and jaw problems, and more rarely, heart defects and vertebral deformities.
If a canal is built where one does not exist, minor complications can arise from the body's natural tendency to heal an open wound closed. Aural Atresia is a very detailed and complicated surgical procedure which requires an expert in atresia repair. While complications from this surgery can arise, the risk of complications is greatly reduced when using a highly experienced otologist. Atresia patients who opt for surgery will temporarily have the canal packed with gelatin sponge and silicone sheeting to prevent closure.
There are several organizations which provide information and support to affected people.
In some countries, the outer ear reconstruction is considered as a prosthetic surgery, which means that it is not necessary, and hence is not covered by the insurance or support groups help.
Some patients may opt to not pursue surgery. This is usually because the child has already adapted to the condition, and unless is driven by self-esteem or cosmetic issues, may prefer to leave the condition unchanged.
# Diagnosis
## Physical Examination
### Ear Nose and Throat
- Congenital microtia (small, malformed auricle / pinna)and external canal atresia.
- Congenital atresia of the external auditory canal. The pinna is rather well formed.
- Congenital microtia without canal atresia.
- Supernumerary auricle.
- Bifid earlobe.
- Incomplete fusion of the incisura intertragica. A probe is inserted in the resulting fistula. The rest of the pinna is well formed. The external canal is open. | Microtia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Microtia (meaning 'Small ear') is a congenital deformity of the pinna] (outer ear). It can be unilateral (one side only) or bilateral (affecting both sides). It occurs in 1 out of about 8,000-10,000 births. In unilateral microtia, the right ear is most typically affected.
# Grading
There are four grades of microtia [2]:
- Grade I: A slightly small ear with identifiable structures and a small but present external ear canal
- Grade II: A partial or hemi-ear with a closed off or stenotic external ear canal producing a conductive hearing loss
- Grade III: Absence of the external ear with a small peanut vestige structure and an absence of the external ear canal and ear drum
- Grade IV: Absence of the total ear or anotia.
Grade III is most common, and can be corrected by surgery. Typically, testing is first done to determine if the inner ear is intact and hearing is normal. If hearing is normal, the next step (if a canal is not visible externally) will be to determine if a canal exists, by CT scan. For younger patients, this is done under sedation. Age when outer ear surgery can be attempted depends on the technique chosen (see below). The earliest age surgery can be attempted is age 3 for Medpor and 5 1/2 for Rib Graft. Less experienced surgeons may recommend waiting until a later age, such as 8-10 when the ear is full adult size.
# Options
There are two separate issues in microtia surgery:
- Auricular reconstruction to restore the visual appearance and form of the outer ear
- Repair of atresia or application of a bone-anchored hearing aid BAHA to restore hearing.
Unilateral deafness is not generally considered a serious disability, especially when the person is able to adjust to it from birth. In some areas the benefits of intervention to enable hearing in the microtic ear are not considered to outweigh the risks, except in bilateral microtia. However, children with untreated unilateral hearing loss are eight to ten times more likely to have to repeat a grade in school. If surgery or aids are not used, special steps should be taken to ensure that the child is accessing and understanding all of the verbal information presented in school settings. Age for BAHA implantation depends on whether you are in Europe (18 months) or the US (age 5). If the child is under the age for surgical implantation, the BAHA can be worn on a headband
For auricular reconstruction, there are four different options:
- Rib-Graft Reconstruction. Because the implant is the patient's own living cartilage, the ear continues to grow as the child does. The procedure is usually performed after age 6, one reason being to ensure that the rib cage is large enough to provide the donor material necessary. This is a three to five stage surgery. The number of surgeries can vary.
- Reconstruct the ear using a Medpor polyethylene plastic implant. This is a two stage surgery which can start around age 3. Note that for patients with both Microtia and Atresia, that when using Medpor for the outer ear reconstruction the atresia repair must be done FIRST (as mentioned above with the rib graft reconstruction, the atresia repair is done AFTER).
- Ear Prosthesis. A craniofacial prosthesis or auricular (ear) prosthesis is custom made by an anaplastologist to mirror the other ear. Prosthetic ears can appear very realistic yet they do require a few minutes of daily care. They are typically made of silicone which is colored to match your individual skin and can be attached using adhesive or with titanium screws inserted into the skull to which the prosthetic is attached with a magnetic or bar/clip type system. These screws are the same as the BAHA (bone anchored hearing aid) screws and can be placed simultaneously. The optimal age to begin wearing an ear prosthesis is between the age of 6 and 9. The child should be mature enough to want and help care for the prosthesis.[1] A person with grade I & II microtia need not consider an ear prosthesis. A person with grade IV (anotia) is best suited for an ear prosthesis. A person with grade III construction has three options for reconstruction.
Leave the skin tags for future surgical reconstructive purposes and make an adhesive retained prosthesis over the top of the existing ear. The advantage is that you can keep your reconstructive options open and you get more definition in the ear than a surgical approach. This allows you to try out the prosthetic approach without burning any bridges. It is also the least expensive approach. The disadvantage is that the ear is typically placed lower and more forward and tends to appear more bulky than the other ear. It will give you a good outline though. Placement is more difficult than prosthetics option '2'. If you like the look of the prosthesis and want to make it more permanent, you can proceed with option '3'.
Remove the skin tags and use an adhesive retained ear. The advantage over prosthetic option '1' is that your prosthetic ear can be a near identical mirror image of your other ear. Placement is much easier as well because the skin is flat. The disadvantage is that you remove the skin tags which are necessary for surgical reconstruction. You always have the option of placing the implants in the future.
Remove the skin tags and simultaneously place the implants for a prosthesis. The visual results are very similar to prosthetic option '2'. The advantage is that placement of the ear becomes even easier and you eliminate the costs of adhesive and the associated daily care. The disadvantage is again that you limit your surgical reconstructive options.
- Leave the skin tags for future surgical reconstructive purposes and make an adhesive retained prosthesis over the top of the existing ear. The advantage is that you can keep your reconstructive options open and you get more definition in the ear than a surgical approach. This allows you to try out the prosthetic approach without burning any bridges. It is also the least expensive approach. The disadvantage is that the ear is typically placed lower and more forward and tends to appear more bulky than the other ear. It will give you a good outline though. Placement is more difficult than prosthetics option '2'. If you like the look of the prosthesis and want to make it more permanent, you can proceed with option '3'.
- Remove the skin tags and use an adhesive retained ear. The advantage over prosthetic option '1' is that your prosthetic ear can be a near identical mirror image of your other ear. Placement is much easier as well because the skin is flat. The disadvantage is that you remove the skin tags which are necessary for surgical reconstruction. You always have the option of placing the implants in the future.
- Remove the skin tags and simultaneously place the implants for a prosthesis. The visual results are very similar to prosthetic option '2'. The advantage is that placement of the ear becomes even easier and you eliminate the costs of adhesive and the associated daily care. The disadvantage is again that you limit your surgical reconstructive options.
- Soft tissue reconstruction: The reasoning for soft tissue reconstruction is that surgically reconstructed ears using rib-graft or implants are sensitive, though the sensation is not the same as for normal ears due to the transplant of skin from other areas of the body.
# Complications
Aural atresia is commonly associated with microtia. Atresia occurs because patients with microtia may not have an external opening to the ear canal, though the cochlea and inner ear are usually present. The grade of microtia correlates to the development of the middle ear[3].
Microtia is usually isolated, but may occur in conjunction with hemifacial microsoma or Treacher-Collins Syndrome[4].
Microtia can cause difficulties with wearing headphones and glasses[5]. It is also occasionally associated with syndromes that can cause balance problems, kidney problems, and jaw problems, and more rarely, heart defects and vertebral deformities.
If a canal is built where one does not exist, minor complications can arise from the body's natural tendency to heal an open wound closed. Aural Atresia is a very detailed and complicated surgical procedure which requires an expert in atresia repair. While complications from this surgery can arise, the risk of complications is greatly reduced when using a highly experienced otologist. Atresia patients who opt for surgery will temporarily have the canal packed with gelatin sponge and silicone sheeting to prevent closure.
There are several organizations which provide information and support to affected people.
In some countries, the outer ear reconstruction is considered as a prosthetic surgery, which means that it is not necessary, and hence is not covered by the insurance or support groups help.
Some patients may opt to not pursue surgery. This is usually because the child has already adapted to the condition, and unless is driven by self-esteem or cosmetic issues, may prefer to leave the condition unchanged.
# Diagnosis
## Physical Examination
### Ear Nose and Throat
- Congenital microtia (small, malformed auricle / pinna)and external canal atresia.[2]
- Congenital atresia of the external auditory canal. The pinna is rather well formed.[3]
- Congenital microtia without canal atresia.[4]
- Supernumerary auricle.
- Bifid earlobe.[5]
- Incomplete fusion of the incisura intertragica. A probe is inserted in the resulting fistula. The rest of the pinna is well formed. The external canal is open. [6] | https://www.wikidoc.org/index.php/Aural_atresia | |
18ce3f26c87dd95fde48b852bb661e6405d7afae | wikidoc | Autosome | Autosome
An autosome is a non-sex chromosome. It is an ordinarily paired type of chromosome that is the same in both sexes of a species. For example, in humans, there are 22 pairs of autosomes. The X and Y chromosomes are not autosomal. Non-autosomal chromosomes are usually referred to as sex chromosomes, allosomes or heterosomes.
Like other chromosomes, autosomes display STR and SNP mutations which can be observed and have been used in genetic testings for ancestry, ethnicity, race and genealogical purposes. Private testing companies which do autosomal STR tests include FamilyTreeDNA and DNAtribes. Whereas companies testing autosomal SNPs include AncestryByDNA and deCODEme.
# Notes
- ↑ In the case of higher ploidy levels than the usual diploid, there will be the same number of an autosome as the ploidy level itself. For example, in a pentaploid, there will be five copies of each autosome. | Autosome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
An autosome is a non-sex chromosome. It is an ordinarily paired[1] type of chromosome that is the same in both sexes of a species. For example, in humans, there are 22 pairs of autosomes. The X and Y chromosomes are not autosomal. Non-autosomal chromosomes are usually referred to as sex chromosomes, allosomes or heterosomes.
Like other chromosomes, autosomes display STR and SNP mutations which can be observed and have been used in genetic testings for ancestry, ethnicity, race and genealogical purposes. Private testing companies which do autosomal STR tests include FamilyTreeDNA and DNAtribes. Whereas companies testing autosomal SNPs include AncestryByDNA and deCODEme.
# Notes
- ↑ In the case of higher ploidy levels than the usual diploid, there will be the same number of an autosome as the ploidy level itself. For example, in a pentaploid, there will be five copies of each autosome. | https://www.wikidoc.org/index.php/Autosomal | |
71e9a4691f23d60127c733f85e35e3a6ead84574 | wikidoc | Autotomy | Autotomy
Autotomy (from the Greek auto = "self-" and tomy = "severing") or self amputation is the act whereby an animal severs one or more of its own appendages, usually as a self-defense mechanism designed to elude a predator's grasp. The lost body part may be regenerated later.
# Reptiles
Geckos, skinks and other lizards that are captured by the tail will shed part of the tail structure and thus be able to flee. The detached tail will continue to wiggle, creating a deceptive sense of continued struggle and attracting the predator's attention away from the fleeing prey animal. The animal can partially regenerate its tail over a period of weeks. The new section will contain cartilage rather than bone, and the skin will have different coloration, typically darker and with little or no pattern.
Autotomy in lizards is enabled by special zones of weakness at regular intervals in the vertebrae below the vent. Essentially, the lizard contracts a muscle to fracture the vertebra itself rather than break the tail between two vertebrae. Sphincter muscles in the tail then contract around the caudal artery to minimize bleeding.
# Invertebrates
Other animals, such as octopuses, crabs, brittle stars, lobsters and spiders, can also lose and regenerate appendages when necessary for survival. Autotomy occurs in some kinds of octopus for survival and for reproduction: the specialised reproductive arm (the hectocotylus) detaches from the male during mating and remains within the female's mantle cavity.
Evisceration, the ejection of the internal organs of sea cucumbers when stressed, is also a form of autotomy, and they regenerate the organ(s) lost.
# Bees: a special case
The sting of various honey bee species is a different case; the sting apparatus is modified in such a way that it tears cleanly away from the bee's body, and has its own ganglion that keeps the musculature of the sting shafts moving (thus embedding the sting deeper) and the venom sac pumping for several minutes after it detaches. Unlike most cases of autotomy, the bee dies shortly afterwards (they do not grow a new sting apparatus). All species of true honey bees (genus Apis) have this form of autotomy. No other stinging insect, including yellowjacket wasps and the Mexican honey wasp, have the sting apparatus modified this way, though they may have barbed stings. The sting of a queen honey bee has no barbs, however, and does not autotomize. Further, the genitalia of male honey bees (drones) also autotomize during copulation, and form a "mating plug" which must be removed by the genitalia of subsequent drones if they are also to mate with the same queen. The drones die within minutes of mating. | Autotomy
Autotomy (from the Greek auto = "self-" and tomy = "severing") or self amputation is the act whereby an animal severs one or more of its own appendages,[1] usually as a self-defense mechanism designed to elude a predator's grasp. The lost body part may be regenerated later.
# Reptiles
Geckos, skinks and other lizards that are captured by the tail will shed part of the tail structure and thus be able to flee. The detached tail will continue to wiggle, creating a deceptive sense of continued struggle and attracting the predator's attention away from the fleeing prey animal. The animal can partially regenerate its tail over a period of weeks. The new section will contain cartilage rather than bone, and the skin will have different coloration, typically darker and with little or no pattern.
Autotomy in lizards is enabled by special zones of weakness at regular intervals in the vertebrae below the vent. Essentially, the lizard contracts a muscle to fracture the vertebra itself rather than break the tail between two vertebrae. Sphincter muscles in the tail then contract around the caudal artery to minimize bleeding.
# Invertebrates
Other animals, such as octopuses, crabs, brittle stars, lobsters and spiders, can also lose and regenerate appendages when necessary for survival. Autotomy occurs in some kinds of octopus for survival and for reproduction: the specialised reproductive arm (the hectocotylus) detaches from the male during mating and remains within the female's mantle cavity.
Evisceration, the ejection of the internal organs of sea cucumbers when stressed, is also a form of autotomy, and they regenerate the organ(s) lost.
# Bees: a special case
The sting of various honey bee species is a different case; the sting apparatus is modified in such a way that it tears cleanly away from the bee's body, and has its own ganglion that keeps the musculature of the sting shafts moving (thus embedding the sting deeper) and the venom sac pumping for several minutes after it detaches. Unlike most cases of autotomy, the bee dies shortly afterwards (they do not grow a new sting apparatus). All species of true honey bees (genus Apis) have this form of autotomy. No other stinging insect, including yellowjacket wasps and the Mexican honey wasp, have the sting apparatus modified this way, though they may have barbed stings. The sting of a queen honey bee has no barbs, however, and does not autotomize. Further, the genitalia of male honey bees (drones) also autotomize during copulation, and form a "mating plug" which must be removed by the genitalia of subsequent drones if they are also to mate with the same queen. The drones die within minutes of mating. | https://www.wikidoc.org/index.php/Autotomy | |
0d3e47850111b3a6319c4451743a2787412cc2a7 | wikidoc | Auxology | Auxology
Auxology is a meta-term covering the study of all aspects of human physical growth; though it is also a fundamental of biology, generally. Auxology is a highly multi-disciplinary science involving health sciences / medicine (pediatrics, general practice, endocrinology, neuroendocrinology, physiology, epidemiology), and to a lesser extent: nutrition, genetics, anthropology, anthropometry, ergonomics, history, economic history, economics, socioeconomics, sociology, public health, and psychology, among others.
# Etymology
Auxology: aux-, pertaining to growth, from Greek auxē, "to increase"; -o-, generic phoenetic combining form, here denoting relationship to growth, stimulation, or acceleration; -logy, pertaining to the study of or science of, from Middle English -logie, from Old French, from Latin -logia, from Greek -logiā, from legein, "to speak", and -logos "word", "speech" and "one who deals with", thus "the character or department of one who speaks or treats of (a certain subject)".
The name of the plant hormone Auxin (which promotes growth in plants) comes from the same root.
# Some Auxologists
- Barry Bogin (anthropologist)
- Noel Cameron (pediatrician)
- J. W. Drukker (economist, historian, ergonomist)
- Stanley Engerman (economist)
- Robert Fogel (economist)
- Theo Gasser (statistician, human biologist)
- Francis E. Johnston (anthropologist)
- John Komlos (economist, anthropometric historian)
- Gregory Livshits (human biologist)
- Robert Margo (economist)
- Alex F. Roche (pediatrician)
- Lawrence M. Schell (anthropologist)
- Nevin Scrimshaw (nutritionist)
- Anne Sheehy (human biologist)
- Richard Steckel (economist, anthropometric historian)
- Pak Sunyoung (anthropologist)
- James M. Tanner (pediatrician)
- Vincent Tassenaar (historian)
- Lucio Vinicius (anthropologist, human biologist)
- Joerg Baten (economist, anthropometric historian) | Auxology
Auxology is a meta-term covering the study of all aspects of human physical growth; though it is also a fundamental of biology, generally. Auxology is a highly multi-disciplinary science involving health sciences / medicine (pediatrics, general practice, endocrinology, neuroendocrinology, physiology, epidemiology), and to a lesser extent: nutrition, genetics, anthropology, anthropometry, ergonomics, history, economic history, economics, socioeconomics, sociology, public health, and psychology, among others.
# Etymology
Auxology: aux-, pertaining to growth, from Greek auxē, "to increase"; -o-, generic phoenetic combining form, here denoting relationship to growth, stimulation, or acceleration; -logy, pertaining to the study of or science of, from Middle English -logie, from Old French, from Latin -logia, from Greek -logiā, from legein, "to speak", and -logos "word", "speech" and "one who deals with", thus "the character or department of one who speaks or treats of (a certain subject)".
The name of the plant hormone Auxin (which promotes growth in plants) comes from the same root.
# Some Auxologists
- Barry Bogin [1] (anthropologist)
- Noel Cameron [2] (pediatrician)
- J. W. Drukker [3] (economist, historian, ergonomist)
- Stanley Engerman [4] (economist)
- Robert Fogel [5] (economist)
- Theo Gasser [6] (statistician, human biologist)
- Francis E. Johnston [7] (anthropologist)
- John Komlos [8] (economist, anthropometric historian)
- Gregory Livshits [9] (human biologist)
- Robert Margo [10] (economist)
- Alex F. Roche [11] (pediatrician)
- Lawrence M. Schell [12] (anthropologist)
- Nevin Scrimshaw [13] (nutritionist)
- Anne Sheehy (human biologist)
- Richard Steckel [14] (economist, anthropometric historian)
- Pak Sunyoung [15] (anthropologist)
- James M. Tanner [16] (pediatrician)
- Vincent Tassenaar [17] (historian)
- Lucio Vinicius [18] (anthropologist, human biologist)
- Joerg Baten [19] (economist, anthropometric historian) | https://www.wikidoc.org/index.php/Auxology | |
3b62b1a83099ccd50426bd18d8969f0108e8b7f1 | wikidoc | Avacopan | Avacopan
# 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
Avacopan is a complement 5a receptor antagonist that is FDA approved for the treatment of severe active anti-neutrophil cytoplasmic autoantibody-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis) in combination with standard therapy, including glucocorticoids. Common adverse reactions include hypertension, blood creatinine increase, fatigue, upper abdominal pain, nausea, headache, vomiting, rash, dizziness, and paresthesia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Three 10 mg capsules (30 mg) taken with food orally, twice daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Avacopan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Avacopan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Avacopan FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Avacopan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Avacopan in pediatric patients.
# Contraindications
- In patients with serious hypersensitivity when taking Avacopan.
- In patients with serious hypersensitivity when taking any of the excipients.
# Warnings
Hepatotoxicity
- Higher incidences of hepatobiliary and transaminase elevations were found in controlled studies of patients taking Avacopan.
- Patients before starting Avacopan treatment, every 4 weeks after start of Avacopan, and for the first 6 months of taking Avacopan as clinically indicated thereafter should take liver test panels.
- Consult medical consultation and promptly pause use of Avacopan in patients who have an elevation in ALT or AST to >3 times the upper limit of normal.
- Discontinue the use of Avacopan until Avacopan-induced liver injury is ruled out in patients who have transaminases >3 times the upper limit of normal with elevation of bilirubin to >2 times the upper limit of normal or AST or ALT is >5 times the upper limit of normal.
- Patients should be advised to not take Avacopan with active, untreated and/or uncontrolled chronic liver disease.
Hypersensitivity Reactions
- Two cases of Angioedema occurred in clinical studies of patients taking Avacopan with one of the cases requiring the hospitalization of a patient.
- Discontinue the use of Avacopan in patients with Angioedema.
- Monitor patients airways and provide appropriate treatment in patients taking Avacopan who experience Angioedema.
- Advise patients about the possible symptoms of a hypersensitivity reaction and immediatly seek medical attention if symptoms of hypersensitivity arise.
Hepatitis B Virus (HBV) Reactivation
- Clincal studies show signs of Hepatitis B virus (HBV) reactivation when taking Avacopan.
- HBV reactivation is defined as an abrupt increase in HBV replication, manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg, in a person who was previously HBsAg negative and anti-HBc positive.
- Before starting Avacopan treatment, measure HBsAg and anti-HBc in patients.
- Consider HBV antiviral therapy for patients who show signs of prior hepatitis B infection before, during, or after Avacopan treatment.
- Patients that show any evidence of current and prior history of HBV infection or HBV reactivation should be monitored during and 6 months after Avacopan treatment.
- Discontinue use of Avacopan and all concomitant drugs asscociated with HBV reactivation in patients who develop signs of reactivation of HBV.
Serious Infections
- Fatal infections such as pneumonia and urinary tract infections were found in patients taking Avacopan.
- Patients with active, serious infections should be advised not to take Avacopan.
- Patients who have been exposed to tuberculosis, have underlying conditions that may predispose them to infection, have chronic or recurrent infection, have a history of a serious or an opportunistic infection, or have resided or traveled in areas of endemic tuberculosis or endemic mycoses should be advised of the risks and benefits of taking Avacopan.
- Signs of infection during or after treatment with Avacopan should be monitored.
- Avacopan treatment should be interrupted if signs of serious or opportunistic infection develop.
- Diagnostic tests should be advised in patients who develop new infections when taking Avacopan.
- Avacopan treatment can be resumed when infection is under control.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trial Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A randomized 1:1 Avacopan or Prednisone was clinically tested on patients that had ANCA-associated vasculitis to see for adverse reactions in a phase 3 trial. Two phase 2 trials were also conducted on patients that also had ANCA-associated vasculitis. The phase 3 trial was conducted on 330 patients with ANCA-associated vasculitis. The patient population was largely Caucasian (84.2%), and included 56.4% men that had a mean age of 60.9 years.
Phase 3 Clinical Data
- Adverse reactions included GPA (3.0% Avacopan vs. 0.6% Prednisone), urinary tract infection (1.8% Avacopan vs. 1.2% Prednisone), acute kidney injury (1.8% Avacopan vs. 0.6% Prednisone), and pneumonia (4.8% Avacopan vs. 3.7% Prednisone).
- 1.2% of patients in the Avacopan treatment and 2.4% of patients in the Prednisone treatment died during a 52 week span.
- Discontinuation of treatments occurred in both groups (4.2% taking Avacopan and 1.2% taking prednisone) due to hepatic-related adverse reactions.
- Hepatic function abnormal (1.8%) was reported by > 1 patient with more being reported by patients in the Avacopan treatment.
Table 1 shows the Adverse Reactions (≥5%) reported more in patients taking Avacopan than Prednisone.
Hepatotoxicity and Elevated Liver Function Tests
- Hepatic-related adverse reactions occurred in both the Avacopan treatment (13.3%) and Prednisone treatment (11.6%) for patients in the Phase 3 trial.
- Liver enzyme abnormalities and hepatobiliary adverse reactieventsons were some of the hepatic-related adverse reactions reported by patients.
- 5.4% of patients in the Avacopan treatment group and 3.7% of patients in the Prednisone treatment group reported serious hepatic-related adverse reaction in the Phase 3 trial.
Angioedema
- 1.2% of patients in the Avacopan treatment reported Angioedema with one patient requiring hospitalization in the Phase 3 trials.
Elevated Creatine Phosphokinase
- 3.6% of patients in the Avacopan treatment group and 0.6% of patients in the Prednisone treatment group reported increased creatine phosphokinase in the Phase 3 trial.
- Discontinuation of treatment occurred in one patient part of the Avacopan treatment group.
## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.
# Drug Interactions
CYP3A4 Inducers
- Co-administration of Avacopan and Rifampin, a strong CYP3A4 enzyme inducer, causes a decrease in Avacopan exposure.
CYP3A4 Inhibitors
- Co-administration of Avacopan and Itraconazole, a strong CYP3A4 enzyme inhibitor, causes an increase in Avacopan exposure.
CYP3A4 Substrates
- Adverse reactions may occur with co-administration of Avacopan and sensitive CYP3A4 substrates with a narrow therapeutic window.
- A CYP3A4 inhibitor is Avacopan.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Reproduction studies done on pregnant hamsters showed no fetal harm to the embryo during organogenesis when using 5 times the MRHD of Avacopan. No structural abnormalities in hamsters were found, but increase in skeletal variations were reported when using 5 times the MRHD of Avacopan. Studies on rabbits showed no fetal harm to the embryo during organogenesis, but showed increased abortions when using 0.6 times the MRHD of Avacopan. Maternal toxicities were reported in rabbits when using 0.6 times the MRHD of Avacopan. These studies display the potential harms and risks in the embryo of pregnant woman when taking Avacopan.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Avacopan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Avacopan during labor and delivery.
### Nursing Mothers
No data has been conducted on nursing in human when taking Avacopan. Based on studies done on hamsters, Avacopan was found in the plasma of nursing offspring. Advise patients about the potential secretion of Avacopan in milk of nursing hamsters.
### Pediatric Use
There is no FDA guidance on the use of Avacopan with respect to pediatric populations.
### Geriatic Use
In the phase 3 randomized clinical trial for ANCA-associated vasculitis, 62 of the 86 geriatric patients were between the ages of 65 to 74 while 24 of the 86 geriatric patients were 75 years or older. All these patients received the Avacopan treatment. No differences among young patients compared to geriatric patients were found when looking at safety and efficacy of Avacopan.
### Gender
There is no FDA guidance on the use of Avacopan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Avacopan with respect to specific racial populations.
### Renal Impairment
Patients with mild and severe renal impairment require no change to dosage usage.
### Hepatic Impairment
Patients with mild and severe hepatic impairment require no change to dosage usage.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Avacopan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance on the use of Avacopan with respect to immunocompromised populations.
# Administration and Monitoring
### Administration
- Before using Avacopan, patients should be advised to conduct liver function tests and conduct HBV screening.
- Instruct patients to not chew, crush, or break tablets.
- Take orally with food.
- If scheduled dosage is missed, skip dosage and wait until next regularly scheduled dosage.
- Advise patients to not double dose if dosage is missed.
### Monitoring
- Advise patients to reduce to 30 mg of Avacopan dosage once daily with concomitant use of Avacopan and strong CYP3A4 inhibitors.
# IV Compatibility
There is limited information regarding the compatibility of Avacopan and IV administrations.
# Overdosage
There is limited information regarding Avacopan overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Avacopan is a complement 5a receptor antagonist.
- Interaction between the anaphylatoxin C5a and C5aR is inhibited by Avacopan. Activation and migration of C5a-mediated neutrophil is blocked through the use of Avacopan.
## Structure
- Avacopan is a complement 5a receptor antagonist for oral administration. It has an empirical formula of C33H35F4N3O2 and a molecular weight of 582 g/mol.
- The chemical name is (2R,3S)-2--1-(2-fluoro-6-methylbenzoyl)-N-piperidine-3-carboxamide.
## Pharmacodynamics
- In human dosage, C5a-induced upregulation of CD11b on neutrophils is blocked by Avacopan.
- Avacopan does not prolong the QT interval when looking at cardiac electrophysiology at the recommended dosages.
## Pharmacokinetics
Steady State Exposure
- 3466 ± 1921 ngh/mL is the mean steady state plasma exposure in the 12-hour area under the plasma drug concentration over time curve within patients who have ANCA-associated vasculitis that are receiving 30 mg twice daily of Avacopan.
- 349 ± 169 ng/mL is the mean steady state plasma exposure in the maximum plasma concentration within patients who have ANCA-associated vasculitis that are receiving 30 mg twice daily of Avacopan.
Absorption
- In high-fat, high-calorie meal, AUC increased by 72% and Cmax increased by 8% when co-administered with 30 mg of Avacopan in capsule formulation.
- In high-fat, high-calorie meal, Tmax is also delayed from 2 hours to 6 hours when co-administered with 30 mg of Avacopan in capsule formulation.
Distribution
- Avacopan and M1 has a plasma protein binding percentage greater than 99.9%.
- 345 L is the volume of distribution found in Avacopan.
Elimination
- 16.3 L is the total apparent body clearance found in Avacopan.
- 97.6 hours is the mean elimination half-live of Avacopan when given a single dose, with food, of 30 mg of Avacopan.
- 55.6 hours is the mean elimination half-live of M1 when given a single dose, with food, of 30 mg of Avacopan.
Metabolism
- An enzyme responsible for the clearance of Avacopan is CYP3A4.
- An enzyme responsible for the clearance and formation of M1 is CYP3A4.
- Avacopan and M1 have the same activity in C5aR.
- In plasma, approximately 12% of the total drug-related materials is M1 present.
Excretion
- In feces, after oral administration of radiolabelled Avacopan, 77% of Avacopan was found in which 7% was found unchanged.
- In urine, after oral administration of radiolabelled Avacopan, 10% of Avacopan was found in which <0.1% was found unchanged.
Specific Populations
- In plasma exposure of M1 and Avacopan, gender, body weight, age, race, and renal function had no significant differences in the clinical data.
Patients with Hepatic Impairment
- When looking at Avacopan and M1, mild or moderate hepatic impairment showed no significant effect when looking at the clinical data for plasma exposure.
- When treated with Avacopan, AUC increased 12% and Cmax decreased 13% in patients with mild hepatic impairment. AUC increased 12% and Cmax decreased 17% in patients with moderate hepatic impairment.
- In M1, AUC increased 11% and Cmax decreased 5% in patients with mild hepatic impairment. AUC increased 18% and Cmax decreased 16% in patients with moderate hepatic impairment.
Drug Interaction Studies
Effects of Other Drugs on Avacopan
- CYP3A4 metabolizes Avacopan. In vitro studies, Avacopan for certain uptake transporters such as BCRP and P-gp efflux or OATP1B1 and OATP1B3 is not a substrate. M1 for certain uptake transporters such as OATP1B1 and OATP1B3 or BCRP efflux is not a substrate. For P-gp, M1 is a substrate.
Table 2 shows Pharmacokinetics Changes in Both M1 and Avacopan when Co-administered Drugs are Present.
Effect of Avacopan on Other Drug Substances
- In vitro studies, CYP2B6, CYP2C8, CYP1A2, CYP2D6, CYP2C9 and CYP2C19 are not inhibited by Avacopan. CYP2B6 and CYP1A2 are not induced by Avacopan. CYP3A4 shows potential signs of both being induced and inhibited by Avacopan. CYP2B6, CYP2C8, CYP2C19, CYP1A2, and CYP2D6 are not inhibited by M1. CYP1A2, CYP2B6, and CYP3A4 have low potential to be induced by M1. CYP3A4 and CYP2C9 potentially may be inhibited by M1. OATP1B3, OCT2, OAT1, OAT3, MATE1, P-gp, BCRP, OATP1B1, and MATE2K are not inhibited by M1 or Avacopan at relevant concentrations clinically.
Table 3 shows Pharmacokinetics Changes in the Presence of Avacopan and Other Drugs.
## Nonclinical Toxicology
Carcinogenesis
- Studies done on both rats and hamsters receiving 100 mg/kg/day orally shows no tumorigenic potential.
Mutagenesis
- Avacopan has shown no signs of it being clastogenic or mutagenic when looking at the data from vitro mouse lymphoma assay, vitro bacterial reverse mutation test, or vivo rat micronucleus test.
Impairment of Fertility
- Studies done on male and female hamsters showed no changes in reproductive performance or fertility after receiving doses of Avacopan up to 1000 mg/kg/day orally.
# Clinical Studies
Double-blind, active-controlled, Phase 3 Clinical Trial
- A phase 3 clinical trial tested the safety and effectiveness of Avacopan on patients that have ANCA-associated vasculitis. 330 patients were part of the study and were either put in Avacopan or Prednisone group. The patient population was largely Caucasian (84.2%), and included 56.4% women, and either had a presence of anti-MPO (57.0%) antibodies or anti-PR3 (43.0%) antibodies. Patients in the Avacopan treatment received a twice daily dosage of 30 mg of Avacopan for 52 weeks, and prednisone-matching placebo for 20 weeks. Patients in the Prednisone group received prednisone and twice daily dosage of an avacopan-matched placebo for 52 weeks. All patients received 1 of the 3 different possible standard immunosuppressive regimens: IV cyclophosphamide, oral cyclophosphamide, or rituximab. Patients from week 15 part of the IV cyclophosphamide group received IV cyclophosphamide 15 mg/kg IV up to 1.2 g maximum every 2 to 3 weeks for 13 weeks followed by oral azathioprine 1 mg/kg/day with titration up to 2 mg/kg/day. 31% of patients in this study received standard immunosuppressive regimen. Patients from week 15 part of the oral cyclophosphamide group received oral cyclophosphamide 2 mg/kg/day for 14 weeks followed by azathioprine 1 mg/kg/day with titration up to 2 mg/kg/day. 4% of patients in this study received this standard immunosuppressive regimen. Patients part of the rituximab group received IV rituximab 375 mg/m2 once weekly for 4 weeks without azathioprine or mycophenolate mofetil. To prevent hypersensitivity reactions from rituximab a pre-medication for Glucocorticoids may be taken. 65% of patients received this standard immunosuppressive regimen. 3 factors determined randomization: proteinase 3 positive or myeloperoxidase positive ANCA-associated vasculitis, newly-diagnosed or relapsing ANCA-associated vasculitis, and the type of immunosuppressive regimen. The goal of the study is to understand how the two treatment groups affect disease remission at week 26 and sustained remission at week 52.
Remission at Week 26 and Sustained Remission at Week 52
- Patients in the Avacopan group had 72.3% of patients achieve remission at Week 26 and 65.7% achieve sustained remission at Week 52. Patients in the Prednisone group had 70.1% of patients achieve remission at Week 26 and 54.9% achieve sustained remission at Week 52. Disease remission was defined as achieving a Birmingham Vasculitis Activity Score (BVAS) of 0 and no use of glucocorticoids for treatment of ANCA-associated vasculitis from Week 22 to Week 26 in this clinical study. Sustained remission was defined as remission at Week 26 and remission at Week 52, without relapse between Week 26 and Week 52 in this clinical study.
Table 4 shows the results of patients that had sustained remission at week 52 in the Double-blind, active-controlled, Phase 3 Clinical Trial.
Figure 1 shows stratification factors and GPA/MPA disease in patients at sustained remission at week 52
# How Supplied
- 10 mg dose pack (180 tablets), bottle seals are child resistant.
- 10 mg dose pack (180 tablets), bottle seals are child resistant.
- Tablets are light orange and opaque yellow.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Dosage and Administration
- Instruct patients to not chew, crush, or break tablets.
- Swallow Avacopan capsules whole.
- If scheduled dosage is missed, skip dosage and wait until next regularly scheduled dosage.
Hypersensitivity Reactions
- Advise patients that experience signs of angioedema to seek immediate medical attention.
- Advise patients with any signs of hypersensitivity reactions to discontinue use of Avacopan until consultation with physician.
Hepatotoxicity
- Seek immediate medical consultation if patients receive symptoms of liver problems such as pain on the upper right side of the stomach area, bruising, bleeding, dark urine, brown urine, or yellowing of the skin, or yellowing of the white part of the eyes during Avacopan treatment.
Infections
- Reactivation of hepatitis B infection is one of many possible serious infections reported by patients when using Avacopan.
- Advise patients to seek immediate medical attention if they show signs of serious infections.
Lactation
- Advise patients about both the risks and benefits of nursing when taking Avacopan.
# Precautions with Alcohol
Alcohol-Avacopan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tavneos
# Look-Alike Drug Names
There is limited information regarding Avacopan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Avacopan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Avacopan is a complement 5a receptor antagonist that is FDA approved for the treatment of severe active anti-neutrophil cytoplasmic autoantibody-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis) in combination with standard therapy, including glucocorticoids. Common adverse reactions include hypertension, blood creatinine increase, fatigue, upper abdominal pain, nausea, headache, vomiting, rash, dizziness, and paresthesia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Three 10 mg capsules (30 mg) taken with food orally, twice daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Avacopan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Avacopan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Avacopan FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Avacopan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Avacopan in pediatric patients.
# Contraindications
- In patients with serious hypersensitivity when taking Avacopan.
- In patients with serious hypersensitivity when taking any of the excipients.
# Warnings
Hepatotoxicity
- Higher incidences of hepatobiliary and transaminase elevations were found in controlled studies of patients taking Avacopan.
- Patients before starting Avacopan treatment, every 4 weeks after start of Avacopan, and for the first 6 months of taking Avacopan as clinically indicated thereafter should take liver test panels.
- Consult medical consultation and promptly pause use of Avacopan in patients who have an elevation in ALT or AST to >3 times the upper limit of normal.
- Discontinue the use of Avacopan until Avacopan-induced liver injury is ruled out in patients who have transaminases >3 times the upper limit of normal with elevation of bilirubin to >2 times the upper limit of normal or AST or ALT is >5 times the upper limit of normal.
- Patients should be advised to not take Avacopan with active, untreated and/or uncontrolled chronic liver disease.
Hypersensitivity Reactions
- Two cases of Angioedema occurred in clinical studies of patients taking Avacopan with one of the cases requiring the hospitalization of a patient.
- Discontinue the use of Avacopan in patients with Angioedema.
- Monitor patients airways and provide appropriate treatment in patients taking Avacopan who experience Angioedema.
- Advise patients about the possible symptoms of a hypersensitivity reaction and immediatly seek medical attention if symptoms of hypersensitivity arise.
Hepatitis B Virus (HBV) Reactivation
- Clincal studies show signs of Hepatitis B virus (HBV) reactivation when taking Avacopan.
- HBV reactivation is defined as an abrupt increase in HBV replication, manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg, in a person who was previously HBsAg negative and anti-HBc positive.
- Before starting Avacopan treatment, measure HBsAg and anti-HBc in patients.
- Consider HBV antiviral therapy for patients who show signs of prior hepatitis B infection before, during, or after Avacopan treatment.
- Patients that show any evidence of current and prior history of HBV infection or HBV reactivation should be monitored during and 6 months after Avacopan treatment.
- Discontinue use of Avacopan and all concomitant drugs asscociated with HBV reactivation in patients who develop signs of reactivation of HBV.
Serious Infections
- Fatal infections such as pneumonia and urinary tract infections were found in patients taking Avacopan.
- Patients with active, serious infections should be advised not to take Avacopan.
- Patients who have been exposed to tuberculosis, have underlying conditions that may predispose them to infection, have chronic or recurrent infection, have a history of a serious or an opportunistic infection, or have resided or traveled in areas of endemic tuberculosis or endemic mycoses should be advised of the risks and benefits of taking Avacopan.
- Signs of infection during or after treatment with Avacopan should be monitored.
- Avacopan treatment should be interrupted if signs of serious or opportunistic infection develop.
- Diagnostic tests should be advised in patients who develop new infections when taking Avacopan.
- Avacopan treatment can be resumed when infection is under control.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trial Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A randomized 1:1 Avacopan or Prednisone was clinically tested on patients that had ANCA-associated vasculitis to see for adverse reactions in a phase 3 trial. Two phase 2 trials were also conducted on patients that also had ANCA-associated vasculitis. The phase 3 trial was conducted on 330 patients with ANCA-associated vasculitis. The patient population was largely Caucasian (84.2%), and included 56.4% men that had a mean age of 60.9 years.
Phase 3 Clinical Data
- Adverse reactions included GPA (3.0% Avacopan vs. 0.6% Prednisone), urinary tract infection (1.8% Avacopan vs. 1.2% Prednisone), acute kidney injury (1.8% Avacopan vs. 0.6% Prednisone), and pneumonia (4.8% Avacopan vs. 3.7% Prednisone).
- 1.2% of patients in the Avacopan treatment and 2.4% of patients in the Prednisone treatment died during a 52 week span.
- Discontinuation of treatments occurred in both groups (4.2% taking Avacopan and 1.2% taking prednisone) due to hepatic-related adverse reactions.
- Hepatic function abnormal (1.8%) was reported by > 1 patient with more being reported by patients in the Avacopan treatment.
Table 1 shows the Adverse Reactions (≥5%) reported more in patients taking Avacopan than Prednisone.
Hepatotoxicity and Elevated Liver Function Tests
- Hepatic-related adverse reactions occurred in both the Avacopan treatment (13.3%) and Prednisone treatment (11.6%) for patients in the Phase 3 trial.
- Liver enzyme abnormalities and hepatobiliary adverse reactieventsons were some of the hepatic-related adverse reactions reported by patients.
- 5.4% of patients in the Avacopan treatment group and 3.7% of patients in the Prednisone treatment group reported serious hepatic-related adverse reaction in the Phase 3 trial.
Angioedema
- 1.2% of patients in the Avacopan treatment reported Angioedema with one patient requiring hospitalization in the Phase 3 trials.
Elevated Creatine Phosphokinase
- 3.6% of patients in the Avacopan treatment group and 0.6% of patients in the Prednisone treatment group reported increased creatine phosphokinase in the Phase 3 trial.
- Discontinuation of treatment occurred in one patient part of the Avacopan treatment group.
## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.
# Drug Interactions
CYP3A4 Inducers
- Co-administration of Avacopan and Rifampin, a strong CYP3A4 enzyme inducer, causes a decrease in Avacopan exposure.
CYP3A4 Inhibitors
- Co-administration of Avacopan and Itraconazole, a strong CYP3A4 enzyme inhibitor, causes an increase in Avacopan exposure.
CYP3A4 Substrates
- Adverse reactions may occur with co-administration of Avacopan and sensitive CYP3A4 substrates with a narrow therapeutic window.
- A CYP3A4 inhibitor is Avacopan.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Reproduction studies done on pregnant hamsters showed no fetal harm to the embryo during organogenesis when using 5 times the MRHD of Avacopan. No structural abnormalities in hamsters were found, but increase in skeletal variations were reported when using 5 times the MRHD of Avacopan. Studies on rabbits showed no fetal harm to the embryo during organogenesis, but showed increased abortions when using 0.6 times the MRHD of Avacopan. Maternal toxicities were reported in rabbits when using 0.6 times the MRHD of Avacopan. These studies display the potential harms and risks in the embryo of pregnant woman when taking Avacopan.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Avacopan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Avacopan during labor and delivery.
### Nursing Mothers
No data has been conducted on nursing in human when taking Avacopan. Based on studies done on hamsters, Avacopan was found in the plasma of nursing offspring. Advise patients about the potential secretion of Avacopan in milk of nursing hamsters.
### Pediatric Use
There is no FDA guidance on the use of Avacopan with respect to pediatric populations.
### Geriatic Use
In the phase 3 randomized clinical trial for ANCA-associated vasculitis, 62 of the 86 geriatric patients were between the ages of 65 to 74 while 24 of the 86 geriatric patients were 75 years or older. All these patients received the Avacopan treatment. No differences among young patients compared to geriatric patients were found when looking at safety and efficacy of Avacopan.
### Gender
There is no FDA guidance on the use of Avacopan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Avacopan with respect to specific racial populations.
### Renal Impairment
Patients with mild and severe renal impairment require no change to dosage usage.
### Hepatic Impairment
Patients with mild and severe hepatic impairment require no change to dosage usage.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Avacopan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance on the use of Avacopan with respect to immunocompromised populations.
# Administration and Monitoring
### Administration
- Before using Avacopan, patients should be advised to conduct liver function tests and conduct HBV screening.
- Instruct patients to not chew, crush, or break tablets.
- Take orally with food.
- If scheduled dosage is missed, skip dosage and wait until next regularly scheduled dosage.
- Advise patients to not double dose if dosage is missed.
### Monitoring
- Advise patients to reduce to 30 mg of Avacopan dosage once daily with concomitant use of Avacopan and strong CYP3A4 inhibitors.
# IV Compatibility
There is limited information regarding the compatibility of Avacopan and IV administrations.
# Overdosage
There is limited information regarding Avacopan overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Avacopan is a complement 5a receptor antagonist.
- Interaction between the anaphylatoxin C5a and C5aR is inhibited by Avacopan. Activation and migration of C5a-mediated neutrophil is blocked through the use of Avacopan.
## Structure
- Avacopan is a complement 5a receptor antagonist for oral administration. It has an empirical formula of C33H35F4N3O2 and a molecular weight of 582 g/mol.
- The chemical name is (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide.
## Pharmacodynamics
- In human dosage, C5a-induced upregulation of CD11b on neutrophils is blocked by Avacopan.
- Avacopan does not prolong the QT interval when looking at cardiac electrophysiology at the recommended dosages.
## Pharmacokinetics
Steady State Exposure
- 3466 ± 1921 ng•h/mL is the mean steady state plasma exposure in the 12-hour area under the plasma drug concentration over time curve within patients who have ANCA-associated vasculitis that are receiving 30 mg twice daily of Avacopan.
- 349 ± 169 ng/mL is the mean steady state plasma exposure in the maximum plasma concentration within patients who have ANCA-associated vasculitis that are receiving 30 mg twice daily of Avacopan.
Absorption
- In high-fat, high-calorie meal, AUC increased by 72% and Cmax increased by 8% when co-administered with 30 mg of Avacopan in capsule formulation.
- In high-fat, high-calorie meal, Tmax is also delayed from 2 hours to 6 hours when co-administered with 30 mg of Avacopan in capsule formulation.
Distribution
- Avacopan and M1 has a plasma protein binding percentage greater than 99.9%.
- 345 L is the volume of distribution found in Avacopan.
Elimination
- 16.3 L is the total apparent body clearance found in Avacopan.
- 97.6 hours is the mean elimination half-live of Avacopan when given a single dose, with food, of 30 mg of Avacopan.
- 55.6 hours is the mean elimination half-live of M1 when given a single dose, with food, of 30 mg of Avacopan.
Metabolism
- An enzyme responsible for the clearance of Avacopan is CYP3A4.
- An enzyme responsible for the clearance and formation of M1 is CYP3A4.
- Avacopan and M1 have the same activity in C5aR.
- In plasma, approximately 12% of the total drug-related materials is M1 present.
Excretion
- In feces, after oral administration of radiolabelled Avacopan, 77% of Avacopan was found in which 7% was found unchanged.
- In urine, after oral administration of radiolabelled Avacopan, 10% of Avacopan was found in which <0.1% was found unchanged.
Specific Populations
- In plasma exposure of M1 and Avacopan, gender, body weight, age, race, and renal function had no significant differences in the clinical data.
Patients with Hepatic Impairment
- When looking at Avacopan and M1, mild or moderate hepatic impairment showed no significant effect when looking at the clinical data for plasma exposure.
- When treated with Avacopan, AUC increased 12% and Cmax decreased 13% in patients with mild hepatic impairment. AUC increased 12% and Cmax decreased 17% in patients with moderate hepatic impairment.
- In M1, AUC increased 11% and Cmax decreased 5% in patients with mild hepatic impairment. AUC increased 18% and Cmax decreased 16% in patients with moderate hepatic impairment.
Drug Interaction Studies
Effects of Other Drugs on Avacopan
- CYP3A4 metabolizes Avacopan. In vitro studies, Avacopan for certain uptake transporters such as BCRP and P-gp efflux or OATP1B1 and OATP1B3 is not a substrate. M1 for certain uptake transporters such as OATP1B1 and OATP1B3 or BCRP efflux is not a substrate. For P-gp, M1 is a substrate.
Table 2 shows Pharmacokinetics Changes in Both M1 and Avacopan when Co-administered Drugs are Present.
Effect of Avacopan on Other Drug Substances
- In vitro studies, CYP2B6, CYP2C8, CYP1A2, CYP2D6, CYP2C9 and CYP2C19 are not inhibited by Avacopan. CYP2B6 and CYP1A2 are not induced by Avacopan. CYP3A4 shows potential signs of both being induced and inhibited by Avacopan. CYP2B6, CYP2C8, CYP2C19, CYP1A2, and CYP2D6 are not inhibited by M1. CYP1A2, CYP2B6, and CYP3A4 have low potential to be induced by M1. CYP3A4 and CYP2C9 potentially may be inhibited by M1. OATP1B3, OCT2, OAT1, OAT3, MATE1, P-gp, BCRP, OATP1B1, and MATE2K are not inhibited by M1 or Avacopan at relevant concentrations clinically.
Table 3 shows Pharmacokinetics Changes in the Presence of Avacopan and Other Drugs.
## Nonclinical Toxicology
Carcinogenesis
- Studies done on both rats and hamsters receiving 100 mg/kg/day orally shows no tumorigenic potential.
Mutagenesis
- Avacopan has shown no signs of it being clastogenic or mutagenic when looking at the data from vitro mouse lymphoma assay, vitro bacterial reverse mutation test, or vivo rat micronucleus test.
Impairment of Fertility
- Studies done on male and female hamsters showed no changes in reproductive performance or fertility after receiving doses of Avacopan up to 1000 mg/kg/day orally.
# Clinical Studies
Double-blind, active-controlled, Phase 3 Clinical Trial
- A phase 3 clinical trial tested the safety and effectiveness of Avacopan on patients that have ANCA-associated vasculitis. 330 patients were part of the study and were either put in Avacopan or Prednisone group. The patient population was largely Caucasian (84.2%), and included 56.4% women, and either had a presence of anti-MPO (57.0%) antibodies or anti-PR3 (43.0%) antibodies. Patients in the Avacopan treatment received a twice daily dosage of 30 mg of Avacopan for 52 weeks, and prednisone-matching placebo for 20 weeks. Patients in the Prednisone group received prednisone and twice daily dosage of an avacopan-matched placebo for 52 weeks. All patients received 1 of the 3 different possible standard immunosuppressive regimens: IV cyclophosphamide, oral cyclophosphamide, or rituximab. Patients from week 15 part of the IV cyclophosphamide group received IV cyclophosphamide 15 mg/kg IV up to 1.2 g maximum every 2 to 3 weeks for 13 weeks followed by oral azathioprine 1 mg/kg/day with titration up to 2 mg/kg/day. 31% of patients in this study received standard immunosuppressive regimen. Patients from week 15 part of the oral cyclophosphamide group received oral cyclophosphamide 2 mg/kg/day for 14 weeks followed by azathioprine 1 mg/kg/day with titration up to 2 mg/kg/day. 4% of patients in this study received this standard immunosuppressive regimen. Patients part of the rituximab group received IV rituximab 375 mg/m2 once weekly for 4 weeks without azathioprine or mycophenolate mofetil. To prevent hypersensitivity reactions from rituximab a pre-medication for Glucocorticoids may be taken. 65% of patients received this standard immunosuppressive regimen. 3 factors determined randomization: proteinase 3 positive or myeloperoxidase positive ANCA-associated vasculitis, newly-diagnosed or relapsing ANCA-associated vasculitis, and the type of immunosuppressive regimen. The goal of the study is to understand how the two treatment groups affect disease remission at week 26 and sustained remission at week 52.
Remission at Week 26 and Sustained Remission at Week 52
- Patients in the Avacopan group had 72.3% of patients achieve remission at Week 26 and 65.7% achieve sustained remission at Week 52. Patients in the Prednisone group had 70.1% of patients achieve remission at Week 26 and 54.9% achieve sustained remission at Week 52. Disease remission was defined as achieving a Birmingham Vasculitis Activity Score (BVAS) of 0 and no use of glucocorticoids for treatment of ANCA-associated vasculitis from Week 22 to Week 26 in this clinical study. Sustained remission was defined as remission at Week 26 and remission at Week 52, without relapse between Week 26 and Week 52 in this clinical study.
Table 4 shows the results of patients that had sustained remission at week 52 in the Double-blind, active-controlled, Phase 3 Clinical Trial.
Figure 1 shows stratification factors and GPA/MPA disease in patients at sustained remission at week 52
# How Supplied
- 10 mg dose pack (180 tablets), bottle seals are child resistant.
- 10 mg dose pack (180 tablets), bottle seals are child resistant.
- Tablets are light orange and opaque yellow.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Dosage and Administration
- Instruct patients to not chew, crush, or break tablets.
- Swallow Avacopan capsules whole.
- If scheduled dosage is missed, skip dosage and wait until next regularly scheduled dosage.
Hypersensitivity Reactions
- Advise patients that experience signs of angioedema to seek immediate medical attention.
- Advise patients with any signs of hypersensitivity reactions to discontinue use of Avacopan until consultation with physician.
Hepatotoxicity
- Seek immediate medical consultation if patients receive symptoms of liver problems such as pain on the upper right side of the stomach area, bruising, bleeding, dark urine, brown urine, or yellowing of the skin, or yellowing of the white part of the eyes during Avacopan treatment.
Infections
- Reactivation of hepatitis B infection is one of many possible serious infections reported by patients when using Avacopan.
- Advise patients to seek immediate medical attention if they show signs of serious infections.
Lactation
- Advise patients about both the risks and benefits of nursing when taking Avacopan.
# Precautions with Alcohol
Alcohol-Avacopan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tavneos
# Look-Alike Drug Names
There is limited information regarding Avacopan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Avacopan | |
08c90f5da3d947b5e93b8bce18dc64956b340dcb | wikidoc | Avanafil | Avanafil
# 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
Avanafil is an erectile dysfunction agent that is FDA approved for the treatment of erectile dysfunction. Common adverse reactions include headache, flushing, nasal congestion, nasopharyngitis, back pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Avanafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction
# Dosage
Erectile Dysfunction
- The recommended starting dose is 100 mg. Avanafil should be taken orally as needed as early as approximately 15 minutes before sexual activity.
- Based on individual efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used.
- The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment.
# Concomitant Medications
Alpha-Blockers
- If avanafil is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating treatment with avanafil, and avanafil should be initiated at the 50 mg dose.
CYP3A4 Inhibitors
- For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin), do not use avanafil.
- For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours
# DOSAGE FORMS AND STRENGTHS
- Avanafil is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strength.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Avanafil in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Avanafil in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Avanafil in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Avanafil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Avanafil in pediatric patients.
# Contraindications
Nitrates
- Administration of avanafil with any form of organic nitrates, either regularly and/or intermittently, is contraindicated. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, avanafil has been shown to potentiate the hypotensive effects of nitrates.
- In a patient who has taken avanafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.
Hypersensitivity Reactions
- Avanafil is contraindicated in patients with a known hypersensitivity to any component of the tablet. Hypersensitivity reactions have been reported, including pruritis and eyelid swelling.
# Warnings
- Evaluation of erectile dysfunction (ED) should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.
- Before prescribing avanafil, it is important to note the following:
Cardiovascular Risks
- There is a potential for cardiac risk during sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for ED, including avanafil, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.
- Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators, including avanafil.
- The following groups of patients were not included in clinical safety and efficacy trials for avanafil, and therefore until further information is available, avanafil is not recommended for the following groups:
- Patients who have suffered a myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization within the last 6 months;
- Patients with resting hypotension (blood pressure less than 90/50 mmHg) or hypertension (blood pressure greater than 170/100 mmHg);
- Patients with unstable angina, angina with sexual intercourse, or New York Heart Association Class 2 or greater congestive heart failure.
- As with other PDE5 inhibitors avanafil has systemic vasodilatory properties and may augment the blood pressure-lowering effect of other anti-hypertensive medications. avanafil 200 mg resulted in transient decreases in sitting blood pressure in healthy volunteers of 8.0 mmHg systolic and 3.3 mmHg diastolic, with the maximum decrease observed at 1 hour after dosing. While this normally would be expected to be of little consequence in most patients, prior to prescribing avanafil, physicians should carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.
Concomitant Use of CYP3A4 Inhibitors
- Avanafil metabolism is principally mediated by the CYP450 isoform 3A4 (CYP3A4). Inhibitors of CYP3A4 may reduce avanafil clearance and increase plasma concentrations of avanafil.
- For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin), do not use avanafil.
- For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours.
Prolonged Erection
- Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported with other PDE5 inhibitors. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If not treated immediately, penile tissue damage and permanent loss of potency could result.
- Avanafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
Effects on Eye
- Physicians should advise patients to stop use of all PDE5 inhibitors, including avanafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors.
- Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
- Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including avanafil, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including avanafil, for this uncommon condition.
Sudden Hearing Loss
- Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Patients experiencing these symptoms should be advised to stop taking avanafil and seek prompt medical attention.
Alpha-Blockers and Other Antihypertensives
- Physicians should discuss with patients the potential for avanafil to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications.
- Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase type 5 inhibitors, including avanafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).
Consideration should be given to the following:
- Patients should be stable on alpha-blocker therapy prior to initiating treatment with a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
- In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose (avanafil 50 mg).
- In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.
- Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.
Alcohol
- Patients should be made aware that both alcohol and PDE5 inhibitors including avanafil act as vasodilators. When vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
Combination with Other PDE5 Inhibitors or Erectile Dysfunction Therapies
- The safety and efficacy of combinations of avanafil with other treatments for ED has not been studied. Therefore, the use of such combinations is not recommended.
Effects on Bleeding
- The safety of avanafil is unknown in patients with bleeding disorders and patients with active peptic ulceration. In vitro studies with human platelets indicate that avanafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor).
Counseling Patients about Sexually Transmitted Diseases
- The use of avanafil offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.
# Adverse Reactions
## Clinical Trials Experience
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.
- Avanafil was administered to 2215 men during clinical trials. In trials of avanafil for use as needed, a total of 493 patients were exposed for greater than or equal to 6 months, and 153 patients were treated for greater than or equal to 12 months.
- In three randomized, double-blind, placebo-controlled trials lasting up to 3 months in duration, the mean age of patients was 56.4 years (range from 23 to 88 years). 83.9% of patients were White, 13.8% were Black, 1.4% Asian, and < 1% Hispanic. 41.1% were current or previous smokers. 30.6% had diabetes mellitus.
- The discontinuation rate due to adverse reactions for patients treated with avanafil 50 mg, 100 mg, or 200 mg was 1.4%, 2.0%, and 2.0%, respectively, compared to 1.7% for placebo-treated patients.
- Table 1 presents the adverse reactions reported when avanafil was taken as recommended (on an as-needed basis) from these 3 clinical trials.
- Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in any avanafil dose group, and greater than placebo included: upper respiratory infection (URI), bronchitis, influenza, sinusitis, sinus congestion, hypertension, dyspepsia, nausea, constipation, and rash.
- In an open-label, long-term extension study of two of these randomized, double-blind, placebo-controlled trials, the total duration of treatment was up to 52 weeks. Among the 712 patients who participated in this open-label extension study, the mean age of the population was 56.4 years (range from 23 to 88 years). The discontinuation rate due to adverse reactions for patients treated with avanafil (50 mg, 100 mg, or 200 mg) was 2.8%.
- In this extension trial, all eligible patients were initially assigned to avanafil 100 mg. At any point during the trial, patients could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment. In total, 536 (approximately 75%) patients increased their dose to 200 mg and 5 (less than 1%) patients reduced their dose to 50 mg.
- Table 2 presents the adverse reactions reported when avanafil was taken as recommended (on an as-needed basis) in this open-label extension trial.
- Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in the open-label extension study included: upper respiratory infection (URI), influenza, sinusitis, bronchitis, dizziness, back pain, arthralgia, hypertension, and diarrhea.
- The following events occurred in less than 1% of patients in the three placebo-controlled 3-month clinical trials and/or the open-label, long-term extension study lasting 12 months. A causal relationship to avanafil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful.
- Body as a whole — edema peripheral, fatigue
- Cardiovascular — angina, unstable angina, deep vein thrombosis, palpitations
- Digestive — gastritis, gastroesophageal reflux disease, hypoglycemia, blood glucose increased, alanine aminotransferase increased, oropharyngeal pain, stomach discomfort, vomiting
- Musculoskeletal — muscle spasms, musculoskeletal pain, myalgia, pain in extremity
- Nervous — depression, insomnia, somnolence, vertigo
- Respiratory — cough, dyspnea exertional, epistaxis, wheezing
- Skin and Appendages – pruritus
- Urogenital – balanitis, erection increased, hematuria, nephrolithiasis, pollakiuria, urinary tract infection
- In an additional randomized, double-blind, placebo-controlled study lasting up to 3 months in 298 men who had undergone bilateral nerve-sparing radical prostatectomy for prostate cancer, the mean age of patients was 58.4 years (range 40 – 70). Table 3 presents the adverse reactions reported in this study.
- A randomized, double-blind, placebo-controlled 2 months study was conducted in 435 subjects with a mean age of 58.2 years (range 24 to 86 years) to determine the time to onset of effect of avanafil, defined as the time to the first occurrence of an erection sufficient for sexual intercourse. Table 4 presents the adverse reactions occurring in ≥ 2% of subjects treated with avanafil.
- Across all trials with any avanafil dose, 1 subject reported a change in color vision.
## Postmarketing Experience
Ophthalmologic:
- Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
# Drug Interactions
Potential for Pharmacodynamic Interactions with avanafil
Nitrates
- Administration of STENDRA to patients who are using any form of organic nitrate is contraindicated. In a clinical pharmacology trial, avanafil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken avanafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.
Alpha-Blockers
- Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including avanafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).
Antihypertensives
- PDE5 inhibitors, including avanafil, are mild systemic vasodilators. A clinical pharmacology trial was conducted to assess the effect of avanafil on the potentiation of the blood pressure-lowering effects of selected antihypertensive medications (amlodipine and enalapril). Additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single 200 mg dose of avanafil with these agents compared with placebo.
Alcohol
- Both alcohol and PDE5 inhibitors, including avanafil, act as vasodilators. When vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
Potential for Other Drugs to Affect Avanafil
- Avanafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure.
Strong CYP3A4 Inhibitors
- Ketoconazole (400 mg daily), a selective and strong inhibitor of CYP3A4, increased avanafil 50 mg single-dose systemic exposure (AUC) and maximum concentration (Cmax) equal to 13-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 9 hours. Other potent inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, and telithromycin) would be expected to have similar effects. Do not use avanafil in patients taking strong CYP3A4 inhibitors .
- HIV Protease inhibitor — Ritonavir (600 mg twice daily), a strong CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose Cmax and AUC equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 9 hours in healthy volunteers. Do not use avanafil in patients taking ritonavir.
Moderate CYP3A4 Inhibitors
- Erythromycin (500 mg twice daily) increased avanafil 200 mg single-dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours in healthy volunteers. Moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. Consequently, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours for patients taking concomitant moderate CYP3A4 inhibitors.
- Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice are likely to increase avanafil exposure.
Weak CYP3A4 Inhibitors
- No in vivo drug-drug interaction studies with weak CYP3A4 inhibitors were conducted.
CYP3A4 Substrate
- When administered with avanafil 200 mg, amlodipine (5 mg daily) increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively.
Cytochrome P450 Inducers
- The potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated. The concomitant use of avanafil and CYP inducers is not recommended.
Potential for Avanafil to Affect Other Drugs
In vitro studies
- Avanafil had no effect on CYP1A1/2, 2A6, 2B6, and 2E1 (IC50 greater than 100 micromolar) and weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4). Major circulating metabolites of avanafil (M4 and M16) had no effect on CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Avanafil and its metabolites (M4 and M16) are unlikely to cause clinically significant inhibition of CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.
In vivo studies
- Warfarin —A single 200 mg dose of avanafil did not alter the changes in PT or INR induced by warfarin, and did not affect collagen-induced platelet aggregation or the AUC or Cmax of R- or S-warfarin, a 2C9 substrate.
- Desipramine — A single avanafil 200 mg dose increased AUC and Cmax of a single 50 mg dose of desipramine, a CYP2D6 substrate, by 5.7% and 5.2%, respectively.
- Omeprazole — A single avanafil 200 mg dose increased AUC and Cmax of a single 40 mg dose of omeprazole, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.
- Rosiglitazone — A single avanafil 200 mg dose increased AUC by 2.0% and decreased Cmax by 14% of a single 8 mg dose of rosiglitazone, a CYP2C8 substrate.
- Amlodipine — A single avanafil 200 mg dose did not affect the pharmacokinetics of amlodipine (5 mg daily), a CYP3A4 substrate .
- Alcohol — A single oral dose of avanafil 200 mg did not affect alcohol (0.5 g ethanol/kg) plasma concentrations
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- Avanafil is not indicated for use in women. There are no adequate and well-controlled studies of avanafil in pregnant women.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Avanafil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Avanafil during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Avanafil with respect to nursing mothers.
### Pediatric Use
- Avanafil is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.
### Geriatic Use
- Of the total number of subjects in clinical studies of avanafil, approximately 23% were 65 and over. No overall differences in efficacy and safety were observed between subjects over 65 years of age compared to younger subjects; therefore no dose adjustment is warranted based on age alone. However, a greater sensitivity to medication in some older individuals should be considered.
### Gender
There is no FDA guidance on the use of Avanafil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Avanafil with respect to specific racial populations.
### Renal Impairment
- In a clinical pharmacology trial using single 200 mg doses of avanafil, avanafil exposure (AUC or Cmax) in normal subjects was comparable to patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate (creatinine clearance greater than or equal to 30 to less than 60 mL/min) renal impairment. No dose adjustment is necessary for patients with mild to moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 90 mL/min). The pharmacokinetics of avanafil in patients with severe renal disease or on renal dialysis has not been studied; do not use avanafil in such patients.
### Hepatic Impairment
- In a clinical pharmacology trial, avanafil AUC and Cmax in patients with mild hepatic impairment (Child-Pugh Class A) was comparable to that in healthy subjects when a dose of 200 mg was administered. Avanafil Cmax was approximately 51% lower and AUC was 11% higher in patients with moderate hepatic impairment (Child Pugh Class B) compared to subjects with normal hepatic function. No dose adjustment is necessary for patients with mild to moderate hepatic impairment (Child Pugh Class A or B). The pharmacokinetics of avanafil in patients with severe hepatic disease has not been studied; do not use avanafil in such patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Avanafil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Avanafil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Avanafil in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Avanafil in the drug label.
# Overdosage
- Single doses up to 800 mg have been given to healthy subjects, and multiple doses up to 300 mg have been given to patients. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance because avanafil is highly bound to plasma proteins and is not significantly eliminated in the urine.
# Pharmacology
## Mechanism of Action
- The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cGMP, producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Avanafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for degradation of cGMP in the corpus cavernosum. Because sexual stimulation is required to initiate the local release of NO, the inhibition of PDE5 has no effect in the absence of sexual stimulation.
- Studies in vitro have shown that avanafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (greater than 100-fold for PDE6; greater than 1,000-fold for PDE4, PDE8, and PDE10; greater than 5,000-fold for PDE2 and PDE7; greater than 10,000-fold for PDE1, PDE3, PDE9, and PDE11). Avanafil is greater than 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by avanafil may be the basis for the enhanced platelet anti-aggregatory activity of NO observed in vitro and peripheral vasodilatation in vivo.
## Structure
- STENDRA (avanafil) is a selective inhibitor of cGMP-specific PDE5.
- Avanafil is designated chemically as (S)-4--2--N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide and has the following structural formula:
- Avanafil occurs as white crystalline powder, molecular formula C23H26ClN7O3 and molecular weight of 483.95 and is slightly soluble in ethanol, practically insoluble in water, and soluble in 0.1 mol/L hydrochloric acid. Avanafil, for oral administration, is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strengths. In addition to the active ingredient, avanafil, each tablet contains the following inactive ingredients: mannitol, fumaric acid, hydroxypropylcellulose, low substituted hydroxypropylcellulose, calcium carbonate, magnesium stearate, and ferric oxide yellow.
## Pharmacodynamics
Effects of Avanafil on Erectile Response
- In a single-blind, placebo-controlled, single-dose trial of 82 patients with either organic and/or psychogenic ED, visual sexual stimulation resulted in improved erections after avanafil administration compared to placebo, as assessed by an objective measurement of hardness and duration of erections (RigiScan®). Efficacy was assessed by RigiScan at discrete time intervals ranging from 20 – 40 minutes after dosing to 100 – 120 minutes after dosing.
Effects of Avanafil on Blood Pressure
- Single oral doses of avanafil (200 mg) administered to healthy male volunteers resulted in mean changes from baseline in systolic/diastolic blood pressure of -5.3/-3.7 mmHg at 1 hour after dosing, compared to mean changes from baseline in the placebo group of 2.7/-0.4 mmHg. The reductions in systolic/diastolic blood pressure at 1 hour after dosing of avanafil 200 mg compared to placebo were 8.0/3.3 mmHg.
Effects on Cardiac Electrophysiology
- The effect of single 100 or 800 mg doses of avanafil on the QT interval were evaluated in a randomized, double-blind, placebo, and active (moxifloxacin) –controlled crossover study in 52 healthy male subjects aged 18 to 45 years. There were no significant effects of the 100 mg dose. The mean QTc (Fridericia QT correction) for avanafil 800 mg relative to placebo was 9.4 milliseconds (two-sided 90% CI=7.2, 11.6). An 800 mg dose of avanafil (4 times the highest recommended dose) was chosen because this dose yields exposures greater than those observed upon co-administration of avanafil with strong CYP3A4 inhibitors. A double-blind, randomized, placebo- and active-controlled (moxifloxacin), thorough QT/QTc trial of avanafil (100 and 800 mg) in healthy male subjects demonstrated that avanafil did not cause any significant changes in QTc interval or ventricular repolarization.
Effects of Avanafil on Blood Pressure When Administered with Nitrates
- In a clinical pharmacology trial, a single dose of avanafil 200 mg was shown to potentiate the hypotensive effect of nitrates. The use of avanafil in patients taking any form of nitrates is contraindicated.
- A trial was conducted to assess the degree of interaction between nitroglycerin and avanafil, should nitroglycerin be required in an emergency situation after avanafil was taken. This was a single-center, double-blind, randomized, 3-way crossover trial of healthy males from 30 to 60 years of age. Subjects were divided among 5 trial groups with the trial group being determined by the time interval between treatment with trial drug and glyceryl trinitrate administration. Subjects were assigned to trial groups sequentially and hemodynamic results from the previous group were reviewed for serious adverse events (SAEs) before the next group received treatment. Each subject was dosed with all 3 study drugs (avanafil 200 mg, sildenafil citrate 100 mg, and placebo) in random order. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified time points, following their dose of trial drug (0.5, 1, 4, 8, or 12 hours). Overall, 14 (15%) subjects treated with placebo and 28 (28%) subjects treated with avanafil, had clinically significant decreases in standing SBP, defined as greater than or equal to 30 mmHg decrease in SBP, after glyceryl trinitrate administration. Mean maximum decreases are shown in Table 5.
- Like other PDE5 inhibitors, avanafil administration with nitrates is contraindicated. In a patient who has taken avanafil, where nitrate administration is deemed medically necessary in a life threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.
Effects of Avanafil on Blood Pressure When Administered with Alpha-Blockers
- A single-center, randomized, double-blinded, placebo-controlled, two-period crossover trial was conducted to investigate the potential interaction of avanafil with alpha-blocker agents in healthy male subjects which consisted of two cohorts:
- Cohort A (N=24): Subjects received oral doses of doxazosin once daily in the morning at 1 mg for 1 day (Day 1), 2 mg for 2 days (Days 2 – 3), 4 mg for 4 days (Days 4 – 7), and 8 mg for 11 days (Days 8 – 18). On Days 15 and 18, the subjects also received a single oral dose of either 200 mg avanafil or placebo, according to the treatment randomization code. The avanafil or placebo doses were administered 1.3 hours after the doxazosin administration on Days 15 and 18. The co-administration was designed so that doxazosin (Tmax ~2 hours) and avanafil (Tmax ~0.7 hours) would reach their peak plasma concentrations at the same time.
- Cohort B (N=24): Subjects received 0.4 mg daily oral doses of tamsulosin in the morning for 11 consecutive days (Days 1 – 11). On Days 8 and 11, the subjects also received a single oral dose of either 200 mg avanafil or placebo, according to the treatment randomization code. The avanafil or placebo doses were administered 3.3 hours after the tamsulosin administration on Days 8 and 11. The co-administration was designed so that tamsulosin (Tmax ~4 hours) and avanafil (Tmax ~0.7 hours) would reach their peak plasma concentrations at the same time.
- Supine and sitting BP and pulse rate measurements were recorded before and after avanafil or placebo dosing.
- A total of seven subjects in Cohort A (doxazosin) experienced potentially clinically important absolute values or changes from baseline in standing SBP or DBP. Three subjects experienced standing SBP values less than 85 mmHg. One subject experienced a decrease from baseline in standing SBP greater than 30 mmHg following avanafil. Two subjects experienced standing DBP values less than 45 mmHg following avanafil. Four subjects experienced decreases from baseline in standing DBP greater than 20 mmHg following avanafil. One subject experienced such decreases following placebo. There were no severe adverse events related to hypotension reported during the trial. There were no cases of syncope.
- A total of five subjects in Cohort B (tamsulosin) experienced potentially clinically important absolute values or changes from baseline in standing SBP or DBP. Two subjects experienced standing SBP values less than 85 mmHg following avanafil. One subject experienced a decrease from baseline in standing SBP greater than 30 mmHg following avanafil. Two subjects experienced standing DBP values less than 45 mmHg following avanafil. Four subjects experienced decreases from baseline in standing DBP greater than 20 mmHg following avanafil; one subject experienced such decreases following placebo. There were no severe adverse events related to hypotension reported during the trial. There were no cases of syncope.
- Table 6 presents the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure results for the 24 subjects who received avanafil 200 mg and matching placebo.
Blood pressure effects (standing SBP) in normotensive men on stable dose doxazosin (8 mg) following administration of avanafil 200 mg or placebo, are shown in Figure 2. Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin (0.4 mg) following administration of avanafil 200 mg or placebo are shown in Figure 3.
Effects of Avanafil on Blood Pressure When Administered with Enalapril
- A trial was conducted to assess the interaction of enalapril (20 mg daily) and avanafil 200 mg. Single doses of 200 mg avanafil co-administered with enalapril caused a mean maximum decrease in supine systolic/diastolic blood pressure of 1.8/3.5 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1.0 bpm.
Effects of Avanafil on Blood Pressure When Administered with Amlodipine
- A trial was conducted to assess the interaction of amlodipine (5 mg daily) and avanafil 200 mg. Single doses of 200 mg avanafil co-administered with amlodipine caused a mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1.0 bpm; the mean maximum decrease in diastolic blood pressure was less than that observed in the placebo group. There was no effect of avanafil on amlodipine plasma concentrations. Concomitant amlodipine was associated with 22% and 70% increases in avanafil Cmax and AUC, respectively.
Effects of Avanafil on Blood Pressure When Administered with Alcohol
- Alcohol and PDE5 inhibitors, including avanafil, are mild systemic vasodilators. The interaction of avanafil with alcohol was evaluated in a clinical pharmacology trial. Alcohol was administered at a dose of 0.5 g/kg, which is equivalent to approximately 3 ounces of 80-proof vodka in a 70-kg male, and avanafil was administered at a dose of 200 mg. All patients consumed the entire alcohol dose within 15 minutes of starting. Blood alcohol levels of 0.057% were confirmed. There were no reports of orthostatic hypotension or dizziness. Additional maximum supine systolic/diastolic blood pressure decreases of 3.5/4.5 mm Hg and additional maximum pulse rate increase of 9.3 bpm were observed when avanafil was taken with alcohol compared to alcohol alone. Avanafil did not affect alcohol plasma concentrations.
Effects of Avanafil on Semen
- A single 200 mg dose of avanafil had no acute effect on sperm motility or sperm morphology in a group of healthy male subjects. The effect of avanafil on human spermatogenesis is unknown.
Effects of Avanafil on Vision
- Single oral doses of Type 5 phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina.
## Pharmacokinetics
- Mean avanafil plasma concentrations measured after the administration of a single oral dose of 50 or 200 mg to healthy male volunteers are depicted in Figure 4. The pharmacokinetics of avanafil are dose proportional from 12.5 to 600 mg.
Absorption and Distribution
- STENDRA is rapidly absorbed after oral administration, with a median Tmax of 30 to 45 minutes in the fasted state. When STENDRA (200 mg) is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 1.12 to 1.25 hours and a mean reduction in Cmax of 39% (200 mg). There was an approximate 3.8% decrease in AUC. The small changes in avanafil Cmax and AUC are considered of minimal clinical significance; therefore, STENDRA may be administered with or without food. The mean accumulation ratio is approximately 1.2. Avanafil is approximately 99% bound to plasma proteins. Protein binding is independent of total drug concentrations, age, renal and hepatic function.
- Based upon measurements of avanafil in semen of healthy volunteers 45-90 minutes after dosing, less than 0.0002% of the administered dose appeared in the semen of patients.
Metabolism and Excretion
- Avanafil is cleared predominantly by hepatic metabolism, mainly by the CYP3A4 enzyme and to a minor extent by CYP2C isoform. The plasma concentrations of the major circulating metabolites, M4 and M16, are approximately 23% and 29% that of the parent compound, respectively. The M4 metabolite has an in vitro inhibitory potency for PDE5, 18% of that of avanafil, and M4 accounts for approximately 4% of the pharmacologic activity of avanafil. The M16 metabolite was inactive against PDE5.
- Avanafil was extensively metabolized in humans. After oral administration, avanafil is excreted as metabolites predominantly in the feces (approximately 62% of administered oral dose) and to a lesser extent in the urine (approximately 21% of the administered oral dose). Avanafil has a terminal elimination half-life of approximately 5 hours.
Geriatric
- The pharmacokinetics of a single 200 mg avanafil administered to fourteen healthy elderly male volunteers (65-80 years) and eighteen healthy younger male volunteers (18-43 years of age) were compared. AUC0-inf increased by 6.8% and Cmax decreased by 2.1% in the elderly group, compared to the younger group. However, greater sensitivity to medications in some older individuals should be considered.
Renal Impairment
- The pharmacokinetics of a single 200 mg avanafil administered to nine patients with mild (creatinine clearance greater than or equal to 60 and less than 90 mL/min) and to ten patients with moderate (creatinine clearance greater than or equal to 30 to less than 60 mL/min) renal impairment were evaluated. AUC0-inf decreased by 2.9% and Cmax increased by 2.8% in patients with mild renal impairment, compared to healthy volunteers with normal renal function. AUC0-inf increased by 9.1% and Cmax decreased by 2.8% in patients with moderate renal impairment, compared to healthy volunteers with normal renal function. There is no data available for subjects with severe renal insufficiency or end-stage renal disease on hemodialysis.
Hepatic Impairment
- The pharmacokinetics of a single 200 mg avanafil administered to eight patients with mild hepatic impairment (Child-Pugh A) and eight patients with moderate hepatic impairment (Child-Pugh B) were evaluated. AUC0-inf increased by 3.8% and Cmax decreased by 2.7% in patients with mild hepatic impairment, compared to healthy volunteers with normal hepatic function. AUC0-inf increased by 11.2% and Cmax decreased by 51% in patients with moderate hepatic impairment, compared to healthy volunteers with normal hepatic function. There is no data available for subjects with severe hepatic impairment (Child-Pugh Class C).
Drug Interactions
- Effect of CYP3A4 Inhibitors on Avanafil: Strong and moderate CYP3A4 inhibitors increase plasma concentrations of avanafil. The effect of strong CYP3A4 inhibitors, ketoconazole and ritonavir, and moderate CYP3A4 inhibitor, erythromycin, on avanafil pharmacokinetics was studied in an open-label, randomized, one-sequence crossover, three-way parallel study.
Strong CYP3A4 Inhibitors
- Fifteen healthy male volunteers received 400 mg ketoconazole (2 tablets containing 200 mg ketoconazole) once daily for 5 days (Days 2-6) and a single 50 mg avanafil on Days 1 and 6. Twenty-four hour pharmacokinetics of avanafil on Days 1 and 6 were compared. Co-administration with the strong CYP3A4 inhibitor ketoconazole resulted in an approximate 13-fold increase in AUC0-inf and 3.1-fold increase in Cmax. Fourteen healthy male volunteers received 300 mg ritonavir (3 tablets containing 100 mg ritonavir) twice daily for 1 day (Day 2), 400 mg twice daily for 1 day (Day 3), 600 mg twice daily for 5 days (Days 4-8), and a single 50 mg avanafil on Days 1 and 8. Twenty-four hour pharmacokinetics of avanafil on Days 1 and 8 were compared. Co-administration with the strong CYP3A4 inhibitor ritonavir resulted in an approximate 13-fold increase in AUC0-inf and 2.4-fold increase in Cmax of avanafil
Moderate CYP3A4 Inhibitors
- Fifteen healthy male volunteers received 500 mg erythromycin (2 tablets containing 250 mg erythromycin) every 12 hrs for 5 days (Days 2-6) and a single 200 mg avanafil (2 tablets containing 100 mg avanafil) on Days 1 and 6. Twenty-four hour pharmacokinetics of avanafil on Days 1 and 6 were compared. Co-administration with the moderate CYP3A4 inhibitor erythromycin resulted in an approximate 3.6-fold increase in AUC0-inf and 2.0-fold increase in Cmax of avanafil.
Effect of Avanafil on Other Drugs:
Warfarin
- The effect of avanafil on warfarin pharmacokinetics and pharmacodynamics was evaluated in a double-blind, randomized, placebo-controlled, two-way crossover study. Twenty-four healthy male volunteers were randomized to receive either 200 mg avanafil or matching placebo for 9 days. On Day 3 of each period, volunteers received a single 25 mg warfarin. Pharmacokinetics of R- and S-warfarin, PT, and INR prior to warfarin dosing and up to 168 hrs after warfarin administration were compared. Platelet aggregation prior to warfarin dosing and up to 24 hrs after warfarin administration were compared. PT, INR, and platelet aggregation did not change with avanafil administration: 23.1 sec, 2.2, and 75.5%, respectively. Co-administration with avanafil resulted in an approximate 1.6% increase in AUC0-inf and 5.2% decrease in Cmax of S-warfarin.
Omeprazole, Rosiglitazone, and Desipramine
- The effect of avanafil on the pharmacokinetics of omeprazole (a CYP2C19 substrate), rosiglitazone (a CYP2C8 substrate), and desipramine (a CYP2D6 substrate) was evaluated in an open-label, three cohort, crossover study. Nineteen healthy male volunteers received a single 40 omeprazole delayed-release capsule once daily for 8 days (Days 1-8), and a single 200 mg avanafil on Day 8. Twelve hour pharmacokinetics of omeprazole on Days 7 and 8 were compared. Co-administration with avanafil resulted in an approximate 5.9% increase in AUC0-inf and 8.6% increase in Cmax of omeprazole. Twenty healthy male volunteers received a single 8 mg rosiglitazone tablet then a single 200 mg avanafil. Twenty-four hour pharmacokinetics of rosiglitazone with and without avanafil were compared. Co-administration with avanafil resulted in an approximate 2.0% increase in AUC0-inf and 14% decrease in Cmax of rosiglitazone. Twenty healthy male volunteers received a single 50 mg desipramine tablet then a single 200 mg avanafil tablet 2 hours after desipramine. Ninety-six hour pharmacokinetics of desipramine with and without avanafil were compared. Co-administration with avanafil resulted in an approximate 5.7% increase in AUC0-inf and 5.2% increase in Cmax of desipramine.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenesis
- Avanafil was not carcinogenic to CD-1 mice when administered daily at doses of 100, 200, or 600 mg/kg/day orally by gavage for at least 98 weeks (approximately 11 times the MRHD on an AUC basis) or to Sprague Dawley rats when administered daily at doses of 100, 300, or 1000 mg/kg/day orally by gavage for at least 100 weeks (approximately 8 times for males and 34 times for females above the MRHD on an AUC basis).
Mutagenesis
- Avanafil was not genotoxic in a series of tests. Avanafil was not mutagenic in Ames assays. Avanafil was not clastogenic in chromosome aberration assays using Chinese hamster ovary and lung cells, or in vivo in the mouse micronucleus assay. Avanafil did not affect DNA repair when tested in the rat unscheduled DNA synthesis assay.
Impairment of Fertility
- In a rat fertility and early embryonic development study administered 100, 300, or 1000 mg/kg/day for 28 days prior to paring and continued until euthanasia for males, and 14 days prior to pairing to gestation day 7 for females, a decrease in fertility, no or reduced sperm motility, altered estrous cycles, and an increased percentage of abnormal sperm (broken sperm with detached heads) occurred at exposures in males approximately 11 times the human exposure at a dose of 200 mg. The altered sperm effects were reversible at the end of a 9-week drug-free period. Systemic exposure at the NOAEL (300 mg/kg/day) was comparable to the human AUC at the MRHD of 200 mg.
# Clinical Studies
- Avanafil was evaluated in three randomized, double-blind, placebo-controlled, parallel group trials of 2 to 3 months in duration. avanafil was taken as needed at doses of 50 mg, 100 mg, and 200 mg (Study 1) and 100 mg and 200 mg (Study 2 and Study 3). Patients were instructed to take 1 dose of study drug approximately 30 minutes (Study 1 and Study 2) or approximately 15 minutes (Study 3) prior to initiation of sexual activity. Food and alcohol intake was not restricted.
- A subset of patients from 2 of these trials were enrolled into an open-label extension trial. In the open-label extension trial, all eligible patients were initially assigned to avanafil 100 mg. At any point during the trial, patients could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment.
- The 3 primary outcome measures in Studies 1 and 2 were the erectile function domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at baseline and at 4-week intervals during treatment. The IIEF erectile function domain has a 30-point total score, where the higher scores reflect better erectile function. The SEP included diary-based measures of erectile function. Patients recorded information regarding each sexual attempt made throughout the trial. Question 2 of the SEP asks "Were you able to insert your penis into your partner's vagina?" Question 3 of the SEP asks "Did your erection last long enough for you to have successful intercourse?"
- In Study 3, the primary efficacy variable was the per-subject proportion of sexual attempts that had an erectogenic effect within approximately 15 minutes following dosing, where an erectogenic effect was defined as an erection sufficient for vaginal penetration and that enabled satisfactory completion of sexual intercourse.
Results in the General ED Population (Study 1):
- Avanafil was evaluated in 646 men with ED of various etiologies (organic, psychogenic, mixed) in a randomized, double-blind, parallel, placebo-controlled fixed dose trial of 3 months in duration. The mean age was 55.7 years (range 23 to 88 years). The population was 85.6% White, 13.2% Black, 0.9% Asian, and 0.3% of other races. The mean duration of ED was approximately 6.5 years. Avanafil at doses of 50 mg, 100 mg, and 200 mg demonstrated statistically significant improvement in all 3 primary efficacy variables relative to placebo (see TABLE 7).
Results in the ED Population with Diabetes Mellitus (Study 2)
Avanafil was evaluated in ED patients (n=390) with type 1 or type 2 diabetes mellitus in a randomized, double-blind, parallel, placebo-controlled fixed dose trial of 3 months in duration. The mean age was 58 years (range 30 to 78 years). The population was 80.5% White, 17.2% Black, 1.5% Asian, and 0.8% of other races. The mean duration of ED was approximately 6 years. In this trial, avanafil at doses of 100 mg and 200 mg demonstrated statistically significant improvement in all 3 primary efficacy variables as measured by the erectile function domain of the IIEF questionnaire; SEP2 and SEP3 (see TABLE 8).
Time to Onset of Effect (Study 3)
- Avanafil was evaluated in 440 subjects with ED including diabetics (16.4%) and subjects with severe ED (41.4%) in a randomized, double-blind, parallel, placebo-controlled study of 2 months duration. The mean age was 58.2 years (range 24 to 86 years). The population was 75.7% White, 21.4% Black, 1.6% Asian, and 1.4% of other races. Subjects were encouraged to attempt intercourse approximately 15 minutes after dosing and used a stopwatch for measurement of time to onset of effect, defined as the time to the first occurrence of an erection sufficient for sexual intercourse.
- Avanafil 100 mg and 200 mg demonstrated statistically significant improvements relative to placebo in the primary efficacy variable, percentage of all attempts resulting in an erection sufficient for penetration at approximately 15 minutes after dosing followed by successful intercourse (SEP3) (see TABLE 9).
# How Supplied
- STENDRA (avanafil) is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strengths.
## Storage
- Recommended Storage: Store at 20-25°C (68-77°F); excursions permitted to 30°C (86°F) .
- Protect from light .
# Images
## Drug Images
## Package and Label Display Panel
File:Avanafil image.jpg
# Patient Counseling Information
Nitrates
- Physicians should discuss with patients the contraindication of avanafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of avanafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
- Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of avanafil. In such a patient, who has taken avanafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Patients who experience anginal chest pain after taking avanafil should seek immediate medical attention.
Cardiovascular Considerations
- Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and should seek immediate medical attention.
Concomitant Use with Drugs Which Lower Blood Pressure
- Physicians should advise patients of the potential for avanafil to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications.
Potential for Drug Interactions
- Patients should be advised to contact the prescribing physician if new medications that may interact with avanafil are prescribed by another healthcare provider.
Priapism
- There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Physicians should advise patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention.
Sudden Loss of Vision
- Physicians should advise patients to stop use of all PDE5 inhibitors, including avanafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision that has been reported rarely in temporal association with the use of PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including avanafil, for these uncommon conditions.
Sudden Hearing Loss
- Physicians should advise patients to stop taking PDE5 inhibitors, including avanafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
Alcohol
- Patients should be made aware that both alcohol and PDE5 inhibitors including avanafil act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
Sexually Transmitted Disease
- The use of avanafil offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
Recommended Administration
- Physicians should discuss with patients the appropriate use of avanafil and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking avanafil. Patients should be counseled regarding the dosing of avanafil. Inform patients that the recommended starting dose of avanafil is 100 mg, taken as early as approximately 15 minutes before initiating sexual activity. Based on efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used. Patients should be advised to contact their healthcare provider for dose modification.
# Precautions with Alcohol
- Alcohol-Avanafil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- STENDRA ®
# Look-Alike Drug Names
There is limited information regarding Avanafil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Avanafil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Avanafil is an erectile dysfunction agent that is FDA approved for the treatment of erectile dysfunction. Common adverse reactions include headache, flushing, nasal congestion, nasopharyngitis, back pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Avanafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction
# Dosage
Erectile Dysfunction
- The recommended starting dose is 100 mg. Avanafil should be taken orally as needed as early as approximately 15 minutes before sexual activity.
- Based on individual efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used.
- The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment.
# Concomitant Medications
Alpha-Blockers
- If avanafil is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating treatment with avanafil, and avanafil should be initiated at the 50 mg dose.
CYP3A4 Inhibitors
- For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin), do not use avanafil.
- For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours
# DOSAGE FORMS AND STRENGTHS
- Avanafil is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strength.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Avanafil in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Avanafil in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Avanafil in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Avanafil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Avanafil in pediatric patients.
# Contraindications
Nitrates
- Administration of avanafil with any form of organic nitrates, either regularly and/or intermittently, is contraindicated. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, avanafil has been shown to potentiate the hypotensive effects of nitrates.
- In a patient who has taken avanafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.
Hypersensitivity Reactions
- Avanafil is contraindicated in patients with a known hypersensitivity to any component of the tablet. Hypersensitivity reactions have been reported, including pruritis and eyelid swelling.
# Warnings
- Evaluation of erectile dysfunction (ED) should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.
- Before prescribing avanafil, it is important to note the following:
Cardiovascular Risks
- There is a potential for cardiac risk during sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for ED, including avanafil, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.
- Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators, including avanafil.
- The following groups of patients were not included in clinical safety and efficacy trials for avanafil, and therefore until further information is available, avanafil is not recommended for the following groups:
- Patients who have suffered a myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization within the last 6 months;
- Patients with resting hypotension (blood pressure less than 90/50 mmHg) or hypertension (blood pressure greater than 170/100 mmHg);
- Patients with unstable angina, angina with sexual intercourse, or New York Heart Association Class 2 or greater congestive heart failure.
- As with other PDE5 inhibitors avanafil has systemic vasodilatory properties and may augment the blood pressure-lowering effect of other anti-hypertensive medications. avanafil 200 mg resulted in transient decreases in sitting blood pressure in healthy volunteers of 8.0 mmHg systolic and 3.3 mmHg diastolic, with the maximum decrease observed at 1 hour after dosing. While this normally would be expected to be of little consequence in most patients, prior to prescribing avanafil, physicians should carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.
Concomitant Use of CYP3A4 Inhibitors
- Avanafil metabolism is principally mediated by the CYP450 isoform 3A4 (CYP3A4). Inhibitors of CYP3A4 may reduce avanafil clearance and increase plasma concentrations of avanafil.
- For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin), do not use avanafil.
- For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours.
Prolonged Erection
- Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported with other PDE5 inhibitors. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If not treated immediately, penile tissue damage and permanent loss of potency could result.
- Avanafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
Effects on Eye
- Physicians should advise patients to stop use of all PDE5 inhibitors, including avanafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors.
- Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
- Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including avanafil, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including avanafil, for this uncommon condition.
Sudden Hearing Loss
- Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Patients experiencing these symptoms should be advised to stop taking avanafil and seek prompt medical attention.
Alpha-Blockers and Other Antihypertensives
- Physicians should discuss with patients the potential for avanafil to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications.
- Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase type 5 inhibitors, including avanafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).
Consideration should be given to the following:
- Patients should be stable on alpha-blocker therapy prior to initiating treatment with a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
- In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose (avanafil 50 mg).
- In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.
- Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.
Alcohol
- Patients should be made aware that both alcohol and PDE5 inhibitors including avanafil act as vasodilators. When vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
Combination with Other PDE5 Inhibitors or Erectile Dysfunction Therapies
- The safety and efficacy of combinations of avanafil with other treatments for ED has not been studied. Therefore, the use of such combinations is not recommended.
Effects on Bleeding
- The safety of avanafil is unknown in patients with bleeding disorders and patients with active peptic ulceration. In vitro studies with human platelets indicate that avanafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor).
Counseling Patients about Sexually Transmitted Diseases
- The use of avanafil offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.
# Adverse Reactions
## Clinical Trials Experience
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.
- Avanafil was administered to 2215 men during clinical trials. In trials of avanafil for use as needed, a total of 493 patients were exposed for greater than or equal to 6 months, and 153 patients were treated for greater than or equal to 12 months.
- In three randomized, double-blind, placebo-controlled trials lasting up to 3 months in duration, the mean age of patients was 56.4 years (range from 23 to 88 years). 83.9% of patients were White, 13.8% were Black, 1.4% Asian, and < 1% Hispanic. 41.1% were current or previous smokers. 30.6% had diabetes mellitus.
- The discontinuation rate due to adverse reactions for patients treated with avanafil 50 mg, 100 mg, or 200 mg was 1.4%, 2.0%, and 2.0%, respectively, compared to 1.7% for placebo-treated patients.
- Table 1 presents the adverse reactions reported when avanafil was taken as recommended (on an as-needed basis) from these 3 clinical trials.
- Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in any avanafil dose group, and greater than placebo included: upper respiratory infection (URI), bronchitis, influenza, sinusitis, sinus congestion, hypertension, dyspepsia, nausea, constipation, and rash.
- In an open-label, long-term extension study of two of these randomized, double-blind, placebo-controlled trials, the total duration of treatment was up to 52 weeks. Among the 712 patients who participated in this open-label extension study, the mean age of the population was 56.4 years (range from 23 to 88 years). The discontinuation rate due to adverse reactions for patients treated with avanafil (50 mg, 100 mg, or 200 mg) was 2.8%.
- In this extension trial, all eligible patients were initially assigned to avanafil 100 mg. At any point during the trial, patients could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment. In total, 536 (approximately 75%) patients increased their dose to 200 mg and 5 (less than 1%) patients reduced their dose to 50 mg.
- Table 2 presents the adverse reactions reported when avanafil was taken as recommended (on an as-needed basis) in this open-label extension trial.
- Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in the open-label extension study included: upper respiratory infection (URI), influenza, sinusitis, bronchitis, dizziness, back pain, arthralgia, hypertension, and diarrhea.
- The following events occurred in less than 1% of patients in the three placebo-controlled 3-month clinical trials and/or the open-label, long-term extension study lasting 12 months. A causal relationship to avanafil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful.
- Body as a whole — edema peripheral, fatigue
- Cardiovascular — angina, unstable angina, deep vein thrombosis, palpitations
- Digestive — gastritis, gastroesophageal reflux disease, hypoglycemia, blood glucose increased, alanine aminotransferase increased, oropharyngeal pain, stomach discomfort, vomiting
- Musculoskeletal — muscle spasms, musculoskeletal pain, myalgia, pain in extremity
- Nervous — depression, insomnia, somnolence, vertigo
- Respiratory — cough, dyspnea exertional, epistaxis, wheezing
- Skin and Appendages – pruritus
- Urogenital – balanitis, erection increased, hematuria, nephrolithiasis, pollakiuria, urinary tract infection
- In an additional randomized, double-blind, placebo-controlled study lasting up to 3 months in 298 men who had undergone bilateral nerve-sparing radical prostatectomy for prostate cancer, the mean age of patients was 58.4 years (range 40 – 70). Table 3 presents the adverse reactions reported in this study.
- A randomized, double-blind, placebo-controlled 2 months study was conducted in 435 subjects with a mean age of 58.2 years (range 24 to 86 years) to determine the time to onset of effect of avanafil, defined as the time to the first occurrence of an erection sufficient for sexual intercourse. Table 4 presents the adverse reactions occurring in ≥ 2% of subjects treated with avanafil.
- Across all trials with any avanafil dose, 1 subject reported a change in color vision.
## Postmarketing Experience
Ophthalmologic:
- Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
# Drug Interactions
Potential for Pharmacodynamic Interactions with avanafil
Nitrates
- Administration of STENDRA to patients who are using any form of organic nitrate is contraindicated. In a clinical pharmacology trial, avanafil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken avanafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.
Alpha-Blockers
- Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including avanafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).
Antihypertensives
- PDE5 inhibitors, including avanafil, are mild systemic vasodilators. A clinical pharmacology trial was conducted to assess the effect of avanafil on the potentiation of the blood pressure-lowering effects of selected antihypertensive medications (amlodipine and enalapril). Additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single 200 mg dose of avanafil with these agents compared with placebo.
Alcohol
- Both alcohol and PDE5 inhibitors, including avanafil, act as vasodilators. When vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
Potential for Other Drugs to Affect Avanafil
- Avanafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure.
Strong CYP3A4 Inhibitors
- Ketoconazole (400 mg daily), a selective and strong inhibitor of CYP3A4, increased avanafil 50 mg single-dose systemic exposure (AUC) and maximum concentration (Cmax) equal to 13-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 9 hours. Other potent inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, and telithromycin) would be expected to have similar effects. Do not use avanafil in patients taking strong CYP3A4 inhibitors .
- HIV Protease inhibitor — Ritonavir (600 mg twice daily), a strong CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose Cmax and AUC equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 9 hours in healthy volunteers. Do not use avanafil in patients taking ritonavir.
Moderate CYP3A4 Inhibitors
- Erythromycin (500 mg twice daily) increased avanafil 200 mg single-dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours in healthy volunteers. Moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. Consequently, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours for patients taking concomitant moderate CYP3A4 inhibitors.
- Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice are likely to increase avanafil exposure.
Weak CYP3A4 Inhibitors
- No in vivo drug-drug interaction studies with weak CYP3A4 inhibitors were conducted.
CYP3A4 Substrate
- When administered with avanafil 200 mg, amlodipine (5 mg daily) increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively.
Cytochrome P450 Inducers
- The potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated. The concomitant use of avanafil and CYP inducers is not recommended.
Potential for Avanafil to Affect Other Drugs
In vitro studies
- Avanafil had no effect on CYP1A1/2, 2A6, 2B6, and 2E1 (IC50 greater than 100 micromolar) and weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4). Major circulating metabolites of avanafil (M4 and M16) had no effect on CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Avanafil and its metabolites (M4 and M16) are unlikely to cause clinically significant inhibition of CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.
In vivo studies
- Warfarin —A single 200 mg dose of avanafil did not alter the changes in PT or INR induced by warfarin, and did not affect collagen-induced platelet aggregation or the AUC or Cmax of R- or S-warfarin, a 2C9 substrate.
- Desipramine — A single avanafil 200 mg dose increased AUC and Cmax of a single 50 mg dose of desipramine, a CYP2D6 substrate, by 5.7% and 5.2%, respectively.
- Omeprazole — A single avanafil 200 mg dose increased AUC and Cmax of a single 40 mg dose of omeprazole, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.
- Rosiglitazone — A single avanafil 200 mg dose increased AUC by 2.0% and decreased Cmax by 14% of a single 8 mg dose of rosiglitazone, a CYP2C8 substrate.
- Amlodipine — A single avanafil 200 mg dose did not affect the pharmacokinetics of amlodipine (5 mg daily), a CYP3A4 substrate [see DOSAGE AND ADMINISTRATION (2.3)].
- Alcohol — A single oral dose of avanafil 200 mg did not affect alcohol (0.5 g ethanol/kg) plasma concentrations
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- Avanafil is not indicated for use in women. There are no adequate and well-controlled studies of avanafil in pregnant women.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Avanafil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Avanafil during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Avanafil with respect to nursing mothers.
### Pediatric Use
- Avanafil is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.
### Geriatic Use
- Of the total number of subjects in clinical studies of avanafil, approximately 23% were 65 and over. No overall differences in efficacy and safety were observed between subjects over 65 years of age compared to younger subjects; therefore no dose adjustment is warranted based on age alone. However, a greater sensitivity to medication in some older individuals should be considered.
### Gender
There is no FDA guidance on the use of Avanafil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Avanafil with respect to specific racial populations.
### Renal Impairment
- In a clinical pharmacology trial using single 200 mg doses of avanafil, avanafil exposure (AUC or Cmax) in normal subjects was comparable to patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate (creatinine clearance greater than or equal to 30 to less than 60 mL/min) renal impairment. No dose adjustment is necessary for patients with mild to moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 90 mL/min). The pharmacokinetics of avanafil in patients with severe renal disease or on renal dialysis has not been studied; do not use avanafil in such patients.
### Hepatic Impairment
- In a clinical pharmacology trial, avanafil AUC and Cmax in patients with mild hepatic impairment (Child-Pugh Class A) was comparable to that in healthy subjects when a dose of 200 mg was administered. Avanafil Cmax was approximately 51% lower and AUC was 11% higher in patients with moderate hepatic impairment (Child Pugh Class B) compared to subjects with normal hepatic function. No dose adjustment is necessary for patients with mild to moderate hepatic impairment (Child Pugh Class A or B). The pharmacokinetics of avanafil in patients with severe hepatic disease has not been studied; do not use avanafil in such patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Avanafil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Avanafil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Avanafil in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Avanafil in the drug label.
# Overdosage
- Single doses up to 800 mg have been given to healthy subjects, and multiple doses up to 300 mg have been given to patients. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance because avanafil is highly bound to plasma proteins and is not significantly eliminated in the urine.
# Pharmacology
## Mechanism of Action
- The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cGMP, producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Avanafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for degradation of cGMP in the corpus cavernosum. Because sexual stimulation is required to initiate the local release of NO, the inhibition of PDE5 has no effect in the absence of sexual stimulation.
- Studies in vitro have shown that avanafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (greater than 100-fold for PDE6; greater than 1,000-fold for PDE4, PDE8, and PDE10; greater than 5,000-fold for PDE2 and PDE7; greater than 10,000-fold for PDE1, PDE3, PDE9, and PDE11). Avanafil is greater than 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by avanafil may be the basis for the enhanced platelet anti-aggregatory activity of NO observed in vitro and peripheral vasodilatation in vivo.
## Structure
- STENDRA (avanafil) is a selective inhibitor of cGMP-specific PDE5.
- Avanafil is designated chemically as (S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide and has the following structural formula:
- Avanafil occurs as white crystalline powder, molecular formula C23H26ClN7O3 and molecular weight of 483.95 and is slightly soluble in ethanol, practically insoluble in water, and soluble in 0.1 mol/L hydrochloric acid. Avanafil, for oral administration, is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strengths. In addition to the active ingredient, avanafil, each tablet contains the following inactive ingredients: mannitol, fumaric acid, hydroxypropylcellulose, low substituted hydroxypropylcellulose, calcium carbonate, magnesium stearate, and ferric oxide yellow.
## Pharmacodynamics
Effects of Avanafil on Erectile Response
- In a single-blind, placebo-controlled, single-dose trial of 82 patients with either organic and/or psychogenic ED, visual sexual stimulation resulted in improved erections after avanafil administration compared to placebo, as assessed by an objective measurement of hardness and duration of erections (RigiScan®). Efficacy was assessed by RigiScan at discrete time intervals ranging from 20 – 40 minutes after dosing to 100 – 120 minutes after dosing.
Effects of Avanafil on Blood Pressure
- Single oral doses of avanafil (200 mg) administered to healthy male volunteers resulted in mean changes from baseline in systolic/diastolic blood pressure of -5.3/-3.7 mmHg at 1 hour after dosing, compared to mean changes from baseline in the placebo group of 2.7/-0.4 mmHg. The reductions in systolic/diastolic blood pressure at 1 hour after dosing of avanafil 200 mg compared to placebo were 8.0/3.3 mmHg.
Effects on Cardiac Electrophysiology
- The effect of single 100 or 800 mg doses of avanafil on the QT interval were evaluated in a randomized, double-blind, placebo, and active (moxifloxacin) –controlled crossover study in 52 healthy male subjects aged 18 to 45 years. There were no significant effects of the 100 mg dose. The mean QTc (Fridericia QT correction) for avanafil 800 mg relative to placebo was 9.4 milliseconds (two-sided 90% CI=7.2, 11.6). An 800 mg dose of avanafil (4 times the highest recommended dose) was chosen because this dose yields exposures greater than those observed upon co-administration of avanafil with strong CYP3A4 inhibitors. A double-blind, randomized, placebo- and active-controlled (moxifloxacin), thorough QT/QTc trial of avanafil (100 and 800 mg) in healthy male subjects demonstrated that avanafil did not cause any significant changes in QTc interval or ventricular repolarization.
Effects of Avanafil on Blood Pressure When Administered with Nitrates
- In a clinical pharmacology trial, a single dose of avanafil 200 mg was shown to potentiate the hypotensive effect of nitrates. The use of avanafil in patients taking any form of nitrates is contraindicated.
- A trial was conducted to assess the degree of interaction between nitroglycerin and avanafil, should nitroglycerin be required in an emergency situation after avanafil was taken. This was a single-center, double-blind, randomized, 3-way crossover trial of healthy males from 30 to 60 years of age. Subjects were divided among 5 trial groups with the trial group being determined by the time interval between treatment with trial drug and glyceryl trinitrate administration. Subjects were assigned to trial groups sequentially and hemodynamic results from the previous group were reviewed for serious adverse events (SAEs) before the next group received treatment. Each subject was dosed with all 3 study drugs (avanafil 200 mg, sildenafil citrate 100 mg, and placebo) in random order. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified time points, following their dose of trial drug (0.5, 1, 4, 8, or 12 hours). Overall, 14 (15%) subjects treated with placebo and 28 (28%) subjects treated with avanafil, had clinically significant decreases in standing SBP, defined as greater than or equal to 30 mmHg decrease in SBP, after glyceryl trinitrate administration. Mean maximum decreases are shown in Table 5.
- Like other PDE5 inhibitors, avanafil administration with nitrates is contraindicated. In a patient who has taken avanafil, where nitrate administration is deemed medically necessary in a life threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.
Effects of Avanafil on Blood Pressure When Administered with Alpha-Blockers
- A single-center, randomized, double-blinded, placebo-controlled, two-period crossover trial was conducted to investigate the potential interaction of avanafil with alpha-blocker agents in healthy male subjects which consisted of two cohorts:
- Cohort A (N=24): Subjects received oral doses of doxazosin once daily in the morning at 1 mg for 1 day (Day 1), 2 mg for 2 days (Days 2 – 3), 4 mg for 4 days (Days 4 – 7), and 8 mg for 11 days (Days 8 – 18). On Days 15 and 18, the subjects also received a single oral dose of either 200 mg avanafil or placebo, according to the treatment randomization code. The avanafil or placebo doses were administered 1.3 hours after the doxazosin administration on Days 15 and 18. The co-administration was designed so that doxazosin (Tmax ~2 hours) and avanafil (Tmax ~0.7 hours) would reach their peak plasma concentrations at the same time.
- Cohort B (N=24): Subjects received 0.4 mg daily oral doses of tamsulosin in the morning for 11 consecutive days (Days 1 – 11). On Days 8 and 11, the subjects also received a single oral dose of either 200 mg avanafil or placebo, according to the treatment randomization code. The avanafil or placebo doses were administered 3.3 hours after the tamsulosin administration on Days 8 and 11. The co-administration was designed so that tamsulosin (Tmax ~4 hours) and avanafil (Tmax ~0.7 hours) would reach their peak plasma concentrations at the same time.
- Supine and sitting BP and pulse rate measurements were recorded before and after avanafil or placebo dosing.
- A total of seven subjects in Cohort A (doxazosin) experienced potentially clinically important absolute values or changes from baseline in standing SBP or DBP. Three subjects experienced standing SBP values less than 85 mmHg. One subject experienced a decrease from baseline in standing SBP greater than 30 mmHg following avanafil. Two subjects experienced standing DBP values less than 45 mmHg following avanafil. Four subjects experienced decreases from baseline in standing DBP greater than 20 mmHg following avanafil. One subject experienced such decreases following placebo. There were no severe adverse events related to hypotension reported during the trial. There were no cases of syncope.
- A total of five subjects in Cohort B (tamsulosin) experienced potentially clinically important absolute values or changes from baseline in standing SBP or DBP. Two subjects experienced standing SBP values less than 85 mmHg following avanafil. One subject experienced a decrease from baseline in standing SBP greater than 30 mmHg following avanafil. Two subjects experienced standing DBP values less than 45 mmHg following avanafil. Four subjects experienced decreases from baseline in standing DBP greater than 20 mmHg following avanafil; one subject experienced such decreases following placebo. There were no severe adverse events related to hypotension reported during the trial. There were no cases of syncope.
- Table 6 presents the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure results for the 24 subjects who received avanafil 200 mg and matching placebo.
Blood pressure effects (standing SBP) in normotensive men on stable dose doxazosin (8 mg) following administration of avanafil 200 mg or placebo, are shown in Figure 2. Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin (0.4 mg) following administration of avanafil 200 mg or placebo are shown in Figure 3.
Effects of Avanafil on Blood Pressure When Administered with Enalapril
- A trial was conducted to assess the interaction of enalapril (20 mg daily) and avanafil 200 mg. Single doses of 200 mg avanafil co-administered with enalapril caused a mean maximum decrease in supine systolic/diastolic blood pressure of 1.8/3.5 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1.0 bpm.
Effects of Avanafil on Blood Pressure When Administered with Amlodipine
- A trial was conducted to assess the interaction of amlodipine (5 mg daily) and avanafil 200 mg. Single doses of 200 mg avanafil co-administered with amlodipine caused a mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1.0 bpm; the mean maximum decrease in diastolic blood pressure was less than that observed in the placebo group. There was no effect of avanafil on amlodipine plasma concentrations. Concomitant amlodipine was associated with 22% and 70% increases in avanafil Cmax and AUC, respectively.
Effects of Avanafil on Blood Pressure When Administered with Alcohol
- Alcohol and PDE5 inhibitors, including avanafil, are mild systemic vasodilators. The interaction of avanafil with alcohol was evaluated in a clinical pharmacology trial. Alcohol was administered at a dose of 0.5 g/kg, which is equivalent to approximately 3 ounces of 80-proof vodka in a 70-kg male, and avanafil was administered at a dose of 200 mg. All patients consumed the entire alcohol dose within 15 minutes of starting. Blood alcohol levels of 0.057% were confirmed. There were no reports of orthostatic hypotension or dizziness. Additional maximum supine systolic/diastolic blood pressure decreases of 3.5/4.5 mm Hg and additional maximum pulse rate increase of 9.3 bpm were observed when avanafil was taken with alcohol compared to alcohol alone. Avanafil did not affect alcohol plasma concentrations.
Effects of Avanafil on Semen
- A single 200 mg dose of avanafil had no acute effect on sperm motility or sperm morphology in a group of healthy male subjects. The effect of avanafil on human spermatogenesis is unknown.
Effects of Avanafil on Vision
- Single oral doses of Type 5 phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina.
## Pharmacokinetics
- Mean avanafil plasma concentrations measured after the administration of a single oral dose of 50 or 200 mg to healthy male volunteers are depicted in Figure 4. The pharmacokinetics of avanafil are dose proportional from 12.5 to 600 mg.
Absorption and Distribution
- STENDRA is rapidly absorbed after oral administration, with a median Tmax of 30 to 45 minutes in the fasted state. When STENDRA (200 mg) is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 1.12 to 1.25 hours and a mean reduction in Cmax of 39% (200 mg). There was an approximate 3.8% decrease in AUC. The small changes in avanafil Cmax and AUC are considered of minimal clinical significance; therefore, STENDRA may be administered with or without food. The mean accumulation ratio is approximately 1.2. Avanafil is approximately 99% bound to plasma proteins. Protein binding is independent of total drug concentrations, age, renal and hepatic function.
- Based upon measurements of avanafil in semen of healthy volunteers 45-90 minutes after dosing, less than 0.0002% of the administered dose appeared in the semen of patients.
Metabolism and Excretion
- Avanafil is cleared predominantly by hepatic metabolism, mainly by the CYP3A4 enzyme and to a minor extent by CYP2C isoform. The plasma concentrations of the major circulating metabolites, M4 and M16, are approximately 23% and 29% that of the parent compound, respectively. The M4 metabolite has an in vitro inhibitory potency for PDE5, 18% of that of avanafil, and M4 accounts for approximately 4% of the pharmacologic activity of avanafil. The M16 metabolite was inactive against PDE5.
- Avanafil was extensively metabolized in humans. After oral administration, avanafil is excreted as metabolites predominantly in the feces (approximately 62% of administered oral dose) and to a lesser extent in the urine (approximately 21% of the administered oral dose). Avanafil has a terminal elimination half-life of approximately 5 hours.
Geriatric
- The pharmacokinetics of a single 200 mg avanafil administered to fourteen healthy elderly male volunteers (65-80 years) and eighteen healthy younger male volunteers (18-43 years of age) were compared. AUC0-inf increased by 6.8% and Cmax decreased by 2.1% in the elderly group, compared to the younger group. However, greater sensitivity to medications in some older individuals should be considered.
Renal Impairment
- The pharmacokinetics of a single 200 mg avanafil administered to nine patients with mild (creatinine clearance greater than or equal to 60 and less than 90 mL/min) and to ten patients with moderate (creatinine clearance greater than or equal to 30 to less than 60 mL/min) renal impairment were evaluated. AUC0-inf decreased by 2.9% and Cmax increased by 2.8% in patients with mild renal impairment, compared to healthy volunteers with normal renal function. AUC0-inf increased by 9.1% and Cmax decreased by 2.8% in patients with moderate renal impairment, compared to healthy volunteers with normal renal function. There is no data available for subjects with severe renal insufficiency or end-stage renal disease on hemodialysis.
Hepatic Impairment
- The pharmacokinetics of a single 200 mg avanafil administered to eight patients with mild hepatic impairment (Child-Pugh A) and eight patients with moderate hepatic impairment (Child-Pugh B) were evaluated. AUC0-inf increased by 3.8% and Cmax decreased by 2.7% in patients with mild hepatic impairment, compared to healthy volunteers with normal hepatic function. AUC0-inf increased by 11.2% and Cmax decreased by 51% in patients with moderate hepatic impairment, compared to healthy volunteers with normal hepatic function. There is no data available for subjects with severe hepatic impairment (Child-Pugh Class C).
Drug Interactions
- Effect of CYP3A4 Inhibitors on Avanafil: Strong and moderate CYP3A4 inhibitors increase plasma concentrations of avanafil. The effect of strong CYP3A4 inhibitors, ketoconazole and ritonavir, and moderate CYP3A4 inhibitor, erythromycin, on avanafil pharmacokinetics was studied in an open-label, randomized, one-sequence crossover, three-way parallel study.
Strong CYP3A4 Inhibitors
- Fifteen healthy male volunteers received 400 mg ketoconazole (2 tablets containing 200 mg ketoconazole) once daily for 5 days (Days 2-6) and a single 50 mg avanafil on Days 1 and 6. Twenty-four hour pharmacokinetics of avanafil on Days 1 and 6 were compared. Co-administration with the strong CYP3A4 inhibitor ketoconazole resulted in an approximate 13-fold increase in AUC0-inf and 3.1-fold increase in Cmax. Fourteen healthy male volunteers received 300 mg ritonavir (3 tablets containing 100 mg ritonavir) twice daily for 1 day (Day 2), 400 mg twice daily for 1 day (Day 3), 600 mg twice daily for 5 days (Days 4-8), and a single 50 mg avanafil on Days 1 and 8. Twenty-four hour pharmacokinetics of avanafil on Days 1 and 8 were compared. Co-administration with the strong CYP3A4 inhibitor ritonavir resulted in an approximate 13-fold increase in AUC0-inf and 2.4-fold increase in Cmax of avanafil
Moderate CYP3A4 Inhibitors
- Fifteen healthy male volunteers received 500 mg erythromycin (2 tablets containing 250 mg erythromycin) every 12 hrs for 5 days (Days 2-6) and a single 200 mg avanafil (2 tablets containing 100 mg avanafil) on Days 1 and 6. Twenty-four hour pharmacokinetics of avanafil on Days 1 and 6 were compared. Co-administration with the moderate CYP3A4 inhibitor erythromycin resulted in an approximate 3.6-fold increase in AUC0-inf and 2.0-fold increase in Cmax of avanafil.
Effect of Avanafil on Other Drugs:
Warfarin
- The effect of avanafil on warfarin pharmacokinetics and pharmacodynamics was evaluated in a double-blind, randomized, placebo-controlled, two-way crossover study. Twenty-four healthy male volunteers were randomized to receive either 200 mg avanafil or matching placebo for 9 days. On Day 3 of each period, volunteers received a single 25 mg warfarin. Pharmacokinetics of R- and S-warfarin, PT, and INR prior to warfarin dosing and up to 168 hrs after warfarin administration were compared. Platelet aggregation prior to warfarin dosing and up to 24 hrs after warfarin administration were compared. PT, INR, and platelet aggregation did not change with avanafil administration: 23.1 sec, 2.2, and 75.5%, respectively. Co-administration with avanafil resulted in an approximate 1.6% increase in AUC0-inf and 5.2% decrease in Cmax of S-warfarin.
Omeprazole, Rosiglitazone, and Desipramine
- The effect of avanafil on the pharmacokinetics of omeprazole (a CYP2C19 substrate), rosiglitazone (a CYP2C8 substrate), and desipramine (a CYP2D6 substrate) was evaluated in an open-label, three cohort, crossover study. Nineteen healthy male volunteers received a single 40 omeprazole delayed-release capsule once daily for 8 days (Days 1-8), and a single 200 mg avanafil on Day 8. Twelve hour pharmacokinetics of omeprazole on Days 7 and 8 were compared. Co-administration with avanafil resulted in an approximate 5.9% increase in AUC0-inf and 8.6% increase in Cmax of omeprazole. Twenty healthy male volunteers received a single 8 mg rosiglitazone tablet then a single 200 mg avanafil. Twenty-four hour pharmacokinetics of rosiglitazone with and without avanafil were compared. Co-administration with avanafil resulted in an approximate 2.0% increase in AUC0-inf and 14% decrease in Cmax of rosiglitazone. Twenty healthy male volunteers received a single 50 mg desipramine tablet then a single 200 mg avanafil tablet 2 hours after desipramine. Ninety-six hour pharmacokinetics of desipramine with and without avanafil were compared. Co-administration with avanafil resulted in an approximate 5.7% increase in AUC0-inf and 5.2% increase in Cmax of desipramine.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenesis
- Avanafil was not carcinogenic to CD-1 mice when administered daily at doses of 100, 200, or 600 mg/kg/day orally by gavage for at least 98 weeks (approximately 11 times the MRHD on an AUC basis) or to Sprague Dawley rats when administered daily at doses of 100, 300, or 1000 mg/kg/day orally by gavage for at least 100 weeks (approximately 8 times for males and 34 times for females above the MRHD on an AUC basis).
Mutagenesis
- Avanafil was not genotoxic in a series of tests. Avanafil was not mutagenic in Ames assays. Avanafil was not clastogenic in chromosome aberration assays using Chinese hamster ovary and lung cells, or in vivo in the mouse micronucleus assay. Avanafil did not affect DNA repair when tested in the rat unscheduled DNA synthesis assay.
Impairment of Fertility
- In a rat fertility and early embryonic development study administered 100, 300, or 1000 mg/kg/day for 28 days prior to paring and continued until euthanasia for males, and 14 days prior to pairing to gestation day 7 for females, a decrease in fertility, no or reduced sperm motility, altered estrous cycles, and an increased percentage of abnormal sperm (broken sperm with detached heads) occurred at exposures in males approximately 11 times the human exposure at a dose of 200 mg. The altered sperm effects were reversible at the end of a 9-week drug-free period. Systemic exposure at the NOAEL (300 mg/kg/day) was comparable to the human AUC at the MRHD of 200 mg.
# Clinical Studies
- Avanafil was evaluated in three randomized, double-blind, placebo-controlled, parallel group trials of 2 to 3 months in duration. avanafil was taken as needed at doses of 50 mg, 100 mg, and 200 mg (Study 1) and 100 mg and 200 mg (Study 2 and Study 3). Patients were instructed to take 1 dose of study drug approximately 30 minutes (Study 1 and Study 2) or approximately 15 minutes (Study 3) prior to initiation of sexual activity. Food and alcohol intake was not restricted.
- A subset of patients from 2 of these trials were enrolled into an open-label extension trial. In the open-label extension trial, all eligible patients were initially assigned to avanafil 100 mg. At any point during the trial, patients could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment.
- The 3 primary outcome measures in Studies 1 and 2 were the erectile function domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at baseline and at 4-week intervals during treatment. The IIEF erectile function domain has a 30-point total score, where the higher scores reflect better erectile function. The SEP included diary-based measures of erectile function. Patients recorded information regarding each sexual attempt made throughout the trial. Question 2 of the SEP asks "Were you able to insert your penis into your partner's vagina?" Question 3 of the SEP asks "Did your erection last long enough for you to have successful intercourse?"
- In Study 3, the primary efficacy variable was the per-subject proportion of sexual attempts that had an erectogenic effect within approximately 15 minutes following dosing, where an erectogenic effect was defined as an erection sufficient for vaginal penetration and that enabled satisfactory completion of sexual intercourse.
Results in the General ED Population (Study 1):
- Avanafil was evaluated in 646 men with ED of various etiologies (organic, psychogenic, mixed) in a randomized, double-blind, parallel, placebo-controlled fixed dose trial of 3 months in duration. The mean age was 55.7 years (range 23 to 88 years). The population was 85.6% White, 13.2% Black, 0.9% Asian, and 0.3% of other races. The mean duration of ED was approximately 6.5 years. Avanafil at doses of 50 mg, 100 mg, and 200 mg demonstrated statistically significant improvement in all 3 primary efficacy variables relative to placebo (see TABLE 7).
Results in the ED Population with Diabetes Mellitus (Study 2)
Avanafil was evaluated in ED patients (n=390) with type 1 or type 2 diabetes mellitus in a randomized, double-blind, parallel, placebo-controlled fixed dose trial of 3 months in duration. The mean age was 58 years (range 30 to 78 years). The population was 80.5% White, 17.2% Black, 1.5% Asian, and 0.8% of other races. The mean duration of ED was approximately 6 years. In this trial, avanafil at doses of 100 mg and 200 mg demonstrated statistically significant improvement in all 3 primary efficacy variables as measured by the erectile function domain of the IIEF questionnaire; SEP2 and SEP3 (see TABLE 8).
Time to Onset of Effect (Study 3)
- Avanafil was evaluated in 440 subjects with ED including diabetics (16.4%) and subjects with severe ED (41.4%) in a randomized, double-blind, parallel, placebo-controlled study of 2 months duration. The mean age was 58.2 years (range 24 to 86 years). The population was 75.7% White, 21.4% Black, 1.6% Asian, and 1.4% of other races. Subjects were encouraged to attempt intercourse approximately 15 minutes after dosing and used a stopwatch for measurement of time to onset of effect, defined as the time to the first occurrence of an erection sufficient for sexual intercourse.
- Avanafil 100 mg and 200 mg demonstrated statistically significant improvements relative to placebo in the primary efficacy variable, percentage of all attempts resulting in an erection sufficient for penetration at approximately 15 minutes after dosing followed by successful intercourse (SEP3) (see TABLE 9).
# How Supplied
- STENDRA (avanafil) is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strengths.
## Storage
- Recommended Storage: Store at 20-25°C (68-77°F); excursions permitted to 30°C (86°F) [see USP Controlled Room Temperature].
- Protect from light [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
File:Avanafil image.jpg
# Patient Counseling Information
Nitrates
- Physicians should discuss with patients the contraindication of avanafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of avanafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
- Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of avanafil. In such a patient, who has taken avanafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Patients who experience anginal chest pain after taking avanafil should seek immediate medical attention.
Cardiovascular Considerations
- Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and should seek immediate medical attention.
Concomitant Use with Drugs Which Lower Blood Pressure
- Physicians should advise patients of the potential for avanafil to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications.
Potential for Drug Interactions
- Patients should be advised to contact the prescribing physician if new medications that may interact with avanafil are prescribed by another healthcare provider.
Priapism
- There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Physicians should advise patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention.
Sudden Loss of Vision
- Physicians should advise patients to stop use of all PDE5 inhibitors, including avanafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision that has been reported rarely in temporal association with the use of PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including avanafil, for these uncommon conditions.
Sudden Hearing Loss
- Physicians should advise patients to stop taking PDE5 inhibitors, including avanafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
Alcohol
- Patients should be made aware that both alcohol and PDE5 inhibitors including avanafil act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
Sexually Transmitted Disease
- The use of avanafil offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
Recommended Administration
- Physicians should discuss with patients the appropriate use of avanafil and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking avanafil. Patients should be counseled regarding the dosing of avanafil. Inform patients that the recommended starting dose of avanafil is 100 mg, taken as early as approximately 15 minutes before initiating sexual activity. Based on efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used. Patients should be advised to contact their healthcare provider for dose modification.
# Precautions with Alcohol
- Alcohol-Avanafil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- STENDRA ®[1]
# Look-Alike Drug Names
There is limited information regarding Avanafil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Avanafil | |
11e489f5939b72a8ede0bfee476f011f2a92418b | wikidoc | Avelumab | Avelumab
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# Overview
Avelumab is a programmed death ligand-1 (PD-L1) blocking antibody that is FDA approved for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) and patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Common adverse reactions include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema in patients with metastatic Merkel cell carcinoma. Most common adverse reactions in patients with locally advanced or metastatic urothelial carcinoma were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Metastatic Merkel Cell Carcinoma
- Avelumab is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Avelumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:
- Have disease progression during or following platinum-containing chemotherapy.
- Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
### Recommended Dosage
- The recommended dose of avelumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
### Dose Modifications
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding avelumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding avelumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Metastatic Merkel Cell Carcinoma
- Avelumab is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Avelumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:
- Have disease progression during or following platinum-containing chemotherapy.
- Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
### Recommended Dosage
- The recommended dose of avelumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
### Dose Modifications
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding avelumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding avelumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Avelumab can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate patients with suspected pneumonitis with radiographic imaging. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper) for Grade 2 or greater pneumonitis. Withhold avelumab for moderate (Grade 2) pneumonitis, and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis.
- Pneumonitis occurred in 1.2% (21/1738) of patients receiving avelumab including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3 pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of avelumab in 0.3% (6/1738) of patients. Among the 21 patients with immune-mediated pneumonitis, the median time to onset was 2.5 months (range: 3 days to 11 months) and the median duration of pneumonitis was 7 weeks (range: 4 days to 4+ months). All 21 patients were treated with systemic corticosteroids; 17 (81%) of the 21 patients received high-dose corticosteroids for a median of 8 days (range: 1 day to 2.3 months). Resolution of pneumonitis occurred in 12 (57%) of the 21 patients at the time of data cut-off.
- Avelumab can cause immune-mediated hepatitis including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper) for Grade 2 or greater hepatitis. Withhold avelumab for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis.
- Immune-mediated hepatitis occurred in 0.9% (16/1738) of patients receiving avelumab including two (0.1%) patients with Grade 5 and 11 (0.6 %) patients with Grade 3 immune-mediated hepatitis. Immune-mediated hepatitis led to permanent discontinuation of avelumab in 0.5% (9/1738) of patients. Among the 16 patients with immune-mediated hepatitis, the median time to onset was 3.2 months (range: 1 week to 15 months), and the median duration of hepatitis was 2.5 months (range: 1 day to 7.4+ months). All 16 patients were treated with corticosteroids; 15 (94%) of the 16 patients received high-dose corticosteroids for a median of 14 days (range: 1 day to 2.5 months). Resolution of hepatitis occurred in nine (56%) of the 16 patients at the time of data cut-off.
- Avelumab can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper) for Grade 2 or greater colitis. Withhold avelumab for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue avelumab for life-threatening (Grade 4) or for recurrent (Grade 3) colitis upon re-initiation of avelumab.
- Immune-mediated colitis occurred in 1.5% (26/1738) of patients receiving avelumab including seven (0.4%) patients with Grade 3 colitis. Immune-mediated colitis led to permanent discontinuation of avelumab in 0.5% (9/1738) of patients. Among the 26 patients with immune-mediated colitis, the median time to onset was 2.1 months (range: 2 days to 11 months) and the median duration of colitis was 6 weeks (range: 1 day to 14+ months). All 26 patients were treated with corticosteroids; 15 (58%) of the 26 patients received high-dose corticosteroids for a median of 19 days (range: 1 day to 2.3 months). Resolution of colitis occurred in 18 (70%) of the patients at the time of data cut-off.
### Immune-Mediated Endocrinopathies
Adrenal Insufficiency
- Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment. Administer corticosteroids as appropriate for adrenal insufficiency. Withhold avelumab for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency.
- Adrenal insufficiency occurred in 0.5% (8/1738) of patients receiving avelumab including one patient (0.1%) with Grade 3 adrenal insufficiency. Immune-mediated adrenal insufficiency led to permanent discontinuation of avelumab in 0.1% (2/1738) of patients. Among the 8 patients with immune-mediated adrenal insufficiency, the median time to onset was 2.5 months (range: 1 day to 8 months). All eight patients were treated with corticosteroids; four (50%) of the eight patients received high-dose corticosteroids for a median of 1 day (range: 1 day to 24 days).
Thyroid Disorders (Hypothyroidism/Hyperthyroidism)
- Avelumab can cause immune-mediated thyroid disorders. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone-replacement therapy. Initiate medical management for control of hyperthyroidism. Withhold avelumab for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders.
- Immune-mediated thyroid disorders occurred in 6% (98/1738) of patients receiving avelumab including 3 (0.2%) Grade 3 immune-mediated thyroid disorders. Immune-mediated thyroid disorders led to discontinuation of avelumab in 0.1% (2/1738) of patients. Hypothyroidism occurred in 90 (5%) patients; hyperthyroidism in seven (0.4%) patients; and thyroiditis in four (0.2%) patients treated with avelumab. Among the 98 patients with immune-mediated thyroid disorders, the median time to onset was 2.8 months (range: 2 weeks to 13 months) and the median duration was not estimable (range: 6 days to more than 26 months). Immune-mediated thyroid disorders resolved in seven (7%) of the 98 patients.
Type 1 Diabetes Mellitus
- Avelumab can cause type 1 diabetes mellitus, including diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold avelumab and administer anti-hyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia. Resume treatment with avelumab when metabolic control is achieved on insulin replacement or anti-hyperglycemics.
- Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients including two cases of Grade 3 hyperglycemia that led to permanent discontinuation of avelumab.
### Immune-Mediated Nephritis and Renal Dysfunction
- Avelumab can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper) for Grade 2 or greater nephritis. Withhold avelumab for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to ≤ Grade 1. Permanently discontinue avelumab for life-threatening (Grade 4) nephritis.
- Immune-mediated nephritis occurred in 0.1% (1/1738) of patients receiving avelumab; avelumab was permanently discontinued in this patient.
### Other Immune-Mediated Adverse Reactions
- Avelumab can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. Most immune-mediated reactions initially manifest during treatment with avelumab; however, immune-mediated adverse reactions can occur after discontinuation of avelumab.
- For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending upon the severity of the adverse reaction, withhold or permanently discontinue avelumab, administer high dose corticosteroids, and if appropriate, initiate hormone replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper. Resume avelumab when the immune-mediated adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue avelumab for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
- The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% of 1738 patients treated with avelumab for each of the following adverse reactions: immune-mediated myocarditis including fatal cases, immune-mediated myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response. The following clinically significant, immune-mediated adverse reactions have been reported with other products in this class: bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis.
### Infusion-Related Reactions
- Avelumab can cause severe or life-threatening infusion-related reactions. Premedicate with antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue avelumab for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions.
- Infusion-related reactions occurred in 25% (439/1738) of patients treated with avelumab including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Ninety-three percent (1615/1738) of patients received premedication with antihistamine and acetaminophen. Eleven (92%) of the 12 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids. Fourteen percent of patients (252/1738) had infusion-related reactions that occurred after the avelumab infusion was completed.
### Embryo-Fetal Toxicity
- Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking avelumab, inform the patient of the potential risk to a fetus. Advise females of childbearing potential to use effective contraception during treatment with avelumab and for at least one month after the last dose of avelumab.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data described in the WARNINGS AND PRECAUTIONS section are based on two trials, in which 1738 patients received avelumab at doses of 10 mg/kg intravenously every two weeks. This included 88 patients with metastatic MCC (JAVELIN Merkel 200 trial) and 242 patients with locally advanced and metastatic UC within the JAVELIN Solid Tumor trial. In the JAVELIN Solid Tumor trial, 1650 patients were treated with avelumab at doses of 10 mg/kg.
- The following criteria were used to classify an adverse reaction as immune-mediated: onset within 90 days after last dose of avelumab, no spontaneous resolution within 7 days of onset, treatment with corticosteroids or other immunosuppressant or hormone replacement therapy, biopsy consistent with immune-mediated reaction, and no other clear etiology.
- The study population characteristics of the 1738 patients were median age of 64 years (range: 19 to 91 years); 52% male; 78% White, 9% Asian, 5% Black or African American, and 8% other ethnic groups; ECOG performance score of 0 (38%), 1 (62%), or > 1 (0.4%); and the underlying malignancies were non-small cell lung cancer (20%), gastric and gastroesophageal cancer (15%), urothelial cancer (14%), ovarian cancer (13%), metastatic breast cancer (10%), head and neck cancer (9%), metastatic MCC (5%), mesothelioma, renal cell carcinoma, melanoma, adrenocortical carcinoma (3% each), colorectal cancer, castrate-resistant prostate cancer, and unknown (1% each). In this population, 24% of patients were exposed to avelumab for ≥ 6 months and 7% were exposed to avelumab for ≥ 12 months.
### Metastatic Merkel Cell Carcinoma
- The data described below reflect exposure to avelumab 10 mg/kg intravenously every 2 weeks in 88 patients with metastatic MCC enrolled in the JAVELIN Merkel 200 trial. Patients with any of the following were excluded: autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; central nervous system (CNS) metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score ≥ 2.
- The median duration of exposure to avelumab was 4 months (range: 2 weeks to 21 months). Forty percent of patients received avelumab for more than 6 months and 14% were treated for more than one year. The study population characteristics were: median age of 73 years (range: 33 to 88), 74% male, 92% White, ECOG performance score of 0 (56%) or 1 (44%), and 65% of patients had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies.
- Avelumab was permanently discontinued for adverse reactions in six (7%) patients; adverse reactions resulting in permanent discontinuation were ileus, Grade 3 transaminitis, Grade 3 creatine kinase elevation, tubulointerstitial nephritis, and Grade 3 pericardial effusion. Avelumab was temporarily discontinued in 21 (24%) patients for adverse events, excluding temporary dose interruption for infusion-related reactions where infusion was restarted the same day. The most common adverse reaction requiring dose interruption was anemia. Serious adverse reactions that occurred in more than one patient were acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis. The most common adverse reactions (≥ 20%) were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.
- Table 2 and Table 3 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving avelumab.
Locally Advanced or Metastatic Urothelial Carcinoma
- Table 4 describes adverse reactions reported in 242 patients with locally advanced or metastatic UC receiving avelumab at 10 mg/kg every 2 weeks in the UC cohorts of the JAVELIN Solid Tumor trial. Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. The median duration of exposure to avelumab was 12 weeks (range: 2 weeks to 92 weeks).
- Fourteen patients (6%) who were treated with avelumab experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.
- Avelumab was permanently discontinued for Grade 1-4 adverse reactions in 30 (12%) patients. The adverse reaction that resulted in permanent discontinuation in > 1% of patients was fatigue. Avelumab was temporarily discontinued in 29% of patients for adverse reactions, excluding temporary dose interruption for infusion-related reactions where infusion was restarted the same day. The adverse reactions that resulted in temporary discontinuation in > 1% of patients were diarrhea, fatigue, dyspnea, urinary tract infection, and rash.
- Grade 1-4 serious adverse reactions were reported in 41% of patients. The most frequent serious adverse reactions reported in ≥ 2% of patients were urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestine obstruction, and pyrexia.
- The most common Grade 3 and 4 adverse reactions (≥ 3%) were anemia, fatigue, hyponatremia, hypertension urinary tract infection, and musculoskeletal pain.
- The most common adverse reactions (≥ 20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.
- Eleven (4.5%) patients received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction.
- Table 4 summarizes the adverse reactions that occurred in at least 10% of patients with locally advanced or metastatic UC receiving avelumab while Table 5 summarizes selected Grade 3-4 laboratory abnormalities that occurred in ≥ 1% of patients treated with avelumab.
### Immunogenicity
- As with all therapeutic proteins, there is 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 the incidence of antibodies to avelumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- Of the 1738 patients treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks, 1558 were evaluable for treatment-emergent anti-drug antibodies (ADA) and 64 (4.1%) tested positive. The development of treatment-emergent ADA against avelumab did not appear to alter the pharmacokinetic profile or risk of infusion-related reactions.
## Postmarketing Experience
There is limited information regarding Avelumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Avelumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Risk Summary
- Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman. There are no available data on the use of avelumab in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death . Human IgG1 immunoglobulins (IgG1) are known to cross the placenta. Therefore, avelumab has the potential to be transmitted from the mother to the developing fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- Data (Animal Data)
- Animal reproduction studies have not been conducted with avelumab to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering avelumab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to avelumab may increase the risk of developing immune-related disorders or altering the normal immune response.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Avelumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Avelumab during labor and delivery.
### Nursing Mothers
- There is no information regarding the presence of avelumab in human milk, the effects on the breastfed infant, or the effects on milk production. Since many drugs including antibodies are excreted in human milk, advise a lactating woman not to breastfeed during treatment and for at least one month after the last dose of avelumab due to the potential for serious adverse reactions in breastfed infants.
### Pediatric Use
- The safety and effectiveness of avelumab have been established in pediatric patients aged 12 years and older for metastatic MCC. Use of avelumab in this age group is supported by evidence from adequate and well-controlled studies of avelumab in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of avelumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MCC is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. The recommended dose in pediatric patients 12 years of age or greater is the same as that in adults.
- Safety and effectiveness of avelumab have not been established in pediatric patients less than 12 years of age.
### Geriatic Use
- Metastatic Merkel Cell Carcinoma
- Clinical studies of avelumab in MCC did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
- Locally Advanced or Metastatic Urothelial Carcinoma
- Of the 226 patients with locally advanced or metastatic UC treated with avelumab, 68% were 65 years or over and 29% were 75 years or over. Among patients 65 years or over who were followed for at least 13 weeks, 14% (22/153) responded to avelumab and 58% (89/153) developed a Grade 3-4 adverse reaction. No overall differences in safety or efficacy were reported between elderly patients and younger patients.
### Gender
There is no FDA guidance on the use of Avelumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Avelumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Avelumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Avelumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Avelumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Avelumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer the diluted solution over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron).
- Do not co-administer other drugs through the same intravenous line.
### Monitoring
- Evidence of disease response or stabilization may indicate efficacy.
- Hyperglycemia or other signs or symptoms of diabetes.
- Liver function tests: Prior to initiation and periodically during therapy.
- Serum creatinine: Prior to initiation and periodically during treatment.
- Thyroid function changes: At initiation and periodically during treatment, and as clinically indicated.
- Signs and symptoms of adrenal insufficiency.
- Signs and symptoms of colitis.
- Signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria.
- Signs and symptoms of pneumonitis: If suspected evaluate with radiographic imaging.
# IV Compatibility
There is limited information regarding the compatibility of Avelumab and IV administrations.
# Overdosage
There is limited information regarding Avelumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the immune response resulting in the restoration of immune responses, including anti-tumor immune responses. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.
## Structure
There is limited information regarding Avelumab Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Avelumab Pharmacodynamics in the drug label.
## Pharmacokinetics
- The pharmacokinetics of avelumab was studied in 1629 patients who received doses ranging from 1 to 20 mg/kg every 2 weeks. The data showed that the exposure of avelumab increased dose-proportionally in the dose range of 10 to 20 mg/kg every 2 weeks. Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) of repeated dosing, and the systemic accumulation was approximately 1.25-fold.
### Distribution
- The geometric mean volume of distribution at steady state for a subject receiving 10 mg/kg was 4.72 L.
### Elimination
- The primary elimination mechanism of avelumab is proteolytic degradation. Based on population pharmacokinetic analyses in patients with solid tumors, the total systemic clearance was 0.59 L/day and the terminal half-life was 6.1 days in patients receiving 10 mg/kg. In a post hoc analysis, avelumab clearance was found to decrease over time in patients with MCC, with a mean maximal reduction (% coefficient of variation ) from baseline value of approximately 41.7% (40.0%), which is not considered clinically important. There was no evidence to suggest a change of avelumab clearance over time in patients with UC.
### Specific Populations
- Body weight was positively correlated with total systemic clearance in population pharmacokinetic analyses. No clinically meaningful differences in pharmacokinetics were observed in the clearance of avelumab based on age; sex; race; PD-L1 status; tumor burden; mild , moderate , or severe renal impairment; and mild or moderate hepatic impairment. There are limited data from patients with severe hepatic impairment , and the effect of severe hepatic impairment on the pharmacokinetics of avelumab is unknown.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No studies have been conducted to assess the potential of avelumab for genotoxicity or carcinogenicity.
- Fertility studies have not been conducted with avelumab; however, an assessment of male and female reproductive organs was included in 3-month repeat-dose toxicity study in Cynomolgus monkeys. Weekly administration of avelumab did not result in any notable effects in the male and female reproductive organs.
### Animal Toxicology and/or Pharmacology
- In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.
# Clinical Studies
- The efficacy and safety of avelumab was demonstrated in the JAVELIN Merkel 200 trial (NCT02155647), an open-label, single-arm, multi-center study conducted in patients with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease. The trial excluded patients with autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; CNS metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score ≥ 2.
- Patients received avelumab 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than 2 weeks, and no need for salvage therapy, could continue treatment. Tumor response assessments were performed every 6 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review committee (IRC) and IRC-assessed duration of response. The efficacy analysis was conducted when the last patient enrolled had completed 12 months of follow-up.
- A total of 88 patients were enrolled. Baseline patient characteristics were a median age of 73 years (range: 33 to 88), 74% of patients were male, 92% were White, and the ECOG performance score was 0 (56%) or 1 (44%). Seventy-five percent of patients were 65 years or older, 35% were 75 or older, and 3% were 85 or older. Sixty-five percent of patients were reported to have had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies. Fifty-three percent of patients had visceral metastases. All patients had tumor samples evaluated for PD-L1 expression; of these, 66% were PD-L1-positive (≥ 1% of tumor cells), 18% were PD-L1 negative, and 16% had non-evaluable results by an investigational immunohistochemistry assay. Archival tumor samples were evaluated for Merkel cell polyomavirus (MCV) using an investigational assay; of the 77 patients with evaluable results, 52% had evidence of MCV.
- Efficacy results are presented in Table 6. Responses were observed in patients regardless of tumor PD-L1 expression or presence of MCV.
- The efficacy and safety of avelumab was demonstrated in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 patients with locally advanced or metastatic urothelial carcinoma (UC) with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients with active or history of central nervous system metastasis; other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Patients with autoimmune disease, other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status.
- Patients received avelumab at a dose of 10 mg/kg intravenously every 2 weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.
- Baseline demographic and disease characteristics for the 226 patients with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), 72% male, 80% White, and 34% and 66% of patients had an ECOG performance status 0 and 1, respectively. Forty-four percent of patients had non-bladder urothelial carcinoma including 23% of patients with upper tract disease, and 83% of patients had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine (4%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens. At baseline, 17% of patients had a hemoglobin < 10 g/dL and 34% of patients had liver metastases.
- Efficacy results are presented in Table 7. The median time to response was 2.0 months (range: 1.3 to 11.0) among patients followed for either ≥ 13 weeks or ≥ 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16% of patients not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding patients followed for ≥ 13 weeks, 22 patients (73%) had an ongoing response of 6 months or longer and 4 patients (13%) had ongoing responses of 12 months or longer. Among the total 26 responding patients followed for ≥ 6 months, 22 patients (85%) had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 12 months or longer.
# How Supplied
- Avelumab Injection is a sterile, preservative-free, and clear, colorless to slightly yellow solution for intravenous infusion supplied as a single-dose vial of 200 mg/10 mL (20 mg/mL), individually packed into a carton (NDC 44087-3535-1).
## Storage
- Store refrigerated at 36°F to 46°F (2°C to 8°C) in original package to protect from light.
- Do not freeze or shake the vial.
- The vial stopper is not made with natural rubber latex.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Immune-Mediated Adverse Reactions
Inform patients of the risk of immune-mediated adverse reactions requiring corticosteroids or hormone replacement therapy, including, but not limited to:
- Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath.
- Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.
- Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain.
- Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus.
- Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction.
### Infusion-Related Reactions
- Advise patients to contact their healthcare provider immediately for signs or symptoms of potential infusion-related reactions.
### Embryo-Fetal Toxicity
- Advise females of reproductive potential that avelumab can cause fetal harm. Instruct females of reproductive potential to use highly effective contraception during and for at least one month after the last dose of avelumab.
### Lactation
- Advise nursing mothers not to breastfeed while taking avelumab and for at least one month after the final dose.
# Precautions with Alcohol
Alcohol-Avelumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Bavencio
# Look-Alike Drug Names
There is limited information regarding Avelumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Avelumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3]
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# Overview
Avelumab is a programmed death ligand-1 (PD-L1) blocking antibody that is FDA approved for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) and patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Common adverse reactions include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema in patients with metastatic Merkel cell carcinoma. Most common adverse reactions in patients with locally advanced or metastatic urothelial carcinoma were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Metastatic Merkel Cell Carcinoma
- Avelumab is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Avelumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:
- Have disease progression during or following platinum-containing chemotherapy.
- Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
### Recommended Dosage
- The recommended dose of avelumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
### Dose Modifications
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding avelumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding avelumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Metastatic Merkel Cell Carcinoma
- Avelumab is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Avelumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:
- Have disease progression during or following platinum-containing chemotherapy.
- Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
### Recommended Dosage
- The recommended dose of avelumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
### Dose Modifications
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding avelumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding avelumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Avelumab can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate patients with suspected pneumonitis with radiographic imaging. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper) for Grade 2 or greater pneumonitis. Withhold avelumab for moderate (Grade 2) pneumonitis, and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis.
- Pneumonitis occurred in 1.2% (21/1738) of patients receiving avelumab including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3 pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of avelumab in 0.3% (6/1738) of patients. Among the 21 patients with immune-mediated pneumonitis, the median time to onset was 2.5 months (range: 3 days to 11 months) and the median duration of pneumonitis was 7 weeks (range: 4 days to 4+ months). All 21 patients were treated with systemic corticosteroids; 17 (81%) of the 21 patients received high-dose corticosteroids for a median of 8 days (range: 1 day to 2.3 months). Resolution of pneumonitis occurred in 12 (57%) of the 21 patients at the time of data cut-off.
- Avelumab can cause immune-mediated hepatitis including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper) for Grade 2 or greater hepatitis. Withhold avelumab for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis.
- Immune-mediated hepatitis occurred in 0.9% (16/1738) of patients receiving avelumab including two (0.1%) patients with Grade 5 and 11 (0.6 %) patients with Grade 3 immune-mediated hepatitis. Immune-mediated hepatitis led to permanent discontinuation of avelumab in 0.5% (9/1738) of patients. Among the 16 patients with immune-mediated hepatitis, the median time to onset was 3.2 months (range: 1 week to 15 months), and the median duration of hepatitis was 2.5 months (range: 1 day to 7.4+ months). All 16 patients were treated with corticosteroids; 15 (94%) of the 16 patients received high-dose corticosteroids for a median of 14 days (range: 1 day to 2.5 months). Resolution of hepatitis occurred in nine (56%) of the 16 patients at the time of data cut-off.
- Avelumab can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper) for Grade 2 or greater colitis. Withhold avelumab for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue avelumab for life-threatening (Grade 4) or for recurrent (Grade 3) colitis upon re-initiation of avelumab.
- Immune-mediated colitis occurred in 1.5% (26/1738) of patients receiving avelumab including seven (0.4%) patients with Grade 3 colitis. Immune-mediated colitis led to permanent discontinuation of avelumab in 0.5% (9/1738) of patients. Among the 26 patients with immune-mediated colitis, the median time to onset was 2.1 months (range: 2 days to 11 months) and the median duration of colitis was 6 weeks (range: 1 day to 14+ months). All 26 patients were treated with corticosteroids; 15 (58%) of the 26 patients received high-dose corticosteroids for a median of 19 days (range: 1 day to 2.3 months). Resolution of colitis occurred in 18 (70%) of the patients at the time of data cut-off.
### Immune-Mediated Endocrinopathies
Adrenal Insufficiency
- Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment. Administer corticosteroids as appropriate for adrenal insufficiency. Withhold avelumab for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency.
- Adrenal insufficiency occurred in 0.5% (8/1738) of patients receiving avelumab including one patient (0.1%) with Grade 3 adrenal insufficiency. Immune-mediated adrenal insufficiency led to permanent discontinuation of avelumab in 0.1% (2/1738) of patients. Among the 8 patients with immune-mediated adrenal insufficiency, the median time to onset was 2.5 months (range: 1 day to 8 months). All eight patients were treated with corticosteroids; four (50%) of the eight patients received high-dose corticosteroids for a median of 1 day (range: 1 day to 24 days).
Thyroid Disorders (Hypothyroidism/Hyperthyroidism)
- Avelumab can cause immune-mediated thyroid disorders. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone-replacement therapy. Initiate medical management for control of hyperthyroidism. Withhold avelumab for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders.
- Immune-mediated thyroid disorders occurred in 6% (98/1738) of patients receiving avelumab including 3 (0.2%) Grade 3 immune-mediated thyroid disorders. Immune-mediated thyroid disorders led to discontinuation of avelumab in 0.1% (2/1738) of patients. Hypothyroidism occurred in 90 (5%) patients; hyperthyroidism in seven (0.4%) patients; and thyroiditis in four (0.2%) patients treated with avelumab. Among the 98 patients with immune-mediated thyroid disorders, the median time to onset was 2.8 months (range: 2 weeks to 13 months) and the median duration was not estimable (range: 6 days to more than 26 months). Immune-mediated thyroid disorders resolved in seven (7%) of the 98 patients.
Type 1 Diabetes Mellitus
- Avelumab can cause type 1 diabetes mellitus, including diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold avelumab and administer anti-hyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia. Resume treatment with avelumab when metabolic control is achieved on insulin replacement or anti-hyperglycemics.
- Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients including two cases of Grade 3 hyperglycemia that led to permanent discontinuation of avelumab.
### Immune-Mediated Nephritis and Renal Dysfunction
- Avelumab can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper) for Grade 2 or greater nephritis. Withhold avelumab for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to ≤ Grade 1. Permanently discontinue avelumab for life-threatening (Grade 4) nephritis.
- Immune-mediated nephritis occurred in 0.1% (1/1738) of patients receiving avelumab; avelumab was permanently discontinued in this patient.
### Other Immune-Mediated Adverse Reactions
- Avelumab can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. Most immune-mediated reactions initially manifest during treatment with avelumab; however, immune-mediated adverse reactions can occur after discontinuation of avelumab.
- For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending upon the severity of the adverse reaction, withhold or permanently discontinue avelumab, administer high dose corticosteroids, and if appropriate, initiate hormone replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper. Resume avelumab when the immune-mediated adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue avelumab for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
- The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% of 1738 patients treated with avelumab for each of the following adverse reactions: immune-mediated myocarditis including fatal cases, immune-mediated myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response. The following clinically significant, immune-mediated adverse reactions have been reported with other products in this class: bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis.
### Infusion-Related Reactions
- Avelumab can cause severe or life-threatening infusion-related reactions. Premedicate with antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue avelumab for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions.
- Infusion-related reactions occurred in 25% (439/1738) of patients treated with avelumab including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Ninety-three percent (1615/1738) of patients received premedication with antihistamine and acetaminophen. Eleven (92%) of the 12 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids. Fourteen percent of patients (252/1738) had infusion-related reactions that occurred after the avelumab infusion was completed.
### Embryo-Fetal Toxicity
- Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking avelumab, inform the patient of the potential risk to a fetus. Advise females of childbearing potential to use effective contraception during treatment with avelumab and for at least one month after the last dose of avelumab.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data described in the WARNINGS AND PRECAUTIONS section are based on two trials, in which 1738 patients received avelumab at doses of 10 mg/kg intravenously every two weeks. This included 88 patients with metastatic MCC (JAVELIN Merkel 200 trial) and 242 patients with locally advanced and metastatic UC within the JAVELIN Solid Tumor trial. In the JAVELIN Solid Tumor trial, 1650 patients were treated with avelumab at doses of 10 mg/kg.
- The following criteria were used to classify an adverse reaction as immune-mediated: onset within 90 days after last dose of avelumab, no spontaneous resolution within 7 days of onset, treatment with corticosteroids or other immunosuppressant or hormone replacement therapy, biopsy consistent with immune-mediated reaction, and no other clear etiology.
- The study population characteristics of the 1738 patients were median age of 64 years (range: 19 to 91 years); 52% male; 78% White, 9% Asian, 5% Black or African American, and 8% other ethnic groups; ECOG performance score of 0 (38%), 1 (62%), or > 1 (0.4%); and the underlying malignancies were non-small cell lung cancer (20%), gastric and gastroesophageal cancer (15%), urothelial cancer (14%), ovarian cancer (13%), metastatic breast cancer (10%), head and neck cancer (9%), metastatic MCC (5%), mesothelioma, renal cell carcinoma, melanoma, adrenocortical carcinoma (3% each), colorectal cancer, castrate-resistant prostate cancer, and unknown (1% each). In this population, 24% of patients were exposed to avelumab for ≥ 6 months and 7% were exposed to avelumab for ≥ 12 months.
### Metastatic Merkel Cell Carcinoma
- The data described below reflect exposure to avelumab 10 mg/kg intravenously every 2 weeks in 88 patients with metastatic MCC enrolled in the JAVELIN Merkel 200 trial. Patients with any of the following were excluded: autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; central nervous system (CNS) metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score ≥ 2.
- The median duration of exposure to avelumab was 4 months (range: 2 weeks to 21 months). Forty percent of patients received avelumab for more than 6 months and 14% were treated for more than one year. The study population characteristics were: median age of 73 years (range: 33 to 88), 74% male, 92% White, ECOG performance score of 0 (56%) or 1 (44%), and 65% of patients had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies.
- Avelumab was permanently discontinued for adverse reactions in six (7%) patients; adverse reactions resulting in permanent discontinuation were ileus, Grade 3 transaminitis, Grade 3 creatine kinase elevation, tubulointerstitial nephritis, and Grade 3 pericardial effusion. Avelumab was temporarily discontinued in 21 (24%) patients for adverse events, excluding temporary dose interruption for infusion-related reactions where infusion was restarted the same day. The most common adverse reaction requiring dose interruption was anemia. Serious adverse reactions that occurred in more than one patient were acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis. The most common adverse reactions (≥ 20%) were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.
- Table 2 and Table 3 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving avelumab.
Locally Advanced or Metastatic Urothelial Carcinoma
- Table 4 describes adverse reactions reported in 242 patients with locally advanced or metastatic UC receiving avelumab at 10 mg/kg every 2 weeks in the UC cohorts of the JAVELIN Solid Tumor trial. Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. The median duration of exposure to avelumab was 12 weeks (range: 2 weeks to 92 weeks).
- Fourteen patients (6%) who were treated with avelumab experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.
- Avelumab was permanently discontinued for Grade 1-4 adverse reactions in 30 (12%) patients. The adverse reaction that resulted in permanent discontinuation in > 1% of patients was fatigue. Avelumab was temporarily discontinued in 29% of patients for adverse reactions, excluding temporary dose interruption for infusion-related reactions where infusion was restarted the same day. The adverse reactions that resulted in temporary discontinuation in > 1% of patients were diarrhea, fatigue, dyspnea, urinary tract infection, and rash.
- Grade 1-4 serious adverse reactions were reported in 41% of patients. The most frequent serious adverse reactions reported in ≥ 2% of patients were urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestine obstruction, and pyrexia.
- The most common Grade 3 and 4 adverse reactions (≥ 3%) were anemia, fatigue, hyponatremia, hypertension urinary tract infection, and musculoskeletal pain.
- The most common adverse reactions (≥ 20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.
- Eleven (4.5%) patients received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction.
- Table 4 summarizes the adverse reactions that occurred in at least 10% of patients with locally advanced or metastatic UC receiving avelumab while Table 5 summarizes selected Grade 3-4 laboratory abnormalities that occurred in ≥ 1% of patients treated with avelumab.
### Immunogenicity
- As with all therapeutic proteins, there is 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 the incidence of antibodies to avelumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- Of the 1738 patients treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks, 1558 were evaluable for treatment-emergent anti-drug antibodies (ADA) and 64 (4.1%) tested positive. The development of treatment-emergent ADA against avelumab did not appear to alter the pharmacokinetic profile or risk of infusion-related reactions.
## Postmarketing Experience
There is limited information regarding Avelumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Avelumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Risk Summary
- Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman. There are no available data on the use of avelumab in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death [see DATA]. Human IgG1 immunoglobulins (IgG1) are known to cross the placenta. Therefore, avelumab has the potential to be transmitted from the mother to the developing fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- Data (Animal Data)
- Animal reproduction studies have not been conducted with avelumab to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering avelumab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to avelumab may increase the risk of developing immune-related disorders or altering the normal immune response.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Avelumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Avelumab during labor and delivery.
### Nursing Mothers
- There is no information regarding the presence of avelumab in human milk, the effects on the breastfed infant, or the effects on milk production. Since many drugs including antibodies are excreted in human milk, advise a lactating woman not to breastfeed during treatment and for at least one month after the last dose of avelumab due to the potential for serious adverse reactions in breastfed infants.
### Pediatric Use
- The safety and effectiveness of avelumab have been established in pediatric patients aged 12 years and older for metastatic MCC. Use of avelumab in this age group is supported by evidence from adequate and well-controlled studies of avelumab in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of avelumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MCC is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. The recommended dose in pediatric patients 12 years of age or greater is the same as that in adults.
- Safety and effectiveness of avelumab have not been established in pediatric patients less than 12 years of age.
### Geriatic Use
- Metastatic Merkel Cell Carcinoma
- Clinical studies of avelumab in MCC did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
- Locally Advanced or Metastatic Urothelial Carcinoma
- Of the 226 patients with locally advanced or metastatic UC treated with avelumab, 68% were 65 years or over and 29% were 75 years or over. Among patients 65 years or over who were followed for at least 13 weeks, 14% (22/153) responded to avelumab and 58% (89/153) developed a Grade 3-4 adverse reaction. No overall differences in safety or efficacy were reported between elderly patients and younger patients.
### Gender
There is no FDA guidance on the use of Avelumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Avelumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Avelumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Avelumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Avelumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Avelumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer the diluted solution over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron).
- Do not co-administer other drugs through the same intravenous line.
### Monitoring
- Evidence of disease response or stabilization may indicate efficacy.
- Hyperglycemia or other signs or symptoms of diabetes.
- Liver function tests: Prior to initiation and periodically during therapy.
- Serum creatinine: Prior to initiation and periodically during treatment.
- Thyroid function changes: At initiation and periodically during treatment, and as clinically indicated.
- Signs and symptoms of adrenal insufficiency.
- Signs and symptoms of colitis.
- Signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria.
- Signs and symptoms of pneumonitis: If suspected evaluate with radiographic imaging.
# IV Compatibility
There is limited information regarding the compatibility of Avelumab and IV administrations.
# Overdosage
There is limited information regarding Avelumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the immune response resulting in the restoration of immune responses, including anti-tumor immune responses. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.
## Structure
There is limited information regarding Avelumab Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Avelumab Pharmacodynamics in the drug label.
## Pharmacokinetics
- The pharmacokinetics of avelumab was studied in 1629 patients who received doses ranging from 1 to 20 mg/kg every 2 weeks. The data showed that the exposure of avelumab increased dose-proportionally in the dose range of 10 to 20 mg/kg every 2 weeks. Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) of repeated dosing, and the systemic accumulation was approximately 1.25-fold.
### Distribution
- The geometric mean volume of distribution at steady state for a subject receiving 10 mg/kg was 4.72 L.
### Elimination
- The primary elimination mechanism of avelumab is proteolytic degradation. Based on population pharmacokinetic analyses in patients with solid tumors, the total systemic clearance was 0.59 L/day and the terminal half-life was 6.1 days in patients receiving 10 mg/kg. In a post hoc analysis, avelumab clearance was found to decrease over time in patients with MCC, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline value of approximately 41.7% (40.0%), which is not considered clinically important. There was no evidence to suggest a change of avelumab clearance over time in patients with UC.
### Specific Populations
- Body weight was positively correlated with total systemic clearance in population pharmacokinetic analyses. No clinically meaningful differences in pharmacokinetics were observed in the clearance of avelumab based on age; sex; race; PD-L1 status; tumor burden; mild [calculated creatinine clearance (CLcr) 60 to 89 mL/min, n=623 as estimated by the Cockcroft-Gault formula], moderate [CLcr 30 to 59 mL/min, n=320], or severe [CLcr 15 to 29 mL/min, n=4] renal impairment; and mild [bilirubin less than or equal to ULN and AST greater than ULN or bilirubin between 1 and 1.5 times ULN, n=217] or moderate [bilirubin between 1.5 and 3 times ULN, n=4] hepatic impairment. There are limited data from patients with severe hepatic impairment [bilirubin greater than 3 times ULN, n=1], and the effect of severe hepatic impairment on the pharmacokinetics of avelumab is unknown.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No studies have been conducted to assess the potential of avelumab for genotoxicity or carcinogenicity.
- Fertility studies have not been conducted with avelumab; however, an assessment of male and female reproductive organs was included in 3-month repeat-dose toxicity study in Cynomolgus monkeys. Weekly administration of avelumab did not result in any notable effects in the male and female reproductive organs.
### Animal Toxicology and/or Pharmacology
- In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.
# Clinical Studies
- The efficacy and safety of avelumab was demonstrated in the JAVELIN Merkel 200 trial (NCT02155647), an open-label, single-arm, multi-center study conducted in patients with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease. The trial excluded patients with autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; CNS metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score ≥ 2.
- Patients received avelumab 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than 2 weeks, and no need for salvage therapy, could continue treatment. Tumor response assessments were performed every 6 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review committee (IRC) and IRC-assessed duration of response. The efficacy analysis was conducted when the last patient enrolled had completed 12 months of follow-up.
- A total of 88 patients were enrolled. Baseline patient characteristics were a median age of 73 years (range: 33 to 88), 74% of patients were male, 92% were White, and the ECOG performance score was 0 (56%) or 1 (44%). Seventy-five percent of patients were 65 years or older, 35% were 75 or older, and 3% were 85 or older. Sixty-five percent of patients were reported to have had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies. Fifty-three percent of patients had visceral metastases. All patients had tumor samples evaluated for PD-L1 expression; of these, 66% were PD-L1-positive (≥ 1% of tumor cells), 18% were PD-L1 negative, and 16% had non-evaluable results by an investigational immunohistochemistry assay. Archival tumor samples were evaluated for Merkel cell polyomavirus (MCV) using an investigational assay; of the 77 patients with evaluable results, 52% had evidence of MCV.
- Efficacy results are presented in Table 6. Responses were observed in patients regardless of tumor PD-L1 expression or presence of MCV.
- The efficacy and safety of avelumab was demonstrated in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 patients with locally advanced or metastatic urothelial carcinoma (UC) with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients with active or history of central nervous system metastasis; other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Patients with autoimmune disease, other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status.
- Patients received avelumab at a dose of 10 mg/kg intravenously every 2 weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.
- Baseline demographic and disease characteristics for the 226 patients with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), 72% male, 80% White, and 34% and 66% of patients had an ECOG performance status 0 and 1, respectively. Forty-four percent of patients had non-bladder urothelial carcinoma including 23% of patients with upper tract disease, and 83% of patients had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine (4%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens. At baseline, 17% of patients had a hemoglobin < 10 g/dL and 34% of patients had liver metastases.
- Efficacy results are presented in Table 7. The median time to response was 2.0 months (range: 1.3 to 11.0) among patients followed for either ≥ 13 weeks or ≥ 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16% of patients not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding patients followed for ≥ 13 weeks, 22 patients (73%) had an ongoing response of 6 months or longer and 4 patients (13%) had ongoing responses of 12 months or longer. Among the total 26 responding patients followed for ≥ 6 months, 22 patients (85%) had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 12 months or longer.
# How Supplied
- Avelumab Injection is a sterile, preservative-free, and clear, colorless to slightly yellow solution for intravenous infusion supplied as a single-dose vial of 200 mg/10 mL (20 mg/mL), individually packed into a carton (NDC 44087-3535-1).
## Storage
- Store refrigerated at 36°F to 46°F (2°C to 8°C) in original package to protect from light.
- Do not freeze or shake the vial.
- The vial stopper is not made with natural rubber latex.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Immune-Mediated Adverse Reactions
Inform patients of the risk of immune-mediated adverse reactions requiring corticosteroids or hormone replacement therapy, including, but not limited to:
- Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath.
- Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.
- Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain.
- Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus.
- Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction.
### Infusion-Related Reactions
- Advise patients to contact their healthcare provider immediately for signs or symptoms of potential infusion-related reactions.
### Embryo-Fetal Toxicity
- Advise females of reproductive potential that avelumab can cause fetal harm. Instruct females of reproductive potential to use highly effective contraception during and for at least one month after the last dose of avelumab.
### Lactation
- Advise nursing mothers not to breastfeed while taking avelumab and for at least one month after the final dose.
# Precautions with Alcohol
Alcohol-Avelumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Bavencio
# Look-Alike Drug Names
There is limited information regarding Avelumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Avelumab | |
ee40a9dc322cd867da91a6d93c7ea68cb6a933af | wikidoc | Axitinib | Axitinib
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# Overview
Axitinib is an tyrosine kinase inhibitor that is FDA approved for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Common adverse reactions include diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Axitinib is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.
- The recommended starting oral dose of Axitinib is 5 mg twice daily. Administer Axitinib doses approximately 12 hours apart with or without food. Axitinib should be swallowed whole with a glass of water.
- If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.
- Dose increase or reduction is recommended based on individual safety and tolerability.
- Over the course of treatment, patients who tolerate Axitinib for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events ), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the Axitinib dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria.
- Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of Axitinib therapy . If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily.
- Strong CYP3A4/5 Inhibitors: The concomitant use of Strong CYP3A4/5 Inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 Inhibition is recommended. *Although Axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of Axitinib by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the Axitinib dose should be returned (after 3 – 5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor .
- Hepatic Impairment: No starting dose adjustment is required when administering Axitinib to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the Axitinib starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C)
## Off-Label Use and Dosage (Adult)
### Non–Guideline-Supported Use
- Metastatic renal cell carcinoma, First-line therapy: initial, 5 mg ORALLY twice daily; increases at 2-week intervals to 7 mg ORALLY twice daily, then 10 mg ORALLY twice daily was used in a clinical trial
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of Axitinib in pediatric patients have not been studied.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
The safety and efficacy of Axitinib in pediatric patients have not been studied.
### Non–Guideline-Supported Use
The safety and efficacy of Axitinib in pediatric patients have not been studied.
# Contraindications
- None
# Warnings
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving Axitinib and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving Axitinib and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of Axitinib treatment and blood pressure increases have been observed as early as 4 days after starting Axitinib. Hypertension was managed with standard antihypertensive therapy. Discontinuation of Axitinib treatment due to hypertension occurred in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib.
- Blood pressure should be well-controlled prior to initiating Axitinib. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the Axitinib dose. Discontinue Axitinib if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of Axitinib, and discontinuation should be considered if there is evidence of hypertensive crisis. If Axitinib is interrupted, patients receiving antihypertensive medications should be monitored for hypotension .
- In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with Axitinib for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving Axitinib and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib.
- In clinical trials with Axitinib, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.
- Use Axitinib with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.
- In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with Axitinib for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving Axitinib and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving Axitinib (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. In clinical trials with Axitinib, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.
- Use Axitinib with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had a venous thromboembolic event within the previous 6 months.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving Axitinib and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving Axitinib (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving Axitinib (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.
- Axitinib has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the Axitinib dose.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving Axitinib and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving Axitinib and 1/355 patients (<1%) receiving sorafenib. *Fatal cardiac failure was reported in 2/359 patients (1%) receiving Axitinib and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with Axitinib. Management of cardiac failure may require permanent discontinuation of Axitinib.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. In clinical trials with Axitinib, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).
- Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with Axitinib.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving Axitinib and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving Axitinib and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving Axitinib and 25/232 patients (11%) receiving sorafenib.
- Monitor thyroid function before initiation of, and periodically throughout, treatment with Axitinib. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.
- No formal studies of the effect of Axitinib on wound healing have been conducted.
- Stop treatment with Axitinib at least 24 hours prior to scheduled surgery. The decision to resume Axitinib therapy after surgery should be based on clinical judgment of adequate wound healing.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib . There were two additional reports of RPLS in other clinical trials with Axitinib.
- RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue Axitinib in patients developing RPLS. *The safety of reinitiating Axitinib therapy in patients previously experiencing RPLS is not known.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving Axitinib and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving Axitinib and 6/355 patients (2%) receiving sorafenib.
- Monitoring for proteinuria before initiation of, and periodically throughout, treatment with Axitinib is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt Axitinib treatment.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the Axitinib arm and 2% of patients on the sorafenib arm.
- Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with Axitinib.
- The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering Axitinib to patients with moderate hepatic impairment (Child-Pugh class B). Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) .
# 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 clinical practice.
- The safety of Axitinib has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to Axitinib in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib.
- The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label. hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, cardiac failure, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, hepatic impairment and fetal development.
- The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received Axitinib and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving Axitinib and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving Axitinib and 46/355 patients (13%) receiving sorafenib.
- The most common (≥20%) adverse reactions observed following treatment with Axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. Table 1 presents adverse reactions reported in ≥10% patients who received Axitinib or sorafenib.
- Selected adverse reactions (all grades) that were reported in <10% of patients treated with Axitinib included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).
- Table 2 presents the most common laboratory abnormalities reported in ≥10% patients who received Axitinib or sorafenib.
- Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with Axitinib included hemoglobin increased (above the upper limit of normal) (9% for Axitinib versus 1% for sorafenib) and hypercalcemia (6% for Axitinib versus 2% for sorafenib).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Axitinib in the drug label.
# Drug Interactions
- Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of Axitinib with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John's wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended . Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Axitinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using Axitinib. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose.
- Women of childbearing potential should be advised to avoid becoming pregnant while receiving Axitinib. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
- There are no adequate and well-controlled studies with Axitinib in pregnant women. Axitinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
- Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Axitinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Axitinib during labor and delivery.
### Nursing Mothers
- It is not known whether axitinib 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 Axitinib, 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
- The safety and efficacy of Axitinib in pediatric patients have not been studied.
- Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.
### Geriatic Use
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, 123/359 patients (34%) treated with Axitinib were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of Axitinib between patients who were ≥65 years of age and younger.
- No dosage adjustment is required in elderly patients
### Gender
There is no FDA guidance on the use of Axitinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Axitinib with respect to specific racial populations.
### Renal Impairment
- No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance CLcr <89 mL/min) . No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min).
### Hepatic Impairment
- In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of Axitinib was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Axitinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Axitinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Advise patients that hypertension may develop during Axitinib treatment and that blood pressure should be monitored regularly during treatment
# IV Compatibility
There is limited information regarding IV Compatibility of Axitinib in the drug label.
# Overdosage
- There is no specific treatment for Axitinib overdose.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).
- In a clinical dose finding study with Axitinib, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis.
- In cases of suspected overdose, Axitinib should be withheld and supportive care instituted.
# Pharmacology
There is limited information regarding Axitinib Pharmacology in the drug label.
## Mechanism of Action
- Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.
## Structure
- Axitinib (axitinib) is a kinase inhibitor. Axitinib has the chemical name N-methyl-2--benzamide. The molecular formula is C22H18N4OS and the molecular weight is 386.47 Daltons. The chemical structure is:
- Axitinib is a white to light-yellow powder with a pKa of 4.8. The solubility of axitinib in aqueous media over the range pH 1.1 to pH 7.8 is in excess of 0.2 µg/mL. The partition coefficient (n-octanol/water) is 3.5.
- Axitinib is supplied as red, film-coated tablets containing either 1 mg or 5 mg of axitinib together with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and Opadry® II red 32K15441 as inactive ingredients. The Opadry II red 32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, titanium dioxide, triacetin (glycerol triacetate), and red iron oxide.
## Pharmacodynamics
- The effect of a single oral dose of Axitinib (5 mg) in the absence and presence of 400 mg ketoconazole on the QTc interval was evaluated in a randomized, single-blinded, two-way crossover study in 35 healthy subjects. No large changes in mean QTc interval (i.e., >20 ms) from placebo were detected up to 3 hours post-dose. However, small increases in mean QTc interval (i.e., <10 ms) cannot be ruled out.
## Pharmacokinetics
- The population pharmacokinetic analysis pooled data from 17 trials in healthy subjects and patients with cancer. A two-compartment disposition model with first-order absorption and lag-time adequately describes the axitinib concentration-time profile.
- Following single oral 5-mg dose administration, the median Tmax ranged from 2.5 to 4.1 hours. Based on the plasma half-life, steady state is expected within 2 to 3 days of dosing. Dosing of axitinib at 5 mg twice daily resulted in approximately 1.4-fold accumulation compared to administration of a single dose. At steady state, axitinib exhibits approximately linear pharmacokinetics within the 1-mg to 20-mg dose range. The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%.
- Compared to overnight fasting, administration of Axitinib with a moderate fat meal resulted in 10% lower AUC and a high fat, high-calorie meal resulted in 19% higher AUC. Axitinib can be administered with or without food .
- Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced RCC (n=20), at the 5 mg twice daily dose in the fed state, the geometric mean (CV%) Cmax and AUC0–24 were 27.8 (79%) ng/mL and 265 (77%) ng.h/mL, respectively. The geometric mean (CV%) clearance and apparent volume of distribution were 38 (80%) L/h and 160 (105%) L, respectively.
- The plasma half life of Axitinib ranges from 2.5 to 6.1 hours. Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral administration of a 5-mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and approximately 23% was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in feces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity.
- The sulfoxide and N-glucuronide metabolites show approximately ≥400-fold less in vitro potency against VEGFR-2 compared to axitinib.
- Effects of Other Drugs on Axitinib: Axitinib is metabolized primarily in the liver by CYP3A4/5. Additionally, the aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility. The effects of a strong CYP3A4/5 inhibitor, a strong CYP3A4/5 inducer, and an antacid on the pharmacokinetics of axitinib are presented in Figure 1
- Effects of Axitinib on Other Drugs: In vitro studies demonstrated that axitinib has the potential to inhibit CYP1A2 and CYP2C8. However, co-administration of axitinib with paclitaxel, a CYP2C8 substrate, did not increase plasma concentrations of paclitaxel in patients.
- In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations. In vitro studies in human hepatocytes indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5.
- Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro. However, Axitinib is not expected to inhibit P-gp at therapeutic plasma concentrations.
- Pediatric Use: Axitinib has not been studied in patients <18 years of age.
- Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of axitinib are presented in Figure 1 .
- Renal Impairment: Population pharmacokinetic analysis (based on pre-existing renal function) was carried out in 590 healthy volunteers and patients, including five with severe renal impairment (15 mL/min ≤CLcr <29 mL/min), 64 with moderate renal impairment (30 mL/min ≤CLcr <59 mL/min), and 139 with mild renal impairment (60 mL/min ≤CLcr <89 mL/min). Mild to severe renal impairment did not have meaningful effects on the pharmacokinetics of axitinib. Data from only one patient with end-stage renal disease are available .
- Other Intrinsic Factors: Population pharmacokinetic analyses indicate that there are no clinically relevant effects of age, gender, race, body weight, body surface area, UGT1A1 genotype, or CYP2C19 genotype on the clearance of axitinib.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with axitinib.
- Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay.
- Axitinib has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively).
- In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose).
# Clinical Studies
The safety and efficacy of Axitinib were evaluated in a randomized, open-label, multicenter Phase 3 study. Patients (N=723) with advanced RCC whose disease had progressed on or after treatment with 1 prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, or cytokine-containing regimens were randomized (1:1) to receive Axitinib (N=361) or sorafenib (N=362). Progression-free survival (PFS) was assessed by a blinded independent central review committee. Other endpoints included objective response rate (ORR) and overall survival (OS).
Of the patients enrolled in this study, 389 patients (54%) had received 1 prior sunitinib-based therapy, 251 patients (35%) had received 1 prior cytokine-based therapy (interleukin-2 or interferon-alfa), 59 patients (8%) had received 1 prior bevacizumab-based therapy, and 24 patients (3%) had received 1 prior temsirolimus-based therapy. The baseline demographic and disease characteristics were similar between the Axitinib and sorafenib groups with regard to age (median 61 years), gender (72% male), race (75% white, 21% Asian), Eastern Cooperative Oncology Group (ECOG) performance status (55% 0, 45% 1), and histology (99% clear cell).
There was a statistically significant advantage for Axitinib over sorafenib for the endpoint of PFS (see TABLE 3 and FIGURE 2). There was no statistically significant difference between the arms in OS.
# How Supplied
- Axitinib tablets are supplied as follows:
1 mg tablets are red film-coated, oval tablets debossed with "Pfizer" on one side and "1 XNB" on the other; available in bottles of 180: NDC 0069-0145-01.
- 5 mg tablets are red film-coated, triangular tablets debossed with "Pfizer" on one side and "5 XNB" on the other; available in bottles of 60: NDC 0069-0151-11.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information)
- Advise patients that hypertension may develop during Axitinib treatment and that blood pressure should be monitored regularly during treatment.
- Advise patients that arterial and venous thromboembolic events have been observed during Axitinib treatment and to inform their doctor if they experience symptoms suggestive of thromboembolic events.
- Advise patients that Axitinib may increase the risk of bleeding and to promptly inform their doctor of any bleeding episodes .
- Advise patients that cardiac failure may develop during Axitinib treatment and that signs or symptoms of cardiac failure should be regularly monitored for during treatment
- Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during Axitinib treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking Axitinib.
- Advise patients that abnormal thyroid function may develop during Axitinib treatment and to inform their doctor if symptoms of abnormal thyroid function occur.
- Advise patients to inform their doctor if they have an unhealed wound or if they have surgery scheduled.
- Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances) .
- Advise patients that Axitinib can cause birth defects or fetal loss and that they should not become pregnant during treatment with Axitinib. Both male and female patients should be counseled to use effective birth control during treatment with Axitinib. Female patients should also be advised against breast-feeding while receiving Axitinib .
- Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements.
# Precautions with Alcohol
- Alcohol-Axitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Axitinib®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Axitinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Axitinib is an tyrosine kinase inhibitor that is FDA approved for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Common adverse reactions include diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Axitinib is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.
- The recommended starting oral dose of Axitinib is 5 mg twice daily. Administer Axitinib doses approximately 12 hours apart with or without food. Axitinib should be swallowed whole with a glass of water.
- If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.
- Dose increase or reduction is recommended based on individual safety and tolerability.
- Over the course of treatment, patients who tolerate Axitinib for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the Axitinib dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria.
- Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of Axitinib therapy . If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily.
- Strong CYP3A4/5 Inhibitors: The concomitant use of Strong CYP3A4/5 Inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 Inhibition is recommended. *Although Axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of Axitinib by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the Axitinib dose should be returned (after 3 – 5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor .
- Hepatic Impairment: No starting dose adjustment is required when administering Axitinib to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the Axitinib starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C)
## Off-Label Use and Dosage (Adult)
### Non–Guideline-Supported Use
- Metastatic renal cell carcinoma, First-line therapy: initial, 5 mg ORALLY twice daily; increases at 2-week intervals to 7 mg ORALLY twice daily, then 10 mg ORALLY twice daily was used in a clinical trial
- [1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of Axitinib in pediatric patients have not been studied.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
The safety and efficacy of Axitinib in pediatric patients have not been studied.
### Non–Guideline-Supported Use
The safety and efficacy of Axitinib in pediatric patients have not been studied.
# Contraindications
- None
# Warnings
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving Axitinib and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving Axitinib and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of Axitinib treatment and blood pressure increases have been observed as early as 4 days after starting Axitinib. Hypertension was managed with standard antihypertensive therapy. Discontinuation of Axitinib treatment due to hypertension occurred in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib.
- Blood pressure should be well-controlled prior to initiating Axitinib. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the Axitinib dose. Discontinue Axitinib if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of Axitinib, and discontinuation should be considered if there is evidence of hypertensive crisis. If Axitinib is interrupted, patients receiving antihypertensive medications should be monitored for hypotension .
- In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with Axitinib for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving Axitinib and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib.
- In clinical trials with Axitinib, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.
- Use Axitinib with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.
- In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with Axitinib for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving Axitinib and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving Axitinib (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. In clinical trials with Axitinib, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.
- Use Axitinib with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had a venous thromboembolic event within the previous 6 months.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving Axitinib and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving Axitinib (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving Axitinib (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.
- Axitinib has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the Axitinib dose.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving Axitinib and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving Axitinib and 1/355 patients (<1%) receiving sorafenib. *Fatal cardiac failure was reported in 2/359 patients (1%) receiving Axitinib and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with Axitinib. Management of cardiac failure may require permanent discontinuation of Axitinib.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. In clinical trials with Axitinib, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).
- Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with Axitinib.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving Axitinib and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving Axitinib and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving Axitinib and 25/232 patients (11%) receiving sorafenib.
- Monitor thyroid function before initiation of, and periodically throughout, treatment with Axitinib. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.
- No formal studies of the effect of Axitinib on wound healing have been conducted.
- Stop treatment with Axitinib at least 24 hours prior to scheduled surgery. The decision to resume Axitinib therapy after surgery should be based on clinical judgment of adequate wound healing.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib . There were two additional reports of RPLS in other clinical trials with Axitinib.
- RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue Axitinib in patients developing RPLS. *The safety of reinitiating Axitinib therapy in patients previously experiencing RPLS is not known.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving Axitinib and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving Axitinib and 6/355 patients (2%) receiving sorafenib.
- Monitoring for proteinuria before initiation of, and periodically throughout, treatment with Axitinib is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt Axitinib treatment.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the Axitinib arm and 2% of patients on the sorafenib arm.
- Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with Axitinib.
- The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering Axitinib to patients with moderate hepatic impairment (Child-Pugh class B). Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) .
# 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 clinical practice.
- The safety of Axitinib has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to Axitinib in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib.
- The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label. hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, cardiac failure, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, hepatic impairment and fetal development.
- The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received Axitinib and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving Axitinib and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving Axitinib and 46/355 patients (13%) receiving sorafenib.
- The most common (≥20%) adverse reactions observed following treatment with Axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. Table 1 presents adverse reactions reported in ≥10% patients who received Axitinib or sorafenib.
- Selected adverse reactions (all grades) that were reported in <10% of patients treated with Axitinib included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).
- Table 2 presents the most common laboratory abnormalities reported in ≥10% patients who received Axitinib or sorafenib.
- Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with Axitinib included hemoglobin increased (above the upper limit of normal) (9% for Axitinib versus 1% for sorafenib) and hypercalcemia (6% for Axitinib versus 2% for sorafenib).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Axitinib in the drug label.
# Drug Interactions
- Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of Axitinib with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John's wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended . Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Axitinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using Axitinib. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose.
- Women of childbearing potential should be advised to avoid becoming pregnant while receiving Axitinib. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
- There are no adequate and well-controlled studies with Axitinib in pregnant women. Axitinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
- Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Axitinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Axitinib during labor and delivery.
### Nursing Mothers
- It is not known whether axitinib 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 Axitinib, 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
- The safety and efficacy of Axitinib in pediatric patients have not been studied.
- Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.
### Geriatic Use
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, 123/359 patients (34%) treated with Axitinib were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of Axitinib between patients who were ≥65 years of age and younger.
- No dosage adjustment is required in elderly patients
### Gender
There is no FDA guidance on the use of Axitinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Axitinib with respect to specific racial populations.
### Renal Impairment
- No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance CLcr <89 mL/min) . No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min).
### Hepatic Impairment
- In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of Axitinib was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Axitinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Axitinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Advise patients that hypertension may develop during Axitinib treatment and that blood pressure should be monitored regularly during treatment
# IV Compatibility
There is limited information regarding IV Compatibility of Axitinib in the drug label.
# Overdosage
- There is no specific treatment for Axitinib overdose.
- In a controlled clinical study with Axitinib for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).
- In a clinical dose finding study with Axitinib, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis.
- In cases of suspected overdose, Axitinib should be withheld and supportive care instituted.
# Pharmacology
There is limited information regarding Axitinib Pharmacology in the drug label.
## Mechanism of Action
- Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.
## Structure
- Axitinib (axitinib) is a kinase inhibitor. Axitinib has the chemical name N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide. The molecular formula is C22H18N4OS and the molecular weight is 386.47 Daltons. The chemical structure is:
- Axitinib is a white to light-yellow powder with a pKa of 4.8. The solubility of axitinib in aqueous media over the range pH 1.1 to pH 7.8 is in excess of 0.2 µg/mL. The partition coefficient (n-octanol/water) is 3.5.
- Axitinib is supplied as red, film-coated tablets containing either 1 mg or 5 mg of axitinib together with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and Opadry® II red 32K15441 as inactive ingredients. The Opadry II red 32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, titanium dioxide, triacetin (glycerol triacetate), and red iron oxide.
## Pharmacodynamics
- The effect of a single oral dose of Axitinib (5 mg) in the absence and presence of 400 mg ketoconazole on the QTc interval was evaluated in a randomized, single-blinded, two-way crossover study in 35 healthy subjects. No large changes in mean QTc interval (i.e., >20 ms) from placebo were detected up to 3 hours post-dose. However, small increases in mean QTc interval (i.e., <10 ms) cannot be ruled out.
## Pharmacokinetics
- The population pharmacokinetic analysis pooled data from 17 trials in healthy subjects and patients with cancer. A two-compartment disposition model with first-order absorption and lag-time adequately describes the axitinib concentration-time profile.
- Following single oral 5-mg dose administration, the median Tmax ranged from 2.5 to 4.1 hours. Based on the plasma half-life, steady state is expected within 2 to 3 days of dosing. Dosing of axitinib at 5 mg twice daily resulted in approximately 1.4-fold accumulation compared to administration of a single dose. At steady state, axitinib exhibits approximately linear pharmacokinetics within the 1-mg to 20-mg dose range. The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%.
- Compared to overnight fasting, administration of Axitinib with a moderate fat meal resulted in 10% lower AUC and a high fat, high-calorie meal resulted in 19% higher AUC. Axitinib can be administered with or without food .
- Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced RCC (n=20), at the 5 mg twice daily dose in the fed state, the geometric mean (CV%) Cmax and AUC0–24 were 27.8 (79%) ng/mL and 265 (77%) ng.h/mL, respectively. The geometric mean (CV%) clearance and apparent volume of distribution were 38 (80%) L/h and 160 (105%) L, respectively.
- The plasma half life of Axitinib ranges from 2.5 to 6.1 hours. Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral administration of a 5-mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and approximately 23% was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in feces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity.
- The sulfoxide and N-glucuronide metabolites show approximately ≥400-fold less in vitro potency against VEGFR-2 compared to axitinib.
- Effects of Other Drugs on Axitinib: Axitinib is metabolized primarily in the liver by CYP3A4/5. Additionally, the aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility. The effects of a strong CYP3A4/5 inhibitor, a strong CYP3A4/5 inducer, and an antacid on the pharmacokinetics of axitinib are presented in Figure 1
- Effects of Axitinib on Other Drugs: In vitro studies demonstrated that axitinib has the potential to inhibit CYP1A2 and CYP2C8. However, co-administration of axitinib with paclitaxel, a CYP2C8 substrate, did not increase plasma concentrations of paclitaxel in patients.
- In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations. In vitro studies in human hepatocytes indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5.
- Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro. However, Axitinib is not expected to inhibit P-gp at therapeutic plasma concentrations.
- Pediatric Use: Axitinib has not been studied in patients <18 years of age.
- Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of axitinib are presented in Figure 1 .
- Renal Impairment: Population pharmacokinetic analysis (based on pre-existing renal function) was carried out in 590 healthy volunteers and patients, including five with severe renal impairment (15 mL/min ≤CLcr <29 mL/min), 64 with moderate renal impairment (30 mL/min ≤CLcr <59 mL/min), and 139 with mild renal impairment (60 mL/min ≤CLcr <89 mL/min). Mild to severe renal impairment did not have meaningful effects on the pharmacokinetics of axitinib. Data from only one patient with end-stage renal disease are available .
- Other Intrinsic Factors: Population pharmacokinetic analyses indicate that there are no clinically relevant effects of age, gender, race, body weight, body surface area, UGT1A1 genotype, or CYP2C19 genotype on the clearance of axitinib.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with axitinib.
- Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay.
- Axitinib has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively).
- In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose).
# Clinical Studies
The safety and efficacy of Axitinib were evaluated in a randomized, open-label, multicenter Phase 3 study. Patients (N=723) with advanced RCC whose disease had progressed on or after treatment with 1 prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, or cytokine-containing regimens were randomized (1:1) to receive Axitinib (N=361) or sorafenib (N=362). Progression-free survival (PFS) was assessed by a blinded independent central review committee. Other endpoints included objective response rate (ORR) and overall survival (OS).
Of the patients enrolled in this study, 389 patients (54%) had received 1 prior sunitinib-based therapy, 251 patients (35%) had received 1 prior cytokine-based therapy (interleukin-2 or interferon-alfa), 59 patients (8%) had received 1 prior bevacizumab-based therapy, and 24 patients (3%) had received 1 prior temsirolimus-based therapy. The baseline demographic and disease characteristics were similar between the Axitinib and sorafenib groups with regard to age (median 61 years), gender (72% male), race (75% white, 21% Asian), Eastern Cooperative Oncology Group (ECOG) performance status (55% 0, 45% 1), and histology (99% clear cell).
There was a statistically significant advantage for Axitinib over sorafenib for the endpoint of PFS (see TABLE 3 and FIGURE 2). There was no statistically significant difference between the arms in OS.
# How Supplied
- Axitinib tablets are supplied as follows:
1 mg tablets are red film-coated, oval tablets debossed with "Pfizer" on one side and "1 XNB" on the other; available in bottles of 180: NDC 0069-0145-01.
- 5 mg tablets are red film-coated, triangular tablets debossed with "Pfizer" on one side and "5 XNB" on the other; available in bottles of 60: NDC 0069-0151-11.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information)
- Advise patients that hypertension may develop during Axitinib treatment and that blood pressure should be monitored regularly during treatment.
- Advise patients that arterial and venous thromboembolic events have been observed during Axitinib treatment and to inform their doctor if they experience symptoms suggestive of thromboembolic events.
- Advise patients that Axitinib may increase the risk of bleeding and to promptly inform their doctor of any bleeding episodes .
- Advise patients that cardiac failure may develop during Axitinib treatment and that signs or symptoms of cardiac failure should be regularly monitored for during treatment
- Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during Axitinib treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking Axitinib.
- Advise patients that abnormal thyroid function may develop during Axitinib treatment and to inform their doctor if symptoms of abnormal thyroid function occur.
- Advise patients to inform their doctor if they have an unhealed wound or if they have surgery scheduled.
- Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances) .
- Advise patients that Axitinib can cause birth defects or fetal loss and that they should not become pregnant during treatment with Axitinib. Both male and female patients should be counseled to use effective birth control during treatment with Axitinib. Female patients should also be advised against breast-feeding while receiving Axitinib .
- Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements.
# Precautions with Alcohol
- Alcohol-Axitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Axitinib®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Axitinib | |
a2bb87ea2c6a7a449d9649a045b02ef573d060a4 | wikidoc | Ayurveda | Ayurveda
# Overview
Ayurveda (Devanagari: आयुर्वेद) or Ayurvedic medicine is an ancient system of health care that is native to the Indian subcontinent. It is presently in daily use by millions of people in India, Nepal, Sri Lanka and indirectly through it being the major influence on Unani, Chinese and Tibetan Medicine. The word "Ayurveda" is a tatpurusha compound of the word Template:IAST meaning "life" or "life principle", and the word Template:IAST, which refers to a system of "knowledge". Thus "Ayurveda" roughly translates as the "knowledge of life". According to Charaka Samhita, "life" itself is defined as the "combination of the body, sense organs, mind and soul, the factor responsible for preventing decay and death, which sustains the body over time, and guides the processes of rebirth" According to this perspective, Ayurveda is concerned with measures to protect "ayus", which includes healthy living along with therapeutic measures that relate to physical, mental, social and spiritual harmony. Ayurveda is also one among the few traditional systems of medicine to contain a sophisticated system of surgery (which is referred to as "salya-chikitsa").
According to the Ayurvedavatarana (the "descent of Ayurveda"), the origin of Ayurveda is stated to be a divine revelation of the ancient Indian creator God Lord Brahma as he awoke to recreate the universe. This knowledge was passed directly to Daksha Prajapati in the form of shloka sung by Lord Brahma., and this was in turn passed down through a successive chain of deities to Lord Indra, the protector of dharma. According to this account, the first human exponent of Ayurveda was Bharadvaja, who learned it directly from Indra. Bharadvaja in turn taught Ayurveda to a group of assembled sages, who then passed down different aspects of this knowledge to their students. According to tradition, Ayurveda was first described in text form by Agnivesha, in his book the Agnivesh tantra. The book was later redacted by Charaka, and became known as the Charaka Samhitā. Another early text of Ayurveda is the Sushruta Samhitā, which was compiled by Sushrut, the primary pupil of Dhanvantri, sometime around 1000 BCE. Dhanvantri is known as the Father of Surgery, and in the Sushrut Samhita, the teachings and surgical techniques of Dhanvantri are compiled and complemented with additional findings and observations of Sushrut regarding topics ranging from obstetrics and orthopedics to ophthalmology. Sushrut Samhita together with Charaka Samhitā, served as the textual material within the ancient Universities of Takshashila and Nalanda. These texts are believed to have been written around the beginning of the Common Era, and are based on a holistic approach rooted in the philosophy of the Vedas and Vedic culture. Holism is central to ayurvedic philosophy and elements of holism is found in several aspects of ayurveda.
# Eight Branches (Ashthanga) of Ayurveda
The eight branches of Ayurveda are:
- Internal medicine - Kayachikitsa
- Surgery - Shalya Tantra
- Ears, eyes, nose and throat - Shalakya tantra
- Pediatrics - Kaumarabhritya Tantra
- Toxicology - Agada Tantra
- Purification of the genetic organs - Bajikarana (or Vajikarana) Tantra
- Health and Longevity - Rasayana Tantra
- Spiritual Healing/Psychiatry - Bhuta Vidya
# History
Documented references to the precise timing of the origins of Ayurveda are not available. The age of Ayurveda has been established on the basis of correlating the evidence with other disciplines as well as circumstantial evidence. Ayurveda is said to have been first compiled as a text by Agnivesha, in his book Agnivesh tantra, which was written during Vedic times. The book was later revised by Charaka, and renamed to Charaka Samhitā (encyclopedia of the physician Charaka). Other early texts of Ayurveda include the Charaka Samhitā and the Sushruta Samhitā The system was orally transferred via the Gurukul system until a script came into existence.
The earliest scripts would have been written on perishable materials such as Taalpatra and Bhojapatra, which could not be readily preserved. The script was later written on stone and copper sheets. Verses dealing with Ayurveda are included in the Atharvaveda, which implies that some form of Ayurveda is as old as the Vedas. Ayurvedic practices have also evolved over time, and some practices may be considered innovations upon earlier Vedic practices, such as the advances made during the Buddhist period in India.
Hinduism attributes the genesis of Ayurveda to several theories in which the knowledge is believed to have been passed on from being to being, initially, through its realization by the divine sages, and gradually into the human sphere by a complex system of mnemonics. Details of Ayurvedic traditions vary between writers, as is expected when oral traditions are transcribed from multiple sources. The earliest authors of Ayurvedic manuscripts recorded divergent forms of the tradition.
# Development
Ayurvedic practice was flourishing during the time of Buddha (around 520 BC) , and in this period the Ayurvedic practitioners were commonly using Mercuric-sulphur combination based medicines. In this period mercury, sulphur and other metals were used in conjunction with herbs to prepare the different medications. An important Ayurvedic practitioner of this period was Nagarjuna, a Buddhist herbologist, famous for inventing various new drugs for the treatment of ailments. Nagarjuna was accompanied by Surananda, Nagbodhi, Yashodhana, Nityanatha, Govinda, Anantdev, Vagbhatta etc. The knowledge of Ayurveda progressed a lot during this period, including development of newer and more effective medicines, and is therefore termed as the Golden Period of Ayurveda.
After emerging victorious at the Kalinga War, Emperor Ashoka (304 BC-232 BC) influenced by the Buddhist teachings, banned any bloodshed in his kingdom in 250 BC. Therefore many Ayurveda practitioners, who were practicing surgery along with medicine, left the surgical intervention and adopted totally new medicinal treatments. In this period, Ayurveda again evolved and flourished with the invention of new drugs, new methodology and new innovations. The practice of the accompanying surgery slowly died out during this period.
During the regime of Chandragupta Maurya (375-415 AD), Ayurveda was part of mainstream Indian medical techniques, and continued to be so until the colonisation by the British.
Chakrapani Dutta (DuttaSharma) was a Vaid Brahman of Bengal who wrote books on Ayurveda such as "Chakradutta" and others. Chakrapani Dutta was the Rajavaidya of Great King Laxman Sen {some says rajVaid of King Nayapala (1038 - 1055)}. It is believed by some practitioners that Chakradutta is the essence of Ayurveda.
Ayurveda has always been preserved by the people of India as a traditional "science of life", despite increasing adoption of European medical techniques during the time of British rule. For several decades the reputation and skills of the various Ayurvedic schools declined markedly as Western medicine and Western-style hospitals were built. However, beginning in the 1970s, a gradual recognition of value of Ayurveda returned, and today Ayurvedic hospitals and practitioners are flourishing throughout all of India. As well, the production and marketing of Ayurvedic herbal medicines has dramatically increased, as well as scientific documentation of benefits. Today, Ayurvedic medicines are available throughout the world.
## Gurukul system of Ayurveda
In the earlier days of its conception, the system of Ayurvedic medicine was orally transferred via the Gurukul system until a written script came into existence.
In this system, the Guru gave a solemn address where he directed the students to a life of chastity, honesty, and vegetarianism. The student was to strive with all his being to heal the sick. He was not to betray patients for his own advantage. He was required to dress modestly and avoid alcohol or drugs. He was to be collected and self-controlled, measured in speech at all times. He was to constantly improve his knowledge and technical skill. At the patient's home, he was to be courteous and modest, directing all attention to the patient's welfare. He was not to divulge any knowledge about the patient and his family. If the patient was incurable, he was to keep this to himself if it was likely to harm the patient or others.
The normal length of the student's training appears to have been seven years. Before graduation, the student was to pass a test. But the physician was to continue to learn through texts, direct observation (pratyaksha), and through inference (anumāna). In addition, the vaidyas attended meetings where knowledge was exchanged. The practitioners also gained knowledge of unusual remedies from laypeople who were outside the huffsteter community such as hillsmen, herdsmen, and forest-dwellers.
# Tridosha system
The central concept of Ayurvedic medicine is the theory that health exists when there is a balance between three fundamental bodily humours or doshas called Vata, Pitta and Kapha.
- Vata is the impulse principle necessary to mobilize the function of the nervous system
- Pitta is the energy principle which uses bile to direct digestion and hence metabolism into the venous system.
- Kapha is the body fluid principle which relates to mucous, lubrication and the carrier of nutrients into the arterial system.
All Ayurvedic physicians believe that these ancient ideas, based in the knowledge discovered by the Rishis and Munis, exist in harmony with physical reality. These Ayurvedic concepts allow physicians to examine the homeostasis of the whole system. People may be of a predominant dosha or constitution, but all doshas have the basic elements within them.
# Ayurvedic tastes
Ayurveda holds that the tastes of foods or herbs have specific physiological effects. Those tastes that transform after digestion (Vipaka) are more powerful.
# Medications
Ayurveda operates on the precept that various materials of vegetable, animal, and mineral origin have some medicinal value. The medicinal properties of these materials have been documented by the practitioners and have been used for centuries to cure illness and/or help maintain good health.
Ayurvedic medicaments are made from herbs or mixtures of herbs, either alone or in combination with minerals, metals and other ingredients of animal origin. The metals, animals and minerals are purified by individual processes before being used for medicinal purposes.
Writers and compilers of Ayurvedic literature such as Charaka, Sushruta, Vagabhatta, Bhav Mishra, Shaligram and others have written about the qualities, characteristics and medicinal uses of the herbs, mineral, metals, chemicals, animal parts, cooked food articles, natural foods, fruits etc. Among them, the Bhav Prakash Nighantu, written by Bhav Mishra, is known for its detail .The composition of the Nighantu part (Ayurvedic Materia Medica) of the Bhav Prakash is part of the classical book. The details of the medicinal herbs are given according to the nature, effects, and curative properties as observed by the Ayurvedic practitioners.
Ayurvedic literature has been written by several authors in languages such as Sanskrit, Hindi, Kannada, Tamil, Telugu and more recently, in English.The Shaligram Nighantu was written in Sanskrit. The Banaushadhi Chandrodaya was written in Hindi.The Indian Materia Medica was written in English.
# Panchakarma and Ayurvedic massage
Panchakarma (the five actions or modalities) is a collection of purification techniques that Ayurveda prescribes for some diseases and for periodic cleansing. A course of Pancharkarma typically includes a short-term dietary prescription, massage, herbs, and may include purgatives, sweat baths, medicated enemas, and nasal cleansing.
Ayurvedic massage is a form of treatment for various age related and other common disorders. Some of the advantages which can be cited are pain relief, improved circulation, stress relief, better sleep, flexibility, athletic performance and emotional benefits. Massage therapy can soothe pain, relax stiff muscles, and reduce the swelling that accompanies arthritis. Advocates claim that, with ayurvedic massage, deep-seated toxins in the joints and tissues are loosened and released into the system for elimination through natural toxin-release processes. Ayurvedic massage is especially developed in Sri Lanka and the Indian state of Kerala
# Current status
In the early 20th century, Ayurvedic physicians began to organize into professional associations and to promote their case for national recognition and funding. This began to become a reality after Indian independence in 1947.
Ayurveda is now a statutory, recognised medical system of health care like other medical systems existing in India. The Central Council of Indian Medicine {CCIM} governs and recommends policies for the research and development of the system. An Encyclopedia on Ayurveda - Ayushveda.com has been developed to promote the knowledge of Ayurveda worldwide.
In India, practitioners in Ayurveda undergo 5 and 1/2 years of training including 1 year of internship in select Ayurveda Medical Schools wherein they earn the professional doctorate degree of Bachelor of Ayurvedic Medicine and Surgery. A Bachelor's degree with a major in Science and a minor in Sanskrit is desirable for candidates interested in taking up the course.
Select institutions like the Banaras Hindu University, Varanasi, offer higher doctorates and postgraduate training such as MD which includes a 3 year residency and a dissertation similar to the MD/MS degrees in modern systems of medicine.
## Ayurvedic institutions and practitioners
Ayurvedic practitioners have been appointed as Honorary Ayurvedic Physician to the President of India. Every year on the occasion of Dhanvantari jayanti, a prestigious Dhanvantari Award is conferred on a famous personality of Medical Sciences including Ayurveda. Kerala is the leading state in India that promotes research and practices of Ayurveda. This has been attributed to Kerala's well established Ayurveda centers, Ayurveda pharmaceutical companies, and Ayurveda medical colleges. For example, there are many Ayurvedic centers (known as Vaidya shalas) all over Kerala. Besides Kerala, others also promoting Ayurveda are Gujarat, Maharastra, and Karnataka.
## Practice in the West
As a result of strong regulations in medical practice in Europe and America, the most commonly practiced Ayurvedic treatments in the west are massage and dietary and herbal advice.
In the United States, the National Institute of Ayurvedic Medicine (established by Scott Gerson) is an example of a research institute that has carried out research into Ayurvedic practices. Gerson has published part of his work on the antifungal activities of certain Ayurvedic plants in medical journals.
Several Pharmecutical companies and Academic Institutions in the west have come into conflict with Indian academic institutions and traditional Ayurvedic practitioners over the intellectual property rights of herbal products researched by the western agencies. The Ayurvedic practitioners have known about the efficacy of such products for centuries and so contend that they carry precedence with regards to patent rights on such products.
On December 1993, the University of Mississippi Medical Center had a patent issued to them by U.S patents and trademarks office on the use of turmeric (U.S. patent No. 5,401,504) for healing. The patent was contested by India's industrial research organization, Council for Scientific and Industrial Research (C.S.I.R), on the grounds that traditional Ayurvedic practitioners were already aware of the healing properties of the substance and have been for centuries, making this patent a case of bio-piracy.
After a complex legal battle, the U.S. Patents and Trademarks Office ruled on August 14,1997 that the patent was invalid because it was not a novel invention, giving the intellectual property rights to the principle back to the traditional practitioners of Ayurveda. R. A. Mashelkar, director-general of the CSIR, was satisfied with the result, saying:
"This success will enhance the confidence of the people and help remove fears about India's helplessness on preventing bio-piracy and appropriation of inventions based on traditional knowledge"
The turmeric patent was just one of the hundreds that the several academic organizations and Pharmecutical companies in the west have claimed by ignoring Ayurvedic knowledge. Vandana Shiva, a global campaigner for a fair and honest Intellectual Property Rights system, says patents on herbal products derived from Neem, Amla, Jar Amla, Anar, Salai, Dudhi, Gulmendhi, Bagbherenda, Karela, Erand, Rangoon-kibel, Vilayetishisham and Chamkura also need to be revoked.
Seven American and four Japanese firms have filed for grant of patents on formulations containing extracts of the herb Ashwagandha. Fruits, leaves and seeds of the Indian medicinal plant withania somnifera have been traditionally used for the Ayurvedic system as aphrodisiacs, diuretics and for treating memory loss. The Japanese patent applications are related to the use of the herb as a skin ointment and for promoting reproductive fertility. The U.S based company Natreon has also obtained a patent for an Ashwagandha extract.
Another US establishment, the New England Deaconess Hospital, has taken a patent on an Ashwagandha formulation claimed to alleviate symptoms associated with arthritis. It is clear that the Ashwagandha plant is catching the attention of scientists and more patents related to Ashwagandha are being filed or granted by different patent offices since 1996.
Ayurvedic wisdom originated in the main Vedas as a part of way of life - a spiritual connection with spirit and nature. This is most evident reading Atharva Veda. Ayurveda was used to remove obstacles on one’s path to Self-Realization. At some point the medical aspects began to take priority over the spiritual forms of healing (ie, focusing on lifestyle, dharma and moksha. Today, these spiritual aspects of Ayurveda have taken a back seat to the medical focus. As Ayurveda becomes a more commercially viable career, the spiritual aspects may continue to lose ground. Yet there are a growing number of practitioners who practice mainly these spiritual therapies and find better results than limiting their approach to the medical, physical realm.
# Criticisms
## Scientific studies and standards
Critics object to the lack of rigorous scientific studies and clinical trials of many ayurvedic products. The National Center for Complementary and Alternative Medicine states that "most clinical trials of Ayurvedic approaches have been small, had problems with research designs, lacked appropriate control groups, or had other issues that affected how meaningful the results were."
In India, scientific research in Ayurveda is largely undertaken by the statutory body of the Central Government, the Central Council for Research in Ayurveda and Siddha (CCRAS), through a national network of research institutes. A large number of non-governmental organisations are also conducting research work on different aspects of Ayurveda. However, "even staunch advocates of Ayurveda like cardiologist Dr. M.S. Valiathan...admit that 'clinical studies that would satisfy the liberal criteria of WHO World Health Organisation have been alarmingly few from India, in spite of patients crowding in Ayurvedic hospitals"'.
## Safety concerns
There is evidence that using some ayurvedic medicine, especially those involving herbs, metals, minerals, or other materials involves potentially serious risks, including toxicity.
A research study published in the Journal of the American Medical Association found significant levels of toxic heavy metals such as lead, mercury and arsenic in 20% of Ayurvedic preparations that were made in South Asia for sale in America. The Journal found that, if taken according to the manufacturers' instructions, this 20% of remedies "could result in heavy metal intakes above published regulatory standards" Similar studies have been performed in India, and have confirmed these results. Cases of metal toxicity from use of ayurvedic medicines are well known. Some practitioners claimed that "heavy metals are integral to some formulations and have been used for centuries. There is no point of doing trials as they have been used safely and have mention in our ancient texts."
There is a technique of detoxification applied to heavy metals and toxic herbs called samskaras, which is similar to the Chinese pao zhi although the Ayurvedic technique is more complex and may involve prayers as well as physical pharmacy techniques. An intriguing study of the effectiveness of the Ayurvedic samskaras was printed in the Journal of Postgrad Medicine:
Crude aconite is an extremely lethal substance. However, the science of Ayurveda looks upon aconite as a therapeutic entity. Crude aconite is always processed i.e. it undergoes 'samskaras' before being utilised in the Ayurvedic formulations. This study was undertaken in mice, to ascertain whether 'processed' aconite is less toxic as compared to the crude or unprocessed one. It was seen that crude aconite was significantly toxic to mice (100% mortality at a dose of 2.6 mg/mouse) whereas the fully processed aconite was absolutely non-toxic (no mortality at a dose even 8 times as high as that of crude aconite). Further, all the steps in the processing were essential for complete detoxification.
The described detoxification is a simple chemical processing which involves four successive rounds of boiling the crude root in cow's urine (twice) and cow's milk (twice). Such processing is reasonably expected to chemically modify both toxic and proposed therapeutic components of the root. It will also lead to extraction of these compounds from the root into the boiling solvents, thereby decreasing their concentration in the final product.
It should also be noted that, while these washes appear to ameliorate the toxicity of the crude root, there is no evidence that the processed root has any therapeutic value. A search of the Citation Index, via Web of Science (isiknowledge.com), returned no mention of any therapeutic value for aconite. However, the literature is replete with instances of aconite poisoning, though no mention of specific processing is made in these poisoning cases.
## "Miracle Cures"
Some critics also question the safety of those Ayurvedic drugs that are said to provide "Miracle Cures". The critics argue that simply following age-old Ayurvedic formulas is no guarantee of safety and the fundamental processes and concepts on which these ancient processes are based must be exposed to serious scientific scrutiny. | Ayurveda
Template:Alternative medical systems
# Overview
Ayurveda (Devanagari: आयुर्वेद) or Ayurvedic medicine is an ancient system of health care that is native to the Indian subcontinent. It is presently in daily use by millions of people in India, Nepal, Sri Lanka and indirectly through it being the major influence on Unani, Chinese and Tibetan Medicine. The word "Ayurveda" is a tatpurusha compound of the word Template:IAST meaning "life" or "life principle", and the word Template:IAST, which refers to a system of "knowledge". Thus "Ayurveda" roughly translates as the "knowledge of life". According to Charaka Samhita, "life" itself is defined as the "combination of the body, sense organs, mind and soul, the factor responsible for preventing decay and death, which sustains the body over time, and guides the processes of rebirth" [1][2] According to this perspective, Ayurveda is concerned with measures to protect "ayus", which includes healthy living along with therapeutic measures that relate to physical, mental, social and spiritual harmony. Ayurveda is also one among the few traditional systems of medicine to contain a sophisticated system of surgery (which is referred to as "salya-chikitsa").
According to the Ayurvedavatarana (the "descent of Ayurveda"), the origin of Ayurveda is stated to be a divine revelation of the ancient Indian creator God Lord Brahma[3] as he awoke to recreate the universe. This knowledge was passed directly to Daksha Prajapati in the form of shloka sung by Lord Brahma.[4], and this was in turn passed down through a successive chain of deities to Lord Indra, the protector of dharma. According to this account, the first human exponent of Ayurveda was Bharadvaja, who learned it directly from Indra. Bharadvaja in turn taught Ayurveda to a group of assembled sages, who then passed down different aspects of this knowledge to their students. According to tradition, Ayurveda was first described in text form by Agnivesha, in his book the Agnivesh tantra. The book was later redacted by Charaka, and became known as the Charaka Samhitā.[5] Another early text of Ayurveda is the Sushruta Samhitā, which was compiled by Sushrut, the primary pupil of Dhanvantri, sometime around 1000 BCE. Dhanvantri is known as the Father of Surgery, and in the Sushrut Samhita, the teachings and surgical techniques of Dhanvantri are compiled and complemented with additional findings and observations of Sushrut regarding topics ranging from obstetrics and orthopedics to ophthalmology. Sushrut Samhita together with Charaka Samhitā, served as the textual material within the ancient Universities of Takshashila and Nalanda.[6] These texts are believed to have been written around the beginning of the Common Era, and are based on a holistic approach rooted in the philosophy of the Vedas and Vedic culture. Holism is central to ayurvedic philosophy and elements of holism is found in several aspects of ayurveda.[7]
# Eight Branches (Ashthanga) of Ayurveda
The eight branches of Ayurveda are:
- Internal medicine - Kayachikitsa
- Surgery - Shalya Tantra
- Ears, eyes, nose and throat - Shalakya tantra
- Pediatrics - Kaumarabhritya Tantra
- Toxicology - Agada Tantra
- Purification of the genetic organs - Bajikarana (or Vajikarana) Tantra
- Health and Longevity - Rasayana Tantra
- Spiritual Healing/Psychiatry - Bhuta Vidya
# History
Documented references to the precise timing of the origins of Ayurveda are not available. The age of Ayurveda has been established on the basis of correlating the evidence with other disciplines as well as circumstantial evidence. Ayurveda is said to have been first compiled as a text by Agnivesha, in his book Agnivesh tantra, which was written during Vedic times.[citation needed] The book was later revised by Charaka, and renamed to Charaka Samhitā (encyclopedia of the physician Charaka).[8] Other early texts of Ayurveda include the Charaka Samhitā and the Sushruta Samhitā[6] The system was orally transferred via the Gurukul system until a script came into existence.
The earliest scripts would have been written on perishable materials such as Taalpatra and Bhojapatra, which could not be readily preserved.[citation needed] The script was later written on stone and copper sheets.[citation needed] Verses dealing with Ayurveda are included in the Atharvaveda, which implies that some form of Ayurveda is as old as the Vedas.[citation needed] Ayurvedic practices have also evolved over time, and some practices may be considered innovations upon earlier Vedic practices, such as the advances made during the Buddhist period in India.[citation needed]
Hinduism attributes the genesis of Ayurveda to several theories in which the knowledge is believed to have been passed on from being to being, initially, through its realization by the divine sages, and gradually into the human sphere by a complex system of mnemonics. Details of Ayurvedic traditions vary between writers, as is expected when oral traditions are transcribed from multiple sources. The earliest authors of Ayurvedic manuscripts recorded divergent forms of the tradition.
# Development
Ayurvedic practice was flourishing during the time of Buddha (around 520 BC) , and in this period the Ayurvedic practitioners were commonly using Mercuric-sulphur combination based medicines.[9] In this period mercury, sulphur and other metals were used in conjunction with herbs to prepare the different medications.[citation needed] An important Ayurvedic practitioner of this period was Nagarjuna, a Buddhist herbologist, famous for inventing various new drugs for the treatment of ailments.[citation needed] Nagarjuna was accompanied by Surananda, Nagbodhi, Yashodhana, Nityanatha, Govinda, Anantdev, Vagbhatta etc. The knowledge of Ayurveda progressed a lot during this period, including development of newer and more effective medicines, and is therefore termed as the Golden Period of Ayurveda.[citation needed]
After emerging victorious at the Kalinga War, Emperor Ashoka (304 BC-232 BC) influenced by the Buddhist teachings, banned any bloodshed in his kingdom in 250 BC. Therefore many Ayurveda practitioners, who were practicing surgery along with medicine, left the surgical intervention and adopted totally new medicinal treatments. In this period, Ayurveda again evolved and flourished with the invention of new drugs, new methodology and new innovations. The practice of the accompanying surgery slowly died out during this period.[citation needed]
During the regime of Chandragupta Maurya (375-415 AD), Ayurveda was part of mainstream Indian medical techniques, and continued to be so until the colonisation by the British.
Chakrapani Dutta (DuttaSharma) was a Vaid Brahman of Bengal who wrote books on Ayurveda such as "Chakradutta" and others. Chakrapani Dutta was the Rajavaidya of Great King Laxman Sen {some says rajVaid of King Nayapala (1038 - 1055)}. It is believed by some practitioners that Chakradutta is the essence of Ayurveda.
Ayurveda has always been preserved by the people of India as a traditional "science of life", despite increasing adoption of European medical techniques during the time of British rule. For several decades the reputation and skills of the various Ayurvedic schools declined markedly as Western medicine and Western-style hospitals were built. However, beginning in the 1970s, a gradual recognition of value of Ayurveda returned, and today Ayurvedic hospitals and practitioners are flourishing throughout all of India. As well, the production and marketing of Ayurvedic herbal medicines has dramatically increased, as well as scientific documentation of benefits. Today, Ayurvedic medicines are available throughout the world.
## Gurukul system of Ayurveda
In the earlier days of its conception, the system of Ayurvedic medicine was orally transferred via the Gurukul system until a written script came into existence.
In this system, the Guru gave a solemn address where he directed the students to a life of chastity, honesty, and vegetarianism. The student was to strive with all his being to heal the sick. He was not to betray patients for his own advantage. He was required to dress modestly and avoid alcohol or drugs. He was to be collected and self-controlled, measured in speech at all times. He was to constantly improve his knowledge and technical skill. At the patient's home, he was to be courteous and modest, directing all attention to the patient's welfare. He was not to divulge any knowledge about the patient and his family. If the patient was incurable, he was to keep this to himself if it was likely to harm the patient or others.
The normal length of the student's training appears to have been seven years. Before graduation, the student was to pass a test. But the physician was to continue to learn through texts, direct observation (pratyaksha), and through inference (anumāna). In addition, the vaidyas attended meetings where knowledge was exchanged. The practitioners also gained knowledge of unusual remedies from laypeople who were outside the huffsteter community such as hillsmen, herdsmen, and forest-dwellers.
# Tridosha system
The central concept of Ayurvedic medicine is the theory that health exists when there is a balance between three fundamental bodily humours or doshas called Vata, Pitta and Kapha.
- Vata is the impulse principle necessary to mobilize the function of the nervous system
- Pitta is the energy principle which uses bile to direct digestion and hence metabolism into the venous system.
- Kapha is the body fluid principle which relates to mucous, lubrication and the carrier of nutrients into the arterial system.
All Ayurvedic physicians believe that these ancient ideas, based in the knowledge discovered by the Rishis and Munis, exist in harmony with physical reality. These Ayurvedic concepts allow physicians to examine the homeostasis of the whole system. People may be of a predominant dosha or constitution, but all doshas have the basic elements within them.
# Ayurvedic tastes
Ayurveda holds that the tastes of foods or herbs have specific physiological effects. Those tastes that transform after digestion (Vipaka) are more powerful.
# Medications
Ayurveda operates on the precept that various materials of vegetable, animal, and mineral origin have some medicinal value. The medicinal properties of these materials have been documented by the practitioners and have been used for centuries to cure illness and/or help maintain good health.
Ayurvedic medicaments are made from herbs or mixtures of herbs, either alone or in combination with minerals, metals and other ingredients of animal origin. The metals, animals and minerals are purified by individual processes before being used for medicinal purposes.
Writers and compilers of Ayurvedic literature such as Charaka, Sushruta, Vagabhatta, Bhav Mishra, Shaligram and others have written about the qualities, characteristics and medicinal uses of the herbs, mineral, metals, chemicals, animal parts, cooked food articles, natural foods, fruits etc. Among them, the Bhav Prakash Nighantu, written by Bhav Mishra, is known for its detail .The composition of the Nighantu part (Ayurvedic Materia Medica) of the Bhav Prakash is part of the classical book. The details of the medicinal herbs are given according to the nature, effects, and curative properties as observed by the Ayurvedic practitioners.
Ayurvedic literature has been written by several authors in languages such as Sanskrit, Hindi, Kannada, Tamil, Telugu and more recently, in English.The Shaligram Nighantu was written in Sanskrit. The Banaushadhi Chandrodaya was written in Hindi.The Indian Materia Medica was written in English.
Template:Seealso
# Panchakarma and Ayurvedic massage
Panchakarma (the five actions or modalities) is a collection of purification techniques that Ayurveda prescribes for some diseases and for periodic cleansing. A course of Pancharkarma typically includes a short-term dietary prescription, massage, herbs, and may include purgatives, sweat baths, medicated enemas, and nasal cleansing.
Ayurvedic massage is a form of treatment for various age related and other common disorders. Some of the advantages which can be cited are pain relief, improved circulation, stress relief, better sleep, flexibility, athletic performance and emotional benefits[citation needed]. Massage therapy can soothe pain, relax stiff muscles, and reduce the swelling that accompanies arthritis[citation needed]. Advocates claim that, with ayurvedic massage, deep-seated toxins in the joints and tissues are loosened and released into the system for elimination through natural toxin-release processes.[10] Ayurvedic massage is especially developed in Sri Lanka and the Indian state of Kerala
# Current status
In the early 20th century, Ayurvedic physicians began to organize into professional associations and to promote their case for national recognition and funding.[citation needed] This began to become a reality after Indian independence in 1947.[citation needed]
Ayurveda is now a statutory, recognised medical system of health care like other medical systems existing in India. The Central Council of Indian Medicine {CCIM} governs and recommends policies for the research and development of the system. An Encyclopedia on Ayurveda - Ayushveda.com[2] has been developed to promote the knowledge of Ayurveda worldwide.
In India, practitioners in Ayurveda undergo 5 and 1/2 years of training including 1 year of internship in select Ayurveda Medical Schools wherein they earn the professional doctorate degree of Bachelor of Ayurvedic Medicine and Surgery[B.A.M.S.]. A Bachelor's degree with a major in Science [Physics, Chemistry, Biology] and a minor in Sanskrit is desirable for candidates interested in taking up the course.
Select institutions like the Banaras Hindu University, Varanasi, offer higher doctorates and postgraduate training such as MD [Ayurveda] which includes a 3 year residency and a dissertation similar to the MD/MS degrees in modern systems of medicine.
## Ayurvedic institutions and practitioners
Ayurvedic practitioners have been appointed as Honorary Ayurvedic Physician to the President of India. Every year on the occasion of Dhanvantari jayanti, a prestigious Dhanvantari Award is conferred on a famous personality of Medical Sciences including Ayurveda. Kerala is the leading state in India that promotes research and practices of Ayurveda. This has been attributed to Kerala's well established Ayurveda centers, Ayurveda pharmaceutical companies, and Ayurveda medical colleges. For example, there are many Ayurvedic centers (known as Vaidya shalas) all over Kerala. Besides Kerala, others also promoting Ayurveda are Gujarat, Maharastra, and Karnataka.
## Practice in the West
As a result of strong regulations in medical practice in Europe and America, the most commonly practiced Ayurvedic treatments in the west are massage and dietary and herbal advice.
In the United States, the National Institute of Ayurvedic Medicine (established by Scott Gerson) is an example of a research institute that has carried out research into Ayurvedic practices.[11] Gerson has published part of his work on the antifungal activities of certain Ayurvedic plants in medical journals.[12]
Several Pharmecutical companies and Academic Institutions in the west have come into conflict with Indian academic institutions and traditional Ayurvedic practitioners over the intellectual property rights of herbal products researched by the western agencies. The Ayurvedic practitioners have known about the efficacy of such products for centuries and so contend that they carry precedence with regards to patent rights on such products.
On December 1993, the University of Mississippi Medical Center had a patent issued to them by U.S patents and trademarks office on the use of turmeric (U.S. patent No. 5,401,504) for healing. The patent was contested by India's industrial research organization, Council for Scientific and Industrial Research (C.S.I.R), on the grounds that traditional Ayurvedic practitioners were already aware of the healing properties of the substance and have been for centuries, making this patent a case of bio-piracy.[13]
After a complex legal battle, the U.S. Patents and Trademarks Office ruled on August 14,1997 that the patent was invalid because it was not a novel invention, giving the intellectual property rights to the principle back to the traditional practitioners of Ayurveda. R. A. Mashelkar, director-general of the CSIR, was satisfied with the result, saying:
"This success will enhance the confidence of the people and help remove fears about India's helplessness on preventing bio-piracy and appropriation of inventions based on traditional knowledge[13]"
The turmeric patent was just one of the hundreds that the several academic organizations and Pharmecutical companies in the west have claimed by ignoring Ayurvedic knowledge. Vandana Shiva, a global campaigner for a fair and honest Intellectual Property Rights system, says patents on herbal products derived from Neem, Amla, Jar Amla, Anar, Salai, Dudhi, Gulmendhi, Bagbherenda, Karela, Erand, Rangoon-kibel, Vilayetishisham and Chamkura also need to be revoked.[13]
Seven American and four Japanese firms have filed for grant of patents on formulations containing extracts of the herb Ashwagandha. Fruits, leaves and seeds of the Indian medicinal plant withania somnifera have been traditionally used for the Ayurvedic system as aphrodisiacs, diuretics and for treating memory loss. The Japanese patent applications are related to the use of the herb as a skin ointment and for promoting reproductive fertility. The U.S based company Natreon has also obtained a patent for an Ashwagandha extract.
Another US establishment, the New England Deaconess Hospital, has taken a patent on an Ashwagandha formulation claimed to alleviate symptoms associated with arthritis. It is clear that the Ashwagandha plant is catching the attention of scientists and more patents related to Ashwagandha are being filed or granted by different patent offices since 1996.[14]
Ayurvedic wisdom originated in the main Vedas as a part of way of life - a spiritual connection with spirit and nature. This is most evident reading Atharva Veda. Ayurveda was used to remove obstacles on one’s path to Self-Realization. At some point the medical aspects began to take priority over the spiritual forms of healing (ie, focusing on lifestyle, dharma and moksha. Today, these spiritual aspects of Ayurveda have taken a back seat to the medical focus. As Ayurveda becomes a more commercially viable career, the spiritual aspects may continue to lose ground. Yet there are a growing number of practitioners who practice mainly these spiritual therapies and find better results than limiting their approach to the medical, physical realm.
# Criticisms
## Scientific studies and standards
Critics object to the lack of rigorous scientific studies and clinical trials of many ayurvedic products. The National Center for Complementary and Alternative Medicine states that "most clinical trials of Ayurvedic approaches have been small, had problems with research designs, lacked appropriate control groups, or had other issues that affected how meaningful the results were."[15]
In India, scientific research in Ayurveda is largely undertaken by the statutory body of the Central Government, the Central Council for Research in Ayurveda and Siddha (CCRAS), through a national network of research institutes.[16] A large number of non-governmental organisations are also conducting research work on different aspects of Ayurveda[3]. However, "even staunch advocates of Ayurveda like cardiologist Dr. M.S. Valiathan...admit that 'clinical studies that would satisfy the liberal criteria of WHO World Health Organisation have been alarmingly few from India, in spite of patients crowding in Ayurvedic hospitals"'.[15]
## Safety concerns
There is evidence that using some ayurvedic medicine, especially those involving herbs, metals, minerals, or other materials involves potentially serious risks, including toxicity.[17][3][18]
A research study published in the Journal of the American Medical Association[19] found significant levels of toxic heavy metals such as lead, mercury and arsenic in 20% of Ayurvedic preparations that were made in South Asia for sale in America. The Journal found that, if taken according to the manufacturers' instructions, this 20% of remedies "could result in heavy metal intakes above published regulatory standards"[19] Similar studies have been performed in India, and have confirmed these results. Cases of metal toxicity from use of ayurvedic medicines are well known.[20] Some practitioners claimed that "heavy metals are integral to some formulations and have been used for centuries. There is no point of doing trials as they have been used safely and have mention in our ancient texts."[20]
There is a technique of detoxification applied to heavy metals and toxic herbs called samskaras, which is similar to the Chinese pao zhi although the Ayurvedic technique is more complex and may involve prayers as well as physical pharmacy techniques.[21] An intriguing study of the effectiveness of the Ayurvedic samskaras was printed in the Journal of Postgrad Medicine[22]:
Crude aconite is an extremely lethal substance. However, the science of Ayurveda looks upon aconite as a therapeutic entity. Crude aconite is always processed i.e. it undergoes 'samskaras' before being utilised in the Ayurvedic formulations. This study was undertaken in mice, to ascertain whether 'processed' aconite is less toxic as compared to the crude or unprocessed one. It was seen that crude aconite was significantly toxic to mice (100% mortality at a dose of 2.6 mg/mouse) whereas the fully processed aconite was absolutely non-toxic (no mortality at a dose even 8 times as high as that of crude aconite). Further, all the steps in the processing were essential for complete detoxification.[23]
The described detoxification is a simple chemical processing which involves four successive rounds of boiling the crude root in cow's urine (twice) and cow's milk (twice). Such processing is reasonably expected to chemically modify both toxic and proposed therapeutic components of the root. It will also lead to extraction of these compounds from the root into the boiling solvents, thereby decreasing their concentration in the final product.
It should also be noted that, while these washes appear to ameliorate the toxicity of the crude root, there is no evidence that the processed root has any therapeutic value. A search of the Citation Index, via Web of Science (isiknowledge.com), returned no mention of any therapeutic value for aconite. However, the literature is replete with instances of aconite poisoning, though no mention of specific processing is made in these poisoning cases.
## "Miracle Cures"
Some critics also question the safety of those Ayurvedic drugs that are said to provide "Miracle Cures". [24] The critics argue that simply following age-old Ayurvedic formulas is no guarantee of safety and the fundamental processes and concepts on which these ancient processes are based must be exposed to serious scientific scrutiny. | https://www.wikidoc.org/index.php/Ayurveda | |
8a72c9f44197b696ceb2b8fc190d50c4f1046f58 | wikidoc | BK virus | BK virus
# Overview
The BK virus is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon.
The BK virus was first recognized from a renal transplant patient. This BK virus is similar to another virus called the JCV since their genome sequence share 75% homology. Both of these viruses can be identified and differentiated from each other by carrying out serological tests using specific antibodies.
The BK virus rarely causes disease since many people who are infected with this virus are asymptomatic. If symptoms do appear then many of them will be mild such as having a respiratory infection or a fever. These are known as the primary infections. Latent infections can occur in the kidneys and sometimes in the brain. A latent infection occurs when the virus becomes reactivated. However it is not known how this virus is transmitted. It is known however that the virus is spread from person to person and not from an animal source. It has been suggested that this virus may be transmitted through respiratory fluids.
Clinically, BK virus becomes relevant in immunocompromised patients. It is notable as a cause for hemorrhagic cystitis in bone marrow transplant recipients. In renal transplant patients, it is associated with ureteral stenosis and interstitial nephritis. In addition, the presence of BK polyoma in the bladder is statistically linked to the development of bladder carcinoma.
This virus can be diagnosed by carrying out a biopsy in the kidneys. PCR techniques and LAMP (Loop mediated isothermal amplification) can also be carried out to identify the virus. Renal transplant patients infected with this virus can be treated by using cidofovir which is an antiviral drug. Cidofovir is a nucleotide analogue that has the ability to interfere with the action of the BK virus. It is known to have treated individuals with a renal transplant that were infected with this virus.
# Treatment
- BK virus treatment
- 1. Immunosuppression should be reduced in kidney transplant patients with definitive polyomavirus associated nephropathy.
- Immunosuppressant drugs
- Preferred regimen (1): Tacrolimus trough levels are commonly targeted to < 6 ng/mL,
- Preferred regimen (2): Cyclosporine trough levels to < 150 ng/mL ,
- Preferred regimen (3): Sirolimus trough levels of < 6 ng/mL, and
- Preferred regimen (4): Mycophenolate mofetil daily dose equivalents of ≤ 1000 mg.
- Note (1): Lower calcineurin inhibitor levels, that is targeting trough levels for Tacrolimus of 3 ng/mL and Cyclosporine of 100 ng/mL may be considered as a first step.
- Note (2): Additional strategies have been switching from Tacrolimus to low-dose Cyclosporine or switching from Mycophenolic acid to Leflunomide, to low-dose Sirolimus, or from calcineurin inhibitor to low-dose Sirolimus.
- Note (3): Immunosuppression is further adapted according to the course of serum creatinine concentration and the plasma viral loads, but responses may require several weeks.
- 2. In patients with sustained high-level plasma BK virus load despite adequately reduced immunosuppression, the adjunctive use of agents with antiviral activity may be considered
- Preferred regimen (1): Cidofovir 0.25 mg/kg-1.0 mg/kg IV at 1–3 weekly intervals, without Probenecid 1 mg/kg, administered weekly as a slow IV infusion after hydration, for up to 10 weeks.
- Preferred regimen (2): Loading dose of Leflunomide 100 mg PO for 5 days, followed by an initial maintenance dose of Leflunomide 40 mg PO.
- Note: Leflunomide is orally administered as a replacement for discontinued Mycophenolic acid.
- Preferred regimen (3): Intravenous immunoglobulins (IVIG) 0.2 g/kg-2.0 g/kg in conjunction with reduced immunosuppression.
- Preferred regimen (4): Fluoroquinolones may inhibit BKV replication.
- Note (1): Acute rejection following reduced immunosuppression for presumptive or definitive polyomavirus associated nephropathy should be treated according to standard protocols.
- Note (2): Anti-rejection treatment administered in patients with a history of BK virus replication with or without polyomavirus associated nephropathy should be accompanied by at least bi-weekly monitoring of the urine and plasma viral load.
# Prevention and prophylaxis
- Kidney transplant recipients should be screened for BKV replication to identify patients at increased risk of polyomavirus associated nephropathy.
- Retransplantation can be considered for patients after loss of a first kidney allograft due to polyomavirus associated nephropathy, but frequent screening for BK virus replication is recommended | BK virus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The BK virus is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon.
The BK virus was first recognized from a renal transplant patient. This BK virus is similar to another virus called the JCV since their genome sequence share 75% homology. Both of these viruses can be identified and differentiated from each other by carrying out serological tests using specific antibodies.
The BK virus rarely causes disease since many people who are infected with this virus are asymptomatic. If symptoms do appear then many of them will be mild such as having a respiratory infection or a fever. These are known as the primary infections. Latent infections can occur in the kidneys and sometimes in the brain. A latent infection occurs when the virus becomes reactivated. However it is not known how this virus is transmitted. It is known however that the virus is spread from person to person and not from an animal source. It has been suggested that this virus may be transmitted through respiratory fluids.
Clinically, BK virus becomes relevant in immunocompromised patients. It is notable as a cause for hemorrhagic cystitis in bone marrow transplant recipients. In renal transplant patients, it is associated with ureteral stenosis and interstitial nephritis. In addition, the presence of BK polyoma in the bladder is statistically linked to the development of bladder carcinoma.[1]
This virus can be diagnosed by carrying out a biopsy in the kidneys. PCR techniques and LAMP (Loop mediated isothermal amplification) can also be carried out to identify the virus.[2] Renal transplant patients infected with this virus can be treated by using cidofovir which is an antiviral drug. Cidofovir is a nucleotide analogue that has the ability to interfere with the action of the BK virus. It is known to have treated individuals with a renal transplant that were infected with this virus.
# Treatment
- BK virus treatment[3]
- 1. Immunosuppression should be reduced in kidney transplant patients with definitive polyomavirus associated nephropathy.
- Immunosuppressant drugs
- Preferred regimen (1): Tacrolimus trough levels are commonly targeted to < 6 ng/mL,
- Preferred regimen (2): Cyclosporine trough levels to < 150 ng/mL ,
- Preferred regimen (3): Sirolimus trough levels of < 6 ng/mL, and
- Preferred regimen (4): Mycophenolate mofetil daily dose equivalents of ≤ 1000 mg.
- Note (1): Lower calcineurin inhibitor levels, that is targeting trough levels for Tacrolimus of 3 ng/mL and Cyclosporine of 100 ng/mL may be considered as a first step.
- Note (2): Additional strategies have been switching from Tacrolimus to low-dose Cyclosporine or switching from Mycophenolic acid to Leflunomide, to low-dose Sirolimus, or from calcineurin inhibitor to low-dose Sirolimus.
- Note (3): Immunosuppression is further adapted according to the course of serum creatinine concentration and the plasma viral loads, but responses may require several weeks.
- 2. In patients with sustained high-level plasma BK virus load despite adequately reduced immunosuppression, the adjunctive use of agents with antiviral activity may be considered
- Preferred regimen (1): Cidofovir 0.25 mg/kg-1.0 mg/kg IV at 1–3 weekly intervals, without Probenecid 1 mg/kg, administered weekly as a slow IV infusion after hydration, for up to 10 weeks.
- Preferred regimen (2): Loading dose of Leflunomide 100 mg PO for 5 days, followed by an initial maintenance dose of Leflunomide 40 mg PO.
- Note: Leflunomide is orally administered as a replacement for discontinued Mycophenolic acid.
- Preferred regimen (3): Intravenous immunoglobulins (IVIG) 0.2 g/kg-2.0 g/kg in conjunction with reduced immunosuppression.
- Preferred regimen (4): Fluoroquinolones may inhibit BKV replication.
- Note (1): Acute rejection following reduced immunosuppression for presumptive or definitive polyomavirus associated nephropathy should be treated according to standard protocols.
- Note (2): Anti-rejection treatment administered in patients with a history of BK virus replication with or without polyomavirus associated nephropathy should be accompanied by at least bi-weekly monitoring of the urine and plasma viral load.
# Prevention and prophylaxis
- Kidney transplant recipients should be screened for BKV replication to identify patients at increased risk of polyomavirus associated nephropathy.
- Retransplantation can be considered for patients after loss of a first kidney allograft due to polyomavirus associated nephropathy, but frequent screening for BK virus replication is recommended | https://www.wikidoc.org/index.php/BK_virus | |
14e15a36211e5511c0cf63a51ed56ca9e64fe791 | wikidoc | Babbling | Babbling
Babbling (also called twaddling) is a stage in child language acquisition, during which an infant appears to be experimenting with uttering sounds of language, but not yet producing any recognizable words. (Crucially, the larynx or voicebox, originally high in the throat to let the baby breathe while swallowing, descends during 'the first year of life', allowing a pharynx to develop and all the sounds of human speech to be formed ). Babbling begins at approximately 5 to 7 months of age, when a baby's noises begin to sound like phonemes. Infants begin to produce recognizable words usually around 12 months, though babbling may continue for some time afterward.
# Types of Babbling
There are two types of babbling. Most people are familiar with the characteristic sounds made during babbling, namely reduplicative and variegated babbling. The former consists of repeated syllables, such as Template:IPA e.g. 'Ba-ba-ba-ba-ba-ba-ba,' whereas variegated babbling consists of a mix of syllables, e.g. 'ka-da-bu-ba-mi-doy-doy-doy.'
Here we must take note that the consonants that babbling infants produce tend to be any of the following : Template:IPA. On the other hand, the following consonants tend to be infrequently produced during phonological development : Template:IPA.
The complex nature of sounds that developing children produce make them difficult to categorize, but the above rules tend to hold true regardless of the language (e.g. Japanese, English, etc.) which children are exposed to.
# Babbling in nonhuman species
Human babies engage in babble as a sort of vocal play that occurs in a few other primate species, all which belong to the family Callitrichidae (marmosets & tamarins) and are cooperative breeders.
Sarah Blaffer Hrdy writes, "...marmoset and tamarin babies also babble. It may be that the infants of cooperative breeders are specially equipped to communicate with caretakers. This is not to say that babbling is not an important part of learning to talk, only to question which came first—babbling so as to develop into a talker, or a predisposition to evolve into a talker because among cooperative breeders, babies that babble are better tended and more likely to survive."
Terrence W. Deacon infers that human infants are not generally excited or upset when babbling, because they will babble spontaneously and incessantly only when emotionally calm. Deacon adds, "It is the first sign that human vocal motor output is at least partially under the control of the cortical motor system because babbling is basically vocal mimickry that happens in correspondence to the maturation of the cortical motor output pathways in the human brain."
Steven Pinker compares a child babbling to a person fiddling with a complex hi-fi system in an attempt to understand what the controls do. Most babbling consists of a small number of sounds, which suggests the child is preparing the basic sounds necessary to speak the language to which it is exposed.
Infants who are deaf also show vocal babbling, suggesting that early babbling arises from inherent human tendencies to use the vocable articulators in particular ways during early language acquisition. If they are exposed to sign language, they will babble with their hands at approximately the same time vocal babbling appears, although sign production appears a few months before word production generally does
in hearing children.
At 0-4 months babies gurgle, and coo (vowel sounds such as "oooh" and "aah"). And at 4-6 months babies may start to babble (adding consonants: "gaga," "dada"). At 6-12 months of age, babies typically
babble and enjoy vocal play as they experiment with a range of sounds. At 12-18 months, toddlers begin to use sound in a meaningful way. They utter
-ne-syllable words, make sounds imitating cars and planes, and say things like, "uh oh." Toddlers also understand the meaning of some words they cannot yet say. They may also use one word to represent a whole sentence. For example, "Juice" may mean, "Mother, I would like some juice,"
"You are drinking juice," or "Oh look, there is juice in the cup." At age
18-24 months, toddlers repeat words and can link words into short sentences. They use approximately 50 words, but can understand many more. They may use short sentences, such as, "She go bye bye." And "What you doing?" They may also use familiar words incorrectly, e.g., a child with a pet dog might describe all large furry animals as "doggie."
According to Menn and Stoel Gammon in The Development of Language, “This early period of prelinguistic vocalization can be divided into five stages,” the first of which begins at about age six months. Stage one is crying, stage two is cooing, stage three is vocal play, and stage four is canonical babbling. The fifth and final stage is conversational babbling, also known as the "jargon stage (usually occurring by about ten months of age). This jargon stage is defined as: “Pre-linguistic vocalizations in which infants use adult like stress and intonation.”
Hence, babbling occurs during the first year of life if the child is developing normally. As the baby grows and changes, his/her vocalizations change as well. Babies use these vocalizations to communicate. They commence vocal development by crying, progress to loud yelling noises, and finally make speech.
Children who can't babble for some physiological reason, such as having a breathing tube in their throat, do subsequently acquire normal pronunciation but their speech development is significantly delayed. | Babbling
Babbling (also called twaddling) is a stage in child language acquisition, during which an infant appears to be experimenting with uttering sounds of language, but not yet producing any recognizable words. (Crucially, the larynx or voicebox, originally high in the throat to let the baby breathe while swallowing, descends during 'the first year of life', allowing a pharynx to develop and all the sounds of human speech to be formed [1]). Babbling begins at approximately 5 to 7 months of age, when a baby's noises begin to sound like phonemes. Infants begin to produce recognizable words usually around 12 months, though babbling may continue for some time afterward.
# Types of Babbling
There are two types of babbling. Most people are familiar with the characteristic sounds made during babbling, namely reduplicative and variegated babbling. The former consists of repeated syllables, such as Template:IPA e.g. 'Ba-ba-ba-ba-ba-ba-ba,' whereas variegated babbling consists of a mix of syllables, e.g. 'ka-da-bu-ba-mi-doy-doy-doy.'
Here we must take note that the consonants that babbling infants produce tend to be any of the following : Template:IPA. On the other hand, the following consonants tend to be infrequently produced during phonological development : Template:IPA.
The complex nature of sounds that developing children produce make them difficult to categorize, but the above rules tend to hold true regardless of the language (e.g. Japanese, English, etc.) which children are exposed to. [2]
# Babbling in nonhuman species
Human babies engage in babble as a sort of vocal play that occurs in a few other primate species, all which belong to the family Callitrichidae (marmosets & tamarins) and are cooperative breeders.
Sarah Blaffer Hrdy writes, "...marmoset and tamarin babies also babble. It may be that the infants of cooperative breeders are specially equipped to communicate with caretakers. This is not to say that babbling is not an important part of learning to talk, only to question which came first—babbling so as to develop into a talker, or a predisposition to evolve into a talker because among cooperative breeders, babies that babble are better tended and more likely to survive." [3]
Terrence W. Deacon infers that human infants are not generally excited or upset when babbling, because they will babble spontaneously and incessantly only when emotionally calm. Deacon adds, "It is the first sign that human vocal motor output is at least partially under the control of the cortical motor system because babbling is basically vocal mimickry that happens in correspondence to the maturation of the cortical motor output pathways in the human brain."
Steven Pinker compares a child babbling to a person fiddling with a complex hi-fi system in an attempt to understand what the controls do. Most babbling consists of a small number of sounds, which suggests the child is preparing the basic sounds necessary to speak the language to which it is exposed.
Infants who are deaf also show vocal babbling, suggesting that early babbling arises from inherent human tendencies to use the vocable articulators in particular ways during early language acquisition. If they are exposed to sign language, they will babble with their hands at approximately the same time vocal babbling appears, although sign production appears a few months before word production generally does
in hearing children.
At 0-4 months babies gurgle, and coo (vowel sounds such as "oooh" and "aah"). And at 4-6 months babies may start to babble (adding consonants: "gaga," "dada"). At 6-12 months of age, babies typically
babble and enjoy vocal play as they experiment with a range of sounds. At 12-18 months, toddlers begin to use sound in a meaningful way. They utter
one-syllable words, make sounds imitating cars and planes, and say things like, "uh oh." Toddlers also understand the meaning of some words they cannot yet say. They may also use one word to represent a whole sentence. For example, "Juice" may mean, "Mother, I would like some juice,"
"You are drinking juice," or "Oh look, there is juice in the cup." At age
18-24 months, toddlers repeat words and can link words into short sentences. They use approximately 50 words, but can understand many more. They may use short sentences, such as, "She go bye bye." And "What you doing?" They may also use familiar words incorrectly, e.g., a child with a pet dog might describe all large furry animals as "doggie."
According to Menn and Stoel Gammon in The Development of Language, “This early period of prelinguistic vocalization can be divided into five stages,” the first of which begins at about age six months. Stage one is crying, stage two is cooing, stage three is vocal play, and stage four is canonical babbling. The fifth and final stage is conversational babbling, also known as the "jargon stage (usually occurring by about ten months of age). This jargon stage is defined as: “Pre-linguistic vocalizations in which infants use adult like stress and intonation.” [4]
Hence, babbling occurs during the first year of life if the child is developing normally. As the baby grows and changes, his/her vocalizations change as well. Babies use these vocalizations to communicate. They commence vocal development by crying, progress to loud yelling noises, and finally make speech.
Children who can't babble for some physiological reason, such as having a breathing tube in their throat, do subsequently acquire normal pronunciation but their speech development is significantly delayed. [5] | https://www.wikidoc.org/index.php/Babbling | |
548940776e6a4b87fdd26ba4593eaa13e8015a4c | wikidoc | Bacillus | Bacillus
# Overview
Bacillus is a genus of rod-shaped, Gram-positive bacteria and a member of the division Firmicutes. Bacillus species are either obligate or facultative aerobes, and test positive for the enzyme catalase. Ubiquitous in nature, Bacillus includes both free-living and pathogenic species. Under stressful environmental conditions, the cells produce oval endospores that can stay dormant for extended periods. These characteristics originally defined the genus, but not all such species are closely related, and many have been moved to other genera.
# Organism
Bacillus subtilis is one of the best understood prokaryotes in terms of molecular biology and cell biology. Its superb genetic amenability and relatively large size have provided the powerful tools required to investigate a bacterium from all possible aspects. Recent improvements in fluorescence microscopy techniques have provided novel and amazing insight into the dynamic structure of a single cell organism. Research on Bacillus subtilis has been at the forefront of bacterial molecular biology and cytology, and the organism is a model for differentiation, gene/protein regulation, and cell cycle events in bacteria.
Two Bacillus species are considered medically significant: B. anthracis, which causes anthrax, and B. cereus, which causes a foodborne illness similar to that of Staphylococcus. A third species, B. thuringiensis, is an important insect pathogen, and is sometimes used to control insect pests. The type species is B. subtilis, an important model organism. It is also a notable food spoiler, causing ropiness in bread and related food. B. coagulans is also important in food spoilage.
An easy way to isolate Bacillus is by placing non-sterile soil in a test tube with water, shaking, placing in melted Mannitol Salt Agar, and incubating at room temperature for at least a day. Colonies are usually large, spreading and irregularly-shaped. Under the microscope, the Bacillus appear as rods, and a substantial portion usually contain an oval endospore at one end, making it bulge.
# The cell wall
The cell wall of Bacillus is a rigid structure on the outside of the cell that forms the first barrier between the bacterium and the environment, and at the same time maintains cell shape and withstands the pressure generated by the cell's turgor. The cell wall is composed of peptidoglycan, teichoic and teichuronic acids. B. subtilis is the first bacterium for which the role of an actin-like cytoskeleton in cell shape determination and peptidoglycan synthesis was identified and for which the entire set of peptidoglycan synthesizing enzymes was localised. The role of the cytoskeleton in shape generation and maintenance is important .
# Word ambiguity
Although Bacillus, capitalized and italicized, specifically refers to the genus, the word 'bacillus' may also be used to describe any rod-shaped bacterium, and in this sense, bacilli are found in many different taxonomic groups of bacteria.
Likewise, Bacilli refers to the particular class Bacillus belongs to, while bacilli are any rod-shaped bacteria.
It should be noted that the cell morphology term bacillus does not necessarily indicate Gram-positive staining, as E. coli is a Gram-negative, rod-shaped bacteria. | Bacillus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bacillus is a genus of rod-shaped, Gram-positive bacteria and a member of the division Firmicutes. Bacillus species are either obligate or facultative aerobes, and test positive for the enzyme catalase.[1] Ubiquitous in nature, Bacillus includes both free-living and pathogenic species. Under stressful environmental conditions, the cells produce oval endospores that can stay dormant for extended periods. These characteristics originally defined the genus, but not all such species are closely related, and many have been moved to other genera.[2]
# Organism
Bacillus subtilis is one of the best understood prokaryotes in terms of molecular biology and cell biology. Its superb genetic amenability and relatively large size have provided the powerful tools required to investigate a bacterium from all possible aspects. Recent improvements in fluorescence microscopy techniques have provided novel and amazing insight into the dynamic structure of a single cell organism. Research on Bacillus subtilis has been at the forefront of bacterial molecular biology and cytology, and the organism is a model for differentiation, gene/protein regulation, and cell cycle events in bacteria. [3]
Two Bacillus species are considered medically significant: B. anthracis, which causes anthrax, and B. cereus, which causes a foodborne illness similar to that of Staphylococcus.[4] A third species, B. thuringiensis, is an important insect pathogen, and is sometimes used to control insect pests. The type species is B. subtilis, an important model organism. It is also a notable food spoiler, causing ropiness in bread and related food. B. coagulans is also important in food spoilage.
An easy way to isolate Bacillus is by placing non-sterile soil in a test tube with water, shaking, placing in melted Mannitol Salt Agar, and incubating at room temperature for at least a day. Colonies are usually large, spreading and irregularly-shaped. Under the microscope, the Bacillus appear as rods, and a substantial portion usually contain an oval endospore at one end, making it bulge.
# The cell wall
The cell wall of Bacillus is a rigid structure on the outside of the cell that forms the first barrier between the bacterium and the environment, and at the same time maintains cell shape and withstands the pressure generated by the cell's turgor. The cell wall is composed of peptidoglycan, teichoic and teichuronic acids. B. subtilis is the first bacterium for which the role of an actin-like cytoskeleton in cell shape determination and peptidoglycan synthesis was identified and for which the entire set of peptidoglycan synthesizing enzymes was localised. The role of the cytoskeleton in shape generation and maintenance is important [5].
# Word ambiguity
Although Bacillus, capitalized and italicized, specifically refers to the genus, the word 'bacillus' may also be used to describe any rod-shaped bacterium, and in this sense, bacilli are found in many different taxonomic groups of bacteria.
Likewise, Bacilli refers to the particular class Bacillus belongs to, while bacilli are any rod-shaped bacteria.
It should be noted that the cell morphology term bacillus does not necessarily indicate Gram-positive staining, as E. coli is a Gram-negative, rod-shaped bacteria. | https://www.wikidoc.org/index.php/Bacillus | |
5015f706506f0d62a94dd19de594e395301e204d | wikidoc | Baclofen | Baclofen
# 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
Baclofen is a skeletal muscle relaxant, spasmolytic that is FDA approved for the treatment of spasticity. Common adverse reactions include cardiovascular: hypotension, gastrointestinal: constipation, nausea, vomiting, musculoskeletal: Poor muscle tone, neurologic: asthenia, dizziness, urinary complication, fatigue, and shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Do not abruptly discontinue or withdraw therapy.
- Signs of overdose may appear suddenly and insidiously.
- Oral
- 5 mg orally 3 times a day; may increase dosage by 15 mg/day increments every 3 days to a max dose of 80 mg/day (3 to 4 divided doses)
- Intrathecal
- Test dose, 50 mcg in 1 mL intrathecally given over at least 1 minute; may increase dosage by 25 mcg increments every 24 hours until a 4- to 8-hour positive clinical response is demonstrated. Patients must respond to a single bolus dose of no greater than 100 mcg/2mL to be acceptable candidates for chronic therapy with the intrathecal infusion pump.
- Post-implant titration, initial (test dose efficacy less than 8 hours), the initial daily dose is double the screening dose administered intrathecally over 24 hour.
- Post-implant titration, initial (test dose efficacy greater than 8 hour), the initial daily dose is the same as the screening dose administered intrathecally over 24 hours.
- Post-implant titration, spinal cord spasticity, no dosage increases during first 24 hours; may slowly increase intrathecal dosage by 10% to 30% once every 24 hours.
- Post-implant titration, cerebral origin spasticity, no dosage increases during the first 24 hours; may slowly increase intrathecal dosage by 5% to 15% once every 24 hours.
- Post-implant maintenance, spinal cord spasticity, intrathecal daily dose may be increased by 10% to 40% (max 40%) OR reduced by 10% to 20% as needed during periodic pump refills. Most patients require gradual increase in dose over time to maintain optimal response. Maintenance dosages usually range between 300 to 800 mcg/day (range 12 to 2003 mcg/day).
- Post-implant maintenance, cerebral origin spasticity, intrathecal daily dose may be increased by 5% to 20% (max 20%) OR reduced by 10% to 20% as needed during periodic pump refills. Most patients require gradual increase in dose over time to maintain optimal response. Maintenance dosages usually range between 90 to 703 mcg/day (range 22 to 1400 mcg/day).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Intractable hiccough
- Spasm of bladder.
- Stiff-man syndrome.
- Tetanus.
- Trigeminal neuralgia.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Baclofen in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of oral baclofen use in children under 12 years of age have not been established.
- Safety and effectiveness have not been established in children under 4 years of age.
- Do not abruptly discontinue or withdraw therapy.
- Signs of overdose may appear suddenly and insidiously.
- Oral
- 2 to 7 years old
- 8 years and older
- Intrathecal
- Test dose, 25 to 50 mcg intrathecally given over at least 1 minute; may increase dosage by 25 mcg increments every 24 hour until a 4- to 8-hour positive clinical response is demonstrated. Patients must respond to a single bolus dose of no greater than 100 mcg/2mL to be acceptable candidates for chronic therapy with the intrathecal infusion pump.
- Post-implant titration, after the first 24 hour, the intrathecal daily dose should be increased slowly by 5% to 15% only once every 24 hour, until the desired clinical effect is achieved.
- Post-implant maintenance, intrathecal daily dose may be increased by 5% to 20% (MAX 20%) OR reduced by 10% to 20% as needed during periodic pump refills. Most patients require gradual increase in dose over time to maintain optimal response. The average maintenance dose for children under age 12 years is 274 mcg/day (range 24 to 1199 mcg/day).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Baclofen in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Baclofen in pediatric patients.
# Contraindications
- Hypersensitivity to baclofen.
# Warnings
- Hallucinations and seizures have occurred on abrupt withdrawal of baclofen. Therefore, except for serious adverse reactions, the dose should be reduced slowly when the drug is discontinued.
- Because baclofen is primarily excreted unchanged through the kidneys, it should be given with caution, and it may be necessary to reduce the dosage.
- Baclofen has not significantly benefited patients with stroke. These patients have also shown poor tolerability to the drug.
- Baclofen has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times the maximum dose recommended for human use, at a dose which caused significant reductions in food intake and weight gain in dams. This abnormality was not seen in mice or rabbits.
- There was also an increased incidence of incomplete sternebral ossification in fetuses of rats given approximately 13 times the maximum recommended human dose, and an increased incidence of unossified phalangeal nuclei of forelimbs and hindlimbs in fetuses of rabbits given approximately 7 times the maximum recommended human dose. In mice, no teratogenic effects were observed, although reductions in mean fetal weight with consequent delays in skeletal ossification were present when dams were given 17 and 34 times the human daily dose. There are no studies in pregnant women. Baclofen should be used during pregnancy only if the benefit clearly justifies the potential risk to the fetus.
# Adverse Reactions
## Clinical Trials Experience
- The most common is transient drowsiness (10-63%). In one controlled study of 175 patients, transient drowsiness was observed in 63% of those receiving baclofen compared to 36% of those in the placebo group. Other common adverse reactions are dizziness (5-15%), weakness (5-15%) and fatigue (2-4%)
### Others reported
- Confusion (1-11%), headache (4-8%), insomnia (2-7%); and rarely, euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic seizure.
- Hypotension (0-9%). Rare instances of dyspnea, palpitation, chest pain, syncope.
- Nausea (4-12%), constipation (2-6%); and rarely, dry mouth, anorexia, taste disorder, abdominal pain, vomiting, diarrhea, and positive test for occult blood in stool.
- Urinary frequency (2-6%); and rarely, enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, hematuria.
- Instances of rash, pruritis, ankle edema, excessive perspiration, weight gain, nasal congestion. Some of the CNS and genitourinary symptoms may be related to the underlying disease rather than to drug therapy. The following laboratory tests have been found to be abnormal in a few patients receiving baclofen; increased SGOT, elevated alkaline phosphatase, and elevation of blood sugar.
## Postmarketing Experience
There is limited information regarding Baclofen Postmarketing Experience in the drug label.
# Drug Interactions
- There is limited information regarding drug interactions of Baclofen.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Baclofen in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Baclofen in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Baclofen during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Baclofen in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Baclofen in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Baclofen in geriatric settings.
### Gender
There is no FDA guidance on the use of Baclofen with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Baclofen with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Baclofen in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Baclofen in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Baclofen in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Baclofen in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The determination of optimal dosage requires individual titration. Start therapy at a low dosage and increase gradually until optimum effect is achieved (usually between 40-80 mg daily).
- The following dosage titration schedule is suggested:
- 5 mg t.i.d. for 3 days
- 10 mg t.i.d. for 3 days
- 15 mg t.i.d. for 3 days
- 20 mg t.i.d. for 3 days
- Thereafter additional increases may be necessary but the total dose should not exceed a maximum of 80 mg daily (20 mg q.i.d).
- The lowest dose compatible with an optimal response is recommended. If benefits are not evident after a reasonable trial period, patients should be slowly withdrawn from the drug (see Warnings Abrupt Drug Withdrawal).
### Monitoring
There is limited information regarding Baclofen Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Baclofen and IV administrations.
# Overdosage
- Vomiting, muscular hypotonia, drowsiness, accommodation disorders, coma, respiratory depression and seizures.
- In the alert patient, empty the stomach promptly by induced emesis followed by lavage. In the obtunded patient, secure the airway with a cuffed endotracheal tube before beginning lavage (do not induce emesis). Maintain adequate respiratory exchange, do not use respiratory stimulants.
# Pharmacology
## Mechanism of Action
- The precise mechanism of action of baclofen is not fully known. Baclofen is capable of inhibiting both monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Although baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA), there is no conclusive evidence that actions on GABA systems are involved in the production of its clinical effects. In studies with animals baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression.
## Structure
- Its chemical name is 4-amino-3-(4-chlorophenyl) butanoic acid. The structural formula is:
## Pharmacodynamics
There is limited information regarding Baclofen Pharmacodynamics in the drug label.
## Pharmacokinetics
- Baclofen is rapidly and extensively absorbed and eliminated. Absorption may be dose-dependent, being reduced with increasing doses. Baclofen is excreted primarily by the kidney in unchanged form and there is relatively large inter-subject variation in absorption and/or elimination.
## Nonclinical Toxicology
There is limited information regarding Baclofen Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Baclofen Clinical Studies in the drug label.
# How Supplied
- Baclofen Tablets, USP, 10 mg are white to off white, round, flat face bevel edge, uncoated tablets debossed ‘291’ on one side and scored on other side are available as follows:
- Baclofen Tablets, USP, 20 mg are white to off white, round, flat face bevel edge, uncoated tablets debossed ‘292’ on one side and scored on other side are available as follows:
- Pharmacist: Dispense in well closed container with child resistant closure as defined in USP.
## Storage
- Store at 20 - 25° C (68 - 77° F) .
C.S. No.: 5532T01
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Baclofen Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Baclofen 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 Baclofen Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Baclofen Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Baclofen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
# Disclaimer
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# Overview
Baclofen is a skeletal muscle relaxant, spasmolytic that is FDA approved for the treatment of spasticity. Common adverse reactions include cardiovascular: hypotension, gastrointestinal: constipation, nausea, vomiting, musculoskeletal: Poor muscle tone, neurologic: asthenia, dizziness, urinary complication, fatigue, and shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Do not abruptly discontinue or withdraw therapy.
- Signs of overdose may appear suddenly and insidiously.
- Oral
- 5 mg orally 3 times a day; may increase dosage by 15 mg/day increments every 3 days to a max dose of 80 mg/day (3 to 4 divided doses)
- Intrathecal
- Test dose, 50 mcg in 1 mL intrathecally given over at least 1 minute; may increase dosage by 25 mcg increments every 24 hours until a 4- to 8-hour positive clinical response is demonstrated. Patients must respond to a single bolus dose of no greater than 100 mcg/2mL to be acceptable candidates for chronic therapy with the intrathecal infusion pump.
- Post-implant titration, initial (test dose efficacy less than 8 hours), the initial daily dose is double the screening dose administered intrathecally over 24 hour.
- Post-implant titration, initial (test dose efficacy greater than 8 hour), the initial daily dose is the same as the screening dose administered intrathecally over 24 hours.
- Post-implant titration, spinal cord spasticity, no dosage increases during first 24 hours; may slowly increase intrathecal dosage by 10% to 30% once every 24 hours.
- Post-implant titration, cerebral origin spasticity, no dosage increases during the first 24 hours; may slowly increase intrathecal dosage by 5% to 15% once every 24 hours.
- Post-implant maintenance, spinal cord spasticity, intrathecal daily dose may be increased by 10% to 40% (max 40%) OR reduced by 10% to 20% as needed during periodic pump refills. Most patients require gradual increase in dose over time to maintain optimal response. Maintenance dosages usually range between 300 to 800 mcg/day (range 12 to 2003 mcg/day).
- Post-implant maintenance, cerebral origin spasticity, intrathecal daily dose may be increased by 5% to 20% (max 20%) OR reduced by 10% to 20% as needed during periodic pump refills. Most patients require gradual increase in dose over time to maintain optimal response. Maintenance dosages usually range between 90 to 703 mcg/day (range 22 to 1400 mcg/day).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Intractable hiccough
- Spasm of bladder.
- Stiff-man syndrome.
- Tetanus.
- Trigeminal neuralgia.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Baclofen in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of oral baclofen use in children under 12 years of age have not been established.
- Safety and effectiveness have not been established in children under 4 years of age.
- Do not abruptly discontinue or withdraw therapy.
- Signs of overdose may appear suddenly and insidiously.
- Oral
- 2 to 7 years old
- 8 years and older
- Intrathecal
- Test dose, 25 to 50 mcg intrathecally given over at least 1 minute; may increase dosage by 25 mcg increments every 24 hour until a 4- to 8-hour positive clinical response is demonstrated. Patients must respond to a single bolus dose of no greater than 100 mcg/2mL to be acceptable candidates for chronic therapy with the intrathecal infusion pump.
- Post-implant titration, after the first 24 hour, the intrathecal daily dose should be increased slowly by 5% to 15% only once every 24 hour, until the desired clinical effect is achieved.
- Post-implant maintenance, intrathecal daily dose may be increased by 5% to 20% (MAX 20%) OR reduced by 10% to 20% as needed during periodic pump refills. Most patients require gradual increase in dose over time to maintain optimal response. The average maintenance dose for children under age 12 years is 274 mcg/day (range 24 to 1199 mcg/day).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Baclofen in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Baclofen in pediatric patients.
# Contraindications
- Hypersensitivity to baclofen.
# Warnings
- Hallucinations and seizures have occurred on abrupt withdrawal of baclofen. Therefore, except for serious adverse reactions, the dose should be reduced slowly when the drug is discontinued.
- Because baclofen is primarily excreted unchanged through the kidneys, it should be given with caution, and it may be necessary to reduce the dosage.
- Baclofen has not significantly benefited patients with stroke. These patients have also shown poor tolerability to the drug.
- Baclofen has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times the maximum dose recommended for human use, at a dose which caused significant reductions in food intake and weight gain in dams. This abnormality was not seen in mice or rabbits.
- There was also an increased incidence of incomplete sternebral ossification in fetuses of rats given approximately 13 times the maximum recommended human dose, and an increased incidence of unossified phalangeal nuclei of forelimbs and hindlimbs in fetuses of rabbits given approximately 7 times the maximum recommended human dose. In mice, no teratogenic effects were observed, although reductions in mean fetal weight with consequent delays in skeletal ossification were present when dams were given 17 and 34 times the human daily dose. There are no studies in pregnant women. Baclofen should be used during pregnancy only if the benefit clearly justifies the potential risk to the fetus.
# Adverse Reactions
## Clinical Trials Experience
- The most common is transient drowsiness (10-63%). In one controlled study of 175 patients, transient drowsiness was observed in 63% of those receiving baclofen compared to 36% of those in the placebo group. Other common adverse reactions are dizziness (5-15%), weakness (5-15%) and fatigue (2-4%)
### Others reported
- Confusion (1-11%), headache (4-8%), insomnia (2-7%); and rarely, euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic seizure.
- Hypotension (0-9%). Rare instances of dyspnea, palpitation, chest pain, syncope.
- Nausea (4-12%), constipation (2-6%); and rarely, dry mouth, anorexia, taste disorder, abdominal pain, vomiting, diarrhea, and positive test for occult blood in stool.
- Urinary frequency (2-6%); and rarely, enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, hematuria.
- Instances of rash, pruritis, ankle edema, excessive perspiration, weight gain, nasal congestion. Some of the CNS and genitourinary symptoms may be related to the underlying disease rather than to drug therapy. The following laboratory tests have been found to be abnormal in a few patients receiving baclofen; increased SGOT, elevated alkaline phosphatase, and elevation of blood sugar.
## Postmarketing Experience
There is limited information regarding Baclofen Postmarketing Experience in the drug label.
# Drug Interactions
- There is limited information regarding drug interactions of Baclofen.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Baclofen in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Baclofen in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Baclofen during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Baclofen in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Baclofen in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Baclofen in geriatric settings.
### Gender
There is no FDA guidance on the use of Baclofen with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Baclofen with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Baclofen in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Baclofen in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Baclofen in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Baclofen in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The determination of optimal dosage requires individual titration. Start therapy at a low dosage and increase gradually until optimum effect is achieved (usually between 40-80 mg daily).
- The following dosage titration schedule is suggested:
- 5 mg t.i.d. for 3 days
- 10 mg t.i.d. for 3 days
- 15 mg t.i.d. for 3 days
- 20 mg t.i.d. for 3 days
- Thereafter additional increases may be necessary but the total dose should not exceed a maximum of 80 mg daily (20 mg q.i.d).
- The lowest dose compatible with an optimal response is recommended. If benefits are not evident after a reasonable trial period, patients should be slowly withdrawn from the drug (see Warnings Abrupt Drug Withdrawal).
### Monitoring
There is limited information regarding Baclofen Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Baclofen and IV administrations.
# Overdosage
- Vomiting, muscular hypotonia, drowsiness, accommodation disorders, coma, respiratory depression and seizures.
- In the alert patient, empty the stomach promptly by induced emesis followed by lavage. In the obtunded patient, secure the airway with a cuffed endotracheal tube before beginning lavage (do not induce emesis). Maintain adequate respiratory exchange, do not use respiratory stimulants.
# Pharmacology
## Mechanism of Action
- The precise mechanism of action of baclofen is not fully known. Baclofen is capable of inhibiting both monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Although baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA), there is no conclusive evidence that actions on GABA systems are involved in the production of its clinical effects. In studies with animals baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression.
## Structure
- Its chemical name is 4-amino-3-(4-chlorophenyl) butanoic acid. The structural formula is:
## Pharmacodynamics
There is limited information regarding Baclofen Pharmacodynamics in the drug label.
## Pharmacokinetics
- Baclofen is rapidly and extensively absorbed and eliminated. Absorption may be dose-dependent, being reduced with increasing doses. Baclofen is excreted primarily by the kidney in unchanged form and there is relatively large inter-subject variation in absorption and/or elimination.
## Nonclinical Toxicology
There is limited information regarding Baclofen Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Baclofen Clinical Studies in the drug label.
# How Supplied
- Baclofen Tablets, USP, 10 mg are white to off white, round, flat face bevel edge, uncoated tablets debossed ‘291’ on one side and scored on other side are available as follows:
- Baclofen Tablets, USP, 20 mg are white to off white, round, flat face bevel edge, uncoated tablets debossed ‘292’ on one side and scored on other side are available as follows:
- Pharmacist: Dispense in well closed container with child resistant closure as defined in USP.
## Storage
- Store at 20 - 25° C (68 - 77° F) [See USP Controlled Room Temperature].
C.S. No.: 5532T01
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Baclofen Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Baclofen 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 Baclofen Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Baclofen Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Baclofen | |
29148f14d0b14c1c59b832ccec2a0a83078599e5 | wikidoc | Bacteria | Bacteria
Bacteria (singular: bacterium) are unicellular microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods to spirals. Bacteria are ubiquitous in every habitat on Earth, growing in soil, Hot spring|acidic hot springs, radioactive waste, seawater, and deep in the Earth's crust. There are typically 40 million bacterial cells in a gram of soil and a million bacterial cells in a millilitre of fresh water; in all, there are approximately five nonillion (5×1030) bacteria on Earth, forming much of the world's biomass. Bacteria are vital in recycling nutrients, and many important steps in nutrient cycles depend on bacteria, such as the fixation of nitrogen from the atmosphere. However, most of these bacteria have not been characterized, and only about half of the phyla of bacteria have species that can be cultured in the laboratory. The study of bacteria is known as bacteriology, a branch of microbiology.
There are approximately ten times as many bacterial cells as human cells in the human body, with large numbers of bacteria on the skin and in the digestive tract. Although the vast majority of these bacteria are rendered harmless by the protective effects of the immune system, and a few are beneficial, some are pathogenic bacteria and cause infectious diseases, including cholera, syphilis, anthrax, leprosy and bubonic plague. The most common fatal bacterial diseases are respiratory infections, with tuberculosis alone killing about 2 million people a year, mostly in sub-Saharan Africa. In developed countries, antibiotics are used to treat bacterial infections and in various agricultural processes, so antibiotic resistance is becoming common. In industry, bacteria are important in processes such as sewage treatment, the production of cheese and yoghurt, and the manufacture of antibiotics and other chemicals.
Bacteria are prokaryotes. Unlike cells of animals and other eukaryotes, bacterial cells do not contain a nucleus and rarely harbour membrane-bound organelles. Although the term bacteria traditionally included all prokaryotes, the scientific classification changed after the discovery in the 1990s that prokaryotic life consists of two very different groups of organisms that evolved independently from an ancient common ancestor. These evolutionary domains are called Bacteria and Archaea.
# History of bacteriology
Bacteria were first observed by Antonie van Leeuwenhoek in 1676, using a single-lens microscope of his own design. He called them "animalcules" and published his observations in a series of letters to the Royal Society. The name bacterium was introduced much later, by Christian Gottfried Ehrenberg in 1838, and is derived from the Greek word βακτήριον -α , bacterion -a , meaning "small staff".
Louis Pasteur demonstrated in 1859 that the fermentation process is caused by the growth of microorganisms, and that this growth is not due to spontaneous generation. (Yeasts and molds, commonly associated with fermentation, are not bacteria, but rather fungi.) Along with his contemporary, Robert Koch, Pasteur was an early advocate of the germ theory of disease.
Robert Koch was a pioneer in medical microbiology and worked on cholera, anthrax and tuberculosis. In his research into tuberculosis, Koch finally proved the germ theory, for which he was awarded a Nobel Prize in 1905. In Koch's postulates, he set out criteria to test if an organism is the cause of a disease; these postulates are still used today.
Though it was known in the nineteenth century that bacteria are the cause of many diseases, no effective antibacterial treatments were available. In 1910, Paul Ehrlich developed the first antibiotic, by changing dyes that selectively stained Treponema pallidum—the spirochaete that causes syphilis—into compounds that selectively killed the pathogen. Ehrlich had been awarded a 1908 Nobel Prize for his work on immunology, and pioneered the use of stains to detect and identify bacteria, with his work being the basis of the Gram stain and the Ziehl-Neelsen stain.
A major step forward in the study of bacteria was the recognition in 1977 by Carl Woese that archaea have a separate line of evolutionary descent from bacteria. This new phylogenetic taxonomy was based on the sequencing of 16S ribosomal RNA, and divided prokaryotes into two evolutionary domains, as part of the three-domain system.
# Origin and early evolution
The ancestors of modern bacteria were single-celled microorganisms that were the first forms of life to develop on earth, about 4 billion years ago. For about 3 billion years, all organisms were microscopic, and bacteria and archaea were the dominant forms of life. Although bacterial fossils exist, such as stromatolites, their lack of distinctive morphology prevents them from being used to examine the past history of bacterial evolution, or to date the time of origin of a particular bacterial species. However, gene sequences can be used to reconstruct the bacterial phylogeny, and these studies indicate that bacteria diverged first from the archaeal/eukaryotic lineage. The most recent common ancestor of bacteria and archaea was probably a hyperthermophile that lived about 2.5 billion–3.2 billion years ago.
Bacteria were also involved in the second great evolutionary divergence, that of the archaea and eukaryotes. Here, eukaryotes resulted from ancient bacteria entering into endosymbiotic associations with the ancestors of eukaryotic cells, which were themselves possibly related to the Archaea. This involved the engulfment by proto-eukaryotic cells of alpha-proteobacterial symbionts to form either mitochondria or hydrogenosomes, which are still being found in all known Eukarya (sometimes in highly reduced form, e.g. in ancient "amitochondrial" protozoa). Later on, an independent second engulfment by some mitochondria-containing eukaryotes of cyanobacterial-like organisms led to the formation of chloroplasts in algae and plants. There are even some algal groups known that clearly originated from subsequent events of endosymbiosis by heterotrophic eukaryotic hosts engulfing a eukaryotic algae that developed into "second-generation" plastids.
# Morphology
Bacteria display a wide diversity of shapes and sizes, called morphologies. Bacterial cells are about one tenth the size of eukaryotic cells and are typically 0.5–5.0 micrometres in length. However, a few species–for example Thiomargarita namibiensis and Epulopiscium fishelsoni–are up to half a millimetre long and are visible to the unaided eye. Among the smallest bacteria are members of the genus Mycoplasma, which measure only 0.3 micrometres, as small as the largest viruses.
Most bacterial species are either spherical, called cocci (sing. coccus, from Greek kókkos, grain, seed) or rod-shaped, called bacilli (sing. bacillus, from Latin baculus, stick). Some rod-shaped bacteria, called vibrio, are slightly curved or comma-shaped; others, can be spiral-shaped, called spirilla, or tightly coiled, called spirochaetes. A small number of species even have tetrahedral or cuboidal shapes. This wide variety of shapes is determined by the bacterial cell wall and cytoskeleton, and is important because it can influence the ability of bacteria to acquire nutrients, attach to surfaces, swim through liquids and escape predators.
Many bacterial species exist simply as single cells, others associate in characteristic patterns: Neisseria form diploids (pairs), Streptococcus form chains, and Staphylococcus group together in "bunch of grapes" clusters. Bacteria can also be elongated to form filaments, for example the Actinobacteria. Filamentous bacteria are often surrounded by a sheath that contains many individual cells; certain types, such as species of the genus Nocardia, even form complex, branched filaments, similar in appearance to fungal mycelia.
Bacteria often attach to surfaces and form dense aggregations called biofilms or bacterial mats. These films can range from a few micrometers in thickness to up to half a meter in depth, and may contain multiple species of bacteria, protists and archaea. Bacteria living in biofilms display a complex arrangement of cells and extracellular components, forming secondary structures such as microcolonies, through which there are networks of channels to enable better diffusion of nutrients. In natural environments, such as soil or the surfaces of plants, the majority of bacteria are bound to surfaces in biofilms. Biofilms are also important for chronic bacterial infections and infections of implanted medical devices, as bacteria protected within these structures are much harder to kill than individual bacteria.
Even more complex morphological changes are sometimes possible. For example, when starved of amino acids, Myxobacteria detect surrounding cells in a process known as quorum sensing, migrate towards each other, and aggregate to form fruiting bodies up to 500 micrometres long and containing approximately 100,000 bacterial cells. In these fruiting bodies, the bacteria perform separate tasks; this type of cooperation is a simple type of multicellular organisation. For example, about one in 10 cells migrate to the top of these fruiting bodies and differentiate into a specialised dormant state called myxospores, which are more resistant to desiccation and other adverse environmental conditions than are ordinary cells.
# Cellular structure
## Intracellular structures
The bacterial cell is surrounded by a lipid membrane, or cell membrane, which encompasses the contents of the cell and acts as a barrier to hold nutrients, proteins and other essential components of the cytoplasm within the cell. As they are prokaryotes, bacteria do not tend to have membrane-bound organelles in their cytoplasm and thus contain few intracellular structures. They consequently lack a nucleus, mitochondria, chloroplasts and the other organelles present in eukaryotic cells, such as the Golgi apparatus and endoplasmic reticulum. However, recent research is identifying increasing amounts of structural complexity in bacteria, such as the discovery of the prokaryotic cytoskeleton.
Many important biochemical reactions, such as energy generation, occur due to concentration gradients across membranes, creating a potential difference analogous to a battery. The absence of internal membranes in bacteria means these reactions, such as electron transport, occur across the cell membrane, between the cytoplasm and the periplasmic space. Additionally, while some transporter proteins consume chemical energy, others harness concentration gradients to import nutrients across the cell membrane or to expel undesired molecules from the cytoplasm.
Bacteria do not have a membrane-bound nucleus, and their genetic material is typically a single circular chromosome located in the cytoplasm in an irregularly shaped body called the nucleoid. The nucleoid contains the chromosome with associated proteins and RNA. Like all living organisms, bacteria contain ribosomes for the production of proteins, but the structure of the bacterial ribosome is different from those of eukaryotes and Archaea. The order Planctomycetes are an exception to the general absence of internal membranes in bacteria, because they have a membrane around their nucleoid and contain other membrane-bound cellular structures.
Some bacteria produce intracellular nutrient storage granules, such as glycogen, polyphosphate, sulfur or polyhydroxyalkanoates. These granules enable bacteria to store compounds for later use. Certain bacterial species, such as the photosynthetic Cyanobacteria, produce internal gas vesicles, which they use to regulate their buoyancy - allowing them to move up or down into water layers with different light intensities and nutrient levels.
## Extracellular structures
Around the outside of the cell membrane is the bacterial cell wall. Bacterial cell walls are made of peptidoglycan (called murein in older sources), which is made from polysaccharide chains cross-linked by unusual peptides containing D-amino acids. Bacterial cell walls are different from the cell walls of plants and fungi, which are made of cellulose and chitin, respectively. The cell wall of bacteria is also distinct from that of Archaea, which do not contain peptidoglycan. The cell wall is essential to the survival of many bacteria, and the antibiotic penicillin is able to kill bacteria by inhibiting a step in the synthesis of peptidoglycan.
There are broadly speaking two different types of cell wall in bacteria, called Gram-positive and Gram-negative. The names originate from the reaction of cells to the Gram stain, a test long-employed for the classification of bacterial species.
Gram-positive bacteria possess a thick cell wall containing many layers of peptidoglycan and teichoic acids. In contrast, Gram-negative bacteria have a relatively thin cell wall consisting of a few layers of peptidoglycan surrounded by a second lipid membrane containing lipopolysaccharides and lipoproteins. Most bacteria have the Gram-negative cell wall, and only the Firmicutes and Actinobacteria (previously known as the low G+C and high G+C Gram-positive bacteria, respectively) have the alternative Gram-positive arrangement. These differences in structure can produce differences in antibiotic susceptibility; for instance, vancomycin can kill only Gram-positive bacteria and is ineffective against Gram-negative pathogens, such as Haemophilus influenzae or Pseudomonas aeruginosa.
In many bacteria an S-layer of rigidly arrayed protein molecules covers the outside of the cell. This layer provides chemical and physical protection for the cell surface and can act as a macromolecular diffusion barrier. S-layers have diverse but mostly poorly understood functions, but are known to act as virulence factors in Campylobacter and contain surface enzymes in Bacillus stearothermophilus.
Flagella are rigid protein structures, about 20 nanometres in diameter and up to 20 micrometres in length, that are used for motility. Flagella are driven by the energy released by the transfer of ions down an electrochemical gradient across the cell membrane.
Fimbriae are fine filaments of protein, just 2–10 nanometres in diameter and up to several micrometers in length. They are distributed over the surface of the cell, and resemble fine hairs when seen under the electron microscope. Fimbriae are believed to be involved in attachment to solid surfaces or to other cells and are essential for the virulence of some bacterial pathogens. Pili (sing. pilus) are cellular appendages, slightly larger than fimbriae, that can transfer genetic material between bacterial cells in a process called conjugation (see bacterial genetics, below).
Capsules or slime layers are produced by many bacteria to surround their cells, and vary in structural complexity: ranging from a disorganised slime layer of extra-cellular polymer, to a highly structured capsule or glycocalyx. These structures can protect cells from engulfment by eukaryotic cells, such as macrophages. They can also act as antigens and be involved in cell recognition, as well as aiding attachment to surfaces and the formation of biofilms.
The assembly of these extracellular structures is dependent on bacterial secretion systems. These transfer proteins from the cytoplasm into the periplasm or into the environment around the cell. Many types of secretion systems are known and these structures are often essential for the virulence of pathogens, so are intensively studied.
## Endospores
Certain genera of Gram-positive bacteria, such as Bacillus, Clostridium, Sporohalobacter, Anaerobacter and Heliobacterium, can form highly resistant, dormant structures called endospores. In almost all cases, one endospore is formed and this is not a reproductive process, although Anaerobacter can make up to seven endospores in a single cell. Endospores have a central core of cytoplasm containing DNA and ribosomes surrounded by a cortex layer and protected by an impermeable and rigid coat.
Endospores show no detectable metabolism and can survive extreme physical and chemical stresses, such as high levels of UV light, gamma radiation, detergents, disinfectants, heat, pressure and desiccation. In this dormant state, these organisms may remain viable for millions of years, and endospores even allow bacteria to survive exposure to the vacuum and radiation in space. Endospore-forming bacteria can also cause disease: for example, anthrax can be contracted by the inhalation of Bacillus anthracis endospores, and contamination of deep puncture wounds with Clostridium tetani endospores causes tetanus.
# Metabolism
In contrast to higher organisms, bacteria exhibit an extremely wide variety of metabolic types. The distribution of metabolic traits within a group of bacteria has traditionally been used to define their taxonomy, but these traits often do not correspond with modern genetic classifications. Bacterial metabolism is classified on the basis of three major criteria: the kind of energy used for growth, the source of carbon, and the electron donors used for growth. An additional criterion of respiratory microorganisms are the electron acceptors used for aerobic or anaerobic respiration.
Carbon metabolism in bacteria is either heterotrophic, where organic carbon compounds are used as carbon sources, or autotrophic, meaning that cellular carbon is obtained by fixing carbon dioxide. Typical autotrophic bacteria are phototrophic cyanobacteria, green sulfur-bacteria and some purple bacteria, but also many chemolithotrophic species, such as nitrifying or sulfur-oxidising bacteria. Energy metabolism of bacteria is either based on phototrophy, the use of light through photosynthesis, or on chemotrophy, the use of chemical substances for energy, which are mostly oxidised at the expense of oxygen or alternative electron acceptors (aerobic/anaerobic respiration).
Finally, bacteria are further divided into lithotrophs that use inorganic electron donors and organotrophs that use organic compounds as electron donors. Chemotrophic organisms use the respective electron donors for energy conservation (by aerobic/anaerobic respiration or fermentation) and biosynthetic reactions (e.g. carbon dioxide fixation), whereas phototrophic organisms use them only for biosynthetic purposes. Respiratory organisms use chemical compounds as a source of energy by taking electrons from the reduced substrate and transferring them to a terminal electron acceptor in a redox reaction. This reaction releases energy that can be used to synthesise ATP and drive metabolism. In aerobic organisms, oxygen is used as the electron acceptor. In anaerobic organisms other inorganic compounds, such as nitrate, sulfate or carbon dioxide are used as electron acceptors. This leads to the ecologically important processes of denitrification, sulfate reduction and acetogenesis, respectively.
Another way of life of chemotrophs in the absence of possible electron acceptors is fermentation, where the electrons taken from the reduced substrates are transferred to oxidised intermediates to generate reduced fermentation products (e.g. lactate, ethanol, hydrogen, butyric acid). Fermentation is possible, because the energy content of the substrates is higher than that of the products, which allows the organisms to synthesise ATP and drive their metabolism.
These processes are also important in biological responses to pollution; for example, sulfate-reducing bacteria are largely responsible for the production of the highly toxic forms of mercury (methyl- and dimethylmercury) in the environment. Non-respiratory anaerobes use fermentation to generate energy and reducing power, secreting metabolic by-products (such as ethanol in brewing) as waste. Facultative anaerobes can switch between fermentation and different terminal electron acceptors depending on the environmental conditions in which they find themselves.
Lithotrophic bacteria can use inorganic compounds as a source of energy. Common inorganic electron donors are hydrogen, carbon monoxide, ammonia (leading to nitrification), ferrous iron and other reduced metal ions, and several reduced sulfur compounds. Unusually, the gas methane can be used by methanotrophic bacteria as both a source of electrons and a substrate for carbon anabolism. In both aerobic phototrophy and chemolithotrophy, oxygen is used as a terminal electron acceptor, while under anaerobic conditions inorganic compounds are used instead. Most lithotrophic organisms are autotrophic, whereas organotrophic organisms are heterotrophic.
In addition to fixing carbon dioxide in photosynthesis, some bacteria also fix nitrogen gas (nitrogen fixation) using the enzyme nitrogenase. This environmentally important trait can be found in bacteria of nearly all the metabolic types listed above, but is not universal.
# Growth and reproduction
Unlike multicellular organisms, increases in the size of bacteria (cell growth) and their reproduction by cell division are tightly linked in unicellular organisms. Bacteria grow to a fixed size and then reproduce through binary fission, a form of asexual reproduction. Under optimal conditions, bacteria can grow and divide extremely rapidly, and bacterial populations can double as quickly as every 9.8 minutes. In cell division, two identical clone daughter cells are produced. Some bacteria, while still reproducing asexually, form more complex reproductive structures that help disperse the newly-formed daughter cells. Examples include fruiting body formation by Myxobacteria and arial hyphae formation by Streptomyces, or budding. Budding involves a cell forming a protrusion that breaks away and produces a daughter cell.
In the laboratory, bacteria are usually grown using solid or liquid media. Solid growth media such as agar plates are used to isolate pure cultures of a bacterial strain. However, liquid growth media are used when measurement of growth or large volumes of cells are required. Growth in stirred liquid media occurs as an even cell suspension, making the cultures easy to divide and transfer, although isolating single bacteria from liquid media is difficult. The use of selective media (media with specific nutrients added or deficient, or with antibiotics added) can help identify specific organisms.
Most laboratory techniques for growing bacteria use high levels of nutrients to produce large amounts of cells cheaply and quickly. However, in natural environments nutrients are limited, meaning that bacteria cannot continue to reproduce indefinitely. This nutrient limitation has led the evolution of different growth strategies (see r/K selection theory). Some organisms can grow extremely rapidly when nutrients become available, such as the formation of algal (and cyanobacterial) blooms that often occur in lakes during the summer. Other organisms have adaptations to harsh environments, such as the production of multiple antibiotics by Streptomyces that inhibit the growth of competing microorganisms. In nature, many organisms live in communities (e.g. biofilms) which may allow for increased supply of nutrients and protection from environmental stresses. These relationships can be essential for growth of a particular organism or group of organisms (syntrophy).
Bacterial growth follows three phases. When a population of bacteria first enter a high-nutrient environment that allows growth, the cells need to adapt to their new environment. The first phase of growth is the lag phase, a period of slow growth when the cells are adapting to the high-nutrient environment and preparing for fast growth. The lag phase has high biosynthesis rates, as proteins necessary for rapid growth are produced. The second phase of growth is the logarithmic phase (log phase), also known as the exponential phase. The log phase is marked by rapid exponential growth. The rate at which cells grow during this phase is known as the growth rate (k), and the time it takes the cells to double is known as the generation time (g). During log phase, nutrients are metabolised at maximum speed until one of the nutrients is depleted and starts limiting growth. The final phase of growth is the stationary phase and is caused by depleted nutrients. The cells reduce their metabolic activity and consume non-essential cellular proteins. The stationary phase is a transition from rapid growth to a stress response state and there is increased expression of genes involved in DNA repair, antioxidant metabolism and nutrient transport.
# Genetics
Most bacteria have a single circular chromosome that can range in size from only 160,000 base pairs in the endosymbiotic bacteria Candidatus Carsonella ruddii, to 12,200,000 base pairs in the soil-dwelling bacteria Sorangium cellulosum. Spirochaetes of the genus Borrelia are a notable exception to this arrangement, with bacteria such as Borrelia burgdorferi, the cause of Lyme disease, containing a single linear chromosome. The genes in bacterial genomes are usually a single continuous stretch of DNA and although several different types of introns do exist in bacteria, these are much more rare than in eukaryotes.
Bacteria may also contain plasmids, which are small extra-chromosomal DNAs that may contain genes for antibiotic resistance or virulence factors. Another type of bacterial DNA are integrated viruses (bacteriophages). Many types of bacteriophage exist, some simply infect and lyse their host bacteria, while others insert into the bacterial chromosome. A bacteriophage can contain genes that contribute to its host's phenotype: for example, in the evolution of Escherichia coli O157:H7 and Clostridium botulinum, the toxin genes in an integrated phage converted a harmless ancestral bacteria into a lethal pathogen.
Bacteria, as asexual organisms, inherit identical copies of their parent's genes (i.e., they are clonal). However, all bacteria can evolve by selection on changes to their genetic material DNA caused by genetic recombination or mutations. Mutations come from errors made during the replication of DNA or from exposure to mutagens. Mutation rates vary widely among different species of bacteria and even among different clones of a single species of bacteria. Genetic changes in bacterial genomes come from either random mutation during replication or "stress-directed mutation", where genes involved in a particular growth-limiting process have an increased mutation rate.
Some bacteria also transfer genetic material between cells. This can occur in three main ways. Firstly, bacteria can take up exogenous DNA from their environment, in a process called transformation. Genes can also be transferred by the process of transduction, when the integration of a bacteriophage introduces foreign DNA into the chromosome. The third method of gene transfer is bacterial conjugation, where DNA is transferred through direct cell contact. This gene acquisition from other bacteria or the environment is called horizontal gene transfer and may be common under natural conditions. Gene transfer is particularly important in antibiotic resistance as it allows the rapid transfer of resistance genes between different pathogens.
# Movement
Motile bacteria can move using flagella, bacterial gliding, twitching motility or changes of buoyancy. In twitching motility, bacterial use their type IV pili as a grappling hook, repeatedly extending it, anchoring it and then retracting it with remarkable force (>80 pN).
Bacterial species differ in the number and arrangement of flagella on their surface; some have a single flagellum (monotrichous), a flagellum at each end (amphitrichous), clusters of flagella at the poles of the cell (lophotrichous), while others have flagella distributed over the entire surface of the cell (peritrichous). The bacterial flagella is the best-understood motility structure in any organism and is made of about 20 proteins, with approximately another 30 proteins required for its regulation and assembly. The flagellum is a rotating structure driven by a motor at the base that uses the electrochemical gradient across the membrane for power. This motor drives the motion of the filament, which acts as a propeller. Many bacteria (such as E. coli) have two distinct modes of movement: forward movement (swimming) and tumbling. The tumbling allows them to reorient and makes their movement a three-dimensional random walk. (See external links below for link to videos.) The flagella of a unique group of bacteria, the spirochaetes, are found between two membranes in the periplasmic space. They have a distinctive helical body that twists about as it moves.
Motile bacteria are attracted or repelled by certain stimuli in behaviors called taxes: these include chemotaxis, phototaxis and magnetotaxis. In one peculiar group, the myxobacteria, individual bacteria move together to form waves of cells that then differentiate to form fruiting bodies containing spores. The myxobacteria move only when on solid surfaces, unlike E. coli which is motile in liquid or solid media.
Several Listeria and Shigella species move inside host cells by usurping the cytoskeleton, which is normally used to move organelles inside the cell. By promoting actin polymerization at one pole of their cells, they can form a kind of tail that pushes them through the host cell's cytoplasm.
# Classification and identification
Classification seeks to describe the diversity of bacterial species by naming and grouping organisms based on similarities. Bacteria can be classified on the basis of cell structure, cellular metabolism or on differences in cell components such as DNA, fatty acids, pigments, antigens and quinones. While these schemes allowed the identification and classification of bacterial strains, it was unclear whether these differences represented variation between distinct species or between strains of the same species. This uncertainty was due to the lack of distinctive structures in most bacteria, as well as lateral gene transfer between unrelated species. Due to lateral gene transfer, some closely related bacteria can have very different morphologies and metabolisms. To overcome this uncertainty, modern bacterial classification emphasizes molecular systematics, using genetic techniques such as guanine cytosine ratio determination, genome-genome hybridization, as well as sequencing genes that have not undergone extensive lateral gene transfer, such as the rRNA gene. Classification of bacteria is determined by publication in the International Journal of Systematic Bacteriology, and Bergey's Manual of Systematic Bacteriology.
The term "bacteria" was traditionally applied to all microscopic, single-celled prokaryotes. However, molecular systematics showed prokaryotic life to consist of two separate domains, originally called Eubacteria and Archaebacteria, but now called Bacteria and Archaea that evolved independently from an ancient common ancestor. The archaea and eukaryotes are more closely-related to each other than either is to the bacteria. These two domains, along with Eukarya, are the basis of the three-domain system, which is currently the most widely used classification system in microbiolology. However, due to the relatively recent introduction of molecular systematics and a rapid increase in the number of genome sequences that are available, bacterial classification remains a changing and expanding field. For example, a few biologists argue that the Archaea and Eukaryotes evolved from Gram-positive bacteria.
Identification of bacteria in the laboratory is particularly relevant in medicine, where the correct treatment is determined by the bacterial species causing an infection. Consequently, the need to identify human pathogens was a major impetus for the development of techniques to identify bacteria.
The Gram stain, developed in 1884 by Hans Christian Gram, characterises bacteria based on the structural characteristics of their cell walls. The thick layers of peptidoglycan in the "Gram-positive" cell wall stain purple, while the thin "Gram-negative" cell wall appears pink. By combining morphology and Gram-staining, most bacteria can be classified as belonging to one of four groups (Gram-positive cocci, Gram-positive bacilli, Gram-negative cocci and Gram-negative bacilli). Some organisms are best identified by stains other than the Gram stain, particularly mycobacteria or Nocardia, which show acid-fastness on Ziehl–Neelsen or similar stains. Other organisms may need to be identified by their growth in special media, or by other techniques, such as serology.
Culture techniques are designed to promote the growth and identify particular bacteria, while restricting the growth of the other bacteria in the sample. Often these techniques are designed for specific specimens; for example, a sputum sample will be treated to identify organisms that cause pneumonia, while stool specimens are cultured on selective media to identify organisms that cause diarrhoea, while preventing growth of non-pathogenic bacteria. Specimens that are normally sterile, such as blood, urine or spinal fluid, are cultured under conditions designed to grow all possible organisms. Once a pathogenic organism has been isolated, it can be further characterised by its morphology, growth patterns such as (aerobic or anaerobic growth, patterns of hemolysis) and staining.
As with bacterial classification, identification of bacteria is increasingly using molecular methods. Diagnostics using such DNA-based tools, such as polymerase chain reaction, are increasingly popular due to their specificity and speed, compared to culture-based methods. These methods also allow the detection and identification of "viable but nonculturable" cells that are metabolically active but non-dividing. However, even using these improved methods, the total number of bacterial species is not known and cannot even be estimated with any certainty. Attempts to quantify bacterial diversity have ranged from 107 to 109 total species, but even these diverse estimates may be out by many orders of magnitude.
# Interactions with other organisms
Despite their apparent simplicity, bacteria can form complex associations with other organisms. These symbiotic associations can be divided into parasitism, mutualism and commensalism. Due to their small size, commensal bacteria are ubiquitous and grow on animals and plants exactly as they will grow on any other surface. However, their growth can be increased by warmth and sweat, and large populations of these organisms in humans are the cause of body odor.
## Mutualists
Certain bacteria form close spatial associations that are essential for their survival. One such mutualistic association, called interspecies hydrogen transfer, occurs between clusters of anaerobic bacteria that consume organic acids such as butyric acid or propionic acid and produce hydrogen, and methanogenic Archaea that consume hydrogen. The bacteria in this association are unable to consume the organic acids as this reaction produces hydrogen that accumulates in their surroundings. Only the intimate association with the hydrogen-consuming Archaea keeps the hydrogen concentration low enough to allow the bacteria to grow.
In soil, microorganisms which reside in the rhizosphere (a zone that includes the root surface and the soil that adheres to the root after gentle shaking) carry out nitrogen fixation, converting nitrogen gas to nitrogenous compounds. This serves to provide an easily absorbable form of nitrogen for many plants, which cannot fix nitrogen themselves. Many other bacteria are found as symbionts in humans and other organisms. For example, the presence of over 1,000 bacterial species in the normal human gut flora of the intestines can contribute to gut immunity, synthesise vitamins such as folic acid, vitamin K and biotin, convert milk protein to lactic acid (see Lactobacillus), as well as fermenting complex undigestible carbohydrates. The presence of this gut flora also inhibits the growth of potentially pathogenic bacteria (usually through competitive exclusion) and these beneficial bacteria are consequently sold as probiotic dietary supplements.
## Pathogens
If bacteria form a parasitic association with other organisms, they are classed as pathogens. Pathogenic bacteria are a major cause of human death and disease and cause infections such as tetanus, typhoid fever, diphtheria, syphilis, cholera, foodborne illness, leprosy and tuberculosis. A pathogenic cause for a known medical disease may only be discovered many years after, as was the case with Helicobacter pylori and peptic ulcer disease. Bacterial diseases are also important in agriculture, with bacteria causing leaf spot, fire blight and wilts in plants, as well as Johne's disease, mastitis, salmonella and anthrax in farm animals.
Each species of pathogen has a characteristic spectrum of interactions with its human hosts. Some organisms, such as Staphylococcus or Streptococcus, can cause skin infections, pneumonia, meningitis and even overwhelming sepsis, a systemic inflammatory response producing shock, massive vasodilation and death. Yet these organisms are also part of the normal human flora and usually exist on the skin or in the nose without causing any disease at all. Other organisms invariably cause disease in humans, such as the Rickettsia, which are obligate intracellular parasites able to grow and reproduce only within the cells of other organisms. One species of Rickettsia causes typhus, while another causes Rocky Mountain spotted fever. Chlamydia, another phylum of obligate intracellular parasites, contains species that can cause pneumonia, or urinary tract infection and may be involved in coronary heart disease. Finally, some species such as Pseudomonas aeruginosa, Burkholderia cenocepacia, and Mycobacterium avium are opportunistic pathogens and cause disease mainly in people suffering from immunosuppression or cystic fibrosis.
Bacterial infections may be treated with antibiotics, which are classified as bacteriocidal if they kill bacteria, or bacteriostatic if they just prevent bacterial growth. There are many types of antibiotics and each class inhibits a process that is different in the pathogen from that found in the host. An example of how antibiotics produce selective toxicity are chloramphenicol and puromycin, which inhibit the bacterial ribosome, but not the structurally different eukaryotic ribosome. Antibiotics are used both in treating human disease and in intensive farming to promote animal growth, where they may be contributing to the rapid development of antibiotic resistance in bacterial populations. Infections can be prevented by antiseptic measures such as sterilizating the skin prior to piercing it with the needle of a syringe, and by proper care of indwelling catheters. Surgical and dental instruments are also sterilized to prevent contamination and infection by bacteria. Disinfectants such as bleach are used to kill bacteria or other pathogens on surfaces to prevent contamination and further reduce the risk of infection.
# Significance in technology and industry
Bacteria, often Lactobacillus in combination with yeasts and molds, have been used for thousands of years in the preparation of fermented foods such as cheese, pickles, soy sauce, sauerkraut, vinegar, wine and yoghurt.
The ability of bacteria to degrade a variety of organic compounds is remarkable and has been used in waste processing and bioremediation. Bacteria capable of digesting the hydrocarbons in petroleum are often used to clean up oil spills. Fertilizer was added to some of the beaches in Prince William Sound in an attempt to promote the growth of these naturally occurring bacteria after the infamous 1989 Exxon Valdez oil spill. These efforts were effective on beaches that were not too thickly covered in oil. Bacteria are also used for the bioremediation of industrial toxic wastes. In the chemical industry, bacteria are most important in the production of enantiomerically pure chemicals for use as pharmaceuticals or agrichemicals.
Bacteria can also be used in the place of pesticides in the biological pest control. This commonly involves Bacillus thuringiensis (also called BT), a Gram-positive, soil dwelling bacterium. Subspecies of this bacteria are used as a Lepidopteran-specific insecticides under trade names such as Dipel and Thuricide. Because of their specificity, these pesticides are regarded as environmentally friendly, with little or no effect on humans, wildlife, pollinators and most other beneficial insects.
Because of their ability to quickly grow and the relative ease with which they can be manipulated, bacteria are the workhorses for the fields of molecular biology, genetics and biochemistry. By making mutations in bacterial DNA and examining the resulting phenotypes, scientists can determine the function of genes, enzymes and metabolic pathways in bacteria, then apply this knowledge to more complex organisms. This aim of understanding the biochemistry of a cell reaches its most complex expression in the synthesis of huge amounts of enzyme kinetic and gene expression data into mathematical models of entire organisms. This is achievable in some well-studied bacteria, with models of Escherichia coli metabolism now being produced and tested. This understanding of bacterial metabolism and genetics allows the use of biotechnology to bioengineer bacteria for the production of therapeutic proteins, such as insulin, growth factors, or antibodies. | Bacteria
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Bacteria (singular: bacterium) are unicellular microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods to spirals. Bacteria are ubiquitous in every habitat on Earth, growing in soil, Hot spring|acidic hot springs, radioactive waste,[1] seawater, and deep in the Earth's crust. There are typically 40 million bacterial cells in a gram of soil and a million bacterial cells in a millilitre of fresh water; in all, there are approximately five nonillion (5×1030) bacteria on Earth,[2] forming much of the world's biomass.[3] Bacteria are vital in recycling nutrients, and many important steps in nutrient cycles depend on bacteria, such as the fixation of nitrogen from the atmosphere. However, most of these bacteria have not been characterized, and only about half of the phyla of bacteria have species that can be cultured in the laboratory.[4] The study of bacteria is known as bacteriology, a branch of microbiology.
There are approximately ten times as many bacterial cells as human cells in the human body, with large numbers of bacteria on the skin and in the digestive tract.[5] Although the vast majority of these bacteria are rendered harmless by the protective effects of the immune system, and a few are beneficial, some are pathogenic bacteria and cause infectious diseases, including cholera, syphilis, anthrax, leprosy and bubonic plague. The most common fatal bacterial diseases are respiratory infections, with tuberculosis alone killing about 2 million people a year, mostly in sub-Saharan Africa.[6] In developed countries, antibiotics are used to treat bacterial infections and in various agricultural processes, so antibiotic resistance is becoming common. In industry, bacteria are important in processes such as sewage treatment, the production of cheese and yoghurt, and the manufacture of antibiotics and other chemicals.[7]
Bacteria are prokaryotes. Unlike cells of animals and other eukaryotes, bacterial cells do not contain a nucleus and rarely harbour membrane-bound organelles. Although the term bacteria traditionally included all prokaryotes, the scientific classification changed after the discovery in the 1990s that prokaryotic life consists of two very different groups of organisms that evolved independently from an ancient common ancestor. These evolutionary domains are called Bacteria and Archaea.[8]
# History of bacteriology
Bacteria were first observed by Antonie van Leeuwenhoek in 1676, using a single-lens microscope of his own design.[9] He called them "animalcules" and published his observations in a series of letters to the Royal Society.[10][11][12] The name bacterium was introduced much later, by Christian Gottfried Ehrenberg in 1838, and is derived from the Greek word βακτήριον -α , bacterion -a , meaning "small staff".[13]
Louis Pasteur demonstrated in 1859 that the fermentation process is caused by the growth of microorganisms, and that this growth is not due to spontaneous generation. (Yeasts and molds, commonly associated with fermentation, are not bacteria, but rather fungi.) Along with his contemporary, Robert Koch, Pasteur was an early advocate of the germ theory of disease.[14]
Robert Koch was a pioneer in medical microbiology and worked on cholera, anthrax and tuberculosis. In his research into tuberculosis, Koch finally proved the germ theory, for which he was awarded a Nobel Prize in 1905.[15] In Koch's postulates, he set out criteria to test if an organism is the cause of a disease; these postulates are still used today.[16]
Though it was known in the nineteenth century that bacteria are the cause of many diseases, no effective antibacterial treatments were available.[17] In 1910, Paul Ehrlich developed the first antibiotic, by changing dyes that selectively stained Treponema pallidum—the spirochaete that causes syphilis—into compounds that selectively killed the pathogen.[18] Ehrlich had been awarded a 1908 Nobel Prize for his work on immunology, and pioneered the use of stains to detect and identify bacteria, with his work being the basis of the Gram stain and the Ziehl-Neelsen stain.[19]
A major step forward in the study of bacteria was the recognition in 1977 by Carl Woese that archaea have a separate line of evolutionary descent from bacteria.[20] This new phylogenetic taxonomy was based on the sequencing of 16S ribosomal RNA, and divided prokaryotes into two evolutionary domains, as part of the three-domain system.[21]
# Origin and early evolution
The ancestors of modern bacteria were single-celled microorganisms that were the first forms of life to develop on earth, about 4 billion years ago. For about 3 billion years, all organisms were microscopic, and bacteria and archaea were the dominant forms of life.[22][23] Although bacterial fossils exist, such as stromatolites, their lack of distinctive morphology prevents them from being used to examine the past history of bacterial evolution, or to date the time of origin of a particular bacterial species. However, gene sequences can be used to reconstruct the bacterial phylogeny, and these studies indicate that bacteria diverged first from the archaeal/eukaryotic lineage.[24] The most recent common ancestor of bacteria and archaea was probably a hyperthermophile that lived about 2.5 billion–3.2 billion years ago.[25][26]
Bacteria were also involved in the second great evolutionary divergence, that of the archaea and eukaryotes. Here, eukaryotes resulted from ancient bacteria entering into endosymbiotic associations with the ancestors of eukaryotic cells, which were themselves possibly related to the Archaea.[27][28] This involved the engulfment by proto-eukaryotic cells of alpha-proteobacterial symbionts to form either mitochondria or hydrogenosomes, which are still being found in all known Eukarya (sometimes in highly reduced form, e.g. in ancient "amitochondrial" protozoa). Later on, an independent second engulfment by some mitochondria-containing eukaryotes of cyanobacterial-like organisms led to the formation of chloroplasts in algae and plants. There are even some algal groups known that clearly originated from subsequent events of endosymbiosis by heterotrophic eukaryotic hosts engulfing a eukaryotic algae that developed into "second-generation" plastids.[29][30]
# Morphology
Bacteria display a wide diversity of shapes and sizes, called morphologies. Bacterial cells are about one tenth the size of eukaryotic cells and are typically 0.5–5.0 micrometres in length. However, a few species–for example Thiomargarita namibiensis and Epulopiscium fishelsoni–are up to half a millimetre long and are visible to the unaided eye.[31] Among the smallest bacteria are members of the genus Mycoplasma, which measure only 0.3 micrometres, as small as the largest viruses.[32]
Most bacterial species are either spherical, called cocci (sing. coccus, from Greek kókkos, grain, seed) or rod-shaped, called bacilli (sing. bacillus, from Latin baculus, stick). Some rod-shaped bacteria, called vibrio, are slightly curved or comma-shaped; others, can be spiral-shaped, called spirilla, or tightly coiled, called spirochaetes. A small number of species even have tetrahedral or cuboidal shapes.[33] This wide variety of shapes is determined by the bacterial cell wall and cytoskeleton, and is important because it can influence the ability of bacteria to acquire nutrients, attach to surfaces, swim through liquids and escape predators.[34][35]
Many bacterial species exist simply as single cells, others associate in characteristic patterns: Neisseria form diploids (pairs), Streptococcus form chains, and Staphylococcus group together in "bunch of grapes" clusters. Bacteria can also be elongated to form filaments, for example the Actinobacteria. Filamentous bacteria are often surrounded by a sheath that contains many individual cells; certain types, such as species of the genus Nocardia, even form complex, branched filaments, similar in appearance to fungal mycelia.[36]
Bacteria often attach to surfaces and form dense aggregations called biofilms or bacterial mats. These films can range from a few micrometers in thickness to up to half a meter in depth, and may contain multiple species of bacteria, protists and archaea. Bacteria living in biofilms display a complex arrangement of cells and extracellular components, forming secondary structures such as microcolonies, through which there are networks of channels to enable better diffusion of nutrients.[37][38] In natural environments, such as soil or the surfaces of plants, the majority of bacteria are bound to surfaces in biofilms.[39] Biofilms are also important for chronic bacterial infections and infections of implanted medical devices, as bacteria protected within these structures are much harder to kill than individual bacteria.[40]
Even more complex morphological changes are sometimes possible. For example, when starved of amino acids, Myxobacteria detect surrounding cells in a process known as quorum sensing, migrate towards each other, and aggregate to form fruiting bodies up to 500 micrometres long and containing approximately 100,000 bacterial cells.[41] In these fruiting bodies, the bacteria perform separate tasks; this type of cooperation is a simple type of multicellular organisation. For example, about one in 10 cells migrate to the top of these fruiting bodies and differentiate into a specialised dormant state called myxospores, which are more resistant to desiccation and other adverse environmental conditions than are ordinary cells.[42]
# Cellular structure
## Intracellular structures
The bacterial cell is surrounded by a lipid membrane, or cell membrane, which encompasses the contents of the cell and acts as a barrier to hold nutrients, proteins and other essential components of the cytoplasm within the cell. As they are prokaryotes, bacteria do not tend to have membrane-bound organelles in their cytoplasm and thus contain few intracellular structures. They consequently lack a nucleus, mitochondria, chloroplasts and the other organelles present in eukaryotic cells, such as the Golgi apparatus and endoplasmic reticulum.[43] However, recent research is identifying increasing amounts of structural complexity in bacteria, such as the discovery of the prokaryotic cytoskeleton.[44][45]
Many important biochemical reactions, such as energy generation, occur due to concentration gradients across membranes, creating a potential difference analogous to a battery. The absence of internal membranes in bacteria means these reactions, such as electron transport, occur across the cell membrane, between the cytoplasm and the periplasmic space.[46] Additionally, while some transporter proteins consume chemical energy, others harness concentration gradients to import nutrients across the cell membrane or to expel undesired molecules from the cytoplasm.
Bacteria do not have a membrane-bound nucleus, and their genetic material is typically a single circular chromosome located in the cytoplasm in an irregularly shaped body called the nucleoid.[47] The nucleoid contains the chromosome with associated proteins and RNA. Like all living organisms, bacteria contain ribosomes for the production of proteins, but the structure of the bacterial ribosome is different from those of eukaryotes and Archaea.[48] The order Planctomycetes are an exception to the general absence of internal membranes in bacteria, because they have a membrane around their nucleoid and contain other membrane-bound cellular structures.[49]
Some bacteria produce intracellular nutrient storage granules, such as glycogen,[50] polyphosphate,[51] sulfur[52] or polyhydroxyalkanoates.[53] These granules enable bacteria to store compounds for later use. Certain bacterial species, such as the photosynthetic Cyanobacteria, produce internal gas vesicles, which they use to regulate their buoyancy - allowing them to move up or down into water layers with different light intensities and nutrient levels.[54]
## Extracellular structures
Around the outside of the cell membrane is the bacterial cell wall. Bacterial cell walls are made of peptidoglycan (called murein in older sources), which is made from polysaccharide chains cross-linked by unusual peptides containing D-amino acids.[55] Bacterial cell walls are different from the cell walls of plants and fungi, which are made of cellulose and chitin, respectively.[56] The cell wall of bacteria is also distinct from that of Archaea, which do not contain peptidoglycan. The cell wall is essential to the survival of many bacteria, and the antibiotic penicillin is able to kill bacteria by inhibiting a step in the synthesis of peptidoglycan.[56]
There are broadly speaking two different types of cell wall in bacteria, called Gram-positive and Gram-negative. The names originate from the reaction of cells to the Gram stain, a test long-employed for the classification of bacterial species.[57]
Gram-positive bacteria possess a thick cell wall containing many layers of peptidoglycan and teichoic acids. In contrast, Gram-negative bacteria have a relatively thin cell wall consisting of a few layers of peptidoglycan surrounded by a second lipid membrane containing lipopolysaccharides and lipoproteins. Most bacteria have the Gram-negative cell wall, and only the Firmicutes and Actinobacteria (previously known as the low G+C and high G+C Gram-positive bacteria, respectively) have the alternative Gram-positive arrangement.[58] These differences in structure can produce differences in antibiotic susceptibility; for instance, vancomycin can kill only Gram-positive bacteria and is ineffective against Gram-negative pathogens, such as Haemophilus influenzae or Pseudomonas aeruginosa.[59]
In many bacteria an S-layer of rigidly arrayed protein molecules covers the outside of the cell.[60] This layer provides chemical and physical protection for the cell surface and can act as a macromolecular diffusion barrier. S-layers have diverse but mostly poorly understood functions, but are known to act as virulence factors in Campylobacter and contain surface enzymes in Bacillus stearothermophilus.[61]
Flagella are rigid protein structures, about 20 nanometres in diameter and up to 20 micrometres in length, that are used for motility. Flagella are driven by the energy released by the transfer of ions down an electrochemical gradient across the cell membrane.[62]
Fimbriae are fine filaments of protein, just 2–10 nanometres in diameter and up to several micrometers in length. They are distributed over the surface of the cell, and resemble fine hairs when seen under the electron microscope. Fimbriae are believed to be involved in attachment to solid surfaces or to other cells and are essential for the virulence of some bacterial pathogens.[63] Pili (sing. pilus) are cellular appendages, slightly larger than fimbriae, that can transfer genetic material between bacterial cells in a process called conjugation (see bacterial genetics, below).[64]
Capsules or slime layers are produced by many bacteria to surround their cells, and vary in structural complexity: ranging from a disorganised slime layer of extra-cellular polymer, to a highly structured capsule or glycocalyx. These structures can protect cells from engulfment by eukaryotic cells, such as macrophages.[65] They can also act as antigens and be involved in cell recognition, as well as aiding attachment to surfaces and the formation of biofilms.[66]
The assembly of these extracellular structures is dependent on bacterial secretion systems. These transfer proteins from the cytoplasm into the periplasm or into the environment around the cell. Many types of secretion systems are known and these structures are often essential for the virulence of pathogens, so are intensively studied.[67]
## Endospores
Certain genera of Gram-positive bacteria, such as Bacillus, Clostridium, Sporohalobacter, Anaerobacter and Heliobacterium, can form highly resistant, dormant structures called endospores.[68] In almost all cases, one endospore is formed and this is not a reproductive process, although Anaerobacter can make up to seven endospores in a single cell.[69] Endospores have a central core of cytoplasm containing DNA and ribosomes surrounded by a cortex layer and protected by an impermeable and rigid coat.
Endospores show no detectable metabolism and can survive extreme physical and chemical stresses, such as high levels of UV light, gamma radiation, detergents, disinfectants, heat, pressure and desiccation.[70] In this dormant state, these organisms may remain viable for millions of years,[71][72] and endospores even allow bacteria to survive exposure to the vacuum and radiation in space.[73] Endospore-forming bacteria can also cause disease: for example, anthrax can be contracted by the inhalation of Bacillus anthracis endospores, and contamination of deep puncture wounds with Clostridium tetani endospores causes tetanus.[74]
# Metabolism
In contrast to higher organisms, bacteria exhibit an extremely wide variety of metabolic types.[75] The distribution of metabolic traits within a group of bacteria has traditionally been used to define their taxonomy, but these traits often do not correspond with modern genetic classifications.[76] Bacterial metabolism is classified on the basis of three major criteria: the kind of energy used for growth, the source of carbon, and the electron donors used for growth. An additional criterion of respiratory microorganisms are the electron acceptors used for aerobic or anaerobic respiration.[77]
Carbon metabolism in bacteria is either heterotrophic, where organic carbon compounds are used as carbon sources, or autotrophic, meaning that cellular carbon is obtained by fixing carbon dioxide. Typical autotrophic bacteria are phototrophic cyanobacteria, green sulfur-bacteria and some purple bacteria, but also many chemolithotrophic species, such as nitrifying or sulfur-oxidising bacteria.[78] Energy metabolism of bacteria is either based on phototrophy, the use of light through photosynthesis, or on chemotrophy, the use of chemical substances for energy, which are mostly oxidised at the expense of oxygen or alternative electron acceptors (aerobic/anaerobic respiration).
Finally, bacteria are further divided into lithotrophs that use inorganic electron donors and organotrophs that use organic compounds as electron donors. Chemotrophic organisms use the respective electron donors for energy conservation (by aerobic/anaerobic respiration or fermentation) and biosynthetic reactions (e.g. carbon dioxide fixation), whereas phototrophic organisms use them only for biosynthetic purposes. Respiratory organisms use chemical compounds as a source of energy by taking electrons from the reduced substrate and transferring them to a terminal electron acceptor in a redox reaction. This reaction releases energy that can be used to synthesise ATP and drive metabolism. In aerobic organisms, oxygen is used as the electron acceptor. In anaerobic organisms other inorganic compounds, such as nitrate, sulfate or carbon dioxide are used as electron acceptors. This leads to the ecologically important processes of denitrification, sulfate reduction and acetogenesis, respectively.
Another way of life of chemotrophs in the absence of possible electron acceptors is fermentation, where the electrons taken from the reduced substrates are transferred to oxidised intermediates to generate reduced fermentation products (e.g. lactate, ethanol, hydrogen, butyric acid). Fermentation is possible, because the energy content of the substrates is higher than that of the products, which allows the organisms to synthesise ATP and drive their metabolism.[79][80]
These processes are also important in biological responses to pollution; for example, sulfate-reducing bacteria are largely responsible for the production of the highly toxic forms of mercury (methyl- and dimethylmercury) in the environment.[81] Non-respiratory anaerobes use fermentation to generate energy and reducing power, secreting metabolic by-products (such as ethanol in brewing) as waste. Facultative anaerobes can switch between fermentation and different terminal electron acceptors depending on the environmental conditions in which they find themselves.
Lithotrophic bacteria can use inorganic compounds as a source of energy. Common inorganic electron donors are hydrogen, carbon monoxide, ammonia (leading to nitrification), ferrous iron and other reduced metal ions, and several reduced sulfur compounds. Unusually, the gas methane can be used by methanotrophic bacteria as both a source of electrons and a substrate for carbon anabolism.[82] In both aerobic phototrophy and chemolithotrophy, oxygen is used as a terminal electron acceptor, while under anaerobic conditions inorganic compounds are used instead. Most lithotrophic organisms are autotrophic, whereas organotrophic organisms are heterotrophic.
In addition to fixing carbon dioxide in photosynthesis, some bacteria also fix nitrogen gas (nitrogen fixation) using the enzyme nitrogenase. This environmentally important trait can be found in bacteria of nearly all the metabolic types listed above, but is not universal.[83]
# Growth and reproduction
Unlike multicellular organisms, increases in the size of bacteria (cell growth) and their reproduction by cell division are tightly linked in unicellular organisms. Bacteria grow to a fixed size and then reproduce through binary fission, a form of asexual reproduction.[84] Under optimal conditions, bacteria can grow and divide extremely rapidly, and bacterial populations can double as quickly as every 9.8 minutes.[85] In cell division, two identical clone daughter cells are produced. Some bacteria, while still reproducing asexually, form more complex reproductive structures that help disperse the newly-formed daughter cells. Examples include fruiting body formation by Myxobacteria and arial hyphae formation by Streptomyces, or budding. Budding involves a cell forming a protrusion that breaks away and produces a daughter cell.
In the laboratory, bacteria are usually grown using solid or liquid media. Solid growth media such as agar plates are used to isolate pure cultures of a bacterial strain. However, liquid growth media are used when measurement of growth or large volumes of cells are required. Growth in stirred liquid media occurs as an even cell suspension, making the cultures easy to divide and transfer, although isolating single bacteria from liquid media is difficult. The use of selective media (media with specific nutrients added or deficient, or with antibiotics added) can help identify specific organisms.[87]
Most laboratory techniques for growing bacteria use high levels of nutrients to produce large amounts of cells cheaply and quickly. However, in natural environments nutrients are limited, meaning that bacteria cannot continue to reproduce indefinitely. This nutrient limitation has led the evolution of different growth strategies (see r/K selection theory). Some organisms can grow extremely rapidly when nutrients become available, such as the formation of algal (and cyanobacterial) blooms that often occur in lakes during the summer.[88] Other organisms have adaptations to harsh environments, such as the production of multiple antibiotics by Streptomyces that inhibit the growth of competing microorganisms.[89] In nature, many organisms live in communities (e.g. biofilms) which may allow for increased supply of nutrients and protection from environmental stresses.[39] These relationships can be essential for growth of a particular organism or group of organisms (syntrophy).[90]
Bacterial growth follows three phases. When a population of bacteria first enter a high-nutrient environment that allows growth, the cells need to adapt to their new environment. The first phase of growth is the lag phase, a period of slow growth when the cells are adapting to the high-nutrient environment and preparing for fast growth. The lag phase has high biosynthesis rates, as proteins necessary for rapid growth are produced.[91] The second phase of growth is the logarithmic phase (log phase), also known as the exponential phase. The log phase is marked by rapid exponential growth. The rate at which cells grow during this phase is known as the growth rate (k), and the time it takes the cells to double is known as the generation time (g). During log phase, nutrients are metabolised at maximum speed until one of the nutrients is depleted and starts limiting growth. The final phase of growth is the stationary phase and is caused by depleted nutrients. The cells reduce their metabolic activity and consume non-essential cellular proteins. The stationary phase is a transition from rapid growth to a stress response state and there is increased expression of genes involved in DNA repair, antioxidant metabolism and nutrient transport.[92]
# Genetics
Most bacteria have a single circular chromosome that can range in size from only 160,000 base pairs in the endosymbiotic bacteria Candidatus Carsonella ruddii,[93] to 12,200,000 base pairs in the soil-dwelling bacteria Sorangium cellulosum.[94] Spirochaetes of the genus Borrelia are a notable exception to this arrangement, with bacteria such as Borrelia burgdorferi, the cause of Lyme disease, containing a single linear chromosome.[95] The genes in bacterial genomes are usually a single continuous stretch of DNA and although several different types of introns do exist in bacteria, these are much more rare than in eukaryotes.[96]
Bacteria may also contain plasmids, which are small extra-chromosomal DNAs that may contain genes for antibiotic resistance or virulence factors. Another type of bacterial DNA are integrated viruses (bacteriophages). Many types of bacteriophage exist, some simply infect and lyse their host bacteria, while others insert into the bacterial chromosome. A bacteriophage can contain genes that contribute to its host's phenotype: for example, in the evolution of Escherichia coli O157:H7 and Clostridium botulinum, the toxin genes in an integrated phage converted a harmless ancestral bacteria into a lethal pathogen.[97]
Bacteria, as asexual organisms, inherit identical copies of their parent's genes (i.e., they are clonal). However, all bacteria can evolve by selection on changes to their genetic material DNA caused by genetic recombination or mutations. Mutations come from errors made during the replication of DNA or from exposure to mutagens. Mutation rates vary widely among different species of bacteria and even among different clones of a single species of bacteria.[98] Genetic changes in bacterial genomes come from either random mutation during replication or "stress-directed mutation", where genes involved in a particular growth-limiting process have an increased mutation rate.[99]
Some bacteria also transfer genetic material between cells. This can occur in three main ways. Firstly, bacteria can take up exogenous DNA from their environment, in a process called transformation. Genes can also be transferred by the process of transduction, when the integration of a bacteriophage introduces foreign DNA into the chromosome. The third method of gene transfer is bacterial conjugation, where DNA is transferred through direct cell contact. This gene acquisition from other bacteria or the environment is called horizontal gene transfer and may be common under natural conditions.[100] Gene transfer is particularly important in antibiotic resistance as it allows the rapid transfer of resistance genes between different pathogens.[101]
# Movement
Motile bacteria can move using flagella, bacterial gliding, twitching motility or changes of buoyancy.[102] In twitching motility, bacterial use their type IV pili as a grappling hook, repeatedly extending it, anchoring it and then retracting it with remarkable force (>80 pN).[103]
Bacterial species differ in the number and arrangement of flagella on their surface; some have a single flagellum (monotrichous), a flagellum at each end (amphitrichous), clusters of flagella at the poles of the cell (lophotrichous), while others have flagella distributed over the entire surface of the cell (peritrichous). The bacterial flagella is the best-understood motility structure in any organism and is made of about 20 proteins, with approximately another 30 proteins required for its regulation and assembly.[102] The flagellum is a rotating structure driven by a motor at the base that uses the electrochemical gradient across the membrane for power. This motor drives the motion of the filament, which acts as a propeller. Many bacteria (such as E. coli) have two distinct modes of movement: forward movement (swimming) and tumbling. The tumbling allows them to reorient and makes their movement a three-dimensional random walk.[104] (See external links below for link to videos.) The flagella of a unique group of bacteria, the spirochaetes, are found between two membranes in the periplasmic space. They have a distinctive helical body that twists about as it moves.[102]
Motile bacteria are attracted or repelled by certain stimuli in behaviors called taxes: these include chemotaxis, phototaxis and magnetotaxis.[105][106] In one peculiar group, the myxobacteria, individual bacteria move together to form waves of cells that then differentiate to form fruiting bodies containing spores.[107] The myxobacteria move only when on solid surfaces, unlike E. coli which is motile in liquid or solid media.
Several Listeria and Shigella species move inside host cells by usurping the cytoskeleton, which is normally used to move organelles inside the cell. By promoting actin polymerization at one pole of their cells, they can form a kind of tail that pushes them through the host cell's cytoplasm.[108]
# Classification and identification
Classification seeks to describe the diversity of bacterial species by naming and grouping organisms based on similarities. Bacteria can be classified on the basis of cell structure, cellular metabolism or on differences in cell components such as DNA, fatty acids, pigments, antigens and quinones.[87] While these schemes allowed the identification and classification of bacterial strains, it was unclear whether these differences represented variation between distinct species or between strains of the same species. This uncertainty was due to the lack of distinctive structures in most bacteria, as well as lateral gene transfer between unrelated species.[109] Due to lateral gene transfer, some closely related bacteria can have very different morphologies and metabolisms. To overcome this uncertainty, modern bacterial classification emphasizes molecular systematics, using genetic techniques such as guanine cytosine ratio determination, genome-genome hybridization, as well as sequencing genes that have not undergone extensive lateral gene transfer, such as the rRNA gene.[110] Classification of bacteria is determined by publication in the International Journal of Systematic Bacteriology,[111] and Bergey's Manual of Systematic Bacteriology.[112]
The term "bacteria" was traditionally applied to all microscopic, single-celled prokaryotes. However, molecular systematics showed prokaryotic life to consist of two separate domains, originally called Eubacteria and Archaebacteria, but now called Bacteria and Archaea that evolved independently from an ancient common ancestor.[113] The archaea and eukaryotes are more closely-related to each other than either is to the bacteria. These two domains, along with Eukarya, are the basis of the three-domain system, which is currently the most widely used classification system in microbiolology.[114] However, due to the relatively recent introduction of molecular systematics and a rapid increase in the number of genome sequences that are available, bacterial classification remains a changing and expanding field.[4][115] For example, a few biologists argue that the Archaea and Eukaryotes evolved from Gram-positive bacteria.[116]
Identification of bacteria in the laboratory is particularly relevant in medicine, where the correct treatment is determined by the bacterial species causing an infection. Consequently, the need to identify human pathogens was a major impetus for the development of techniques to identify bacteria.
The Gram stain, developed in 1884 by Hans Christian Gram, characterises bacteria based on the structural characteristics of their cell walls.[57] The thick layers of peptidoglycan in the "Gram-positive" cell wall stain purple, while the thin "Gram-negative" cell wall appears pink. By combining morphology and Gram-staining, most bacteria can be classified as belonging to one of four groups (Gram-positive cocci, Gram-positive bacilli, Gram-negative cocci and Gram-negative bacilli). Some organisms are best identified by stains other than the Gram stain, particularly mycobacteria or Nocardia, which show acid-fastness on Ziehl–Neelsen or similar stains.[118] Other organisms may need to be identified by their growth in special media, or by other techniques, such as serology.
Culture techniques are designed to promote the growth and identify particular bacteria, while restricting the growth of the other bacteria in the sample. Often these techniques are designed for specific specimens; for example, a sputum sample will be treated to identify organisms that cause pneumonia, while stool specimens are cultured on selective media to identify organisms that cause diarrhoea, while preventing growth of non-pathogenic bacteria. Specimens that are normally sterile, such as blood, urine or spinal fluid, are cultured under conditions designed to grow all possible organisms.[119][87] Once a pathogenic organism has been isolated, it can be further characterised by its morphology, growth patterns such as (aerobic or anaerobic growth, patterns of hemolysis) and staining.
As with bacterial classification, identification of bacteria is increasingly using molecular methods. Diagnostics using such DNA-based tools, such as polymerase chain reaction, are increasingly popular due to their specificity and speed, compared to culture-based methods.[120] These methods also allow the detection and identification of "viable but nonculturable" cells that are metabolically active but non-dividing.[121] However, even using these improved methods, the total number of bacterial species is not known and cannot even be estimated with any certainty. Attempts to quantify bacterial diversity have ranged from 107 to 109 total species, but even these diverse estimates may be out by many orders of magnitude.[122][123]
# Interactions with other organisms
Despite their apparent simplicity, bacteria can form complex associations with other organisms. These symbiotic associations can be divided into parasitism, mutualism and commensalism. Due to their small size, commensal bacteria are ubiquitous and grow on animals and plants exactly as they will grow on any other surface. However, their growth can be increased by warmth and sweat, and large populations of these organisms in humans are the cause of body odor.
## Mutualists
Certain bacteria form close spatial associations that are essential for their survival. One such mutualistic association, called interspecies hydrogen transfer, occurs between clusters of anaerobic bacteria that consume organic acids such as butyric acid or propionic acid and produce hydrogen, and methanogenic Archaea that consume hydrogen.[124] The bacteria in this association are unable to consume the organic acids as this reaction produces hydrogen that accumulates in their surroundings. Only the intimate association with the hydrogen-consuming Archaea keeps the hydrogen concentration low enough to allow the bacteria to grow.
In soil, microorganisms which reside in the rhizosphere (a zone that includes the root surface and the soil that adheres to the root after gentle shaking) carry out nitrogen fixation, converting nitrogen gas to nitrogenous compounds.[125] This serves to provide an easily absorbable form of nitrogen for many plants, which cannot fix nitrogen themselves. Many other bacteria are found as symbionts in humans and other organisms. For example, the presence of over 1,000 bacterial species in the normal human gut flora of the intestines can contribute to gut immunity, synthesise vitamins such as folic acid, vitamin K and biotin, convert milk protein to lactic acid (see Lactobacillus), as well as fermenting complex undigestible carbohydrates.[126][127][128] The presence of this gut flora also inhibits the growth of potentially pathogenic bacteria (usually through competitive exclusion) and these beneficial bacteria are consequently sold as probiotic dietary supplements.[129]
## Pathogens
If bacteria form a parasitic association with other organisms, they are classed as pathogens. Pathogenic bacteria are a major cause of human death and disease and cause infections such as tetanus, typhoid fever, diphtheria, syphilis, cholera, foodborne illness, leprosy and tuberculosis. A pathogenic cause for a known medical disease may only be discovered many years after, as was the case with Helicobacter pylori and peptic ulcer disease. Bacterial diseases are also important in agriculture, with bacteria causing leaf spot, fire blight and wilts in plants, as well as Johne's disease, mastitis, salmonella and anthrax in farm animals.
Each species of pathogen has a characteristic spectrum of interactions with its human hosts. Some organisms, such as Staphylococcus or Streptococcus, can cause skin infections, pneumonia, meningitis and even overwhelming sepsis, a systemic inflammatory response producing shock, massive vasodilation and death.[130] Yet these organisms are also part of the normal human flora and usually exist on the skin or in the nose without causing any disease at all. Other organisms invariably cause disease in humans, such as the Rickettsia, which are obligate intracellular parasites able to grow and reproduce only within the cells of other organisms. One species of Rickettsia causes typhus, while another causes Rocky Mountain spotted fever. Chlamydia, another phylum of obligate intracellular parasites, contains species that can cause pneumonia, or urinary tract infection and may be involved in coronary heart disease.[131] Finally, some species such as Pseudomonas aeruginosa, Burkholderia cenocepacia, and Mycobacterium avium are opportunistic pathogens and cause disease mainly in people suffering from immunosuppression or cystic fibrosis.[132][133]
Bacterial infections may be treated with antibiotics, which are classified as bacteriocidal if they kill bacteria, or bacteriostatic if they just prevent bacterial growth. There are many types of antibiotics and each class inhibits a process that is different in the pathogen from that found in the host. An example of how antibiotics produce selective toxicity are chloramphenicol and puromycin, which inhibit the bacterial ribosome, but not the structurally different eukaryotic ribosome.[134] Antibiotics are used both in treating human disease and in intensive farming to promote animal growth, where they may be contributing to the rapid development of antibiotic resistance in bacterial populations.[135] Infections can be prevented by antiseptic measures such as sterilizating the skin prior to piercing it with the needle of a syringe, and by proper care of indwelling catheters. Surgical and dental instruments are also sterilized to prevent contamination and infection by bacteria. Disinfectants such as bleach are used to kill bacteria or other pathogens on surfaces to prevent contamination and further reduce the risk of infection.
# Significance in technology and industry
Bacteria, often Lactobacillus in combination with yeasts and molds, have been used for thousands of years in the preparation of fermented foods such as cheese, pickles, soy sauce, sauerkraut, vinegar, wine and yoghurt.[136][137]
The ability of bacteria to degrade a variety of organic compounds is remarkable and has been used in waste processing and bioremediation. Bacteria capable of digesting the hydrocarbons in petroleum are often used to clean up oil spills.[138] Fertilizer was added to some of the beaches in Prince William Sound in an attempt to promote the growth of these naturally occurring bacteria after the infamous 1989 Exxon Valdez oil spill. These efforts were effective on beaches that were not too thickly covered in oil. Bacteria are also used for the bioremediation of industrial toxic wastes.[139] In the chemical industry, bacteria are most important in the production of enantiomerically pure chemicals for use as pharmaceuticals or agrichemicals.[140]
Bacteria can also be used in the place of pesticides in the biological pest control. This commonly involves Bacillus thuringiensis (also called BT), a Gram-positive, soil dwelling bacterium. Subspecies of this bacteria are used as a Lepidopteran-specific insecticides under trade names such as Dipel and Thuricide.[141] Because of their specificity, these pesticides are regarded as environmentally friendly, with little or no effect on humans, wildlife, pollinators and most other beneficial insects.[142][143]
Because of their ability to quickly grow and the relative ease with which they can be manipulated, bacteria are the workhorses for the fields of molecular biology, genetics and biochemistry. By making mutations in bacterial DNA and examining the resulting phenotypes, scientists can determine the function of genes, enzymes and metabolic pathways in bacteria, then apply this knowledge to more complex organisms.[144] This aim of understanding the biochemistry of a cell reaches its most complex expression in the synthesis of huge amounts of enzyme kinetic and gene expression data into mathematical models of entire organisms. This is achievable in some well-studied bacteria, with models of Escherichia coli metabolism now being produced and tested.[145][146] This understanding of bacterial metabolism and genetics allows the use of biotechnology to bioengineer bacteria for the production of therapeutic proteins, such as insulin, growth factors, or antibodies.[147][148] | https://www.wikidoc.org/index.php/Bacteria | |
e8cfbc859c99a286464c0dfa96d994e9e8fa759a | wikidoc | Bad trip | Bad trip
A bad trip is a frightening experience associated with use of a hallucinogenic drug such as LSD, salvinorin A, mescaline, or psilocybin. These experiences can range from something which is not present in the real world to a moment of extreme paranoia. The term is also used to describe people who have had panic attacks while using cannabis. Such effects are not seen as threatening or negative for some in the therapeutic community, and may have the potential to be highly beneficial to the user when properly resolved. They have been attributed to the inexperience or irresponsibility of the user, lack of proper preparation and environment for the trip, or unresolved psychological tensions triggered during the course of the experience.
It is suggested that, at a minimum, such crises be managed by preventing the individual from harming oneself or others by whatever means necessary up to and including physical restraint, providing him or her with a safe and comfortable space, and supervising him or her until all effects of the drug have completely worn off.
# Aspects
A multitude of reactions can occur during a psychedelic crisis. Users can experience many general senses of fear. Some users may be catapulted into a anxiety attack, a disabling reaction in which one is overcome with extreme fright. A user may be overwhelmed with the disconnection many psychedelics cause, and fear that they are going insane or will never return to reality. This can cause the user to fall into a profound depression. Other reactions include an amplification of nameless fears; that is, fears that are unfounded and are usually not encountered in normality.
Users may exhibit actions suggesting harm to themselves or others around them. This harm could take the form of suicidal ideation, or full blown suicide attempts. Because of the magnification of emotions many psychedelics cause, death or thoughts of death can cause intensely adverse reactions in some users. Users can believe that their death is imminent or that the very universe itself is collapsing. Rapidly accelerated aging of other people may be experienced, irritating the aforementioned fears even more.
Some users may experience disorientation. The normal views of time, space, and person can be substantially altered, causing fear. Some can worsen their condition by trying to fight the psychedelic experience after embarkment. There can be illusions of insects crawling over or into one's self, or of being in dirty places such as sewers.
## Unpredictability of the experience
The effects of psychedelic drugs vary widely from one individual to the next, and from one experience to the next. Sometimes individuals under the influence of such drugs forget that they have taken them, and believe that the wildly distorted world they perceive is real and will be with them indefinitely. In cases where the individual cannot be kept safe, hospitalization may be useful, though the value of this practice for individuals not mentally ill is disputed by proponents of investigative or recreational use of psychoactive compounds. Psychosis is exacerbated in individuals already suffering from this condition.
# Intervention
Generally, a person experiencing a psychedelic crisis can be helped to either resolve the impasse, bypass it, or, failing that, to terminate the experience.
## Psychologically
In the event of a psychedelic crisis, one possible intervention is a well lit space. Darkness enhances the inner experience. A change of environment can immediately calm the person, as new stimulus automatically generates new and different experiences. It's helpful to have around a trusted friend (who, ideally, has taken or is educated on the drug(s)-in-action) that can support or "talk down" the individual going through a deep, difficult period of a drug experience. This "trip-sitter" must first get a feel for how distorted or disconnected the tripper feels; it's important for the sitter not to react to these exclamations/lamentations in a way that might make the tripper feel more disconnected, i.e. "Whoa, you must be really high," "You have to calm down," etc. This will only create a sense of urgency. Remind the distressed individual that the emotions and physical sensations they are experiencing are almost certainly just an effect of the drug, they are normal and will eventually pass. It should be noted here that with hallucinogens in particular, the mental high is undulating and dynamic; the intensity is likely just a part of the first few waves, it will not last for the duration of the trip. And so it may be helpful to remind them of the passing time (a bad trip can make time feel intensely dilated, if not destroyed) and to show them how everything around them is okay; there is nothing to panic over and the turbulence is only in their mind. It is also very important to talk calmly to the individual and not become agitated by their behavior, as this will only amplify the most negative aspects of whatever their mind is processing during the bad trip. An experienced or even unexperienced recreational drug user can also "talk" himself down using CBT (Cognitive Behavioural Therapy), slow breathing and thinking techniques, it is, however recommended that the individual does have someone he trusts to help him or her through.
## Medically
Medical treatment consists of supportive therapy and minimization of external stimuli. In some cases, sedation is used when necessary to control self-destructive behavior, or when hyperthermia occurs. Valium is the most frequently used sedative for such treatment, but other benzodiazepines such as Ativan are also effective. Such sedatives will only decrease fear and anxiety, but will not subdue hallucinations. In severe cases, antipsychotics such as haloperidol can reduce or stop hallucinations, but this treatment is only effective against the so-called "classical" hallucinogens (LSD, psilocybin and mescaline, among others). Antipsychotics are not effective against dissociatives such as PCP and ketamine, and should not be used if these drugs are involved. According to Timothy Leary, a simple temporary fix to a bad trip is sugar (in the form of candy, oranges, etc.), since crises may often be the result of people forgetting to eat and experiencing hyperawareness of low blood sugar.
# Potential Causes
According to Timothy Leary, a crisis can be a result of wrong set and setting. Leary advised that users of psychedelics be sure that they are comfortable before taking the drugs. Leary claimed that the frequency of difficult trips was highly exaggerated by anecdotes and fabrications in the popular press, and was actually about 1 in 1000.
Alternatively, psychologist R. D. Laing held that psychedelic crises and other such extreme experiences, drug-induced or not, were not necessarily artificial terrors to be suppressed but rather signs of internal conflict and opportunities for self-healing. The greater the pain and pathos of an experience, the greater the urgency to explore and resolve it, rather than attempt to cover it up or dismiss it.
Likewise, Stanislav Grof suggested that painful and difficult experiences during a trip could be a result of the mind reliving experiences associated with birth, and that experiences of imprisonment, eschatological terror, or suffering far beyond anything imaginable in a normal state, if seen through to conclusion, often resolve into emotional, intellectual and spiritual breakthroughs. From this perspective, interrupting a bad trip, while initially seen as beneficial, can trap the tripper in unresolved psychological states. Grof also suggests that many cathartic experiences within psychedelic states, while not necessarily crises, may be the effects of consciousness entering a perinatal space.
# Effects of cannabis
Though cannabis can lead to panic states in some cases, it does not usually cause "bad trips" when used by itself in moderate dosages. It can however cause anxiety or panic attacks at moderate dosages. Because cannabis can induce anxiety attacks, it could trigger a psychedelic crisis in a user already under the influence of a hallucinogen especially at a difficult moment. It is likely to exacerbate confusion, panic and paranoia.
At very high dosages, cannabis is itself hallucinogenic and it is likely that it can cause psychedelic crises directly comparable to those caused by other hallucinogens. As is the case with other hallucinogenic drugs, this effect has not been studied and proven clinically.
In some cases, however, cannabis can calm someone under a hallucinogenic trip, and somewhat put the trip on "hold" until they are calm enough to allow themselves to continue on. | Bad trip
A bad trip is a frightening experience associated with use of a hallucinogenic drug such as LSD, salvinorin A, mescaline, or psilocybin. These experiences can range from something which is not present in the real world to a moment of extreme paranoia. The term is also used to describe people who have had panic attacks while using cannabis. Such effects are not seen as threatening or negative for some in the therapeutic community, and may have the potential to be highly beneficial to the user when properly resolved. They have been attributed to the inexperience or irresponsibility of the user, lack of proper preparation and environment for the trip, or unresolved psychological tensions triggered during the course of the experience.[1]
It is suggested that, at a minimum, such crises be managed by preventing the individual from harming oneself or others by whatever means necessary up to and including physical restraint, providing him or her with a safe and comfortable space, and supervising him or her until all effects of the drug have completely worn off.
# Aspects
A multitude of reactions can occur during a psychedelic crisis. Users can experience many general senses of fear. Some users may be catapulted into a anxiety attack, a disabling reaction in which one is overcome with extreme fright.[2] A user may be overwhelmed with the disconnection many psychedelics cause, and fear that they are going insane or will never return to reality. This can cause the user to fall into a profound depression. Other reactions include an amplification of nameless fears; that is, fears that are unfounded and are usually not encountered in normality.
Users may exhibit actions suggesting harm to themselves or others around them.[3] This harm could take the form of suicidal ideation, or full blown suicide attempts. Because of the magnification of emotions many psychedelics cause, death or thoughts of death can cause intensely adverse reactions in some users. Users can believe that their death is imminent or that the very universe itself is collapsing.[3] Rapidly accelerated aging of other people may be experienced, irritating the aforementioned fears even more.
Some users may experience disorientation. The normal views of time, space, and person can be substantially altered, causing fear. Some can worsen their condition by trying to fight the psychedelic experience after embarkment. There can be illusions of insects crawling over or into one's self, or of being in dirty places such as sewers.
## Unpredictability of the experience
The effects of psychedelic drugs vary widely from one individual to the next, and from one experience to the next. Sometimes individuals under the influence of such drugs forget that they have taken them, and believe that the wildly distorted world they perceive is real and will be with them indefinitely. In cases where the individual cannot be kept safe, hospitalization may be useful, though the value of this practice for individuals not mentally ill is disputed by proponents of investigative or recreational use of psychoactive compounds. Psychosis is exacerbated in individuals already suffering from this condition.
# Intervention
Generally, a person experiencing a psychedelic crisis can be helped to either resolve the impasse, bypass it, or, failing that, to terminate the experience.
## Psychologically
In the event of a psychedelic crisis, one possible intervention is a well lit space. Darkness enhances the inner experience. A change of environment can immediately calm the person, as new stimulus automatically generates new and different experiences. It's helpful to have around a trusted friend (who, ideally, has taken or is educated on the drug(s)-in-action) that can support or "talk down" the individual going through a deep, difficult period of a drug experience. This "trip-sitter" must first get a feel for how distorted or disconnected the tripper feels; it's important for the sitter not to react to these exclamations/lamentations in a way that might make the tripper feel more disconnected, i.e. "Whoa, you must be really high," "You have to calm down," etc. This will only create a sense of urgency. Remind the distressed individual that the emotions and physical sensations they are experiencing are almost certainly just an effect of the drug, they are normal and will eventually pass. It should be noted here that with hallucinogens in particular, the mental high is undulating and dynamic; the intensity is likely just a part of the first few waves, it will not last for the duration of the trip. And so it may be helpful to remind them of the passing time (a bad trip can make time feel intensely dilated, if not destroyed) and to show them how everything around them is okay; there is nothing to panic over and the turbulence is only in their mind. It is also very important to talk calmly to the individual and not become agitated by their behavior, as this will only amplify the most negative aspects of whatever their mind is processing during the bad trip. An experienced or even unexperienced recreational drug user can also "talk" himself down using CBT (Cognitive Behavioural Therapy), slow breathing and thinking techniques, it is, however recommended that the individual does have someone he trusts to help him or her through.
## Medically
Medical treatment consists of supportive therapy and minimization of external stimuli. In some cases, sedation is used when necessary to control self-destructive behavior, or when hyperthermia occurs. Valium is the most frequently used sedative for such treatment, but other benzodiazepines such as Ativan are also effective. Such sedatives will only decrease fear and anxiety, but will not subdue hallucinations. In severe cases, antipsychotics such as haloperidol can reduce or stop hallucinations, but this treatment is only effective against the so-called "classical" hallucinogens (LSD, psilocybin and mescaline, among others). Antipsychotics are not effective against dissociatives such as PCP and ketamine, and should not be used if these drugs are involved. According to Timothy Leary, a simple temporary fix to a bad trip is sugar (in the form of candy, oranges, etc.), since crises may often be the result of people forgetting to eat and experiencing hyperawareness of low blood sugar.
# Potential Causes
According to Timothy Leary, a crisis can be a result of wrong set and setting. Leary advised that users of psychedelics be sure that they are comfortable before taking the drugs. Leary claimed that the frequency of difficult trips was highly exaggerated by anecdotes and fabrications in the popular press, and was actually about 1 in 1000.
Alternatively, psychologist R. D. Laing held that psychedelic crises and other such extreme experiences, drug-induced or not, were not necessarily artificial terrors to be suppressed but rather signs of internal conflict and opportunities for self-healing. The greater the pain and pathos of an experience, the greater the urgency to explore and resolve it, rather than attempt to cover it up or dismiss it.
Likewise, Stanislav Grof suggested that painful and difficult experiences during a trip could be a result of the mind reliving experiences associated with birth, and that experiences of imprisonment, eschatological terror, or suffering far beyond anything imaginable in a normal state, if seen through to conclusion, often resolve into emotional, intellectual and spiritual breakthroughs. From this perspective, interrupting a bad trip, while initially seen as beneficial, can trap the tripper in unresolved psychological states. Grof also suggests that many cathartic experiences within psychedelic states, while not necessarily crises, may be the effects of consciousness entering a perinatal space.
# Effects of cannabis
Though cannabis can lead to panic states in some cases, it does not usually cause "bad trips" when used by itself in moderate dosages. It can however cause anxiety or panic attacks at moderate dosages.[citation needed] Because cannabis can induce anxiety attacks, it could trigger a psychedelic crisis in a user already under the influence of a hallucinogen especially at a difficult moment. It is likely to exacerbate confusion, panic and paranoia.
At very high dosages, cannabis is itself hallucinogenic and it is likely that it can cause psychedelic crises directly comparable to those caused by other hallucinogens. As is the case with other hallucinogenic drugs, this effect has not been studied and proven clinically.
In some cases, however, cannabis can calm someone under a hallucinogenic trip, and somewhat put the trip on "hold" until they are calm enough to allow themselves to continue on. | https://www.wikidoc.org/index.php/Bad_trip | |
98118ae833ef491a1e47bc3dacbd811e9b002f8d | wikidoc | Bag Balm | Bag Balm
Bag Balm is a salve originally intended to soothe irritation on cows' udders. Although the product only mentions use "For chapped conditions and superficial abrasions" it is used as a treatment for chapped and irritated skin on humans and can be found in drug stores and ski resorts. It has also gained popularity as a post-tattoo skin soother.
Bag Balm is made by the Dairy Association Co. in Lyndonville, Vermont and Rock Island, Quebec. The product is known for its characteristic 10 oz green tins featuring a cow's head and red clovers on the lid. It has been in production since 1899.
The active ingredients of Bag Balm are 8-hydroxyquinoline sulfate 0.3% (antiseptic) in a petrolatum and lanolin base.
Bag Balm used to contain 0.002% mercury. This earlier formulation was much more effective at fighting infection in wounds and was known to completely clear infected wounds overnight. | Bag Balm
Bag Balm is a salve originally intended to soothe irritation on cows' udders. Although the product only mentions use "For chapped conditions and superficial abrasions" it is used as a treatment for chapped and irritated skin on humans and can be found in drug stores and ski resorts. It has also gained popularity as a post-tattoo skin soother.
Bag Balm is made by the Dairy Association Co. in Lyndonville, Vermont and Rock Island, Quebec. The product is known for its characteristic 10 oz green tins featuring a cow's head and red clovers on the lid. It has been in production since 1899.
The active ingredients of Bag Balm are 8-hydroxyquinoline sulfate 0.3% (antiseptic) in a petrolatum and lanolin base.
Bag Balm used to contain 0.002% mercury. This earlier formulation was much more effective at fighting infection in wounds and was known to completely clear infected wounds overnight.
# External links
- Bag Balm, Vermont's Original
- Bag Balm, Canada
Template:Agri-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Bag_Balm | |
85747589aeecb41df848218f4ffe62186b15e1af | wikidoc | Band 4.1 | Band 4.1
Erythrocyte membrane protein band 4.1 (elliptocytosis 1, RH-linked), also known as EPB41, is a human gene.
Elliptocytosis is a hematologic disorder characterized by elliptically shaped erythrocytes and a variable degree of hemolytic anemia. Inherited as an autosomal dominant, elliptocytosis results from mutation in any one of several genes encoding proteins of the red cell membrane skeleton. The form discussed here is the one found in the 1950s to be linked to Rh blood group and more recently shown to be caused by a defect in protein 4.1. 'Rh-unlinked' forms of elliptocytosis are caused by mutation in the alpha-spectrin gene (MIM 182860), the beta-spectrin gene (MIM 182870), or the band 3 gene (MIM 109270).
Band 4.1 is a protein associated with the cytoskeleton of the red blood cell. | Band 4.1
Erythrocyte membrane protein band 4.1 (elliptocytosis 1, RH-linked), also known as EPB41, is a human gene.
Elliptocytosis is a hematologic disorder characterized by elliptically shaped erythrocytes and a variable degree of hemolytic anemia. Inherited as an autosomal dominant, elliptocytosis results from mutation in any one of several genes encoding proteins of the red cell membrane skeleton. The form discussed here is the one found in the 1950s to be linked to Rh blood group and more recently shown to be caused by a defect in protein 4.1. 'Rh-unlinked' forms of elliptocytosis are caused by mutation in the alpha-spectrin gene (MIM 182860), the beta-spectrin gene (MIM 182870), or the band 3 gene (MIM 109270).[supplied by OMIM][1]
Band 4.1 is a protein associated with the cytoskeleton of the red blood cell. | https://www.wikidoc.org/index.php/Band_4.1 | |
24746877bc9f872e9643efd26ed727219aa67679 | wikidoc | Barbital | Barbital
Barbital (marketed under the brand name Veronal), also called barbitone, was the first commercially marketed barbiturate. It was used as a sleeping aid (hypnotic) from 1903 until the mid-1950s. The chemical names for barbital are diethylmalonyl urea or diethylbarbituric acid. Its chemical formula is (C2H5)2C~CO NH]ICO (sodium 5,5-diethyl barbiturate). Veronal was prepared by condensing diethylmalonic ester with urea in the presence of sodium ethylate, or by adding ethyl iodide to the silver salt of malonylurea. The result was an odorless, slightly bitter, white crystalline powder.
Barbital was first synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering. They published their discovery in 1903 and it was marketed in 1904 by the Bayer company as “Veronal”. A soluble salt of barbital was marketed by the Schering company as “Medinal.” It was dispensed for “insomnia induced by nervous excitability”. It was provided in either capsules or cachets. The therapeutic dose was ten to fifteen grains (0.65-0.97 grams). 3.5 to 4.4 grams is the deadly dose but sleep has also been prolonged up to ten days with recovery.
Veronal was considered to be a great improvement over the existing hypnotics. Its taste was slightly bitter, but an improvement over the strong, unpleasant taste of the commonly used bromides. It had few side effects. Its therapeutic dose was far below the toxic dose. However, prolonged usage resulted in tolerance to the drug, requiring higher doses to reach the desired effect. Fatal overdoses of this slow acting hypnotic were not uncommon. | Barbital
Barbital (marketed under the brand name Veronal), also called barbitone, was the first commercially marketed barbiturate. It was used as a sleeping aid (hypnotic) from 1903 until the mid-1950s. The chemical names for barbital are diethylmalonyl urea or diethylbarbituric acid. Its chemical formula is (C2H5)2C~CO NH]ICO (sodium 5,5-diethyl barbiturate). Veronal was prepared by condensing diethylmalonic ester with urea in the presence of sodium ethylate, or by adding ethyl iodide to the silver salt of malonylurea. The result was an odorless, slightly bitter, white crystalline powder.
Barbital was first synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering. They published their discovery in 1903 and it was marketed in 1904 by the Bayer company as “Veronal”. A soluble salt of barbital was marketed by the Schering company as “Medinal.” It was dispensed for “insomnia induced by nervous excitability”. [1] It was provided in either capsules or cachets. The therapeutic dose was ten to fifteen grains (0.65-0.97 grams). 3.5 to 4.4 grams is the deadly dose but sleep has also been prolonged up to ten days with recovery.
Veronal was considered to be a great improvement over the existing hypnotics. Its taste was slightly bitter, but an improvement over the strong, unpleasant taste of the commonly used bromides. It had few side effects. Its therapeutic dose was far below the toxic dose. However, prolonged usage resulted in tolerance to the drug, requiring higher doses to reach the desired effect. Fatal overdoses of this slow acting hypnotic were not uncommon. | https://www.wikidoc.org/index.php/Barbital | |
c425b172d0b7e1a2d86eb9ab8d665b047615057a | wikidoc | Barnacle | Barnacle
A barnacle is a type of arthropod belonging to infraclass Cirripedia in the subphylum Crustacea, and is hence distantly related to crabs and lobsters. Barnacles are exclusively marine, and tend to live in shallow and tidal waters, typically in erosive settings. They are sessile suspension feeders, and have two nektonic larval stages.
Around 1,220 barnacle species are currently known. The name "Cirripedia" is Latin, meaning "curl-footed".
# Ecology
Barnacles are encrusters, attaching themselves permanently to a hard substrate. The most common, "acorn barnacles" (Sessilia) are sessile, growing their shells directly onto the substrate. The order Pedunculata ("goose barnacles" and others) attach themselves by means of a stalk.
Most barnacles are suspension feeders; they dwell continually in their shell - which is usually constructed of six plates - and reach into the water column with modified legs. These feathery appendages beat rhythmically to draw plankton and detritus into the shell for consumption.
Other members of the class have quite a different mode of life. For example, members of the genus Sacculina are parasitic, dwelling within crabs.
Although they have been found at water depths up to 600m, most barnacles inhabit shallow waters, with 75% of species living in water depths of less than 100m, and 25% inhabiting the Template:Wict zone.
Within the intertidal zone, different species of barnacle live in very tightly constrained locations, allowing the exact height of an assemblage above or below sea level to be precisely determined.
Since the intertidal zone periodically desiccates, barnacles are well adapted against water loss. Their calcite shells are impermeable, and they possess two plates which they can slide across their aperture when not feeding. These plates also protect against predation.
Barnacles are displaced by limpets and mussels, who compete for space. They also have numerous predators.
They employ two strategies to overwhelm their competitors: "swamping", and fast growth. In the swamping strategy, vast numbers of barnacles settle in the same place at once, covering a large patch of substrate, allowing at least some to survive in the balance of probabilities. Fast growth allows the suspension feeders to access higher levels of the water column then their competitors, and to be large enough to resist displacement; species employing this response, such as the aptly named Megabalanus, can reach 7 cm in length; other species may grow larger still.
Competitors may include other barnacles, and there is (disputed) evidence that balanoid barnacles competitively displaced chthalamoid barnacles. Balanoids gained their advantage over the chthalamoids in the Oligocene, when they evolved a tubular skeleton. This provides better anchorage to the substrate, and allows them to grow faster, undercutting, crushing and smothering by the latter group.
# Life cycle
Barnacles have 2 distinct larval stages, the nauplius and the cyprid, before developing into a mature adult.
## Nauplius stage
A fertilized egg hatches into a nauplius: a one eyed larva comprising a head and a telson, without a thorax or abdomen. This undergoes 6 molts before transforming into the bivalved cyprid stage. Nauplii are typically initially brooded by the parent, and released as free-swimming larvae after the first molt.
## Cyprid stage
The cyprid stage lasts from days to weeks. During this part of the life cycle, the barnacle searches for a place to settle. It explores potential surfaces with modified antennules structures; once it has found a potentially suitable spot, it attaches head-first using its antennules, and a secreted glycoproteinous substance. Larvae are thought to assess surfaces based upon their surface texture, chemistry, relative wettability, colour and the presence/absence and composition of a surface biofilm; swarming species are also more likely to attach near to other barnacles. As the larva exhausts its finite energy reserves, so it becomes less picky in the sites it selects. If the spot is to its liking, it cementing down permanently with another proteinacous compound. This accomplished, it undergoes metamorphosis into a juvenile barnacle.
## Adult stage
Typical acorn barnacles develop six hard calcareous plates to surround and protect their bodies. For the rest of their lives they are cemented to the ground, using their feathery legs (cirri) to capture plankton.
Once metamorphosis is over and they have reached their adult form, barnacles will continue to grow by adding new material to their heavily calcified plates. These plates are not moulted; however, like all ecdysozoans, the barnacle itself will still molt its cuticle.
## Sexual reproduction
Most barnacles are hermaphroditic, although a few species are gonochoric or androdioecious. Typically, recently molted hermaphroditic individuals are receptive as females. Self-fertilization, although theoretically possible, has been experimentally shown to be rare in barnacles .
The sessile lifestyle of barnacles makes sexual reproduction difficult, as the organisms cannot leave their shells to mate. To facilitate genetic transfer between isolated individuals, barnacles have extraordinarily long penises, up to 15cm in length: the largest penis to body size ratio of the animal kingdom.
# Fossil record
The geological history of barnacles can be traced back to the early Palaeozoic (in the order of 4-500 million years ago), although they do not become common in the fossil record until the Neogene (last 20 million years). In part their poor preservation is due to their restriction to high-energy environments, which tend to be erosional - therefore it is more common for their shells to be ground up by wave action than for them to reach a depositional setting. It is also possible that the group was more minor in the past.
Barnacles can play an important role in estimating palæo-water depths. The degree of disarticluation of fossils suggests the distance they have been transported, and since many species have narrow ranges of water depths, it can be assumed that the animals lived in shallow water and broke up as they were washed down-slope. The completeness of fossils, and nature of damage, can thus be used to constrain the tectonic history of regions.
# In human culture
Barnacles were first fully studied and classified by Charles Darwin who published a series of monographs in 1851 and 1854. Darwin undertook this study at the suggestion of his friend Joseph Dalton Hooker, in order to thoroughly understand at least one species before making the generalisations needed for his theory of evolution by natural selection .
Barnacles are of economic consequence as they often attach themselves to man-made structures, sometimes to the structure's detriment. Particularly in the case of ships, they are classified as fouling organisms.
Some barnacles are edible by humans, and goose barnacles (e.g. Pollicipes polymerus) are treasured as a delicacy in many Mediterranean countries. The resemblance of this barnacle's fleshy stalk to a goose's neck gave rise in ancient times to the notion that geese, or at least certain seagoing species of wild goose, literally grew from the barnacle. Most notably, the wild Barnacle Goose (Branta leucopsis), whose eggs and young were rarely seen by humans because it breeds in the remote Arctic, got its popular name because it was imagined to grow from gooseneck barnacles.
# Classification
Some authorities regard Cirripedia as a full class or subclass, and the orders listed above are sometimes treated as superorders.
This article follows Martin and Davis in placing Cirripedia as an infraclass of Thecostraca and in the following classification of cirripedes down to the level of orders Template:Lopsided:
Infraclass Cirripedia Burmeister, 1834
- Superorder Acrothoracica Gruvel, 1905
Order Pygophora Berndt, 1907
Order Apygophora Berndt, 1907
- Order Pygophora Berndt, 1907
- Order Apygophora Berndt, 1907
- Superorder Rhizocephala Müller, 1862
Order Kentrogonida Delage, 1884
Order Akentrogonida Häfele, 1911
- Order Kentrogonida Delage, 1884
- Order Akentrogonida Häfele, 1911
- Superorder Thoracica Darwin, 1854
Order Pedunculata Lamarck, 1818
Order Sessilia Lamarck, 1818
- Order Pedunculata Lamarck, 1818
- Order Sessilia Lamarck, 1818 | Barnacle
A barnacle is a type of arthropod belonging to infraclass Cirripedia in the subphylum Crustacea, and is hence distantly related to crabs and lobsters. Barnacles are exclusively marine, and tend to live in shallow and tidal waters, typically in erosive settings. They are sessile suspension feeders, and have two nektonic larval stages.
Around 1,220 barnacle species are currently known.[3] The name "Cirripedia" is Latin, meaning "curl-footed".
# Ecology
Barnacles are encrusters, attaching themselves permanently to a hard substrate. The most common, "acorn barnacles" (Sessilia) are sessile, growing their shells directly onto the substrate.[2] The order Pedunculata ("goose barnacles" and others) attach themselves by means of a stalk.[2]
Most barnacles are suspension feeders; they dwell continually in their shell - which is usually constructed of six plates[2] - and reach into the water column with modified legs. These feathery appendages beat rhythmically to draw plankton and detritus into the shell for consumption.[citation needed]
Other members of the class have quite a different mode of life. For example, members of the genus Sacculina are parasitic, dwelling within crabs.[4]
Although they have been found at water depths up to 600m,[2] most barnacles inhabit shallow waters, with 75% of species living in water depths of less than 100m,[2] and 25% inhabiting the Template:Wict zone.[2]
Within the intertidal zone, different species of barnacle live in very tightly constrained locations, allowing the exact height of an assemblage above or below sea level to be precisely determined.[2]
Since the intertidal zone periodically desiccates, barnacles are well adapted against water loss. Their calcite shells are impermeable, and they possess two plates which they can slide across their aperture when not feeding. These plates also protect against predation.[verification needed]
Barnacles are displaced by limpets and mussels, who compete for space. They also have numerous predators.[2]
They employ two strategies to overwhelm their competitors: "swamping", and fast growth. In the swamping strategy, vast numbers of barnacles settle in the same place at once, covering a large patch of substrate, allowing at least some to survive in the balance of probabilities.[2] Fast growth allows the suspension feeders to access higher levels of the water column then their competitors, and to be large enough to resist displacement; species employing this response, such as the aptly named Megabalanus, can reach 7 cm in length;[2] other species may grow larger still.
Competitors may include other barnacles, and there is (disputed) evidence that balanoid barnacles competitively displaced chthalamoid barnacles. Balanoids gained their advantage over the chthalamoids in the Oligocene, when they evolved a tubular skeleton. This provides better anchorage to the substrate, and allows them to grow faster, undercutting, crushing and smothering by the latter group.[5]
# Life cycle
Barnacles have 2 distinct larval stages, the nauplius and the cyprid, before developing into a mature adult.
## Nauplius stage
A fertilized egg hatches into a nauplius: a one eyed larva comprising a head and a telson, without a thorax or abdomen. This undergoes 6 molts before transforming into the bivalved cyprid stage. Nauplii are typically initially brooded by the parent, and released as free-swimming larvae after the first molt.
## Cyprid stage
The cyprid stage lasts from days to weeks. During this part of the life cycle, the barnacle searches for a place to settle. It explores potential surfaces with modified antennules structures; once it has found a potentially suitable spot, it attaches head-first using its antennules, and a secreted glycoproteinous substance. Larvae are thought to assess surfaces based upon their surface texture, chemistry, relative wettability, colour and the presence/absence and composition of a surface biofilm; swarming species are also more likely to attach near to other barnacles. As the larva exhausts its finite energy reserves, so it becomes less picky in the sites it selects. If the spot is to its liking, it cementing down permanently with another proteinacous compound. This accomplished, it undergoes metamorphosis into a juvenile barnacle.
## Adult stage
Typical acorn barnacles develop six[citation needed] hard calcareous plates to surround and protect their bodies. For the rest of their lives they are cemented to the ground, using their feathery legs (cirri) to capture plankton.
Once metamorphosis is over and they have reached their adult form, barnacles will continue to grow by adding new material to their heavily calcified plates. These plates are not moulted; however, like all ecdysozoans, the barnacle itself will still molt its cuticle[6].
## Sexual reproduction
Most barnacles are hermaphroditic, although a few species are gonochoric or androdioecious. Typically, recently molted hermaphroditic individuals are receptive as females. Self-fertilization, although theoretically possible, has been experimentally shown to be rare in barnacles [7] [8].
The sessile lifestyle of barnacles makes sexual reproduction difficult, as the organisms cannot leave their shells to mate. To facilitate genetic transfer between isolated individuals, barnacles have extraordinarily long penises, up to 15cm in length: the largest penis to body size ratio of the animal kingdom.[9]
# Fossil record
The geological history of barnacles can be traced back to the early Palaeozoic (in the order of 4-500 million years ago),[1] although they do not become common in the fossil record until the Neogene (last 20 million years). In part their poor preservation is due to their restriction to high-energy environments, which tend to be erosional - therefore it is more common for their shells to be ground up by wave action than for them to reach a depositional setting. It is also possible that the group was more minor in the past.[verification needed]
Barnacles can play an important role in estimating palæo-water depths. The degree of disarticluation of fossils suggests the distance they have been transported, and since many species have narrow ranges of water depths, it can be assumed that the animals lived in shallow water and broke up as they were washed down-slope. The completeness of fossils, and nature of damage, can thus be used to constrain the tectonic history of regions.[2]
# In human culture
Barnacles were first fully studied and classified by Charles Darwin who published a series of monographs in 1851 and 1854. Darwin undertook this study at the suggestion of his friend Joseph Dalton Hooker, in order to thoroughly understand at least one species before making the generalisations needed for his theory of evolution by natural selection [10].
Barnacles are of economic consequence as they often attach themselves to man-made structures, sometimes to the structure's detriment. Particularly in the case of ships, they are classified as fouling organisms.[citation needed]
Some barnacles are edible by humans, and goose barnacles (e.g. Pollicipes polymerus) are treasured as a delicacy in many Mediterranean countries.[citation needed] The resemblance of this barnacle's fleshy stalk to a goose's neck gave rise in ancient times to the notion that geese, or at least certain seagoing species of wild goose, literally grew from the barnacle.[citation needed] Most notably, the wild Barnacle Goose (Branta leucopsis), whose eggs and young were rarely seen by humans because it breeds in the remote Arctic, got its popular name because it was imagined to grow from gooseneck barnacles.[citation needed]
# Classification
Some authorities regard Cirripedia as a full class or subclass, and the orders listed above are sometimes treated as superorders.
This article follows Martin and Davis in placing Cirripedia as an infraclass of Thecostraca and in the following classification of cirripedes down to the level of orders [11]Template:Lopsided:
Infraclass Cirripedia Burmeister, 1834
- Superorder Acrothoracica Gruvel, 1905
Order Pygophora Berndt, 1907
Order Apygophora Berndt, 1907
- Order Pygophora Berndt, 1907
- Order Apygophora Berndt, 1907
- Superorder Rhizocephala Müller, 1862
Order Kentrogonida Delage, 1884
Order Akentrogonida Häfele, 1911
- Order Kentrogonida Delage, 1884
- Order Akentrogonida Häfele, 1911
- Superorder Thoracica Darwin, 1854
Order Pedunculata Lamarck, 1818
Order Sessilia Lamarck, 1818
- Order Pedunculata Lamarck, 1818
- Order Sessilia Lamarck, 1818
# External links
- Rock barnacle at Aquascope
- Barnacles from the Marine Education Society of Australasia
- Barnacles in Spain Article on barnacles in Spain, and their collection and gastronomy.
- [1] Newcastle University's barnacle and biofouling information site. | https://www.wikidoc.org/index.php/Barnacle | |
30d3bd2954d5a9aa97eb04876e8f620e72248d57 | wikidoc | Fuchsine | Fuchsine
Fuchsine or rosaniline hydrochloride is a magenta dye with chemical formula C20H19N3·HCl. There are other similar chemical formulations of products sold as fuchsine, and several dozen other synonyms of this molecule.
It becomes magenta when dissolved in water; as a solid, it forms dark green crystals. As well as dying textiles, fuchsine is used to stain bacteria and sometimes as a disinfectant.
# History
Fuchsine, named by its original manufacturer Renard frères et Franc, is usually cited with one of two etymologies: from the color of the flowers of the plant genus Fuchsia, named in honor of botanist Leonhart Fuchs, or as the German translation Fuchs of the French name Renard, which means fox. An 1861 article in Répertoire de Pharmacie said that the name was chosen for both reasons.
# Acid fuchsine
Acid fuchsine is a mixture of homologues of basic fuchsin, modified by addition of sulfonic groups. While this yields twelve possible isomers, all of them are satisfactory despite slight differences in their properties.
# Basic fuchsine
Basic fuchsine is a mixture of rosanilin, pararosanilin, and Magenta II. Formulations usable for making of Schiff reagent must have high content of pararosanilin. The actual composition of basic fuchsine tends to somewhat vary by vendor and batch, making the batches differently suitable for different purposes.
In solution with phenol as an accentuator it is called carbol fuchsin and is used for the staining of the bacterium which cause tuberculosis. | Fuchsine
Template:Chembox new
Fuchsine or rosaniline hydrochloride is a magenta dye with chemical formula C20H19N3·HCl.[1][2] There are other similar chemical formulations of products sold as fuchsine, and several dozen other synonyms of this molecule.[1]
It becomes magenta when dissolved in water; as a solid, it forms dark green crystals. As well as dying textiles, fuchsine is used to stain bacteria and sometimes as a disinfectant.
# History
Fuchsine, named by its original manufacturer Renard frères et Franc,[3] is usually cited with one of two etymologies: from the color of the flowers of the plant genus Fuchsia,[4] named in honor of botanist Leonhart Fuchs, or as the German translation Fuchs of the French name Renard, which means fox.[5] An 1861 article in Répertoire de Pharmacie said that the name was chosen for both reasons.[6]
# Acid fuchsine
Acid fuchsine is a mixture of homologues of basic fuchsin, modified by addition of sulfonic groups. While this yields twelve possible isomers, all of them are satisfactory despite slight differences in their properties.
# Basic fuchsine
Basic fuchsine is a mixture of rosanilin, pararosanilin, and Magenta II. Formulations usable for making of Schiff reagent must have high content of pararosanilin. The actual composition of basic fuchsine tends to somewhat vary by vendor and batch, making the batches differently suitable for different purposes.
In solution with phenol as an accentuator it is called carbol fuchsin and is used for the staining of the bacterium which cause tuberculosis. | https://www.wikidoc.org/index.php/Basic_fuchsin | |
c6badd6926d5d9f95f7bdb3d5b55aa259cb1a8c5 | wikidoc | Bed rest | Bed rest
Bed rest is a doctor's prescription to spend a longer period of time in bed.
# Adverse effects
Prolonged bed rest has long been known to have deleterious physiological effects, such as muscle atrophy and other forms of deconditioning. Besides lack of physical exercise in was shown that another important factor is that the hydrostatic pressure (caused by gravity) acts anomalously, resulting in altered distribution of body fluids. Even physical exercise in bed fails to address certain adverse effects.
# Common cases
Bed rest is commonly prescribed in the following cases.
- For sufferers of acute pain in spine or joints; for example, in the case of backache the unloading of the corresponding spinal segment decreases the intradiscal pressure, and it would bring relief in cases such as compression of spinal nerve. The prescribed duration of bed rest vary and opinions differ.
- Bed rest is prescribed for some maternal or fetal complications of pregnancy, such as preterm labor, high blood pressure, incompetent cervix, or fetal growth problems. In the past it was a general prescription during any kind of pregnancy, now deprecated.
- Heart diseases
- Bed rest is an important measure in the cases of chorea. In the mild cases in may suffice for treatment. | Bed rest
Bed rest is a doctor's prescription to spend a longer period of time in bed.
# Adverse effects
Prolonged bed rest has long been known to have deleterious physiological effects, such as muscle atrophy and other forms of deconditioning. Besides lack of physical exercise in was shown that another important factor is that the hydrostatic pressure (caused by gravity) acts anomalously, resulting in altered distribution of body fluids. Even physical exercise in bed fails to address certain adverse effects.[1]
# Common cases
Bed rest is commonly prescribed in the following cases.
- For sufferers of acute pain in spine or joints; for example, in the case of backache the unloading of the corresponding spinal segment decreases the intradiscal pressure, and it would bring relief in cases such as compression of spinal nerve. The prescribed duration of bed rest vary and opinions differ. [2]
- Bed rest is prescribed for some maternal or fetal complications of pregnancy, such as preterm labor, high blood pressure, incompetent cervix, or fetal growth problems. In the past it was a general prescription during any kind of pregnancy, now deprecated.[3]
- Heart diseases
- Bed rest is an important measure in the cases of chorea. In the mild cases in may suffice for treatment.[4] | https://www.wikidoc.org/index.php/Bed-rest | |
47b2dffa21b6a054e816572f0ddddee0824ba9a2 | wikidoc | Behavior | Behavior
Behavior or behaviour (see spelling differences) refers to the actions or reactions of an object or organism, usually in relation to the environment. Behavior can be conscious or unconscious, overt or covert, and voluntary or involuntary. In animals, behavior is controlled by the endocrine system and the nervous system. The complexity of the behavior of an organism is related to the complexity of its nervous system. Generally, organisms with complex nervous systems have a greater capacity to learn new responses and thus adjust their behavior. Human behavior (and that of other organisms and mechanisms) can be common, unusual, acceptable, or unacceptable. Humans evaluate the acceptability of behavior using social norms and regulate behavior by means of social control. In sociology, behavior is considered as having no meaning, being not directed at other people and thus is the most basic human action. Animal behavior is studied in comparative psychology, ethology, behavioral ecology and sociobiology.
Because of the many associations with the term, it is difficult to characterize a term like behavior without specifying a context of discourse in which it is to take on meaning. One such context is Psychology, which has, at various times, been defined as the study or science of behavior. Oddly enough, despite the centrality of the construct to psychology, in regular introductory textbooks, such as Myers, etc. , a full characterization of the term and its meaning is avoided in favor of an immediate turn to the subject of genetics and the biological basis for all behavior, animal as well as human. This is unfortunate, for whereas discussion of the biological or evolutionary basis of human behavior is important, it would be better if it took place against a backdrop in which the term had achieved some degree of definitional coherence. This is what is being attempted here.
There are, broadly speaking, four categories of human behavior, some of which, it will be seen quickly, overlap with and are probable extensions of animal behavior. The first category may be illustrated as follows. Invoking ordinary language usage, we often say: "she behaved badly" or "he was behaving oddly." In such statements, the term has two attributes. Behavior is something we can see or hear or otherwise detect with our senses. The term is linked to sensation and the manner in which we take in information from our immediate surroundings. By contrast is the term "thinking”—also a subject for psychology—which denotes something typically invisible to an observer. Second, as used in these two examples, the term takes on a normative cast. In the first case, there is behavior that appears to contravene expectations of a moral kind. People who steal are behaving badly. So are people who lie. In the second sense of normativity, there are expectations of a social kind. You do not pick your nose in public (see, though, car drivers at stop lights for exceptions to this generally iron clad rule). You walk in a straight line down the sidewalk. Any 'contraventions' of these norms will lead to the label of odd behavior, though here it is assumed that there is nothing inherently immoral about the behavior in question. So behavior, as the term is often used in ordinary language, connotes norms or expectations, of the moral kind and of the social kind. A synonym in this case might be conduct. Someone who is behaving "badly" may also be said to be conducting himself "badly."
A second category of behavior produces a broad descriptive sweep. It takes in all behavior we might label purposive or goal-driven. In some contexts , the term “action” is preferred over behavior, and we say that humans engage in actions, meaning that what we observe about them publicly are behaviors which have an underlying purpose. Seeing someone have lunch in the college cafeteria we are observing the behavior of eating. Had we seen that person earlier in the morning, we might have observed her parking her car in the new structure. A description of her actions in both situations would link them through conversations which would reveal that she is a student at the college: she drives to class in the morning, takes two classes, has lunch, leaves for paid employment in the afternoon, etc. The point of all this is that her actions over a broad range of her day are governed by a sense of purpose, that she is a student and expects to graduate from college in four years with a degree in nursing. While at any point in time it is likely that she does not feel this sense of purpose, that is how she would analyze her actions and make sense of them to a stranger, if asked.
A third category often falls within the second as a sub-category though nevertheless is a domain in its own right. This is the category of performance or skilled behavior. Behavior that demonstrates skills of various kinds from work to sports, from behaviors involving psychomotor motions of the body, e.g. playing tennis, to those involving linguistic and extra-linguistics interactions with others, e.g. a car salesman. Again, we take examples from ordinary language usage. While watching a friend play tennis, we might say: he is playing very badly. If in the same game, he throws his racket on the ground in exasperation, we respond: Now, he’s behaving very badly. So we easily, in our everyday usage, distinguish between behavior that is under the control of or guided by learned skills and behavior that is under the control of or guided by social norms. In any game we are watching, we see players perform skillfully but behave or conduct themselves very badly and vice versa, as when we witness lack of skills on the part of someone who, at the same time, by his (normative) behavior, evokes the spirit of the game. We can dislike the first and admire the second. But again, we distinguish between a repertoire of behaviors that fall under the heading of skill and those that can be labeled socially desirable or undesirable.
Finally, there is a fourth category, which at first sight, seems to belong to the goal-driven domain, since we appear to see goals at work. If so, then the goals are mostly of a ‘low-level,’ physical kind we might term instinctual, having to do with the anatomical or physiological nature of the organism. Behavior in this category is determined by the need or desire to avoid pain and embrace pleasure. Going back to our example of the student in the dining room, part of her behavior is distantly motivated or can be explained by her goal of obtaining a degree. At the same time, that she has chosen to eat certain food but avoid other choices can be explained by what has sometimes been called the “pleasure principle.” There is food that she likes and food that she doesn’t like. Such choices and experiences are often conversation items for friends engaged in eating together. In the movie, the Matrix, the character called Cipher betrays his friends because the lofty goal of embracing reality is too distant to guide him any longer, when he can experience the complex sensuous pleasures of good wine and food, though, as he acknowledges in a scene in a restaurant with two Agents, he knows that none of it is real.
In summary then, behavior is something we ourselves do and something we experience from others. Behavior is sensuous in that what it is can be experienced through one or more of the senses. Lacking this sensational dimension, whatever the “it” is would not constitute behavior. Second, there are four basic categories. Behavior that we term conduct denotes a broad range of activity under the guidance of social-moral norms. Behavior that we term performance denotes a range of activity governed by skill repertoires. Behavior we sometimes term experience refers to actions and choices of action that maximize comfort or pleasure and minimize discomfort or pain. Finally, there is no particular other term for the very broad range of actions that fall under the heading of purposive or goal-driven, behavior that appears dictated by a sense of who we are and what we want to become.
Behavior became an important construct in early 20th century Psychology with the advent of the paradigm known subsequently as "behaviorism." Behaviorism was a reaction against so-called "faculty" psychology which purported to see into or understand the mind without the benefit of scientific testing. Behaviorism insisted on working only with what can be seen or manipulated and in the early views of John B. Watson, a founder of the field, nothing was inferred as to the nature of the entity that produced the behavior. Subsequent modifications of Watson's perspective and that of so-called "classical conditioning" (see under Ivan Pavlov led to the rise of Operant Conditioning, a theory advocated by B.F. Skinner, which took over the academic establishment up through the 1950s and was synonymous with "behaviorism" for many.
For studies on behavior ethograms are used. | Behavior
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Behavior or behaviour (see spelling differences) refers to the actions or reactions of an object or organism, usually in relation to the environment. Behavior can be conscious or unconscious, overt or covert, and voluntary or involuntary. In animals, behavior is controlled by the endocrine system and the nervous system. The complexity of the behavior of an organism is related to the complexity of its nervous system. Generally, organisms with complex nervous systems have a greater capacity to learn new responses and thus adjust their behavior. Human behavior (and that of other organisms and mechanisms) can be common, unusual, acceptable, or unacceptable. Humans evaluate the acceptability of behavior using social norms and regulate behavior by means of social control. In sociology, behavior is considered as having no meaning, being not directed at other people and thus is the most basic human action. Animal behavior is studied in comparative psychology, ethology, behavioral ecology and sociobiology.
Because of the many associations with the term, it is difficult to characterize a term like behavior without specifying a context of discourse in which it is to take on meaning. One such context is Psychology, which has, at various times, been defined as the study or science of behavior. Oddly enough, despite the centrality of the construct to psychology, in regular introductory textbooks, such as Myers, etc. [references to be supplied], a full characterization of the term and its meaning is avoided in favor of an immediate turn to the subject of genetics and the biological basis for all behavior, animal as well as human. This is unfortunate, for whereas discussion of the biological or evolutionary basis of human behavior is important, it would be better if it took place against a backdrop in which the term had achieved some degree of definitional coherence. This is what is being attempted here.
There are, broadly speaking, four categories of human behavior, some of which, it will be seen quickly, overlap with and are probable extensions of animal behavior. The first category may be illustrated as follows. Invoking ordinary language usage, we often say: "she behaved badly" or "he was behaving oddly." In such statements, the term has two attributes. Behavior is something we can see or hear or otherwise detect with our senses. The term is linked to sensation and the manner in which we take in information from our immediate surroundings. By contrast is the term "thinking”—also a subject for psychology—which denotes something typically invisible to an observer. Second, as used in these two examples, the term takes on a normative cast. In the first case, there is behavior that appears to contravene expectations of a moral kind. People who steal are behaving badly. So are people who lie. In the second sense of normativity, there are expectations of a social kind. You do not pick your nose in public (see, though, car drivers at stop lights for exceptions to this generally iron clad rule). You walk in a straight line down the sidewalk. Any 'contraventions' of these norms will lead to the label of odd behavior, though here it is assumed that there is nothing inherently immoral about the behavior in question. So behavior, as the term is often used in ordinary language, connotes norms or expectations, of the moral kind and of the social kind. A synonym in this case might be conduct. Someone who is behaving "badly" may also be said to be conducting himself "badly."
A second category of behavior produces a broad descriptive sweep. It takes in all behavior we might label purposive or goal-driven. In some contexts [ref to be supplied], the term “action” is preferred over behavior, and we say that humans engage in actions, meaning that what we observe about them publicly are behaviors which have an underlying purpose. Seeing someone have lunch in the college cafeteria we are observing the behavior of eating. Had we seen that person earlier in the morning, we might have observed her parking her car in the new structure. A description of her actions in both situations would link them through conversations which would reveal that she is a student at the college: she drives to class in the morning, takes two classes, has lunch, leaves for paid employment in the afternoon, etc. The point of all this is that her actions over a broad range of her day are governed by a sense of purpose, that she is a student and expects to graduate from college in four years with a degree in nursing. While at any point in time it is likely that she does not feel this sense of purpose, that is how she would analyze her actions and make sense of them to a stranger, if asked.
A third category often falls within the second as a sub-category though nevertheless is a domain in its own right. This is the category of performance or skilled behavior. Behavior that demonstrates skills of various kinds from work to sports, from behaviors involving psychomotor motions of the body, e.g. playing tennis, to those involving linguistic and extra-linguistics interactions with others, e.g. a car salesman. Again, we take examples from ordinary language usage. While watching a friend play tennis, we might say: he is playing very badly. If in the same game, he throws his racket on the ground in exasperation, we respond: Now, he’s behaving very badly. So we easily, in our everyday usage, distinguish between behavior that is under the control of or guided by learned skills and behavior that is under the control of or guided by social norms. In any game we are watching, we see players perform skillfully but behave or conduct themselves very badly and vice versa, as when we witness lack of skills on the part of someone who, at the same time, by his (normative) behavior, evokes the spirit of the game. We can dislike the first and admire the second. But again, we distinguish between a repertoire of behaviors that fall under the heading of skill and those that can be labeled socially desirable or undesirable.
Finally, there is a fourth category, which at first sight, seems to belong to the goal-driven domain, since we appear to see goals at work. If so, then the goals are mostly of a ‘low-level,’ physical kind we might term instinctual, having to do with the anatomical or physiological nature of the organism. Behavior in this category is determined by the need or desire to avoid pain and embrace pleasure. Going back to our example of the student in the dining room, part of her behavior is distantly motivated or can be explained by her goal of obtaining a degree. At the same time, that she has chosen to eat certain food but avoid other choices can be explained by what has sometimes been called the “pleasure principle.” There is food that she likes and food that she doesn’t like. Such choices and experiences are often conversation items for friends engaged in eating together. In the movie, the Matrix, the character called Cipher betrays his friends because the lofty goal of embracing reality is too distant to guide him any longer, when he can experience the complex sensuous pleasures of good wine and food, though, as he acknowledges in a scene in a restaurant with two Agents, he knows that none of it is real.
In summary then, behavior is something we ourselves do and something we experience from others. Behavior is sensuous in that what it is can be experienced through one or more of the senses. Lacking this sensational dimension, whatever the “it” is would not constitute behavior. Second, there are four basic categories. Behavior that we term conduct denotes a broad range of activity under the guidance of social-moral norms. Behavior that we term performance denotes a range of activity governed by skill repertoires. Behavior we sometimes term experience refers to actions and choices of action that maximize comfort or pleasure and minimize discomfort or pain. Finally, there is no particular other term for the very broad range of actions that fall under the heading of purposive or goal-driven, behavior that appears dictated by a sense of who we are and what we want to become.
Behavior became an important construct in early 20th century Psychology with the advent of the paradigm known subsequently as "behaviorism." Behaviorism was a reaction against so-called "faculty" psychology which purported to see into or understand the mind without the benefit of scientific testing. Behaviorism insisted on working only with what can be seen or manipulated and in the early views of John B. Watson, a founder of the field, nothing was inferred as to the nature of the entity that produced the behavior. Subsequent modifications of Watson's perspective and that of so-called "classical conditioning" (see under Ivan Pavlov led to the rise of Operant Conditioning, a theory advocated by B.F. Skinner, which took over the academic establishment up through the 1950s and was synonymous with "behaviorism" for many.
For studies on behavior ethograms are used. | https://www.wikidoc.org/index.php/Behavior | |
c87496b4bf171faff8866ab3f61df176194f4157 | wikidoc | Benadryl | Benadryl
Benadryl is a brand name that Johnson & Johnson (acquired fall 2006) and Pfizer use for several different allergy medicines.
- In the U.S., Benadryl is diphenhydramine, a first generation antihistamine. It is also formulated in combination with other active ingredients and sold under variations of the Benadryl name.
- In the U.K., Benadryl Allergy Relief is acrivastine, a second generation antihistamine.
- In the U.K., Benadryl Once a Day is cetirizine, a second generation antihistamine. | Benadryl
Template:Otheruses4
Benadryl is a brand name that Johnson & Johnson (acquired fall 2006) and Pfizer use for several different allergy medicines.
- In the U.S., Benadryl is diphenhydramine, a first generation antihistamine. It is also formulated in combination with other active ingredients and sold under variations of the Benadryl name.
- In the U.K., Benadryl Allergy Relief is acrivastine, a second generation antihistamine.
- In the U.K., Benadryl Once a Day is cetirizine, a second generation antihistamine.
Template:Disambig
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Benadryl | |
f7df16d2daa9bd7d26e81e2c53fae2943f6c070d | wikidoc | Bepridil | Bepridil
# Overview
Bepridil (trade name Vascor) is a calcium channel blocker once used to treat angina. It is no longer sold in the United States.
It is nonselective.
It has been discussed as a possible option in the treatment of atrial fibrillation.
It has been implicated in causing ventricular arrhythmia (Torsade de pointes). | Bepridil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bepridil (trade name Vascor) is a calcium channel blocker once used to treat angina. It is no longer sold in the United States.
It is nonselective.[1]
It has been discussed as a possible option in the treatment of atrial fibrillation.[2]
It has been implicated in causing ventricular arrhythmia (Torsade de pointes). | https://www.wikidoc.org/index.php/Bepridil | |
e3b64b73337040cb8057c2c81097b277ffd1ce58 | wikidoc | Carotene | Carotene
# Overview
The term carotene is used for several related substances having the formula C40H56. Carotene is an orange photosynthetic pigment important for photosynthesis.
It is responsible for the orange colour of the carrot and many other fruits and vegetables. It contributes to photosynthesis by transmitting the light energy it absorbs to chlorophyll.
Chemically, carotene is a terpene, synthesized biochemically from eight isoprene units. It comes in two primary forms designated by characters from the Greek alphabet: alpha-carotene (α-carotene) and beta-carotene (β-carotene). Gamma, delta and epsilon (γ, δ and ε-carotene) also exist. Beta-carotene is composed of two retinyl groups, and is broken down in the mucosa of the small intestine by beta-carotene dioxygenase to retinol, a form of vitamin A.
Carotene can be stored in the liver and converted to vitamin A as needed, thus making it a provitamin.
# Dietary sources
The following foods are particularly rich in carotenes:
- Sweet potatoes
- carrots
- kale
- spinach
- cantaloupe melon
- turnip greens
- winter squash
- collard greens
- cilantro
- fresh thyme
- Romaine lettuce
- goji berries
- Ivy gourd
- Cassava
- mango
Absorption from these foods is enhanced if eaten with fats, as carotenes are fat soluble, and if the food is cooked for a few minutes until the plant cell wall splits and the colour is released into any liquid.
# The two forms
The two primary isomers of carotene, α-carotene and β-carotene, differ in the position of double bonds in the cyclic group at the end.
β-Carotene is the more common form and can be found in yellow, orange, and green leafy fruits and vegetables. These can be carrots, spinach, lettuce, tomatoes, sweet potatoes, broccoli, cantaloupe, oranges, and winter squash. As a rule of thumb, the greater the intensity of the colour of the fruit or vegetable, the more β-carotene it contains.
β-carotene is present in yellow orange bell peppers (called yellow capsicum in Australia) but is not the principal colour in red bell peppers, chillis and other varieties and species in the genus Capsicum. A wide range of carotenoids and other colourful compounds abound in the plant kingdom. We can attribute benefits to the plant in expending resources to produce these compounds from their role in attracting insects for pollination and alluring animals for seed distribution, to protecting vital cell functions against the destructive effects of ultraviolet light.
β-Carotene is an anti-oxidant and as such can be useful for curbing the excess of damaging free radicals in the body. However, the usefulness of β-carotene as a dietary supplement (i.e. taken as a pill) in cancer prevention is still subject to debate. β-Carotene is fat-soluble.
# Beta-carotene and cancer
It has been shown in trials that the use of synthetically-produced beta carotene (that is, beta carotene in supplement form such as the pills typically sold in stores) increases the rate of lung cancer and prostate cancer, and increases mortality in smokers. These results have been observed in beta carotene supplements and not in foods with naturally occurring beta carotene.
An article on the American Cancer Society says that The Cancer Research Campaign has called for warning labels on beta carotene supplements to caution smokers that such supplements may increase the risk of lung cancer.
The New England Journal of Medicine published an article in 1994 about a trial which examined the relationship between daily supplementation of beta carotene and vitamin E (alpha-tocopherol) and the incidence of lung cancer. The study was done using supplements and researchers were aware of the relationship between carotenoid-rich fruits and vegetables and lower lung cancer rates. The research concluded that no reduction in lung cancer was found in the participants using these supplements (beta-carotene), and furthermore, these supplements may, in fact, have harmful effects.
The Journal of the National Cancer Institute published an article in 1996 about a trial that was conducted to determine if vitamin A (in the form of retinyl palmitate) and beta carotene had any beneficial effects to prevent cancer. The results indicate an increased risk of lung cancer for the participants who consumed the beta-carotene supplement.
A review of all randomized controlled trials in the scientific literature by the Cochrane Collaboration published in JAMA in 2007 found that beta carotene increased mortality by 5% (Relative Risk 1.05, 95% confidence interval 1.01-1.08).
# Carotenemia
Carotene is often labeled as good for you. However, your body converts this yellow pigment to Vitamin A, and too much Vitamin A can be harmful to your body.
Carotenemia or hypercarotenemia is excess carotene, but unlike excess vitamin A, carotene is non-toxic. Although hypercarotenemia is not particularly dangerous, it can lead to a yellowing of the skin (carotenodermia). It is most commonly associated with consumption of an abundance of carrots, but it also can be a medical sign of more dangerous conditions.
A randomised trial into the use of β-carotene and vitamin A for prevention of lung cancer had to be stopped early due to the apparent increase in the incidence of lung cancer in those with lung irritation from smoking or asbestos exposure.
# Production
Most of the world's synthetic supply of carotene comes from a manufacturing complex located in Freeport, Texas and owned by DSM. In Spain Vitatene produces natural beta carotene form Blakeslea trispora. In Australia, organic beta-carotene is produced by Aquacarotene Limited from dried marine algae Dunaliella salina grown in harvesting ponds situated in Karratha, Western Australia.
Carotene is also found in corn, and in the milk of Guernsey dairy cows. Carotene causes the milk of the Guernsey cow to turn yellow.
## Total synthesis
There are currently two commonly used methods of total synthesis of β-carotene. The first was developed by the Badische Anilin- & Soda-Fabrik (BASF) and is based on the Wittig reaction. The second is a Grignard reaction, elaborated by Hoffman-La Roche from the original synthesis of Inhoffen et al. They are both symmetrical; the BASF synthesis is C20 + C20 , and the Hoffman-La Roche synthesis is C19 + C2 + C19.
# Nomenclature
Carotenes are carotenoids containing no oxygen. Carotenoids containing some oxygen are known as xanthophylls.
The two ends of the β-carotene molecule are structurally identical, and are called β-rings. Specifically, the group of nine carbon atoms at each end form a β-ring.
The α-carotene molecule has a β-ring at one end; the other end is called an ε-ring. There is no such thing as an "α-ring".
These and similar names for the ends of the carotenoid molecules form the basis of a systematic naming scheme, according to which:
- α-carotene is β,ε-carotene;
- β-carotene is β,β-carotene;
- γ-carotene (with one β ring and one uncyclized end that is labelled psi) is β,ψ-carotene;
- δ-carotene (with one ε ring and one uncyclized end) is ε,ψ-carotene;
- ε-carotene is ε,ε-carotene
6 μg of dietary β-carotene supplies the equivalent of 1 μg of retinol, or 1 RE (Retinol Equivalent). This is equivalent to 3⅓ IU of vitamin A.
# Use in Medications
## Pill Images | Carotene
# Overview
The term carotene is used for several related substances having the formula C40H56. Carotene is an orange photosynthetic pigment important for photosynthesis.
It is responsible for the orange colour of the carrot and many other fruits and vegetables. It contributes to photosynthesis by transmitting the light energy it absorbs to chlorophyll.
Chemically, carotene is a terpene, synthesized biochemically from eight isoprene units. It comes in two primary forms designated by characters from the Greek alphabet: alpha-carotene (α-carotene) and beta-carotene (β-carotene). Gamma, delta and epsilon (γ, δ and ε-carotene) also exist. Beta-carotene is composed of two retinyl groups, and is broken down in the mucosa of the small intestine by beta-carotene dioxygenase to retinol, a form of vitamin A.
Carotene can be stored in the liver and converted to vitamin A as needed, thus making it a provitamin.
# Dietary sources
The following foods are particularly rich in carotenes:
- Sweet potatoes[1]
- carrots[1]
- kale[1]
- spinach[1]
- cantaloupe melon[2]
- turnip greens[1]
- winter squash[1]
- collard greens[1]
- cilantro[1]
- fresh thyme[1]
- Romaine lettuce[1]
- goji berries
- Ivy gourd
- Cassava
- mango
Absorption from these foods is enhanced if eaten with fats, as carotenes are fat soluble, and if the food is cooked for a few minutes until the plant cell wall splits and the colour is released into any liquid.
# The two forms
The two primary isomers of carotene, α-carotene and β-carotene, differ in the position of double bonds in the cyclic group at the end.
β-Carotene is the more common form and can be found in yellow, orange, and green leafy fruits and vegetables. These can be carrots, spinach, lettuce, tomatoes, sweet potatoes, broccoli, cantaloupe, oranges, and winter squash. As a rule of thumb, the greater the intensity of the colour of the fruit or vegetable, the more β-carotene it contains.
β-carotene is present in yellow orange bell peppers (called yellow capsicum in Australia) but is not the principal colour in red bell peppers, chillis and other varieties and species in the genus Capsicum. A wide range of carotenoids and other colourful compounds abound in the plant kingdom. We can attribute benefits to the plant in expending resources to produce these compounds from their role in attracting insects for pollination and alluring animals for seed distribution, to protecting vital cell functions against the destructive effects of ultraviolet light.
β-Carotene is an anti-oxidant and as such can be useful for curbing the excess of damaging free radicals in the body. However, the usefulness of β-carotene as a dietary supplement (i.e. taken as a pill) in cancer prevention is still subject to debate.[3] β-Carotene is fat-soluble.
# Beta-carotene and cancer
It has been shown in trials that the use of synthetically-produced beta carotene (that is, beta carotene in supplement form such as the pills typically sold in stores) increases the rate of lung cancer and prostate cancer, and increases mortality in smokers. These results have been observed in beta carotene supplements and not in foods with naturally occurring beta carotene.[4]
An article on the American Cancer Society says that The Cancer Research Campaign has called for warning labels on beta carotene supplements to caution smokers that such supplements may increase the risk of lung cancer.[5]
The New England Journal of Medicine published an article[6] in 1994 about a trial which examined the relationship between daily supplementation of beta carotene and vitamin E (alpha-tocopherol) and the incidence of lung cancer. The study was done using supplements and researchers were aware of the relationship between carotenoid-rich fruits and vegetables and lower lung cancer rates. The research concluded that no reduction in lung cancer was found in the participants using these supplements (beta-carotene), and furthermore, these supplements may, in fact, have harmful effects.
The Journal of the National Cancer Institute published an article in 1996[7] about a trial that was conducted to determine if vitamin A (in the form of retinyl palmitate) and beta carotene had any beneficial effects to prevent cancer. The results indicate an increased risk of lung cancer for the participants who consumed the beta-carotene supplement.
A review of all randomized controlled trials in the scientific literature by the Cochrane Collaboration published in JAMA in 2007 found that beta carotene increased mortality by 5% (Relative Risk 1.05, 95% confidence interval 1.01-1.08).[8]
# Carotenemia
Carotene is often labeled as good for you. However, your body converts this yellow pigment to Vitamin A, and too much Vitamin A can be harmful to your body.
Carotenemia or hypercarotenemia is excess carotene, but unlike excess vitamin A, carotene is non-toxic. Although hypercarotenemia is not particularly dangerous, it can lead to a yellowing of the skin (carotenodermia). It is most commonly associated with consumption of an abundance of carrots, but it also can be a medical sign of more dangerous conditions.
A randomised trial into the use of β-carotene and vitamin A for prevention of lung cancer had to be stopped early due to the apparent increase in the incidence of lung cancer in those with lung irritation from smoking or asbestos exposure.[3]
# Production
Most of the world's synthetic supply of carotene comes from a manufacturing complex located in Freeport, Texas and owned by DSM. In Spain Vitatene produces natural beta carotene form Blakeslea trispora. In Australia, organic beta-carotene is produced by Aquacarotene Limited from dried marine algae Dunaliella salina grown in harvesting ponds situated in Karratha, Western Australia.
Carotene is also found in corn, and in the milk of Guernsey dairy cows. Carotene causes the milk of the Guernsey cow to turn yellow.
## Total synthesis
There are currently two commonly used methods of total synthesis of β-carotene. The first was developed by the Badische Anilin- & Soda-Fabrik (BASF) and is based on the Wittig reaction. The second is a Grignard reaction, elaborated by Hoffman-La Roche from the original synthesis of Inhoffen et al. They are both symmetrical; the BASF synthesis is C20 + C20 , and the Hoffman-La Roche synthesis is C19 + C2 + C19.
# Nomenclature
Carotenes are carotenoids containing no oxygen. Carotenoids containing some oxygen are known as xanthophylls.
The two ends of the β-carotene molecule are structurally identical, and are called β-rings. Specifically, the group of nine carbon atoms at each end form a β-ring.
The α-carotene molecule has a β-ring at one end; the other end is called an ε-ring. There is no such thing as an "α-ring".
These and similar names for the ends of the carotenoid molecules form the basis of a systematic naming scheme, according to which:
- α-carotene is β,ε-carotene;
- β-carotene is β,β-carotene;
- γ-carotene (with one β ring and one uncyclized end that is labelled psi) is β,ψ-carotene;
- δ-carotene (with one ε ring and one uncyclized end) is ε,ψ-carotene;
- ε-carotene is ε,ε-carotene
6 μg of dietary β-carotene supplies the equivalent of 1 μg of retinol, or 1 RE (Retinol Equivalent). This is equivalent to 3⅓ IU of vitamin A.
# Use in Medications
## Pill Images
# External links
- Beta-carotene website by Martha Evens, School of Chemistry, University of Bristol
- Berkeley Wellness Guide to Dietary Supplements
- Beta-carotene on University of Maryland
- Carotene at the US National Library of Medicine Medical Subject Headings (MeSH) | https://www.wikidoc.org/index.php/Beta-Carotene | |
ad4394519bcf47aae4e7ef0a0ba1e429278cf8a6 | wikidoc | Betadine | Betadine
Betadine is the name of Purdue Pharma's brand of consumer-available povidone-iodine (PVPI) topical antiseptics.
Betadine, like most PVPI products, is available in two formulations:
1. A solution, sold over-the-counter (OTC) for cleaning minor wounds and used in hospitals to prepare a patient's skin prior to surgery. Solutions are 10% povidone-iodine in water.
2. A 'surgical scrub', which is a mixture of povidone-iodine and detergent, sold OTC as a skin cleaner and disinfectant hand wash and used for cleansing hands prior to surgery and other aseptic procedures. | Betadine
Betadine is the name of Purdue Pharma's brand of consumer-available povidone-iodine (PVPI) topical antiseptics.
Betadine, like most PVPI products, is available in two formulations:
1. A solution, sold over-the-counter (OTC) for cleaning minor wounds[1] and used in hospitals to prepare a patient's skin prior to surgery.[2] Solutions are 10% povidone-iodine in water.
2. A 'surgical scrub', which is a mixture of povidone-iodine and detergent, sold OTC as a skin cleaner and disinfectant hand wash[1] and used for cleansing hands prior to surgery and other aseptic procedures.[2] | https://www.wikidoc.org/index.php/Betadine | |
9397726f93cd6ab36cb63bb4f66cab1cabdd4665 | wikidoc | Betaines | Betaines
# Overview
A betaine in chemistry is any neutral chemical compound with a positively charged cationic functional group such as an ammonium ion or phosphonium ion (generally: onium ions) which bears no hydrogen atom and with a negatively charged functional group such as a carboxylate group which may not be adjacent to the cationic site. Historically the term was reserved for trimethylglycine only.
Phosphonium betaines are intermediates in the Wittig reaction.
In biological systems, many betaines serve as organic osmolytes, substances synthesised or taken up from the environment by cells for protection against osmotic stress, drought, high salinity or high temperature. Intracellular accumulation of betaines, non-perturbing to enzyme function, protein structure and membrane integrity, permits water retention in cells, thus protecting from the effects of dehydration. It is also a methyl donor of increasing significance.
# Glycine betaine
Betaine (N,N,N-trimethylglycine) was named after its discovery in sugar beets (Beta vulgaris) in the 19th century. It is a small N-trimethylated amino acid, existing in zwitterionic form at neutral pH. This substance is often called ‘‘glycine betaine’’ to distinguish it from other betaines that are widely distributed in microorganisms, plants and animals. | Betaines
# Overview
A betaine in chemistry is any neutral chemical compound with a positively charged cationic functional group such as an ammonium ion or phosphonium ion (generally: onium ions) which bears no hydrogen atom and with a negatively charged functional group such as a carboxylate group which may not be adjacent to the cationic site. Historically the term was reserved for trimethylglycine only.
Phosphonium betaines are intermediates in the Wittig reaction.
In biological systems, many betaines serve as organic osmolytes, substances synthesised or taken up from the environment by cells for protection against osmotic stress, drought, high salinity or high temperature. Intracellular accumulation of betaines, non-perturbing to enzyme function, protein structure and membrane integrity, permits water retention in cells, thus protecting from the effects of dehydration. It is also a methyl donor of increasing significance.
# Glycine betaine
Betaine (N,N,N-trimethylglycine) was named after its discovery in sugar beets (Beta vulgaris) in the 19th century. It is a small N-trimethylated amino acid, existing in zwitterionic form at neutral pH. This substance is often called ‘‘glycine betaine’’ to distinguish it from other betaines that are widely distributed in microorganisms, plants and animals. | https://www.wikidoc.org/index.php/Betaines | |
5bfd19ef536bcb1b7b7560a0e2d5dc65d0d3cfb6 | wikidoc | Betalain | Betalain
Betalains are a class of red and yellow indole-derived pigments found in plants of the Caryophyllales. They are most often noticeable in the petals of flowers, but may color the fruits, leaves, stems, and roots of plants that contain them.
# Description
The name "betalain" comes from the Latin name of the common beet (Beta vulgaris), from which betalains were first extracted. The deep red color of beets, bougainvillea, amaranth, and many cacti results from the presence of betalain pigments. The particular shades of red to purple are distinctive and unlike that of anthocyanin pigments found in most plants. Betalains may occur in any part of the plant, including the petals of flowers, fruits, leaves, stems, and roots.
There are two categories of betalains:
- Betacyanins include the reddish to violet betalain pigments.
- Betaxanthins are those betalain pigments which appear yellow to orange.
Plant physiologists are uncertain of the function that betalains serve in those plants which possess them, but there is some preliminary evidence that they may have fungicidal properties.
# Chemistry
It was once thought that betalains were related to anthocyanins, the reddish pigments found in most plants. Both betalains and anthocyanins are water-soluble pigments found in the vacuoles of plant cells. However, betalains are structurally and chemically unlike anthocyanins. For example, betalains contain nitrogen whereas anthocyanins do not.
It is now known that betalains are aromatic indole derivatives synthesized from tyrosine. They are not related chemically to the anthocyanins and are not even flavonoids. Each betalain is a glycoside, and consists of a sugar and a colored portion. Their synthesis is promoted by light.
The most heavily studied betalain is betanin, also called beetroot red after the fact that it may be extracted from red beet roots. Betanin is a glucoside, and hydrolyzes into the sugar glucose and betanidin. It is used as a food coloring agent, and the color is sensitive to pH. Other betalains known to occur in beets are isobetanin, probetanin, and neobetanin.
Other important betacyanins are amaranthine and isoamaranthine, isolated from species of Amaranthus.
# Taxonomic significance
Betalain pigments occur only in the Caryophyllales and some Basidiomycota (mushrooms). Where they occur in plants, they sometimes coexist with anthoxanthins (yellow to orange flavonoids), but never occur in plant species with anthocyanins.
Among the flowering plant order Caryophyllales, most members produce betalains and lack anthocyanins. Of all the families in the Caryophyllales, only the Caryophyllaceae (carnation family) and Molluginaceae produce anthocyanins instead of betalains. The limited distribution of betalains among plants is a synapomorphy for the Caryophyllales, though their production has been lost in two families.
Recently, betalain-like compounds have been discovered in carnivorous plants that were not previously considered related to the Caryophyllales, but which have been added to that order under the APG II system. Betalains are now known from species of Drosera (sundew) and Nepenthes.
# Economic uses
Betanin is commercially used as a natural food dye. It can cause beeturia (red urine and faeces) in some people who are unable to break it down. The interest of the food industry in betalains has grown since they were identified as natural antioxidants which may have positive health effects in humans.
The 'Hopi Red Dye' amaranth produces red flowers which the Hopi Amerindians used as the source of a deep red dye. | Betalain
Betalains are a class of red and yellow indole-derived pigments found in plants of the Caryophyllales. They are most often noticeable in the petals of flowers, but may color the fruits, leaves, stems, and roots of plants that contain them.
# Description
The name "betalain" comes from the Latin name of the common beet (Beta vulgaris), from which betalains were first extracted. The deep red color of beets, bougainvillea, amaranth, and many cacti results from the presence of betalain pigments.[1] The particular shades of red to purple are distinctive and unlike that of anthocyanin pigments found in most plants. Betalains may occur in any part of the plant, including the petals of flowers, fruits, leaves, stems, and roots.
There are two categories of betalains:[2]
- Betacyanins include the reddish to violet betalain pigments.
- Betaxanthins are those betalain pigments which appear yellow to orange.
Plant physiologists are uncertain of the function that betalains serve in those plants which possess them, but there is some preliminary evidence that they may have fungicidal properties.[3]
# Chemistry
It was once thought that betalains were related to anthocyanins, the reddish pigments found in most plants. Both betalains and anthocyanins are water-soluble pigments found in the vacuoles of plant cells. However, betalains are structurally and chemically unlike anthocyanins. For example, betalains contain nitrogen whereas anthocyanins do not.[1]
It is now known that betalains are aromatic indole derivatives synthesized from tyrosine. They are not related chemically to the anthocyanins and are not even flavonoids.[4] Each betalain is a glycoside, and consists of a sugar and a colored portion. Their synthesis is promoted by light.[2]
The most heavily studied betalain is betanin, also called beetroot red after the fact that it may be extracted from red beet roots. Betanin is a glucoside, and hydrolyzes into the sugar glucose and betanidin.[1] It is used as a food coloring agent, and the color is sensitive to pH. Other betalains known to occur in beets are isobetanin, probetanin, and neobetanin.
Other important betacyanins are amaranthine and isoamaranthine, isolated from species of Amaranthus.
# Taxonomic significance
Betalain pigments occur only in the Caryophyllales and some Basidiomycota (mushrooms).[5] Where they occur in plants, they sometimes coexist with anthoxanthins (yellow to orange flavonoids), but never occur in plant species with anthocyanins.
Among the flowering plant order Caryophyllales, most members produce betalains and lack anthocyanins. Of all the families in the Caryophyllales, only the Caryophyllaceae (carnation family) and Molluginaceae produce anthocyanins instead of betalains.[5] The limited distribution of betalains among plants is a synapomorphy for the Caryophyllales, though their production has been lost in two families.
Recently, betalain-like compounds have been discovered in carnivorous plants that were not previously considered related to the Caryophyllales, but which have been added to that order under the APG II system. Betalains are now known from species of Drosera (sundew) and Nepenthes.[citation needed]
# Economic uses
Betanin is commercially used as a natural food dye. It can cause beeturia (red urine and faeces) in some people who are unable to break it down. The interest of the food industry in betalains has grown since they were identified as natural antioxidants[6] which may have positive health effects in humans.[7]
The 'Hopi Red Dye' amaranth produces red flowers which the Hopi Amerindians used as the source of a deep red dye. | https://www.wikidoc.org/index.php/Betalain | |
9923e0ae840007c3f45a339d61a2aa0a071e3ebe | wikidoc | Betatron | Betatron
A betatron is a particle accelerator developed by Donald Kerst at the University of Illinois in 1940 to accelerate electrons. The betatron is essentially a transformer with a torus-shaped vacuum tube as its secondary coil. An alternating current in the primary coils accelerates electrons in the vacuum around a circular path. The name "betatron" (a reference to the beta particle, a fast electron) was chosen during a departmental contest. Other proposals were rheotron, inductron, and even Ausserordentlichhochgeschwindigkeitelektronenentwickelndenschwerarbeitsbeigollitron, supposedly German for "extraordinarily high-speed electron producing hard work by golly-tron.".
In a betatron, the magnetic field spins the injected electrons and accelerates them at the center where there is a ring-shaped vacuum tube changing the magnetic field and producing an electric field in the vacuum ring.
The stable orbit for the electrons satisfies \theta_0=2\pi r_0^2 H_0 where \theta_0 is the flux with the orbit at r_0 is the radius and H_0 is the magnetic field at r_0. In other words, the magnetic field at the orbit must be half the average magnetic field over its circular cross section.
Betatrons were historically employed in particle physics experiments to provide high energy beams of electrons—up to about 300 MeV. If the electron beam is directed at a metal plate, the betatron can be used as a source of energetic x-rays or gamma rays; these x-rays may be used in industrial and medical applications (historically in radiation oncology).
Because the mass of the electron increases at relativistic speeds, the cyclotron becomes less efficient at higher energies, placing an upper limit on its beam energy. These relativistic effects are accommodated in the next generation of accelerators, the Synchrotrons.
The Radiation Center, the first private medical center to treat cancer patients with a betatron was opened by Dr. O. Arthur Stiennon, in a suburb of Madison, Wisconsin in the late 1950s.
# Trivia
Frank Black met a good man who owns a betatron. ("Los Angeles" song) | Betatron
A betatron is a particle accelerator developed by Donald Kerst at the University of Illinois in 1940 to accelerate electrons. The betatron is essentially a transformer with a torus-shaped vacuum tube as its secondary coil. An alternating current in the primary coils accelerates electrons in the vacuum around a circular path. The name "betatron" (a reference to the beta particle, a fast electron) was chosen during a departmental contest. Other proposals were rheotron, inductron, and even Ausserordentlichhochgeschwindigkeitelektronenentwickelndenschwerarbeitsbeigollitron, supposedly German for "extraordinarily high-speed electron producing hard work by golly-tron.".
In a betatron, the magnetic field spins the injected electrons and accelerates them at the center where there is a ring-shaped vacuum tube changing the magnetic field and producing an electric field in the vacuum ring.
The stable orbit for the electrons satisfies <math>\theta_0=2\pi r_0^2 H_0</math> where <math>\theta_0</math> is the flux with the orbit at <math>r_0</math> is the radius and <math>H_0</math> is the magnetic field at <math>r_0</math>. In other words, the magnetic field at the orbit must be half the average magnetic field over its circular cross section.
Betatrons were historically employed in particle physics experiments to provide high energy beams of electrons—up to about 300 MeV. If the electron beam is directed at a metal plate, the betatron can be used as a source of energetic x-rays or gamma rays; these x-rays may be used in industrial and medical applications (historically in radiation oncology).
Because the mass of the electron increases at relativistic speeds, the cyclotron becomes less efficient at higher energies, placing an upper limit on its beam energy. These relativistic effects are accommodated in the next generation of accelerators, the Synchrotrons.
The Radiation Center, the first private medical center to treat cancer patients with a betatron was opened by Dr. O. Arthur Stiennon, in a suburb of Madison, Wisconsin in the late 1950s[1].
# Trivia
Frank Black met a good man who owns a betatron. ("Los Angeles" song) | https://www.wikidoc.org/index.php/Betatron | |
f5b7c62dc5e2f6c660fc3a1ffa55423baa5ac1c0 | wikidoc | Betazole | Betazole
# Overview
Betazole is a histamine H2 receptor agonist. Also known as Ametazole. Betazole hydrochloride is known as gastramine and histalog.
It has been used as a gastric stimulant to test for maximal production of gastric secretion activity The test can be used in diagnosis of diseases such as Zollinger-Ellison syndrome where there is excess acid production, in this case driven by over production of gastrin. The volume of acid secretion is measured following administration of betazole, diagnosis being secretion greater than 60% of the maximal acid secretion following betazole stimulation. This procedure can lead to complications and should be avoided in subjects with coronary artery disease
It is also used in diagnosis of gastritis in association with a test for secretin activity
Betazole is used as a stimulant in preference to histamine because of its specificity for the H2 receptor and its advantage of not generating the undesirable side effects that histamine would induce. It therefore does not require concomitant use of antihistaminic compounds to block the actions of histamine at other histamine receptor types.
Its action in stimulating histamine release can be of use when testing the effectiveness of H2 receptor blocking drugs such as Nizatidine. | Betazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Betazole is a histamine H2 receptor agonist. Also known as Ametazole. Betazole hydrochloride is known as gastramine and histalog.
It has been used as a gastric stimulant to test for maximal production of gastric secretion activity [1] The test can be used in diagnosis of diseases such as Zollinger-Ellison syndrome where there is excess acid production, in this case driven by over production of gastrin. The volume of acid secretion is measured following administration of betazole, diagnosis being secretion greater than 60% of the maximal acid secretion following betazole stimulation. This procedure can lead to complications and should be avoided in subjects with coronary artery disease [2]
It is also used in diagnosis of gastritis in association with a test for secretin activity
Betazole is used as a stimulant in preference to histamine because of its specificity for the H2 receptor and its advantage of not generating the undesirable side effects that histamine would induce. It therefore does not require concomitant use of antihistaminic compounds to block the actions of histamine at other histamine receptor types.
Its action in stimulating histamine release can be of use when testing the effectiveness of H2 receptor blocking drugs such as Nizatidine.[3] | https://www.wikidoc.org/index.php/Betazole | |
1283318a220c401e93ee55534e3f1a7d108583c5 | wikidoc | Bifocals | Bifocals
# Overview
Bifocals are eyeglasses whose corrective lenses each contain regions with two distinct optical powers. Bifocals are most commonly prescribed to people with presbyopia who also require a correction for myopia, hypermetropia, and/or astigmatism.
# History
Benjamin Franklin is usually credited with the creation of the first pair of bifocals in the early 1760's, though the first indication of his double spectacles comes from a political cartoon printed in 1764. A great number of letters and publications from that time period refer to Dr. Franklin's double spectacles, including his first reference to them in a letter dated August 21, 1784.
John Isaac Hawkins, the inventor of trifocals, coined the term bifocals in 1824 and credited Dr. Franklin with their invention.
# Construction
Franklin's original bifocals were designed with the most convex lenses (for close viewing) in the lower half of the frame and the least convex lenses on the upper. Up until the beginning of the 20th century two separate lenses were cut in half and combined together in the rim of the frame. The mounting of two half lenses into a single frame led to a number of early complications and rendered such spectacles quite fragile. A method for fusing the sections of the lenses together was developed by Louis de Wecker at the end of the 19th century and patented by Dr. John L. Borsch, Jr. in 1908.
Today most bifocals are created by molding a reading segment into a primary lens and are available with the reading segments in a variety of shapes and sizes. The most popular is the flat-top (a.k.a. straight-top or D-segment), 28 mm wide.
They are available at most eye doctors.
# Problems
Bifocals' division of the field of vision has been known to cause headaches and even dizziness in some users. Acclimation to the small field of view offered by the reading segment of bifocals can take some time, as the user learns to move either the head or the reading material rather than the eyes. Computer monitors are generally placed directly in front of users and can lead to muscle fatigue due to the unusual angle and constant movement of the head. This trouble is mitigated by the use of trifocal lenses.
# Future
Research continues in an attempt to eliminate the limited field of vision present in current bifocals. New materials and technologies may provide a method which can selectively adjust the optical power of a lens. Researchers at the University of Arizona have constructed such a switchable lens using a liquid crystal layer sandwiched between two glass substrates. When electricity is applied the effective refractive index changes, varying the optical power of the lens. | Bifocals
# Overview
Bifocals are eyeglasses whose corrective lenses each contain regions with two distinct optical powers. Bifocals are most commonly prescribed to people with presbyopia who also require a correction for myopia, hypermetropia, and/or astigmatism.
# History
Benjamin Franklin is usually credited with the creation of the first pair of bifocals in the early 1760's, though the first indication of his double spectacles comes from a political cartoon printed in 1764. A great number of letters and publications from that time period refer to Dr. Franklin's double spectacles, including his first reference to them in a letter dated August 21, 1784.
John Isaac Hawkins, the inventor of trifocals, coined the term bifocals in 1824 and credited Dr. Franklin with their invention.
# Construction
Franklin's original bifocals were designed with the most convex lenses (for close viewing) in the lower half of the frame and the least convex lenses on the upper. Up until the beginning of the 20th century two separate lenses were cut in half and combined together in the rim of the frame. The mounting of two half lenses into a single frame led to a number of early complications and rendered such spectacles quite fragile. A method for fusing the sections of the lenses together was developed by Louis de Wecker at the end of the 19th century and patented by Dr. John L. Borsch, Jr. in 1908.
Today most bifocals are created by molding a reading segment into a primary lens and are available with the reading segments in a variety of shapes and sizes. The most popular is the flat-top (a.k.a. straight-top or D-segment), 28 mm wide.
They are available at most eye doctors.
# Problems
Bifocals' division of the field of vision has been known to cause headaches and even dizziness in some users. Acclimation to the small field of view offered by the reading segment of bifocals can take some time, as the user learns to move either the head or the reading material rather than the eyes. Computer monitors are generally placed directly in front of users and can lead to muscle fatigue due to the unusual angle and constant movement of the head. This trouble is mitigated by the use of trifocal lenses.
# Future
Research continues in an attempt to eliminate the limited field of vision present in current bifocals. New materials and technologies may provide a method which can selectively adjust the optical power of a lens. Researchers at the University of Arizona have constructed such a switchable lens using a liquid crystal layer sandwiched between two glass substrates. When electricity is applied the effective refractive index changes, varying the optical power of the lens. | https://www.wikidoc.org/index.php/Bifocal | |
8854aa6ff9a28f8d631ba71186db8873af3c2569 | wikidoc | Bigender | Bigender
Bigender (bi+gender) is a tendency to move between masculine and feminine gender-typed behaviour depending on context, expressing a distinctly "en femme" persona and a distinctly "en homme" persona, feminine and masculine respectively. It is a subset of transgender.
While an androgynous person retains the same gender-typed behaviour across situations, the bigendered person consciously or unconsciously changes their gender-role behaviour from primarily masculine to primarily feminine, or vice versa.
# Use of Term
It is worth noting that this concept emerged from within the transgender community itself, rather than being adopted after it was created by another sub-culture (for example, transsexual was defined first by the mental health community).
Because bigender is still a self-applied label, it is not possible to give a definitive outline of the typical bigender. Any description of a bigender is just an example of what someone who identifies as bigender might be like. Although there are patterns, the only firm characteristic is the sense of dual gender.
# Expression
Some express their bigender identity through crossdressing or performing as a drag king/drag queen; others may adopt a strictly masculine, feminine, or androgynous appearance and experience the shift between genders on a purely mental, or only subtly physical, level.
# Bigender and Sexual Orientation
It might seem that a bigender identity must go with a bisexual identity but gender identity and sexual orientation are independent. It is possible to be bigender and not bisexual, or bisexual but not bigender.
For some bigenders, labels like gay, lesbian or bisexual can seem less relevant or satisfactory due to their focus on physiological sex. Some might prefer terms that refer to gender (see Gynephilia and androphilia) while others might prefer to not specify a sexual orientation at all. Since bigender is a gender-related term, not an erotic one, a bigender can of course be asexual.
# Bigender in Popular Culture
While performers such as David Bowie and Boy George are known for combining masculine and feminine aspects, performers who switch between a primarily masculine or feminine image, such as Eddie Izzard and Annie Lennox, better fit the bigender label. It is good to keep in mind, however, that crossdressing is not always related to gender identity, as it can be a purely erotic act. | Bigender
Bigender (bi+gender) is a tendency to move between masculine and feminine gender-typed behaviour depending on context, expressing a distinctly "en femme" persona and a distinctly "en homme" persona, feminine and masculine respectively. It is a subset of transgender.
While an androgynous person retains the same gender-typed behaviour across situations, the bigendered person consciously or unconsciously changes their gender-role behaviour from primarily masculine to primarily feminine, or vice versa.
# Use of Term
It is worth noting that this concept emerged from within the transgender community itself, rather than being adopted after it was created by another sub-culture (for example, transsexual was defined first by the mental health community).
Because bigender is still a self-applied label, it is not possible to give a definitive outline of the typical bigender. Any description of a bigender is just an example of what someone who identifies as bigender might be like. Although there are patterns, the only firm characteristic is the sense of dual gender.
# Expression
Some express their bigender identity through crossdressing or performing as a drag king/drag queen; others may adopt a strictly masculine, feminine, or androgynous appearance and experience the shift between genders on a purely mental, or only subtly physical, level.
# Bigender and Sexual Orientation
It might seem that a bigender identity must go with a bisexual identity but gender identity and sexual orientation are independent. It is possible to be bigender and not bisexual, or bisexual but not bigender.
For some bigenders, labels like gay, lesbian or bisexual can seem less relevant or satisfactory due to their focus on physiological sex. Some might prefer terms that refer to gender (see Gynephilia and androphilia) while others might prefer to not specify a sexual orientation at all. Since bigender is a gender-related term, not an erotic one, a bigender can of course be asexual.
# Bigender in Popular Culture
While performers such as David Bowie and Boy George are known for combining masculine and feminine aspects, performers who switch between a primarily masculine or feminine image, such as Eddie Izzard and Annie Lennox, better fit the bigender label. It is good to keep in mind, however, that crossdressing is not always related to gender identity, as it can be a purely erotic act. | https://www.wikidoc.org/index.php/Bigender | |
983922d55dfc0a564281546af21aa6367abbc155 | wikidoc | Biglycan | Biglycan
Biglycan is a small leucine-rich repeat proteoglycan (SLRP) which is found in a variety of extracellular matrix tissues, including bone, cartilage and tendon. In humans, biglycan is encoded by the BGN gene which is located on the X chromosome.
The name "biglycan" was proposed in an article by Fisher, Termine and Young in an article in the Journal of Biological Chemistry in 1989 because the proteoglycan contained two GAG chains; formerly it was known as proteoglycan-I (PG-I).
# Structure
Biglycan consists of a protein core containing leucine-rich repeat regions and two glycosaminoglycan (GAG) chains consisting of either chondroitin sulfate (CS) or dermatan sulfate (DS), with DS being more abundant in most connective tissues. The CS/DS chains are attached at amino acids 5 and 10 in human biglycan. The composition of the GAG chains has been reported as varying according to tissue of origin. Non-glycanated forms of biglycan (no GAG chains) increase with age in human articular cartilage.
The composition of GAG chains of biglycan and decorin originating from the same tissue has been reported to be similar.
The structure of biglycan core protein is highly conserved across species; over 90% homology has been reported for rat, mouse, bovine and human biglycan core proteins.
# Function
Biglycan is believed to play a role in the mineralization of bone. Knock-out mice that have had the gene for biglycan suppressed (Bgn -/-) have an osteoporosis-like phenotype with reduced growth rate and lower bone mass than mice that can express biglycan.
Biglycan core protein binds to the growth factors BMP-4 and influences its bioactivity. It has also been reported that the presence of biglycan is necessary for BMP-4 to exert its effects on osteoblasts. There is also evidence that biglycan binds to TGF-beta 1.
# Interactions
Biglycan interacts with collagen, both via the core protein and GAG chains. It has been reported that biglycan interacts more strongly with collagen type II than collagen type I. Biglycan has been reported to compete with decorin for the same binding site on collagen.
Biglycan has been shown to interact with SGCA.
Biglycan is a particularly important proteoglycan for binding to lipoprotein in human blood vessels, thus being a significant cause of atherosclerosis. | Biglycan
Biglycan is a small leucine-rich repeat proteoglycan (SLRP) which is found in a variety of extracellular matrix tissues, including bone, cartilage and tendon. In humans, biglycan is encoded by the BGN gene[1] which is located on the X chromosome.
The name "biglycan" was proposed in an article by Fisher, Termine and Young in an article in the Journal of Biological Chemistry in 1989 because the proteoglycan contained two GAG chains; formerly it was known as proteoglycan-I (PG-I).[2]
# Structure
Biglycan consists of a protein core containing leucine-rich repeat regions and two glycosaminoglycan (GAG) chains consisting of either chondroitin sulfate (CS) or dermatan sulfate (DS), with DS being more abundant in most connective tissues. The CS/DS chains are attached at amino acids 5 and 10 in human biglycan.[3] The composition of the GAG chains has been reported as varying according to tissue of origin. Non-glycanated forms of biglycan (no GAG chains) increase with age in human articular cartilage.[4]
The composition of GAG chains of biglycan and decorin originating from the same tissue has been reported to be similar.[5]
The structure of biglycan core protein is highly conserved across species; over 90% homology has been reported for rat, mouse, bovine and human biglycan core proteins.
# Function
Biglycan is believed to play a role in the mineralization of bone. Knock-out mice that have had the gene for biglycan suppressed (Bgn -/-) have an osteoporosis-like phenotype with reduced growth rate and lower bone mass than mice that can express biglycan.[6]
Biglycan core protein binds to the growth factors BMP-4 and influences its bioactivity.[7] It has also been reported that the presence of biglycan is necessary for BMP-4 to exert its effects on osteoblasts.[8] There is also evidence that biglycan binds to TGF-beta 1.
# Interactions
Biglycan interacts with collagen, both via the core protein and GAG chains.[9][10] It has been reported that biglycan interacts more strongly with collagen type II than collagen type I.[11][12] Biglycan has been reported to compete with decorin for the same binding site on collagen.[9]
Biglycan has been shown to interact with SGCA.[13]
Biglycan is a particularly important proteoglycan for binding to lipoprotein in human blood vessels, thus being a significant cause of atherosclerosis.[14] | https://www.wikidoc.org/index.php/Biglycan | |
4990f78afea8a0f44abc2c42fa93a2960fa6692a | wikidoc | Bilberry | Bilberry
Bilberry is a name given to several species of low-growing shrubs in the genus Vaccinium (family Ericaceae) that bear tasty fruits. The species most often referred to is Vaccinium myrtillus L., also known as blaeberry, whortleberry, whinberry (or winberry), myrtle blueberry, fraughan, and probably other names regionally. They were called black-hearts in 19th century southern England, according to Thomas Hardy's 1878 novel, The Return of the Native, (pg. 311, Oxford World's Classics edition).
The word bilberry is also sometimes used in the common names of other species of the genus, including Vaccinium uliginosum L. (bog bilberry, bog blueberry, bog whortleberry, bog huckleberry, northern bilberry), Vaccinium caespitosum Michx. (dwarf bilberry), Vaccinium deliciosum Piper (Cascade bilberry), Vaccinium membranaceum (mountain bilberry, black mountain huckleberry, black huckleberry, twin-leaved huckleberry), and Vaccinium ovalifolium (oval-leafed blueberry, oval-leaved bilberry, mountain blueberry, high-bush blueberry).
Bilberries are found in damp, acidic soils throughout the temperate and subarctic regions of the world. They are closely related to North American wild and cultivated blueberries and huckleberries in the genus Vaccinium. The easiest way to distinguish the bilberry is that it produces single or pairs of berries on the bush instead of clusters like the blueberry. Another way to distinguish them is that while blueberry fruit meat is light green, bilberry is red or purple. In this way you can also distinguish the bilberry eater from the blueberry eater by his red fingers and lips. Bilberry is used as a food plant by the larvae of some Lepidoptera species - see list of Lepidoptera which feed on Vaccinium.
Bilberries are rarely cultivated but fruits are sometimes collected from wild plants growing on publicly accessible lands, notably in Fennoscandia, Scotland, Ireland and Poland. Notice that in Fennoscandia, it is an everyman's right to collect bilberries, irrespective of land ownership. In Ireland the fruit is known as fraughan in English, from the Irish fraochán, and is traditionally gathered on the last Sunday in July, known as Fraughan Sunday.
Bilberries were also collected at Lughnassadh in August, the first traditional harvest festival of the year, as celebrated by the Gaelic people. The crop of bilberries was said to indicate how well the rest of the crops would fare in their harvests later in the year.
The fruits can be eaten fresh, but are more usually made into jams, fools, juices or pies. In France they are used as a base for liqueurs and are a popular flavouring for sorbets and other desserts. In Brittany they are often used as a flavouring for crêpes, and in the Vosges and the Massif Central bilberry tart (tarte aux myrtilles) is the most traditional dessert.
# Medicinal uses
Bilberry is often said to improve night vision, and the story is told of RAF pilots in World War II using bilberry for that purpose. A recent study by the U.S. Navy found no effect, however, and the origins of the RAF story are unclear; it does not appear to be well known in the RAF itself.. Studies (, ) have shown that bilberry can reduce or reverse effects of degenerative eye disorders such as macular degeneration. The overall therapeutic use of bilberry is still clinically unproven.
On the other hand, the RAF story about bilberries was more likely a cover to conceal the British access to radar, still an official secret at the time of World War II. See, for example:
It may have other beneficial effects on capillaries due to the strong antioxidant properties of its anthocyanidin flavonoids.
The leaves have historically been used to treat gastrointestinal ailments, applied topically or made into infusions. The effects claimed have not been reproduced in the laboratory, however. | Bilberry
Bilberry is a name given to several species of low-growing shrubs in the genus Vaccinium (family Ericaceae) that bear tasty fruits. The species most often referred to is Vaccinium myrtillus L., also known as blaeberry, whortleberry, whinberry (or winberry), myrtle blueberry, fraughan, and probably other names regionally. They were called black-hearts in 19th century southern England, according to Thomas Hardy's 1878 novel, The Return of the Native, (pg. 311, Oxford World's Classics edition).
The word bilberry is also sometimes used in the common names of other species of the genus, including Vaccinium uliginosum L. (bog bilberry, bog blueberry, bog whortleberry, bog huckleberry, northern bilberry), Vaccinium caespitosum Michx. (dwarf bilberry), Vaccinium deliciosum Piper (Cascade bilberry), Vaccinium membranaceum (mountain bilberry, black mountain huckleberry, black huckleberry, twin-leaved huckleberry), and Vaccinium ovalifolium (oval-leafed blueberry, oval-leaved bilberry, mountain blueberry, high-bush blueberry).
Bilberries are found in damp, acidic soils throughout the temperate and subarctic regions of the world. They are closely related to North American wild and cultivated blueberries and huckleberries in the genus Vaccinium. The easiest way to distinguish the bilberry is that it produces single or pairs of berries on the bush instead of clusters like the blueberry. Another way to distinguish them is that while blueberry fruit meat is light green, bilberry is red or purple. In this way you can also distinguish the bilberry eater from the blueberry eater by his red fingers and lips. Bilberry is used as a food plant by the larvae of some Lepidoptera species - see list of Lepidoptera which feed on Vaccinium.
Bilberries are rarely cultivated but fruits are sometimes collected from wild plants growing on publicly accessible lands, notably in Fennoscandia, Scotland, Ireland and Poland. Notice that in Fennoscandia, it is an everyman's right to collect bilberries, irrespective of land ownership. In Ireland the fruit is known as fraughan in English, from the Irish fraochán, and is traditionally gathered on the last Sunday in July, known as Fraughan Sunday.
Bilberries were also collected at Lughnassadh in August, the first traditional harvest festival of the year, as celebrated by the Gaelic people. The crop of bilberries was said to indicate how well the rest of the crops would fare in their harvests later in the year.
The fruits can be eaten fresh, but are more usually made into jams, fools, juices or pies. In France they are used as a base for liqueurs and are a popular flavouring for sorbets and other desserts. In Brittany they are often used as a flavouring for crêpes, and in the Vosges and the Massif Central bilberry tart (tarte aux myrtilles) is the most traditional dessert.
# Medicinal uses
Bilberry is often said to improve night vision, and the story is told of RAF pilots in World War II using bilberry for that purpose. A recent study [1] by the U.S. Navy found no effect, however, and the origins of the RAF story are unclear; it does not appear to be well known in the RAF itself.[2]. Studies ([3], [4]) have shown that bilberry can reduce or reverse effects of degenerative eye disorders such as macular degeneration. The overall therapeutic use of bilberry is still clinically unproven.
On the other hand, the RAF story about bilberries was more likely a cover to conceal the British access to radar, still an official secret at the time of World War II. See, for example: http://www.brps.org.uk/White/W_Newsletter_Spring_2001.html
It may have other beneficial effects on capillaries due to the strong antioxidant properties of its anthocyanidin flavonoids.
The leaves have historically been used to treat gastrointestinal ailments, applied topically or made into infusions. The effects claimed have not been reproduced in the laboratory, however.
# External links
- Species profile: Blaeberry
- Bilberry and Herbal Medicine
- Den virtuelle floran - Distribution | https://www.wikidoc.org/index.php/Bilberry | |
27105ffc17c599af3fdf42d38ef682f824606d33 | wikidoc | Bivalvia | Bivalvia
Bivalves are mollusks belonging to the class Bivalvia. They typically have two-part shells, with both valves being symmetrical along the hinge line. The class has 30,000 species, including scallops, clams, oysters and mussels. Other names for the class include Bivalva, Pelecypoda, and Lamellibranchia.
Bivalves are exclusively aquatic; they include both marine and freshwater forms.
Bivalves lack a radula and feed by siphoning and filtering large particles from water. Some bivalves are epifaunal: that is, they attach themselves to surfaces in the water, by means of a byssus or organic cementation. Others are infaunal: they bury themselves in sand or other sediments. These forms typically have a strong digging foot. Some bivalves, such as scallops, can swim.
# Systematics
The systematic layout presented here is according to Newell's 1965 classification based on hinge teeth morphology. There exists no robust phylogeny, and due to the plethora of fossil lineages, DNA sequence data is only of limited use should the subclasses turn out to be paraphyletic. The monophyly of the Anomalosdesmata is especially disputed, but this is of less consequence as that group does not include higher-level prehistoric taxa.
Subclass Palaeotaxodonta
- Nuculoida
Subclass Cryptodonta
- †Praecardioida
- Solemyoida
Subclass Pteriomorphia (oysters, mussels, etc)
- Arcoida
- †Cyrtodontoida
- Mytiloida
- Ostreoida - formerly included in Pterioida
- †Praecardioida
- Pterioida
Subclass Paleoheterodonta
- †Trigonioida
- Unionoida (typical freshwater mussels)
- †Modiomorpha
Subclass Heterodonta (typical clams, cockles, rudists, etc)
- †Cycloconchidae
- †Hippuritoida
- †Lyrodesmatidae
- Myoida
- †Redoniidae
- Veneroida
Subclass Anomalosdesmata
- Pholadomyoida
There also exists an alternative systematic scheme according to gill morphology (Franc 1960). This distinguishes between Protobranchia, Filibranchia, and Eulamellibranchia. The first corresponds to Newell's Palaeotaxodonta + Cryptodonta, the second to his Pteriomorphia, and the last contains all other groups. In addition, Franc separated the Septibranchia from his eulamellibranchs, but this would seem to make the latter paraphyletic.
# Anatomy
Bivalves are filter-feeders which extract organic matter from the water in which they live. They have an open circulatory system that bathes the organs in hemolymph. Nephridia remove the waste material.
Bivalves are laterally combined and have a shell composed of two valves. The valved shell makes them superficially similar to brachiopods, but the construction of the shell is completely different in the two groups: in brachiopods, the two valves are on the upper and lower surfaces of the body, while in bivalves, they are on the left and right sides.
- Drawing of oyster anatomy
Drawing of oyster anatomy
- Photo of anatomy of Crassostrea gigas
Photo of anatomy of Crassostrea gigas
- Drawing of anatomy of Freshwater pearl mussel Margaritifera margaritifera
Drawing of anatomy of Freshwater pearl mussel Margaritifera margaritifera
- Internal anatomy of the valve
Internal anatomy of the valve
# Pre-history
Bivalves appeared late in the Cambrian explosion and came to dominate over brachiopods during the Palaeozoic; indeed, by the end-Permian extinction, bivalves were undergoing a huge radiation in numbers while brachiopods (along with ~95% of all species) were devastated.
This raises two questions: how did the bivalves come to challenge the brachiopoda niche before the extinction event, and how did the bivalves escape the fate of extinction? Although inevitable biases exist in the fossil record and our documentation thereof, bivalves essentially appear to be better adapted to aquatic life. Far more sophisticated than the brachiopods, bivalves use an energetically-efficient ligament-muscle system for opening valves, and thus require less food to subsist. Furthermore, their ability to burrow allows for evasion of predators: buried bivalves feed by extending a siphon to the surface (indicated by the presence of a palial sinus, the size of which is proportional to the burrowing depth, and represented by their hinge teeth). Some bivalves can bore directly into rock and wood, a process known as bioerosion. Additionally, some bivalves became much more mobile: many of the scallops eject water vigorously by suddenly closing the valves, and this created rapid propulsion and permits the scallop to evade slower predators such as starfish.
With such a wide range of adaptations it is unsurprising that the shapes of bivalve shells vary greatly - some are rounded and globular, others are flattened and plate-like, while still others, such as the razor shell Ensis, have become greatly elongated in order to aid burrowing. The shipworms of the family Teredinidae have greatly elongated bodies, but the shell valves are much reduced and restricted to the anterior end of the body, where they function as burrowing organs, allowing the animal to dig tunnels through wood.
# Readle Right Hand Rule
A method used to interperate whether a Bivalve valve is the left or right using the orientation of the umbone | Bivalvia
Bivalves are mollusks belonging to the class Bivalvia. They typically have two-part shells, with both valves being symmetrical along the hinge line. The class has 30,000 species, including scallops, clams, oysters and mussels. Other names for the class include Bivalva, Pelecypoda, and Lamellibranchia.
Bivalves are exclusively aquatic; they include both marine and freshwater forms.
Bivalves lack a radula and feed by siphoning and filtering large particles from water. Some bivalves are epifaunal: that is, they attach themselves to surfaces in the water, by means of a byssus or organic cementation. Others are infaunal: they bury themselves in sand or other sediments. These forms typically have a strong digging foot. Some bivalves, such as scallops, can swim.
# Systematics
The systematic layout presented here is according to Newell's 1965 classification based on hinge teeth morphology. There exists no robust phylogeny, and due to the plethora of fossil lineages, DNA sequence data is only of limited use should the subclasses turn out to be paraphyletic. The monophyly of the Anomalosdesmata is especially disputed, but this is of less consequence as that group does not include higher-level prehistoric taxa.
Subclass Palaeotaxodonta
- Nuculoida
Subclass Cryptodonta
- †Praecardioida
- Solemyoida
Subclass Pteriomorphia (oysters, mussels, etc)
- Arcoida
- †Cyrtodontoida
- Mytiloida
- Ostreoida - formerly included in Pterioida
- †Praecardioida
- Pterioida
Subclass Paleoheterodonta
- †Trigonioida
- Unionoida (typical freshwater mussels)
- †Modiomorpha
Subclass Heterodonta (typical clams, cockles, rudists, etc)
- †Cycloconchidae
- †Hippuritoida
- †Lyrodesmatidae
- Myoida
- †Redoniidae
- Veneroida
Subclass Anomalosdesmata
- Pholadomyoida
There also exists an alternative systematic scheme according to gill morphology (Franc 1960). This distinguishes between Protobranchia, Filibranchia, and Eulamellibranchia. The first corresponds to Newell's Palaeotaxodonta + Cryptodonta, the second to his Pteriomorphia, and the last contains all other groups. In addition, Franc separated the Septibranchia from his eulamellibranchs, but this would seem to make the latter paraphyletic.
# Anatomy
Bivalves are filter-feeders which extract organic matter from the water in which they live. They have an open circulatory system that bathes the organs in hemolymph. Nephridia remove the waste material.
Bivalves are laterally combined and have a shell composed of two valves. The valved shell makes them superficially similar to brachiopods, but the construction of the shell is completely different in the two groups: in brachiopods, the two valves are on the upper and lower surfaces of the body, while in bivalves, they are on the left and right sides.
- Drawing of oyster anatomy
Drawing of oyster anatomy
- Photo of anatomy of Crassostrea gigas
Photo of anatomy of Crassostrea gigas
- Drawing of anatomy of Freshwater pearl mussel Margaritifera margaritifera
Drawing of anatomy of Freshwater pearl mussel Margaritifera margaritifera
- Internal anatomy of the valve
Internal anatomy of the valve
# Pre-history
Bivalves appeared late in the Cambrian explosion and came to dominate over brachiopods during the Palaeozoic; indeed, by the end-Permian extinction, bivalves were undergoing a huge radiation in numbers while brachiopods (along with ~95% of all species) were devastated.
This raises two questions: how did the bivalves come to challenge the brachiopoda niche before the extinction event, and how did the bivalves escape the fate of extinction? Although inevitable biases exist in the fossil record and our documentation thereof, bivalves essentially appear to be better adapted to aquatic life. Far more sophisticated than the brachiopods, bivalves use an energetically-efficient ligament-muscle system for opening valves, and thus require less food to subsist. Furthermore, their ability to burrow allows for evasion of predators: buried bivalves feed by extending a siphon to the surface (indicated by the presence of a palial sinus, the size of which is proportional to the burrowing depth, and represented by their hinge teeth). Some bivalves can bore directly into rock and wood, a process known as bioerosion. Additionally, some bivalves became much more mobile: many of the scallops eject water vigorously by suddenly closing the valves, and this created rapid propulsion and permits the scallop to evade slower predators such as starfish.
With such a wide range of adaptations it is unsurprising that the shapes of bivalve shells vary greatly - some are rounded and globular, others are flattened and plate-like, while still others, such as the razor shell Ensis, have become greatly elongated in order to aid burrowing. The shipworms of the family Teredinidae have greatly elongated bodies, but the shell valves are much reduced and restricted to the anterior end of the body, where they function as burrowing organs, allowing the animal to dig tunnels through wood.
# Readle Right Hand Rule
A method used to interperate whether a Bivalve valve is the left or right using the orientation of the umbone | https://www.wikidoc.org/index.php/Bivalvia | |
5f814289d7f55cb20509b8ac793acf142efe7663 | wikidoc | Laxative | Laxative
# Overview
Laxatives (or purgatives) are foods, compounds, or drugs taken to induce bowel movements or to loosen the stool, most often taken to treat constipation. Certain stimulant, lubricant, and saline laxatives are used to evacuate the colon for rectal and bowel examinations, and may be supplemented by enemas in that circumstance. Sufficiently high doses of laxatives will cause diarrhea.
Laxatives only work to hasten the elimination of undigested remains of food in the large intestine and colon.
There are several types of laxatives, listed below. Some laxatives combine more than one type of active ingredient to produce a combination of the effects mentioned. Laxatives may be oral or in suppository form.
Constipation with no known organic cause, i.e. no medical explanation, exhibits gender differences in prevalence: females are more often affected than males. Not surprisingly, some advertisers promote their brands as being more feminine and thereby tailor their message to the market. The way laxatives function in males and females, however, does not exhibit significant differences.
# Vegetables and foods regarded or have known to be laxatives
Some vegetables and foods can be eaten to cure constipation and act as laxatives, although the effectiveness may vary. These include:
- Almonds
- Aloe Vera
- Apple Juice
- Beets
- Chicken Broth
- Chicory
- Chocolate
- Coconut
- Coffee
- Dandelion
- Dates
- Dried apricots
- Endive
- Figs
- Flaxseed
- Grapes
- Hot Tea w/ Lemon
- Liquorice
- Mangos
- Molasses
- Olives
- Papayas
- Parsley
- Peach/Apricots
- Pears
- Persimmons
- Pineapple
- Plums
- Prunes/Prune Juice
- Rhubarb
- Soybeans
- Spicy Foods
- Turnips
- Walnuts
- Watercress
# Bulk-producing agents
- Site of Action: Small and large intestine
- Onset of Action: 12 - 72 hours
- Examples: psyllium husk (Metamucil), methylcellulose (Citrucel), polycarbophil, dietary fiber, apples
Also known as bulking agents or roughage, these include dietary fiber. Bulk-Producing agents cause the stool to be bulkier and to retain more water, as well as forming an emollient gel, making it easier for peristaltic action to move it along. They should be taken with plenty of water. Bulk-producing agents have the gentlest of effects among laxatives and can be taken just for maintaining regular bowel movements.
# Stool softeners / Surfactants
- Site of Action: Small and large intestine
- Onset of Action: 12 - 72 hours
- Examples: docusate (Colace, Diocto)
These cause water & fats to penetrate the stool, making it easier to move along. Many of these quickly produce a tolerance effect and so become ineffective with prolonged use. Their strength is between that of the bulk producers and the stimulants, and they can be used for patients with occasional constipation or those with anorectal conditions for whom passage of a firm stool is painful.
# Lubricants / Emollient
- Site of Action: Colon
- Onset of Action: 6 - 8 hours
These simply make the stool slippery, so that it slides through the intestine more easily. An example is mineral oil, which also retards colonic absorption of water, softening the stool. Mineral oil may decrease the absorption of fat-soluble vitamins (A, D, E and K).
# Hydrating agents (osmotics)
These cause the intestines to hold more water within, softening the stool. There are two principal types, saline and hyperosmotic.
## Saline
- Site of Action: Small and large intestine
- Onset of Action: 0.5 - 6 hours
- Examples: Dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of magnesia), magnesium sulfate (which is Epsom salt) , monobasic sodium phosphate, sodium biphosphate.
Saline laxatives attract and retain water in the intestinal lumen, increasing intraluminal pressure and thus softening the stool. They will also cause the release of cholecystokinin, which stimulates the digestion of fat and protein. Saline laxatives may alter a patient's fluid and electrolyte balance.
Sulfate salts are considered the most potent.
## Hyperosmotic agents
- Site of Action: Colon
- Onset of Action: 0.5 - 3 hours
- Examples: Glycerin suppositories, Sorbitol, Lactulose, and Polyethylene glycol (PEG).
Lactulose works by the osmotic effect, which retains water in the colon, lowering the pH and increasing colonic peristalsis. Lactulose is also indicated in Portal-systemic encephalopathy. Glycerin suppositories work mostly by hyperosmotic action, but also the sodium stearate in the preparation causes local irritation to the colon.
Solutions of polyethylene glycol and electrolytes (sodium chloride, sodium bicarbonate, potassium chloride, and sometimes sodium sulfate) are used for whole bowel irrigation, a process designed to prepare the bowel for surgery or colonoscopy and to treat certain types of poisoning. Brand names for these solutions include GoLytely, GlycoLax, CoLyte, NuLytely, and others.
### Effectiveness
For adults, a randomized controlled trial found PEG 17 grams once per day better than tegaserod 6 mg twice per day. A randomized controlled trial found greater improvement from 2 sachets (26 grams) of PEG versus or 2 sachets (20 grams) of lactulose . 17 grams/day of PEG has been effective and safe in a randomized controlled trial for six months. Another randomized controlled trial found no difference between sorbitol and lactulose .
For children, PEG was found to be more effective than lactulose.
# Stimulant / Irritant
- Site of Action: Colon
- Examples:
These stimulate peristaltic action and can be dangerous under certain circumstances. Long term use can lead to 'cathartic colon'. Stimulant laxatives act on the intestinal mucosa, or nerve plexus; they also alter water and electrolyte secretion. They are the most severe among laxatives and should be used only in extreme conditions. Castor oil may be preferred when more complete evacuation is required.
## Castor oil
- Site of Action: Small intestine
Castor oil acts directly on intestinal mucosa or nerve plexus and alters water and electrolyte secretion. It is converted into ricinoleic acid (the active component) in the gut.
# Serotonin agonist
Tegaserod is a motility stimulant that works through activation of 5-HT4 receptors of the enteric nervous system in the gastrointestinal tract. However caution must be taken due to potentially harmful cardiovascular side-effects.
# Uses
Bowel Prep.
Chronic constipation.
Chronic immobility.
# Problems with use
## Laxative Abuse
Laxative abuse is potentially serious since it can lead to intestinal paralysis, Irritable Bowel Syndrome (IBS), pancreatitis, renal failure, and other problems.
## Laxative gut
Physicians generally warn against the chronic use of stimulant laxatives due to concern that chronic use causes the colonic tissues to get worn out over time and not be able to expel feces due to long term overstimulation. The evidence for this was never too strong, and it was always unclear whether the elongated and poorly moving colon of a patient with chronic constipation was a result of or was just a cause for patients' use of stimulant laxatives. A common finding in patients who have used stimulant laxatives is a brown pigment deposited in the intestinal tissue, known as Melanosis coli.
## Eating Disorders
Laxatives are often used by people with an eating disorder. In many cases of Bulimia Nervosa the patient will abuse laxatives in an attempt to purge themselves of food in the intestines before it becomes digested. Frequently, patients with eating disorders had chronic digestive problems in childhood and found laxatives an effective treatment. The laxative use later may substitute of more appropriate treatment such as a better diet. Treatment of patients with eating disorders and gastrointestinal illnesses can be challenging. | Laxative
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
For patient information, click here
Laxatives (or purgatives) are foods, compounds, or drugs taken to induce bowel movements or to loosen the stool, most often taken to treat constipation. Certain stimulant, lubricant, and saline laxatives are used to evacuate the colon for rectal and bowel examinations, and may be supplemented by enemas in that circumstance. Sufficiently high doses of laxatives will cause diarrhea.
Laxatives only work to hasten the elimination of undigested remains of food in the large intestine and colon.
There are several types of laxatives, listed below. Some laxatives combine more than one type of active ingredient to produce a combination of the effects mentioned. Laxatives may be oral or in suppository form.
Constipation with no known organic cause, i.e. no medical explanation, exhibits gender differences in prevalence: females are more often affected than males.[1] Not surprisingly, some advertisers promote their brands as being more feminine and thereby tailor their message to the market. The way laxatives function in males and females, however, does not exhibit significant differences.
# Vegetables and foods regarded or have known to be laxatives
Some vegetables and foods can be eaten to cure constipation and act as laxatives, although the effectiveness may vary. These include:
- Almonds
- Aloe Vera
- Apple Juice
- Beets
- Chicken Broth
- Chicory
- Chocolate
- Coconut
- Coffee
- Dandelion
- Dates
- Dried apricots
- Endive
- Figs
- Flaxseed
- Grapes
- Hot Tea w/ Lemon
- Liquorice
- Mangos
- Molasses
- Olives
- Papayas
- Parsley
- Peach/Apricots
- Pears
- Persimmons
- Pineapple
- Plums
- Prunes/Prune Juice
- Rhubarb
- Soybeans
- Spicy Foods
- Turnips
- Walnuts
- Watercress
# Bulk-producing agents
- Site of Action: Small and large intestine
- Onset of Action: 12 - 72 hours
- Examples: psyllium husk (Metamucil), methylcellulose (Citrucel), polycarbophil, dietary fiber, apples
Also known as bulking agents or roughage, these include dietary fiber. Bulk-Producing agents cause the stool to be bulkier and to retain more water, as well as forming an emollient gel, making it easier for peristaltic action to move it along. They should be taken with plenty of water. Bulk-producing agents have the gentlest of effects among laxatives and can be taken just for maintaining regular bowel movements.
# Stool softeners / Surfactants
- Site of Action: Small and large intestine
- Onset of Action: 12 - 72 hours
- Examples: docusate (Colace, Diocto)
These cause water & fats to penetrate the stool, making it easier to move along. Many of these quickly produce a tolerance effect and so become ineffective with prolonged use. Their strength is between that of the bulk producers and the stimulants, and they can be used for patients with occasional constipation or those with anorectal conditions for whom passage of a firm stool is painful.
# Lubricants / Emollient
- Site of Action: Colon
- Onset of Action: 6 - 8 hours
These simply make the stool slippery, so that it slides through the intestine more easily. An example is mineral oil, which also retards colonic absorption of water, softening the stool. Mineral oil may decrease the absorption of fat-soluble vitamins (A, D, E and K).
# Hydrating agents (osmotics)
These cause the intestines to hold more water within, softening the stool. There are two principal types, saline and hyperosmotic.
## Saline
- Site of Action: Small and large intestine
- Onset of Action: 0.5 - 6 hours
- Examples: Dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of magnesia), magnesium sulfate (which is Epsom salt) , monobasic sodium phosphate, sodium biphosphate.
Saline laxatives attract and retain water in the intestinal lumen, increasing intraluminal pressure and thus softening the stool. They will also cause the release of cholecystokinin, which stimulates the digestion of fat and protein. Saline laxatives may alter a patient's fluid and electrolyte balance.
Sulfate salts are considered the most potent.
## Hyperosmotic agents
- Site of Action: Colon
- Onset of Action: 0.5 - 3 hours
- Examples: Glycerin suppositories, Sorbitol, Lactulose, and Polyethylene glycol (PEG).
Lactulose works by the osmotic effect, which retains water in the colon, lowering the pH and increasing colonic peristalsis. Lactulose is also indicated in Portal-systemic encephalopathy. Glycerin suppositories work mostly by hyperosmotic action, but also the sodium stearate in the preparation causes local irritation to the colon.
Solutions of polyethylene glycol and electrolytes (sodium chloride, sodium bicarbonate, potassium chloride, and sometimes sodium sulfate) are used for whole bowel irrigation, a process designed to prepare the bowel for surgery or colonoscopy and to treat certain types of poisoning. Brand names for these solutions include GoLytely, GlycoLax, CoLyte, NuLytely, and others.
### Effectiveness
For adults, a randomized controlled trial found PEG [MiraLax or GlycoLax] 17 grams once per day better than tegaserod 6 mg twice per day.[2] A randomized controlled trial found greater improvement from 2 sachets (26 grams) of PEG versus or 2 sachets (20 grams) of lactulose [3]. 17 grams/day of PEG has been effective and safe in a randomized controlled trial for six months.[4] Another randomized controlled trial found no difference between sorbitol and lactulose [5].
For children, PEG was found to be more effective than lactulose.[6]
# Stimulant / Irritant
- Site of Action: Colon
- Examples:
These stimulate peristaltic action and can be dangerous under certain circumstances. Long term use can lead to 'cathartic colon'.[7] Stimulant laxatives act on the intestinal mucosa, or nerve plexus; they also alter water and electrolyte secretion. They are the most severe among laxatives and should be used only in extreme conditions. Castor oil may be preferred when more complete evacuation is required.
## Castor oil
- Site of Action: Small intestine
Castor oil acts directly on intestinal mucosa or nerve plexus and alters water and electrolyte secretion. It is converted into ricinoleic acid (the active component) in the gut.
# Serotonin agonist
Tegaserod is a motility stimulant that works through activation of 5-HT4 receptors of the enteric nervous system in the gastrointestinal tract. However caution must be taken due to potentially harmful cardiovascular side-effects.
# Uses
Bowel Prep.
Chronic constipation.
Chronic immobility.
# Problems with use
## Laxative Abuse
Laxative abuse is potentially serious since it can lead to intestinal paralysis, Irritable Bowel Syndrome (IBS), pancreatitis, renal failure,[8] and other problems.
## Laxative gut
Physicians generally warn against the chronic use of stimulant laxatives due to concern that chronic use causes the colonic tissues to get worn out over time and not be able to expel feces due to long term overstimulation. The evidence for this was never too strong, and it was always unclear whether the elongated and poorly moving colon of a patient with chronic constipation was a result of or was just a cause for patients' use of stimulant laxatives. A common finding in patients who have used stimulant laxatives is a brown pigment deposited in the intestinal tissue, known as Melanosis coli.
## Eating Disorders
Laxatives are often used by people with an eating disorder. In many cases of Bulimia Nervosa the patient will abuse laxatives in an attempt to purge themselves of food in the intestines before it becomes digested. Frequently, patients with eating disorders had chronic digestive problems in childhood and found laxatives an effective treatment. The laxative use later may substitute of more appropriate treatment such as a better diet. Treatment of patients with eating disorders and gastrointestinal illnesses can be challenging. | https://www.wikidoc.org/index.php/Black_Draught | |
bc4d8a69a1345da7414c7259af4533f83c721321 | wikidoc | Blastula | Blastula
The blastula is an early stage of embryonic development in animals. It is also called blastosphere. It is produced by cleavage of a fertilized ovum and consists of a spherical layer of around 128 cells surrounding a central fluid-filled cavity called the blastocoel. The blastula follows the morula and precedes the gastrula in the developmental sequence.
# Research
A whitefish blastula is often used to help study the processes of mitosis in animal cells. The blastula is prevented from multiplying during the nuclear-injection stage.
# Formation of blastocyst
In mammals, blastulation leads to the formation of the blastocyst, which must not be confused with the blastula; even though they are similar in structure, their cells have different fates. The blastocyst consists of two primary cell lines:
- the inner cell mass, also known as the "embryoblast"
- the trophoblast
The former is the source of embryonic stem cells and gives rise to all later structures of the adult organism. The latter combines with the maternal endometrium to form the placenta in eutherian mammals. | Blastula
Template:Infobox Embryology
The blastula is an early stage of embryonic development in animals. It is also called blastosphere. It is produced by cleavage of a fertilized ovum and consists of a spherical layer of around 128 cells surrounding a central fluid-filled cavity called the blastocoel. The blastula follows the morula and precedes the gastrula in the developmental sequence.
# Research
A whitefish blastula is often used to help study the processes of mitosis in animal cells.[1] The blastula is prevented from multiplying during the nuclear-injection stage.
# Formation of blastocyst
In mammals, blastulation leads to the formation of the blastocyst, which must not be confused with the blastula; even though they are similar in structure, their cells have different fates. The blastocyst consists of two primary cell lines:
- the inner cell mass, also known as the "embryoblast"
- the trophoblast
The former is the source of embryonic stem cells and gives rise to all later structures of the adult organism. The latter combines with the maternal endometrium to form the placenta in eutherian mammals. | https://www.wikidoc.org/index.php/Blastula | |
0da6c056f0a612edb165af6200655925803b2827 | wikidoc | Blebitis | Blebitis
# Overview
Blebitis is the inflammation of the ocular bleb as a result of bacterial infection. It is a possible complication of a trabeculectomy performed to treat glaucoma. The causative pathogens are usually Staphylococcus or Streptococcus bacteria. Trabulectomy creates a point of possible infiltration in the bleb; the prolonged use of anti-metabolites following trabeculectomy increases the risk of bleb infection via cyst formation, epithelial wall thinning and erosion, and goblet cell depletion and decreased mucin production. Membrane deterioration, in conjunction with an inferior location for the bleb, creates a flow pathway for bacterial infiltration through the bleb's aqueous humor. Symptoms of blebitis include ocular pain, photophobia and loss of vision, intraocular pressure, and fluid discharge. Physical examination may reveal erythema and hyperemia of the affected eye, as well as thinning and whitening of the bleb. The presence of maculopathic purulent infiltrate can also be found upon physical exam. The mainstays of therapy for blebitis are fortified topical antimicrobial and antibacterial agents, as well as topical corticosteroids. With treatment, the prognosis for blebitis is good. Without treatment, blebitis can result in bleb-related endophthalmitis, leading to a much worse prognosis, including permanent vision loss and death. Blebitis is very rare; the incidence in the United States was estimated to be 550 per 100,000 individuals (.55%) from 2007-2011.
# Historical Perspective
Blebitis was officially identified by Dr. R.H. Brown in 1994 to classify bleb-infection not associated with the vitreous.
# Classification
There is no diagnostic classification schema for blebitis. However, blebitis is considered Stage I of the bleb-related infection classification system.
## Bleb-related Infection Classification
# Pathophysiology
## Pathogenesis
The pathogenesis of blebitis is characterized by the infiltration of staphylococcus and streptococcus bacteria into the bleb following trabeculectomy. The removal of the trabecula and adjacent structures creates a point of infiltration for pathogenic bacteria. The prolonged use of anti-metabolites following trabeculectomy increases the risk of bleb infection. Anti-metabolite drug use results in epithelial thinning, which heightens the risk of infiltration..
Additional pathogenic factors include:
- Post-operative goblet cell depletion decreases the amount of protective mucin.
- Inferior placement of the bleb heightens the risk of infection by the increased risk of leakage, providing a flow pathway for pathogenic bacteria to travel from the lacrimal lake to the bleb.
Lack of protection from the eyelid for inferior bleb placements contributes to infection risk.
- Lack of protection from the eyelid for inferior bleb placements contributes to infection risk.
## Gross Pathology
On gross pathology, maculopathic purulent infiltrate, edematous erythema, hyperaemia and hypopyon are characteristics of blebitis.
## Microscopic Pathology
On microscopic histopathological analysis, goblet cell-depletion and epithelial thinning are characteristic of blebitis. Observation of the basement layer of conjunctival epithelial cells may demonstrate thinning, missing segments, or total absence.
# Causes
Blebitis may be caused by bacterial infection, predominantly Staphylococcus spp. and Streptococcus spp. Less commonly,Corynebacterium, Pseudomonas aeruginosa, and Nocardia have been isolated in cases of blebitis.
# Differentiating Blebitis from Other Diseases
Blebitis must be differentiated from other diseases that cause ocular erythema and hyperaemia, as well as pain, pressure, loss of vision, and photophobia.
# Epidemiology and Demographics
From 2007-2011, the incidence of blebitis in the United States was approximately 550 per 100,000 individuals.
## Age
Blebitis patients are usually less than 40 years old. Blebitis is also commonly seen in African American patients older than 40 years old and Mexican Americans older than 60 years old, due to the higher incidence of the precursory glaucoma surgery.
## Gender
Males are more commonly affected with blebitis than females.
## Race
African-Americans are more commonly affected with blebitis than other races. Inuit are more prone to blebitis due to the higher incidence of glaucoma in that population.
# Risk Factors
Common risk factors in the development of Blebitis include:
- Undergoing trabeculectomy for glaucoma
- Experiencing a bleb-leak
- Persistent use of anti-fibrotic topical agents
- Being male
- Being young
- Being African-American
- Experiencing recurrent bacterial conjunctivitis
- Inferior location of the filtering bleb
- Use of contact lenses
- Immunocompromise
# Natural History, Complications and Prognosis
## Natural History
Blebitis will require topical antibiotic therapy to resolve. Without treatment, blebitis may lead to bleb leakage and bleb-related endopthalmitis. Recurrence of infection and blebitis is likely without treatment.
## Complications
Without treatment, a possible complication of blebitis is endophthalmitis. Endophthalmitis is caused when the pathogen causing blebitis, previously limited to the bleb, spreads past the anterior chamber of the eye and into the vitreous body.
## Prognosis
With treatment, the prognosis for blebitis is good. Risk of permanent vision loss is minimal with effective therapy.
Without treatment, the prognosis for blebitis is worse due to the increased risk of developing bleb-related endophthalmitis.
# Diagnosis
## Symptoms
Symptoms of blebitis may include:
- Ocular pain of the filtering bleb
- Excessive sensitivity to light
- Vision loss
- Intraocular pressure
- Fluid discharge
## Physical Examination
Physical examination may be remarkable for:
- Hyperemia in the affected eye
- Erythema of the affected eye due to presence of hypopyon
- Thinning of the bleb epithelium
- Whitening of the bleb
- Presence of maculopathic purulent infiltrate
## Laboratory Findings
A positive test for staphylococcus or streptococcus bacteria is diagnostic of blebitis.
- This is obtained via a culture and gram stain of the aqueous humor, swabbed from the surface of the bleb.
- Polymerase chain reaction (PCR) testing of the aqueous humor will reveal bacterial infection.
## Imaging Findings
There are no imaging findings associated with blebitis.
## Other Diagnostic Studies
Physical examination and microscopic histopathological analysis of suspected blebitis is sufficient for diagnosis.
# Treatment
## Medical Therapy
The mainstays of therapy for blebitis are fortified topical antimicrobial and antibacterial agents:
- fluoroquinolone
moxifloxacin
gatifloxacin
- moxifloxacin
- gatifloxacin
- chloramphenicol
- aminoglycoside
- vancomycin
- cephalosporin
Topical corticosteroids are often used in conjunction with antimicrobial therapy.
## Surgery
Surgery is rarely indicated for blebitis for cases such that the bleb displays positive Seidel-test results for leakage.
- Surgery will be performed to repair the bleb but is only indicated when the chance of reinfection is eliminated.
## Prevention
Effective measures for the primary prevention of blebitis include those that minimize the possibility of ocular bacterial infection following a trabeculectomy:
- Minimizing use of topical corticosteroids to prevent bleb-leakage that predisposes blebitis.
- Avoiding prolonged use of topical antibiotics beyond the prescribed time period post-trabeculectomy.
- Avoiding inferior or nasal placement of the bleb to reduce the risk of leakage. | Blebitis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.
# Overview
Blebitis is the inflammation of the ocular bleb as a result of bacterial infection. It is a possible complication of a trabeculectomy performed to treat glaucoma. The causative pathogens are usually Staphylococcus or Streptococcus bacteria. Trabulectomy creates a point of possible infiltration in the bleb; the prolonged use of anti-metabolites following trabeculectomy increases the risk of bleb infection via cyst formation, epithelial wall thinning and erosion, and goblet cell depletion and decreased mucin production. Membrane deterioration, in conjunction with an inferior location for the bleb, creates a flow pathway for bacterial infiltration through the bleb's aqueous humor. Symptoms of blebitis include ocular pain, photophobia and loss of vision, intraocular pressure, and fluid discharge. Physical examination may reveal erythema and hyperemia of the affected eye, as well as thinning and whitening of the bleb. The presence of maculopathic purulent infiltrate can also be found upon physical exam. The mainstays of therapy for blebitis are fortified topical antimicrobial and antibacterial agents, as well as topical corticosteroids. With treatment, the prognosis for blebitis is good. Without treatment, blebitis can result in bleb-related endophthalmitis, leading to a much worse prognosis, including permanent vision loss and death. Blebitis is very rare; the incidence in the United States was estimated to be 550 per 100,000 individuals (.55%) from 2007-2011.
# Historical Perspective
Blebitis was officially identified by Dr. R.H. Brown in 1994 to classify bleb-infection not associated with the vitreous.[1]
# Classification
There is no diagnostic classification schema for blebitis. However, blebitis is considered Stage I of the bleb-related infection classification system.[2][3][4][5]
## Bleb-related Infection Classification
# Pathophysiology
## Pathogenesis
The pathogenesis of blebitis is characterized by the infiltration of staphylococcus and streptococcus bacteria into the bleb following trabeculectomy.[6] The removal of the trabecula and adjacent structures creates a point of infiltration for pathogenic bacteria.[7] The prolonged use of anti-metabolites following trabeculectomy increases the risk of bleb infection. Anti-metabolite drug use results in epithelial thinning, which heightens the risk of infiltration.[8][9].
Additional pathogenic factors include:
- Post-operative goblet cell depletion decreases the amount of protective mucin.
- Inferior placement of the bleb heightens the risk of infection by the increased risk of leakage, providing a flow pathway for pathogenic bacteria to travel from the lacrimal lake to the bleb[10].
Lack of protection from the eyelid for inferior bleb placements contributes to infection risk.
- Lack of protection from the eyelid for inferior bleb placements contributes to infection risk.
## Gross Pathology
On gross pathology, maculopathic purulent infiltrate, edematous erythema, hyperaemia and hypopyon are characteristics of blebitis.[9]
## Microscopic Pathology
On microscopic histopathological analysis, goblet cell-depletion and epithelial thinning are characteristic of blebitis.[11] Observation of the basement layer of conjunctival epithelial cells may demonstrate thinning, missing segments, or total absence.
# Causes
Blebitis may be caused by bacterial infection, predominantly Staphylococcus spp. and Streptococcus spp.[5][12] [9] Less commonly,Corynebacterium, Pseudomonas aeruginosa, and Nocardia have been isolated in cases of blebitis.[13][14]
# Differentiating Blebitis from Other Diseases
Blebitis must be differentiated from other diseases that cause ocular erythema and hyperaemia, as well as pain, pressure, loss of vision, and photophobia.[15]
# Epidemiology and Demographics
From 2007-2011, the incidence of blebitis in the United States was approximately 550 per 100,000 individuals.[17]
## Age
Blebitis patients are usually less than 40 years old.[18] Blebitis is also commonly seen in African American patients older than 40 years old and Mexican Americans older than 60 years old, due to the higher incidence of the precursory glaucoma surgery.
## Gender
Males are more commonly affected with blebitis than females.[19]
## Race
African-Americans are more commonly affected with blebitis than other races.[19] Inuit are more prone to blebitis due to the higher incidence of glaucoma in that population.[20]
# Risk Factors
Common risk factors in the development of Blebitis include:[19]
- Undergoing trabeculectomy for glaucoma
- Experiencing a bleb-leak
- Persistent use of anti-fibrotic topical agents
- Being male
- Being young
- Being African-American
- Experiencing recurrent bacterial conjunctivitis
- Inferior location of the filtering bleb
- Use of contact lenses
- Immunocompromise[6]
# Natural History, Complications and Prognosis
## Natural History
Blebitis will require topical antibiotic therapy to resolve.[21] Without treatment, blebitis may lead to bleb leakage and bleb-related endopthalmitis. Recurrence of infection and blebitis is likely without treatment.
## Complications
Without treatment, a possible complication of blebitis is endophthalmitis.[22] Endophthalmitis is caused when the pathogen causing blebitis, previously limited to the bleb, spreads past the anterior chamber of the eye and into the vitreous body.
## Prognosis
With treatment, the prognosis for blebitis is good.[23] Risk of permanent vision loss is minimal with effective therapy.
Without treatment, the prognosis for blebitis is worse due to the increased risk of developing bleb-related endophthalmitis.[12]
# Diagnosis
## Symptoms
Symptoms of blebitis may include:[24]
- Ocular pain of the filtering bleb
- Excessive sensitivity to light[25]
- Vision loss
- Intraocular pressure
- Fluid discharge[9]
## Physical Examination
Physical examination may be remarkable for:
- Hyperemia in the affected eye
- Erythema of the affected eye due to presence of hypopyon[24]
- Thinning of the bleb epithelium
- Whitening of the bleb[1]
- Presence of maculopathic purulent infiltrate
## Laboratory Findings
A positive test for staphylococcus or streptococcus bacteria is diagnostic of blebitis.[6]
- This is obtained via a culture and gram stain of the aqueous humor, swabbed from the surface of the bleb.
- Polymerase chain reaction (PCR) testing of the aqueous humor will reveal bacterial infection.
## Imaging Findings
There are no imaging findings associated with blebitis.
## Other Diagnostic Studies
Physical examination and microscopic histopathological analysis of suspected blebitis is sufficient for diagnosis.
# Treatment
## Medical Therapy
The mainstays of therapy for blebitis are fortified topical antimicrobial and antibacterial agents:[15]
- fluoroquinolone
moxifloxacin
gatifloxacin
- moxifloxacin
- gatifloxacin
- chloramphenicol
- aminoglycoside
- vancomycin
- cephalosporin
Topical corticosteroids are often used in conjunction with antimicrobial therapy.
## Surgery
Surgery is rarely indicated for blebitis for cases such that the bleb displays positive Seidel-test results for leakage.[15]
- Surgery will be performed to repair the bleb but is only indicated when the chance of reinfection is eliminated.
## Prevention
Effective measures for the primary prevention of blebitis include those that minimize the possibility of ocular bacterial infection following a trabeculectomy:
- Minimizing use of topical corticosteroids to prevent bleb-leakage that predisposes blebitis.[6]
- Avoiding prolonged use of topical antibiotics beyond the prescribed time period post-trabeculectomy.
- Avoiding inferior or nasal placement of the bleb to reduce the risk of leakage.[10] | https://www.wikidoc.org/index.php/Blebitis | |
3a0daa93552d9f674abdb2e163502dc5dfae3c32 | wikidoc | Bloating | Bloating
Synonyms and keywords: Post-prandial abdominal fullness
# Overview
Bloating is described as a sensation of elevated abdominal pressure that may or may not be accompanied by objective abdominal distension, i.e. noticeable enlargement of the waist. Bloating and abdominal distension may be symptoms of organic disease and possible causes should be considered first in the differential diagnosis. It is one of the most frequent problems in a wide proportion of patients with gastrointestinal disorders, but the most common cause is constipation. Bloating also results from irritable bowel syndrome, gastroparesis, small intestinal bacterial overgrowth and gynecological conditions. The pathophysiology of bloating is not well understood and suggested underlying causes include visceral hypersensitivity, behavioral mediated irregular abdominal wall-phrenic reflexes, poorly ingested fermentable carbohydrates, and microbiome modification. Usually, patients are evaluated with a thorough history and physical examination, but organic disorders should be ruled out. The management strategy includes dietary modification, behavioral therapy, microbiome modulation, and medical therapy.
# Historical Perspective
- Bernheim in 1891 described a woman who said, "I go up and down like an accordion." Later, in 1900, Kaplan wrote on ventre en accordéon.
- Nongaseous form of bloating was first described by Sir James Y. Simpson.
- According to Kaplan, in the 19th century in Europe, the intestines of the patient were punctured with a trocar in cases of suspected intestinal obstruction. In this way, it was discovered that there was no gas involved in cases of hysteric bloating.
- It was also considered a "tumor" that vanished when the patient was anesthetized and returned when they were conscious.
- Lordosis association with bloating was described by Krukenberg in 1884.
- Bloating was first described by Alvarez of the Mayo Clinic in 1949 in a woman with a psychiatric problem.
# Classification
There is no established system for the classification of bloating.
# Pathophysiology
## Abnormal Gut Microbiota
There is a relationship between the types of gas produced by colonic microflora and bloating. The role of methanogenic flora has always been in question when the pathogenesis of bloating is discussed. During the experiments involving the ingestion of sorbitol and fiber, it was determined that there was a significant increase in bloating in individuals with low producers of methane vs high producers.
## Small Intestinal Bacterial Overgrowth
Bacterial fermentation and the subsequent gas production is the potential cause of bloating in patients with irritable bowel syndrome.
## Intestinal Gas Accumulation
Increase levels of intestinal gas has been linked with bloating. After consuming a large meal, there is 65% increase in postprandial gas volume in pelvic colon. Whereas during fasting, GI tract produces about 100ml of gas which spreads between the liver, small intestine, ascending colon, transverse colon, descending colon, and distal (pelvic) colon.
## Altered Gut Motility
Gut motility is affected in many disorders mainly labeled as Intestinal dysmotility. It affects the evacuation of excessive gas produced in the GI tract during fasting as well as post-prandial.
## Abnormal Abdominal-diaphragmatic Reflexes
Mechanism which leads to bloating are not well understood but studies have shown a role of abdominal-diaphragmatic reflexes, which are involves the combination of increase in the anterior wall tone and diaphragm relaxation. These reflexes are abnormal in individuals with bloating.
## Visceral Hypersensitivity
The sensation of bloating may originate from abdominal viscera in patients with a functional gastrointestinal disorder, in whom normal stimuli or small variations of gas content within the gut may be perceived as bloating. The autonomic nervous system may also contribute to the modulation of visceral sensitivity and sympathetic activation is known to increase the perception of intestinal distention in these patients.
## Food Intolerance and Carbohydrate Malabsorption
A high FODMAP diet has demonstrated prolonged hydrogen production in the intestine, colonic distension by fermentation, increased colonic fluid delivery by osmotic load within the bowel lumen, and GI symptom generation.
## Hard stool/Constipation
Distension of the rectum by retained feces induces alteration of gut motility and increases bacterial fermentation.
# Causes
The most common cause of bloating is Constipation, Pregnancy, IBS, Celiac disease, Lactose, fructose, and other carbohydrates intolerance, Pancreatic insufficiency, Gastroparesis, Diabetes mellitus, Hypothyroidism, Scleroderma, Chronic idiopathic pseudo-obstruction, Small bowel bacterial overgrowth, Acute gastroenteritis, Gastric malignancy, Ovarian malignancy, and Ascites.
# Differentiating bloating from other Diseases
Bloating must be differentiated from Lactose intolerance, Fructose intolerance, Celiac disease, Pancreatic insufficiency, Irritable bowel syndrome, Functional dyspepsia, Functional bloating, Constipation, Diabetes, Scleroderma, Pseudo-obstruction: acute or chronic, Gastroparesis, Acute adynamic ileus, Gastric outlet obstruction, Small bowel obstruction, SMA syndrome, Colonic obstruction, Volvulus, Gastrointestinal/Ovarian Malignancy, Ascites, Pregnancy, and Obesity/adiposity.
# Epidemiology and Demographics
- In the USA, 15-30% of the general population has been reported to experience bloating.
- A telephone survey reported a prevalence of 16% in US adults who were asked about bloating or distention during the last month.
- Women were more likely than men to report bloating.
- There is no racial predilection to bloating.
# Risk Factors
Risk factors include chewing gum, hard candy, and carbonated beverages such as soda or beer. Foods that can produce excess bowel gas include leafy greens, beans, and bran foods. Dairy products can lead to bloating and flatulence in people who are lactose intolerant.
# Screening
There is insufficient evidence to recommend routine screening for bloating.
# Natural History, Complications, and Prognosis
The sensation of abdominal bloating is often attributed to excessive gas in patients. However, the relationship between the volume of intestinal gas and the effects is not clear. Patients with chronic complaints of bloating and distension have heightened sensitivity to gaseous distension or exaggerated motor response to normal amounts of gas. Pains that are due to bloating will feel sharp and cause the stomach to cramp. These pains may occur anywhere in the body and can change locations quickly.
Bloating is typically benign, although it can be due to severe conditions such as intestinal obstruction and malignancy.
Patients with mild functional bloating may need merely reassurance that the condition is benign.
# Diagnosis
## Diagnostic Study of Choice
Rome IV criteria for establishing the diagnosis of functional bloating include both of the following (for at least three months with symptom onset at least six months prior to diagnosis).
●Recurrent bloating or distension, on average, at least one day per week; abdominal bloating and/or distension predominates over other symptoms
●Insufficient criteria for a diagnosis of IBS, functional constipation, functional diarrhea, or postprandial distress syndrome
## History and Symptoms
History includes the onset of symptoms, the relationship to diet (eg, wheat, dairy, fructose, fiber, nonabsorbable sugars) diurnal variation, and the presence of symptoms suggestive of other functional gastrointestinal disorders, including constipation, diarrhea, and abdominal pain or postprandial fullness. Functional bloating usually have a diurnal pattern which may accompany the consumption of such foods, frequently accompanied by excessive burping or flattening. Patients may complain about deteriorating symptoms as the day progresses, particularly after meals, but they may be relieved overnight.
## Physical Examination
Common physical examination findings of bloating include abdominal distention with or without altered bowel sounds. However, if occult fecal blood, cutaneous findings (sclerodactyly with scleroderma, dermatitis herpetiformis in celiac disease), peripheral or autonomic neuropathy, cachexia, jaundice, or palpable masses is present then it suggests underlying organic disease.
## Laboratory Findings
### Complete blood count
To evaluate for anemia
### Serologies for Celiac Sprue
- anti-tissue transglutaminase (tTG) antibodies
- endomysial antibodies (EMA)
- deamidated gliadin peptide (DGP) antibodies
### Hydrogen Breath Test
For the evaluation of small intestinal bacterial overgrowth and lactose intolerance.
### Thyroid Function tests
### Fasting Cortisol Levels
### Antinuclear antibodies and Scleroderma antibodies
To evaluate for collagen vascular disease
### Antinuclear neuronal antibodies
To screen for paraneoplastic visceral neuropathy
### Stool analysis
Antigen testing for Giardia
## Electrocardiogram
There are no ECG findings associated with bloating.
## X-ray
An abdominal x-ray may be helpful to rule out intestinal obstruction.
## Echocardiography or Ultrasound
Abdominal/Pelvic Ultrasound to look for ascites and rule out ovarian cancer.
## CT scan
There are no CT scan findings associated with bloating. However, it can be used to rule out intestinal obstruction.
## MRI
There are no MRI findings associated with bloating.
## Other Imaging Findings
### Upper GI Endoscopy
The presence of alarm features including weight loss, abdominal pain, dysphagia, heartburn, and regurgitation are an indication for a diagnostic evaluation with upper endoscopy.
## Other Diagnostic Studies
There are no other diagnostic studies associated with bloating.
# Treatment
## Medical Therapy
### Education, treatment of associated disorders, and behavioral therapy
Management requires instruction to minimize air swallowing and reassurance that belching is a benign condition. Relevant behavioural interventions include the avoidance of gum chewing, smoking, consuming carbonated drinks, and gulping of food and liquids. Treatment should be started in people with persistent depression or anxiety. Patients with co-existing acid reflux may need an acid reduction treatment for the control of GERD.
Effective management with excessive belching by a therapist (e.g. cognitive behavioral therapy or speech therapist) with specific experience of diaphragmatic relaxation exercises has been linked with a decrease of symptoms. Diaphragmatic breathing decreases postprandial intragastric pressure and raises the pressure of the esophagogastric junction region, restoring the gradient of the gastroesophageal pressure.
### Reflux inhibitors for refractory symptoms
Baclofen 10 mg three times daily can be prescribed to reduce transient lower esophageal sphincter relaxations and centrally suppress the swallowing rate, and may decrease both supragastric and gastric belching.
## Surgery
Surgical intervention is not recommended for the management of bloating.
## Primary Prevention
There are no established measures for the primary prevention of bloating.
## Secondary Prevention
There are no established measures for the secondary prevention of bloating. | Bloating
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Ibtisam Ashraf, M.B.B.S.[2]
Synonyms and keywords: Post-prandial abdominal fullness
# Overview
Bloating is described as a sensation of elevated abdominal pressure that may or may not be accompanied by objective abdominal distension, i.e. noticeable enlargement of the waist. Bloating and abdominal distension may be symptoms of organic disease and possible causes should be considered first in the differential diagnosis. It is one of the most frequent problems in a wide proportion of patients with gastrointestinal disorders, but the most common cause is constipation. Bloating also results from irritable bowel syndrome, gastroparesis, small intestinal bacterial overgrowth and gynecological conditions. The pathophysiology of bloating is not well understood and suggested underlying causes include visceral hypersensitivity, behavioral mediated irregular abdominal wall-phrenic reflexes, poorly ingested fermentable carbohydrates, and microbiome modification. Usually, patients are evaluated with a thorough history and physical examination, but organic disorders should be ruled out. The management strategy includes dietary modification, behavioral therapy, microbiome modulation, and medical therapy.
# Historical Perspective
- Bernheim in 1891 described a woman who said, "I go up and down like an accordion."[1] Later, in 1900, Kaplan wrote on ventre en accordéon.[2]
- Nongaseous form of bloating was first described by Sir James Y. Simpson. [3]
- According to Kaplan, in the 19th century in Europe, the intestines of the patient were punctured with a trocar in cases of suspected intestinal obstruction. In this way, it was discovered that there was no gas involved in cases of hysteric bloating.
- It was also considered a "tumor" that vanished when the patient was anesthetized and returned when they were conscious.[4]
- Lordosis association with bloating was described by Krukenberg in 1884. [2]
- Bloating was first described by Alvarez of the Mayo Clinic in 1949 in a woman with a psychiatric problem.[2]
-
# Classification
There is no established system for the classification of bloating.
# Pathophysiology
## Abnormal Gut Microbiota
There is a relationship between the types of gas produced by colonic microflora and bloating. The role of methanogenic flora has always been in question when the pathogenesis of bloating is discussed. During the experiments involving the ingestion of sorbitol and fiber, it was determined that there was a significant increase in bloating in individuals with low producers of methane vs high producers. [5]
## Small Intestinal Bacterial Overgrowth
Bacterial fermentation and the subsequent gas production is the potential cause of bloating in patients with irritable bowel syndrome.[6]
## Intestinal Gas Accumulation
Increase levels of intestinal gas has been linked with bloating. After consuming a large meal, there is 65% increase in postprandial gas volume in pelvic colon. Whereas during fasting, GI tract produces about 100ml of gas which spreads between the liver, small intestine, ascending colon, transverse colon, descending colon, and distal (pelvic) colon.[7]
## Altered Gut Motility
Gut motility is affected in many disorders mainly labeled as Intestinal dysmotility. It affects the evacuation of excessive gas produced in the GI tract during fasting as well as post-prandial.
## Abnormal Abdominal-diaphragmatic Reflexes
Mechanism which leads to bloating are not well understood but studies have shown a role of abdominal-diaphragmatic reflexes, which are involves the combination of increase in the anterior wall tone and diaphragm relaxation. These reflexes are abnormal in individuals with bloating.[8]
## Visceral Hypersensitivity
The sensation of bloating may originate from abdominal viscera in patients with a functional gastrointestinal disorder, in whom normal stimuli or small variations of gas content within the gut may be perceived as bloating. The autonomic nervous system may also contribute to the modulation of visceral sensitivity and sympathetic activation is known to increase the perception of intestinal distention in these patients.
## Food Intolerance and Carbohydrate Malabsorption
A high FODMAP diet has demonstrated prolonged hydrogen production in the intestine, colonic distension by fermentation, increased colonic fluid delivery by osmotic load within the bowel lumen, and GI symptom generation. [9]
## Hard stool/Constipation
Distension of the rectum by retained feces induces alteration of gut motility and increases bacterial fermentation.
# Causes
The most common cause of bloating is Constipation, Pregnancy, IBS, Celiac disease, Lactose, fructose, and other carbohydrates intolerance, Pancreatic insufficiency, Gastroparesis, Diabetes mellitus, Hypothyroidism, Scleroderma, Chronic idiopathic pseudo-obstruction, Small bowel bacterial overgrowth, Acute gastroenteritis, Gastric malignancy, Ovarian malignancy, and Ascites.[10]
# Differentiating bloating from other Diseases
Bloating must be differentiated from Lactose intolerance, Fructose intolerance, Celiac disease, Pancreatic insufficiency, Irritable bowel syndrome, Functional dyspepsia, Functional bloating, Constipation, Diabetes, Scleroderma, Pseudo-obstruction: acute or chronic, Gastroparesis, Acute adynamic ileus, Gastric outlet obstruction, Small bowel obstruction, SMA syndrome, Colonic obstruction, Volvulus, Gastrointestinal/Ovarian Malignancy, Ascites, Pregnancy, and Obesity/adiposity.[11]
# Epidemiology and Demographics
- In the USA, 15-30% of the general population has been reported to experience bloating.[12]
- A telephone survey reported a prevalence of 16% in US adults who were asked about bloating or distention during the last month.[13]
- Women were more likely than men to report bloating.[12]
- There is no racial predilection to bloating.[14]
# Risk Factors
Risk factors include chewing gum, hard candy, and carbonated beverages such as soda or beer. Foods that can produce excess bowel gas include leafy greens, beans, and bran foods. Dairy products can lead to bloating and flatulence in people who are lactose intolerant.
# Screening
There is insufficient evidence to recommend routine screening for bloating.
# Natural History, Complications, and Prognosis
The sensation of abdominal bloating is often attributed to excessive gas in patients. However, the relationship between the volume of intestinal gas and the effects is not clear. Patients with chronic complaints of bloating and distension have heightened sensitivity to gaseous distension or exaggerated motor response to normal amounts of gas. Pains that are due to bloating will feel sharp and cause the stomach to cramp. These pains may occur anywhere in the body and can change locations quickly.
Bloating is typically benign, although it can be due to severe conditions such as intestinal obstruction and malignancy.
Patients with mild functional bloating may need merely reassurance that the condition is benign. [10]
# Diagnosis
## Diagnostic Study of Choice
Rome IV criteria for establishing the diagnosis of functional bloating include both of the following (for at least three months with symptom onset at least six months prior to diagnosis).[15]
●Recurrent bloating or distension, on average, at least one day per week; abdominal bloating and/or distension predominates over other symptoms
●Insufficient criteria for a diagnosis of IBS, functional constipation, functional diarrhea, or postprandial distress syndrome
## History and Symptoms
History includes the onset of symptoms, the relationship to diet (eg, wheat, dairy, fructose, fiber, nonabsorbable sugars) diurnal variation, and the presence of symptoms suggestive of other functional gastrointestinal disorders, including constipation, diarrhea, and abdominal pain or postprandial fullness. Functional bloating usually have a diurnal pattern which may accompany the consumption of such foods, frequently accompanied by excessive burping or flattening. Patients may complain about deteriorating symptoms as the day progresses, particularly after meals, but they may be relieved overnight.[16]
## Physical Examination
Common physical examination findings of bloating include abdominal distention with or without altered bowel sounds. However, if occult fecal blood, cutaneous findings (sclerodactyly with scleroderma, dermatitis herpetiformis in celiac disease), peripheral or autonomic neuropathy, cachexia, jaundice, or palpable masses is present then it suggests underlying organic disease. [11]
## Laboratory Findings
### Complete blood count
To evaluate for anemia
### Serologies for Celiac Sprue[17]
- anti-tissue transglutaminase (tTG) antibodies
- endomysial antibodies (EMA)
- deamidated gliadin peptide (DGP) antibodies
### Hydrogen Breath Test
For the evaluation of small intestinal bacterial overgrowth and lactose intolerance.
### Thyroid Function tests[18]
### Fasting Cortisol Levels[19]
### Antinuclear antibodies and Scleroderma antibodies[20]
To evaluate for collagen vascular disease
### Antinuclear neuronal antibodies[21]
To screen for paraneoplastic visceral neuropathy
### Stool analysis
Antigen testing for Giardia
## Electrocardiogram
There are no ECG findings associated with bloating.
## X-ray
An abdominal x-ray may be helpful to rule out intestinal obstruction.
## Echocardiography or Ultrasound
Abdominal/Pelvic Ultrasound to look for ascites and rule out ovarian cancer.
## CT scan
There are no CT scan findings associated with bloating. However, it can be used to rule out intestinal obstruction.
## MRI
There are no MRI findings associated with bloating.
## Other Imaging Findings
### Upper GI Endoscopy
The presence of alarm features including weight loss, abdominal pain, dysphagia, heartburn, and regurgitation are an indication for a diagnostic evaluation with upper endoscopy.
## Other Diagnostic Studies
There are no other diagnostic studies associated with bloating.
# Treatment
## Medical Therapy
### Education, treatment of associated disorders, and behavioral therapy
Management requires instruction to minimize air swallowing and reassurance that belching is a benign condition. Relevant behavioural interventions include the avoidance of gum chewing, smoking, consuming carbonated drinks, and gulping of food and liquids. Treatment should be started in people with persistent depression or anxiety.[22] Patients with co-existing acid reflux may need an acid reduction treatment for the control of GERD.
Effective management with excessive belching by a therapist (e.g. cognitive behavioral therapy or speech therapist)[23] with specific experience of diaphragmatic relaxation exercises has been linked with a decrease of symptoms. Diaphragmatic breathing decreases postprandial intragastric pressure and raises the pressure of the esophagogastric junction region, restoring the gradient of the gastroesophageal pressure.
### Reflux inhibitors for refractory symptoms
Baclofen 10 mg three times daily can be prescribed to reduce transient lower esophageal sphincter relaxations and centrally suppress the swallowing rate, and may decrease both supragastric and gastric belching.[24]
## Surgery
Surgical intervention is not recommended for the management of bloating.
## Primary Prevention
There are no established measures for the primary prevention of bloating.
## Secondary Prevention
There are no established measures for the secondary prevention of bloating. | https://www.wikidoc.org/index.php/Bloating | |
9e87899f68c5bf0b6a41818493891fbc1124e4d4 | wikidoc | Thrombus | Thrombus
Synonyms and keywords: Thrombosis
# Overview
A thrombus, or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system (i.e. clotting factors). A thrombus is physiologic in cases of injury, but pathologic in case of thrombosis.
# Causes
- Drugs
Desogestrel and Ethinyl Estradiol
Tranexamic acid
- Desogestrel and Ethinyl Estradiol
- Tranexamic acid
# Pathophysiology
Specifically, a thrombus is a blood clot in an intact blood vessel. A thrombus in a large blood vessel will decrease blood flow through that vessel. In a small blood vessel, blood flow may be completely cut-off resulting in death of tissue supplied by that vessel. If a thrombus dislodges and becomes free-floating, it is an embolus.
Some of the conditions which elevate risk of blood clots developing include atrial fibrillation (a form of cardiac arrhythmia), heart valve replacement, a recent heart attack, extended periods of inactivity (see deep venous thrombosis), and genetic or disease-related deficiencies in the blood's clotting abilities.
Preventing blood clots reduces the risk of stroke, heart attack and pulmonary embolism. Heparin and warfarin are often used to inhibit the formation and growth of existing blood clots, thereby allowing the body to shrink and dissolve the blood clots through normal methods (see anticoagulant).
A thrombus differs from a hematoma by:
- Having high hematocrit
- Being non-laminar
- Being soft and friable
- Having an absence of circulation
### Virchow's Triad
Virchow's Triad describes the conditions necessary for thrombus formation:
- Changes in vessel wall morphology (e.g. trauma, atheroma)
- Changes in blood flow through the vessel (e.g. valvulitis, aneurysm)
- Changes in blood composition (e.g. leukaemia, hypercoagulability disorders)
Disseminated intravascular coagulation (DIC) involves widespread microthrombi formation throughout the majority of the blood vessels. This is due to excessive consumption of coagulation factors and fibrinolysis using all of the body's available platelets and clotting factors. The end result is ischaemic necrosis of the affected tissue/organs and spontaneous bleeding due to the lack of clotting factors. Causes are septicaemia, acute leukaemia, shock, snake bites or severe trauma. Treatment involves the use of fresh, frozen plasma to restore the level of clotting factors in the blood.
### Thrombogenecity
Thrombogenicity refers to the tendency of a material in contact with the blood to produce a thrombus, or clot. It not only refers to fixed thrombi but also to emboli, thrombi which have become detached and travel through the bloodstream. Thrombogenicity can also encompass events such as the activation of immune pathways and the complement system. All materials are considered to be thrombogenic with the exception of the endothelial cells which line the vasculature. Certain medical implants appear non-thrombogenic due to high flow rates of blood past the implant, but in reality all are thrombogenic to a degree.
A thrombogenic implant will eventually be covered by a fibrous capsule, the thickness of this capsule can be considered one measure of thrombogenicity, and if extreme can lead to the failure of the implant.
### Arterial thrombus
The pathogenic process of arterial thrombosis involves the formation of platelet-rich “white clots” after the rupture of atherosclerotic plaques and exposure of procoagulant material such as lipid-rich macrophages (foam cells), collagen, tissue factor, and/or endothelial breach, in a high shear environment. The exposed material come from within the plaque and also from the activation and aggregation of platelets. Platelet accumulation and fibrin deposition cause an occlusive platelet-rich intravascular thrombus. The growing thrombus increases the degree of narrowing, which may result in extremely high shear rates within the stenotic region. This phenomenon is responsible for a turbulent flow which is developed downstream of the stenosis depending on stenosis geometry and location in the vasculature.
### Venous thrombus
The pathophysiology of venous thrombosis or thromboembolism is associated to plasma hypercoagulability triggered by the expression of procoagulant activity, in intact endothelium, from inflammation or reduced/static blood flow resulting in prolonged immobility. Therefore the venous clots are slowly formed involving the formation of fibrin-rich “red clots” which have regions or layers showing substantial erythrocyte incorporation. Finally, the venous thrombi may initiate behind valve pockets, in which the reduced or static flow decreases wall shear stress that normally regulates endothelial cell phenotype. Thus, this phenomenum makes the venous endotelium more likely to develop inappropriate expression of intravascular procoagulant activity and so to trigger venous thromboembolism.
# Clinical Significance
### Arterial Thrombosis
- Acute ischemic stroke
- Myocardial infarction
### Venous Thrombosis
- Atrial fibrillation
- Budd-Chiari syndrome
- Cerebral venous sinus thrombosis
- Deep vein thrombosis
- Jugular vein thrombosis
- Mesenteric ischemia
- Paget-Schroetter disease
- Portal vein thrombosis
- Pulmonary embolism
- Renal vein thrombosis
# Treatment
Thrombolysis is the breakdown of blood clots. It is colloquially referred to as clot busting for this reason. It works by stimulating fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator, the protein that normally activates plasmin. | Thrombus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vanessa Cherniauskas, M.D. [2]
Synonyms and keywords: Thrombosis
# Overview
A thrombus, or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system (i.e. clotting factors). A thrombus is physiologic in cases of injury, but pathologic in case of thrombosis.
# Causes
- Drugs
Desogestrel and Ethinyl Estradiol
Tranexamic acid
- Desogestrel and Ethinyl Estradiol
- Tranexamic acid
# Pathophysiology
Specifically, a thrombus is a blood clot in an intact blood vessel. A thrombus in a large blood vessel will decrease blood flow through that vessel. In a small blood vessel, blood flow may be completely cut-off resulting in death of tissue supplied by that vessel. If a thrombus dislodges and becomes free-floating, it is an embolus.
Some of the conditions which elevate risk of blood clots developing include atrial fibrillation (a form of cardiac arrhythmia), heart valve replacement, a recent heart attack, extended periods of inactivity (see deep venous thrombosis), and genetic or disease-related deficiencies in the blood's clotting abilities.
Preventing blood clots reduces the risk of stroke, heart attack and pulmonary embolism. Heparin and warfarin are often used to inhibit the formation and growth of existing blood clots, thereby allowing the body to shrink and dissolve the blood clots through normal methods (see anticoagulant).
A thrombus differs from a hematoma by:
- Having high hematocrit
- Being non-laminar
- Being soft and friable
- Having an absence of circulation
### Virchow's Triad
Virchow's Triad describes the conditions necessary for thrombus formation:
- Changes in vessel wall morphology (e.g. trauma, atheroma)
- Changes in blood flow through the vessel (e.g. valvulitis, aneurysm)
- Changes in blood composition (e.g. leukaemia, hypercoagulability disorders)
Disseminated intravascular coagulation (DIC) involves widespread microthrombi formation throughout the majority of the blood vessels. This is due to excessive consumption of coagulation factors and fibrinolysis using all of the body's available platelets and clotting factors. The end result is ischaemic necrosis of the affected tissue/organs and spontaneous bleeding due to the lack of clotting factors. Causes are septicaemia, acute leukaemia, shock, snake bites or severe trauma. Treatment involves the use of fresh, frozen plasma to restore the level of clotting factors in the blood.
### Thrombogenecity
Thrombogenicity refers to the tendency of a material in contact with the blood to produce a thrombus, or clot. It not only refers to fixed thrombi but also to emboli, thrombi which have become detached and travel through the bloodstream. Thrombogenicity can also encompass events such as the activation of immune pathways and the complement system. All materials are considered to be thrombogenic with the exception of the endothelial cells which line the vasculature. Certain medical implants appear non-thrombogenic due to high flow rates of blood past the implant, but in reality all are thrombogenic to a degree.
A thrombogenic implant will eventually be covered by a fibrous capsule, the thickness of this capsule can be considered one measure of thrombogenicity, and if extreme can lead to the failure of the implant.
### Arterial thrombus
The pathogenic process of arterial thrombosis involves the formation of platelet-rich “white clots” after the rupture of atherosclerotic plaques and exposure of procoagulant material such as lipid-rich macrophages (foam cells), collagen, tissue factor, and/or endothelial breach, in a high shear environment. The exposed material come from within the plaque and also from the activation and aggregation of platelets. Platelet accumulation and fibrin deposition cause an occlusive platelet-rich intravascular thrombus. The growing thrombus increases the degree of narrowing, which may result in extremely high shear rates within the stenotic region. This phenomenon is responsible for a turbulent flow which is developed downstream of the stenosis depending on stenosis geometry and location in the vasculature.[1][2]
### Venous thrombus
The pathophysiology of venous thrombosis or thromboembolism is associated to plasma hypercoagulability triggered by the expression of procoagulant activity, in intact endothelium, from inflammation or reduced/static blood flow resulting in prolonged immobility. Therefore the venous clots are slowly formed involving the formation of fibrin-rich “red clots” which have regions or layers showing substantial erythrocyte incorporation. Finally, the venous thrombi may initiate behind valve pockets, in which the reduced or static flow decreases wall shear stress that normally regulates endothelial cell phenotype.[2] Thus, this phenomenum makes the venous endotelium more likely to develop inappropriate expression of intravascular procoagulant activity and so to trigger venous thromboembolism.[3][4]
# Clinical Significance
### Arterial Thrombosis
- Acute ischemic stroke
- Myocardial infarction
### Venous Thrombosis
- Atrial fibrillation
- Budd-Chiari syndrome
- Cerebral venous sinus thrombosis
- Deep vein thrombosis
- Jugular vein thrombosis
- Mesenteric ischemia
- Paget-Schroetter disease
- Portal vein thrombosis
- Pulmonary embolism
- Renal vein thrombosis
# Treatment
Thrombolysis is the breakdown of blood clots. It is colloquially referred to as clot busting for this reason. It works by stimulating fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator, the protein that normally activates plasmin. | https://www.wikidoc.org/index.php/Blood-clot | |
f7639be07c1678c31d73a74f465ee387bd60fb81 | wikidoc | Platelet | Platelet
# Overview
Platelets, or thrombocytes, are the cells circulating in the blood that are involved in the cellular mechanisms of primary hemostasis leading to the formation of blood clots. Dysfunction or low levels of platelets predisposes to bleeding, while high levels, although usually asymptomatic, may increase the risk of thrombosis. An abnormality or disease of the platelets is called a thrombocytopathy.
# Histology
Like red blood cells, platelets in mammals are anuclear (no cell nucleus) and discoid (disc shaped); they measure 1.5–3.0 μm in diameter. The body has a very limited reserve of platelets, so they can be rapidly depleted. They contain RNA, mitochondria, a canalicular system, and several different types of granules: lysosomes (containing acid hydrolases), dense bodies (containing ADP, ATP, serotonin, histamine, and calcium) and alpha granules (containing fibrinogen, factor V, vitronectin, thrombospondin and von Willebrand factor). The contents of the granules are released upon activation of the platelet.
# Production and degradation
Platelets are produced in hematopoiesis by budding off from megakaryocytes. Each megakaryocyte produces 5,000 and 10,000 platelets.
They circulate for approximately one week, and are then destroyed by the spleen and by Kuppfer cells in the liver.
# Function
Functions of Platelets can be generalised into a number of categories:
- Adhesion
- Aggregation
- Clot retraction
- Pro-coagulation
- Cytokine signalling
- Phagocytosis
## Activation
Platelets are activated when brought into contact with collagen (which is exposed when the endothelial blood vessel lining is damaged), thrombin (primarily through PAR-1), ADP receptors (P2Y1 and P2Y12) expressed on platelets, a negatively charged surface (e.g. glass), or several other activating factors. Once activated, they release a number of different coagulation factors and platelet activating factors.
Platelet activation further results in the scramblase-mediated transport of negatively charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase and prothrombinase complexes.
## Adhesion and aggregation
The platelets adhere to each other via adhesion receptors or integrins, and to the endothelial cells in the wall of the blood vessel forming a haemostatic plug in conjunction with fibrin. The high concentration of myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug.
The most abundant platelet adhesion receptor is glycoprotein (GP) IIb/IIIa; this is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin and von Willebrand factor (vWF). Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen).
Platelet aggregation is stimulated by thromboxane and α2 receptor-activation, but inhibited by other inflammatory products like PGI2 and PGD2.
## Cytokine signalling
Besides being the chief cellular effector of hemostasis, platelets are rapidly deployed to sites of injury or infection and potentially modulate inflammatory processes by interacting with leukocytes and by secreting cytokines, chemokines and other inflammatory mediators
It also secretes e.g. platelet-derived growth factor (PDGF).
# Role in disease
## High and low counts
A normal platelet count in a healthy person is between 150,000 and 400,000 per mm³ of blood (150–400 x 109/L). 95% of healthy people will have platelet counts in this range. Some will have statistically abnormal platelet counts while having no abnormality, although the likelihood increases if the platelet count is either very low or very high.
Both thrombocytopenia (or thrombopenia) and thrombocytosis may present with coagulation problems. Generally, low platelet counts increase bleeding risks (although there are exceptions, e.g. immune heparin-induced thrombocytopenia) and thrombocytosis (high counts) may lead to thrombosis (although this is mainly when the elevated count is due to myeloproliferative disorder).
Low platelet counts are generally not corrected by transfusion unless the patient is bleeding or the count has fallen below 5 x 109/L; it is contraindicated in thrombotic thrombocytopenic purpura (TTP) as it fuels the coagulopathy. In patients having surgery, a level below 50 x 109/L) is associated with abnormal surgical bleeding, and regional anaesthetic procedures such as epidurals are avoided for levels below 80-100.
Normal platelet counts are not a guarantee of adequate function. In some states the platelets, while being adequate in number, are dysfunctional. For instance, aspirin irreversibly disrupts platelet function by inhibiting cyclooxygenase-1 (COX1), and hence normal hemostasis; normal platelet function may not return until the aspirin has ceased and all the affected platelets have been replaced by new ones, which can take over a week. Similarly, uremia (a consequence of renal failure) leads to platelet dysfunction that may be ameliorated by the administration of desmopressin.
## Medications
Oral agents, often used to alter/suppress platelet function:
- aspirin
- clopidogrel
- cilostazol
- ticlopidine
Intravenous agents, often used to alter/suppress platelet function:
- abciximab
- eptifibatide
- tirofiban
Drugs that decreased platelets count:
- Artemether and lumefantrin
- Meropenem
## Diseases
Disorders leading to a reduced platelet count:
- Thrombocytopenia
Idiopathic thrombocytopenic purpura - also known as immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura
Drug-induced thrombocytopenia, e.g. heparin-induced thrombocytopenia (HIT)
- Idiopathic thrombocytopenic purpura - also known as immune thrombocytopenic purpura (ITP)
- Thrombotic thrombocytopenic purpura
- Drug-induced thrombocytopenia, e.g. heparin-induced thrombocytopenia (HIT)
- Gaucher's disease
- Aplastic anemia
Alloimmune disorders
- Fetomaternal alloimmune thrombocytopenia
- Some transfusion reactions
Disorders leading to platelet dysfunction or reduced count:
- HELLP syndrome
- Hemolytic-uremic syndrome
- Chemotherapy
- Dengue
- Alpha–Delta platelet storage pool deficiency (αδSPD) is a rare inherited bleeding disorder.
Disorders featuring an elevated count:
- Thrombocytosis, including benign essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease); may feature dysfunctional platelets
Disorders of platelet adhesion or aggregation:
- Bernard-Soulier syndrome
- Glanzmann's thrombasthenia
- Scott's syndrome
- von Willebrand disease
- Hermansky-Pudlak Syndrome
Disorders of platelet metabolism
- Decreased cyclooxygenase activity, induced or congenital
- Storage pool defects, acquired or congenital
Disorders that indirectly compromise platelet function:
- Haemophilia
Disorders in which platelets play a key role:
- Atherosclerosis
- Coronary artery disease, CAD and myocardial infarction, MI
- Cerebrovascular disease and Stroke, CVA (cerebrovascular accident)
- Peripheral artery occlusive disease (PAOD)
- Cancer
# Discovery
Brewer traced the history of the discovery of the platelet. Although red blood cells had been known since van Leeuwenhoek, it was the German anatomist Max Schultze (1825-1874) who first offered a description of the platelet in his newly founded journal Archiv für mikroscopische Anatomie. He describes "spherules" much smaller than red blood cells that are occasionally clumped and may participate in collections of fibrous material. He recommends further study of the findings.
Giulio Bizzozero (1846-1901), building on Schultze's findings, used "living circulation" to study blood cells of amphibians microscopically in vivo. One of his findings was the fact that platelets clump at the site of blood vessel injury, which precedes the formation of a blood clot. This observation confirmed the role of platelets in coagulation.
# Additional images
- Blood cell lineage
# In transfusion medicine
Platelets are either isolated from collected units of Whole Blood and pooled to make a therapeutic dose or collected by Apheresis, sometimes concurrently with Plasma or Red Blood Cells. The industry standard is for platelets to be tested for bacteria before transfusion to avoid septic reactions, which can be fatal.
Pooled Whole Blood Platelets, sometimes called "random" platelets, are made by taking a unit of Whole Blood from a donor that has not been cooled and placing it into a large centrifuge in what is referred to as a "soft spin." This splits the blood into three layers: the plasma, a "buffy coat" layer which includes the platelets, and the red blood cells. These are expressed into different bags for storage. From four to six of these are typically pooled into a single bag for a therapeutic dose, though individual components can also be used.
Apheresis Platelets are collected using a device which draws blood from the donor and centrifuges the collected blood to separate out the platelets and other components to be collected. The remaining blood is returned to the donor. The advantage to this method is that a single donation provides at least one therapeutic dose, as opposed to the multiple donations for Whole Blood Platelets. This means that a recipient is not exposed to as many different donors and has less risk of transfusion transmitted disease and other complications. Sometimes a person such as a cancer patient who requires routine transfusions of platelets will receive repeated donations from a specific donor to further minimize the risk.
Platelets are not crossmatched unless they contain a significant amount of RBCs, which results in a reddish-orange color to the product. This is usually associated with whole blood platelets, as apheresis methods are more efficient than "soft spin" centrifugation at isolating the specific components of blood. An effort is usually made to issue type specific platelets, but this is not as critical as it is with Red Blood Cells.
Platelets collected by either method have a very short shelf life, typically five or seven days depending on the system used. This results in frequent problems with short supply, as testing the donations often uses up a full day of this time. Since there are no effective preservative solutions for platelets, they lose potency quickly and are best when fresh.
Platelets, either apheresis or random donor platelets, can be processed through a volume reduction process. In this process, the platelets are spun in a centrifuge and the excess plasma is removed, leaving 10 to 100 ml of platelet concentrate. Volume reduced platelets are normally only transfused to neonatal and pediatric patients when a large volume of plasma could overload the child's small circulatory system. The lower volume of plasma also reduces the chances of an adverse transfusion reaction to plasma protiens. Volume reduced platelets have a shelf life of only four hours. | Platelet
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Platelets, or thrombocytes, are the cells circulating in the blood that are involved in the cellular mechanisms of primary hemostasis leading to the formation of blood clots. Dysfunction or low levels of platelets predisposes to bleeding, while high levels, although usually asymptomatic, may increase the risk of thrombosis. An abnormality or disease of the platelets is called a thrombocytopathy.
# Histology
Like red blood cells, platelets in mammals are anuclear (no cell nucleus) and discoid (disc shaped); they measure 1.5–3.0 μm in diameter. The body has a very limited reserve of platelets, so they can be rapidly depleted. They contain RNA, mitochondria, a canalicular system, and several different types of granules: lysosomes (containing acid hydrolases), dense bodies (containing ADP, ATP, serotonin, histamine, and calcium) and alpha granules (containing fibrinogen, factor V, vitronectin, thrombospondin and von Willebrand factor). The contents of the granules are released upon activation of the platelet.
# Production and degradation
Platelets are produced in hematopoiesis by budding off from megakaryocytes. Each megakaryocyte produces 5,000 and 10,000 platelets.
They circulate for approximately one week, and are then destroyed by the spleen and by Kuppfer cells in the liver.
# Function
Functions of Platelets can be generalised into a number of categories:
- Adhesion
- Aggregation
- Clot retraction
- Pro-coagulation
- Cytokine signalling
- Phagocytosis[1]
## Activation
Platelets are activated when brought into contact with collagen (which is exposed when the endothelial blood vessel lining is damaged), thrombin (primarily through PAR-1), ADP receptors (P2Y1 and P2Y12) expressed on platelets, a negatively charged surface (e.g. glass), or several other activating factors. Once activated, they release a number of different coagulation factors and platelet activating factors.
Platelet activation further results in the scramblase-mediated transport of negatively charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase and prothrombinase complexes.
## Adhesion and aggregation
The platelets adhere to each other via adhesion receptors or integrins, and to the endothelial cells in the wall of the blood vessel forming a haemostatic plug in conjunction with fibrin. The high concentration of myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug.
The most abundant platelet adhesion receptor is glycoprotein (GP) IIb/IIIa; this is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin and von Willebrand factor (vWF). Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen).
Platelet aggregation is stimulated by thromboxane and α2 receptor-activation, but inhibited by other inflammatory products like PGI2 and PGD2.
## Cytokine signalling
Besides being the chief cellular effector of hemostasis, platelets are rapidly deployed to sites of injury or infection and potentially modulate inflammatory processes by interacting with leukocytes and by secreting cytokines, chemokines and other inflammatory mediators[2]
[3]
[4]
[5].
It also secretes e.g. platelet-derived growth factor (PDGF).
# Role in disease
## High and low counts
A normal platelet count in a healthy person is between 150,000 and 400,000 per mm³ of blood (150–400 x 109/L). 95% of healthy people will have platelet counts in this range. Some will have statistically abnormal platelet counts while having no abnormality, although the likelihood increases if the platelet count is either very low or very high.
Both thrombocytopenia (or thrombopenia) and thrombocytosis may present with coagulation problems. Generally, low platelet counts increase bleeding risks (although there are exceptions, e.g. immune heparin-induced thrombocytopenia) and thrombocytosis (high counts) may lead to thrombosis (although this is mainly when the elevated count is due to myeloproliferative disorder).
Low platelet counts are generally not corrected by transfusion unless the patient is bleeding or the count has fallen below 5 x 109/L; it is contraindicated in thrombotic thrombocytopenic purpura (TTP) as it fuels the coagulopathy. In patients having surgery, a level below 50 x 109/L) is associated with abnormal surgical bleeding, and regional anaesthetic procedures such as epidurals are avoided for levels below 80-100.
Normal platelet counts are not a guarantee of adequate function. In some states the platelets, while being adequate in number, are dysfunctional. For instance, aspirin irreversibly disrupts platelet function by inhibiting cyclooxygenase-1 (COX1), and hence normal hemostasis; normal platelet function may not return until the aspirin has ceased and all the affected platelets have been replaced by new ones, which can take over a week. Similarly, uremia (a consequence of renal failure) leads to platelet dysfunction that may be ameliorated by the administration of desmopressin.
## Medications
Oral agents, often used to alter/suppress platelet function:
- aspirin
- clopidogrel
- cilostazol
- ticlopidine
Intravenous agents, often used to alter/suppress platelet function:
- abciximab
- eptifibatide
- tirofiban
Drugs that decreased platelets count:
- Artemether and lumefantrin
- Meropenem
## Diseases
Disorders leading to a reduced platelet count:
- Thrombocytopenia
Idiopathic thrombocytopenic purpura - also known as immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura
Drug-induced thrombocytopenia, e.g. heparin-induced thrombocytopenia (HIT)
- Idiopathic thrombocytopenic purpura - also known as immune thrombocytopenic purpura (ITP)
- Thrombotic thrombocytopenic purpura
- Drug-induced thrombocytopenia, e.g. heparin-induced thrombocytopenia (HIT)
- Gaucher's disease
- Aplastic anemia
Alloimmune disorders
- Fetomaternal alloimmune thrombocytopenia
- Some transfusion reactions
Disorders leading to platelet dysfunction or reduced count:
- HELLP syndrome
- Hemolytic-uremic syndrome
- Chemotherapy
- Dengue
- Alpha–Delta platelet storage pool deficiency (αδSPD) is a rare inherited bleeding disorder.[6]
Disorders featuring an elevated count:
- Thrombocytosis, including benign essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease); may feature dysfunctional platelets
Disorders of platelet adhesion or aggregation:
- Bernard-Soulier syndrome
- Glanzmann's thrombasthenia
- Scott's syndrome
- von Willebrand disease
- Hermansky-Pudlak Syndrome
Disorders of platelet metabolism
- Decreased cyclooxygenase activity, induced or congenital
- Storage pool defects, acquired or congenital
Disorders that indirectly compromise platelet function:
- Haemophilia
Disorders in which platelets play a key role:
- Atherosclerosis
- Coronary artery disease, CAD and myocardial infarction, MI
- Cerebrovascular disease and Stroke, CVA (cerebrovascular accident)
- Peripheral artery occlusive disease (PAOD)
- Cancer [7]
# Discovery
Brewer[8] traced the history of the discovery of the platelet. Although red blood cells had been known since van Leeuwenhoek, it was the German anatomist Max Schultze (1825-1874) who first offered a description of the platelet in his newly founded journal Archiv für mikroscopische Anatomie[9]. He describes "spherules" much smaller than red blood cells that are occasionally clumped and may participate in collections of fibrous material. He recommends further study of the findings.
Giulio Bizzozero (1846-1901), building on Schultze's findings, used "living circulation" to study blood cells of amphibians microscopically in vivo. One of his findings was the fact that platelets clump at the site of blood vessel injury, which precedes the formation of a blood clot. This observation confirmed the role of platelets in coagulation[10].
# Additional images
- Blood cell lineage
# In transfusion medicine
Platelets are either isolated from collected units of Whole Blood and pooled to make a therapeutic dose or collected by Apheresis, sometimes concurrently with Plasma or Red Blood Cells. The industry standard is for platelets to be tested for bacteria before transfusion to avoid septic reactions, which can be fatal.
Pooled Whole Blood Platelets, sometimes called "random" platelets, are made by taking a unit of Whole Blood from a donor that has not been cooled and placing it into a large centrifuge in what is referred to as a "soft spin." This splits the blood into three layers: the plasma, a "buffy coat" layer which includes the platelets, and the red blood cells. These are expressed into different bags for storage. From four to six of these are typically pooled into a single bag for a therapeutic dose, though individual components can also be used.
Apheresis Platelets are collected using a device which draws blood from the donor and centrifuges the collected blood to separate out the platelets and other components to be collected. The remaining blood is returned to the donor. The advantage to this method is that a single donation provides at least one therapeutic dose, as opposed to the multiple donations for Whole Blood Platelets. This means that a recipient is not exposed to as many different donors and has less risk of transfusion transmitted disease and other complications. Sometimes a person such as a cancer patient who requires routine transfusions of platelets will receive repeated donations from a specific donor to further minimize the risk.
Platelets are not crossmatched unless they contain a significant amount of RBCs, which results in a reddish-orange color to the product. This is usually associated with whole blood platelets, as apheresis methods are more efficient than "soft spin" centrifugation at isolating the specific components of blood. An effort is usually made to issue type specific platelets, but this is not as critical as it is with Red Blood Cells.
Platelets collected by either method have a very short shelf life, typically five or seven days depending on the system used. This results in frequent problems with short supply, as testing the donations often uses up a full day of this time. Since there are no effective preservative solutions for platelets, they lose potency quickly and are best when fresh.
Platelets, either apheresis or random donor platelets, can be processed through a volume reduction process. In this process, the platelets are spun in a centrifuge and the excess plasma is removed, leaving 10 to 100 ml of platelet concentrate. Volume reduced platelets are normally only transfused to neonatal and pediatric patients when a large volume of plasma could overload the child's small circulatory system. The lower volume of plasma also reduces the chances of an adverse transfusion reaction to plasma protiens.[11] Volume reduced platelets have a shelf life of only four hours.[12] | https://www.wikidoc.org/index.php/Blood_platelet | |
7c89f57254ae7fba18973c13083b96a0753eb310 | wikidoc | Heredity | Heredity
# Overview
Heredity (the adjective is hereditary) is the transfer of characteristics from parent to offspring through their genes, or the transfer of a title, style or social status through the social convention known as inheritance (for example, a Hereditary Title may be passed down according to relevant customs and/or laws).
It was apparent to ancient humans that offsprings resembled their parents. For example, Genesis 30-46 tells how Jacob and Labans split their sheep into white and speckled varieties so they could distinguish the two to ensure none were later stolen. Although it was clear that traits were hereditary, the precise mechanism of heredity was not clear.
# Ancient Concepts of Heredity
The Greek philosophers had a variety of ideas about heredity: Theophrastus proposed that male flowers caused female flowers to ripen; Hippocrates speculated that "seeds" were produced by various body parts and transmitted to offspring at the time of conception, and Aristotle thought that male and female semen mixed at conception. Aeschylus, in 458 BC, proposed the male as the parent, with the female as a "nurse for the young life sown within her".
Various hereditary mechanisms were envisaged without being properly tested or quantified. These included blending inheritance and the inheritance of acquired traits. Nevertheless, people were able to develop domestic breeds of animals as well as crops through artificial selection. The inheritance of acquired traits also formed a part of early Lamarckian ideas on evolution.
During the 1700s, Dutch microscopist Antoine van Leeuwenhoek (1632-1723) discovered "animalcules" in the sperm of humans and other animals. Some scientists speculated they saw a "little man" (homunculus) inside each sperm. These scientists formed a school of thought known as the "spermists". They contended the only contributions of the female to the next generation were the womb in which the homunculus grew, and prenatal influences of the womb. An opposing school of thought, the ovists, believed that the future human was in the egg, and that sperm merely stimulated the growth of the egg. Ovists thought women carried eggs containing boy and girl children, and that the gender of the offspring was determined well before conception.
Pangenesis was an idea that males and females formed "pangenes" in every organ. These pangenes subsequently moved through their blood to the genitals and then to the children. The concept originated with the ancient Greeks and influenced biology until little over 100 years ago. The terms "blood relative", "full-blooded", and "royal blood" are relicts of pangenesis. Francis Galton, Charles Darwin's cousin, experimentally tested and disproved pangenesis during the 1870s.
# Charles Darwin: Theory of Evolution
Charles Darwin proposed a theory of evolution in 1859 and one of its major problems was the lack of an underlying mechanism for heredity. Darwin believed in a mix of blending inheritance and the inheritance of acquired traits (pangenesis). Blending inheritance would lead to uniformity across populations in only a few generations and thus would remove variation from a population on which natural selection could act. This led to Darwin adopting some Lamarckian ideas in later editions of The Origin and his later biological works. Darwin's primary approach to heredity was to outline how it appeared to work (noticing that traits could be inherited which were not expressed explicitly in the parent at the time of reproduction, that certain traits could be sex-linked, etc.) rather than suggesting mechanisms.
Darwin's initial model of heredity was adopted by, and then heavily modified by, his cousin Francis Galton, who laid the framework for the biometric school of heredity. Galton rejected the aspects of Darwin's pangenesis model which relied on acquired traits.
The inheritance of acquired traits was shown to have little basis in the 1880s when August Weismann cut the tails off many generations of mice to find that their offspring did continue to develop tails.
# Gregor Mendel: Father of Modern Genetics
The idea of particulate inheritance of genes can be attributed to the Moravian monk Gregor Mendel who published his work on pea plants in 1865. However, his work was not widely known and was rediscovered in 1901. It was initially assumed the Mendelian inheritance only accounted for large (qualitative) differences, such as those seen by Mendel in his pea plants — and the idea of additive effect of (quantitative) genes was not realised until R.A. Fisher's (1918) paper on The Correlation Between Relatives on the Supposition of Mendelian Inheritance. For the subsequent history of genetics, see history of genetics.
# Modern Development of Genetics and Heredity
In the 1930s, work by Fisher and others resulted in a combination of Mendelian and biometric schools into the modern synthesis of evolution.
Trofim Lysenko however caused a backlash of what is now called Lysenkoism in the Soviet Union when he emphasised Lamarckian ideas on the inheritance of acquired traits. This movement affected agricultural research and led to food shortages in the 1960s and seriously affected the USSR.
The social institution is called inheritance. One's bloodline is one's familial ancestry.
A few countries still award places in their legislatures according to the hereditary principle, including the small African kingdom of Lesotho (Senate includes traditional chiefs) and the United Kingdom (House of Lords includes 92 hereditary lords). But on 7 March 2007, Members of the elected British House of Commons finally voted to abolish the herditary principle altogether and move to a wholly elected second chamber. This will take some years to implement. | Heredity
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Heredity (the adjective is hereditary) is the transfer of characteristics from parent to offspring through their genes, or the transfer of a title, style or social status through the social convention known as inheritance (for example, a Hereditary Title may be passed down according to relevant customs and/or laws).
It was apparent to ancient humans that offsprings resembled their parents. For example, Genesis 30-46 tells how Jacob and Labans split their sheep into white and speckled varieties so they could distinguish the two to ensure none were later stolen. Although it was clear that traits were hereditary, the precise mechanism of heredity was not clear.
# Ancient Concepts of Heredity
The Greek philosophers had a variety of ideas about heredity: Theophrastus proposed that male flowers caused female flowers to ripen; Hippocrates speculated that "seeds" were produced by various body parts and transmitted to offspring at the time of conception, and Aristotle thought that male and female semen mixed at conception. Aeschylus, in 458 BC, proposed the male as the parent, with the female as a "nurse for the young life sown within her".
Various hereditary mechanisms were envisaged without being properly tested or quantified. These included blending inheritance and the inheritance of acquired traits. Nevertheless, people were able to develop domestic breeds of animals as well as crops through artificial selection. The inheritance of acquired traits also formed a part of early Lamarckian ideas on evolution.
During the 1700s, Dutch microscopist Antoine van Leeuwenhoek (1632-1723) discovered "animalcules" in the sperm of humans and other animals. Some scientists speculated they saw a "little man" (homunculus) inside each sperm. These scientists formed a school of thought known as the "spermists". They contended the only contributions of the female to the next generation were the womb in which the homunculus grew, and prenatal influences of the womb. An opposing school of thought, the ovists, believed that the future human was in the egg, and that sperm merely stimulated the growth of the egg. Ovists thought women carried eggs containing boy and girl children, and that the gender of the offspring was determined well before conception.
Pangenesis was an idea that males and females formed "pangenes" in every organ. These pangenes subsequently moved through their blood to the genitals and then to the children. The concept originated with the ancient Greeks and influenced biology until little over 100 years ago. The terms "blood relative", "full-blooded", and "royal blood" are relicts of pangenesis. Francis Galton, Charles Darwin's cousin, experimentally tested and disproved pangenesis during the 1870s.
# Charles Darwin: Theory of Evolution
Charles Darwin proposed a theory of evolution in 1859 and one of its major problems was the lack of an underlying mechanism for heredity. Darwin believed in a mix of blending inheritance and the inheritance of acquired traits (pangenesis). Blending inheritance would lead to uniformity across populations in only a few generations and thus would remove variation from a population on which natural selection could act. This led to Darwin adopting some Lamarckian ideas in later editions of The Origin and his later biological works. Darwin's primary approach to heredity was to outline how it appeared to work (noticing that traits could be inherited which were not expressed explicitly in the parent at the time of reproduction, that certain traits could be sex-linked, etc.) rather than suggesting mechanisms.
Darwin's initial model of heredity was adopted by, and then heavily modified by, his cousin Francis Galton, who laid the framework for the biometric school of heredity. Galton rejected the aspects of Darwin's pangenesis model which relied on acquired traits.
The inheritance of acquired traits was shown to have little basis in the 1880s when August Weismann cut the tails off many generations of mice to find that their offspring did continue to develop tails.
# Gregor Mendel: Father of Modern Genetics
The idea of particulate inheritance of genes can be attributed to the Moravian[1] monk Gregor Mendel who published his work on pea plants in 1865. However, his work was not widely known and was rediscovered in 1901. It was initially assumed the Mendelian inheritance only accounted for large (qualitative) differences, such as those seen by Mendel in his pea plants — and the idea of additive effect of (quantitative) genes was not realised until R.A. Fisher's (1918) paper on The Correlation Between Relatives on the Supposition of Mendelian Inheritance. For the subsequent history of genetics, see history of genetics.
# Modern Development of Genetics and Heredity
In the 1930s, work by Fisher and others resulted in a combination of Mendelian and biometric schools into the modern synthesis of evolution.
Trofim Lysenko however caused a backlash of what is now called Lysenkoism in the Soviet Union when he emphasised Lamarckian ideas on the inheritance of acquired traits. This movement affected agricultural research and led to food shortages in the 1960s and seriously affected the USSR.
The social institution is called inheritance. One's bloodline is one's familial ancestry.
A few countries still award places in their legislatures according to the hereditary principle, including the small African kingdom of Lesotho (Senate includes traditional chiefs) and the United Kingdom (House of Lords includes 92 hereditary lords). But on 7 March 2007, Members of the elected British House of Commons finally voted to abolish the herditary principle altogether and move to a wholly elected second chamber. This will take some years to implement. | https://www.wikidoc.org/index.php/Bloodline | |
e6e329ae45c674ef1bc294164c474da2623137a2 | wikidoc | Blushing | Blushing
To blush is to display redness in one's face; the term is seldom applied except when the redness is construed as a result of embarrassment, shame, or modesty. Blushing is generally distinguished, despite a close physiological relation, from flushing, which is more intensive and extends over more of the body, and seldom has a mental source.
If redness persists for abnormal amounts of time after blushing, then it may be considered an early sign of rosacea.
A medical condition known as Idiopathic craniofacial erythema exists, in which the sufferer blushes strongly with little or no provocation.
Erythrophobia (literally "fear of redness") refers to pathological blushing.
# Physiological anatomy of the cutaneous blood circulation in humans
The function of cutaneous blood flow is nutrition of the skin and regulation of body heat. The higher the cutaneous blood flow, the more heat radiates. Restriction of cutaneous blood flow curtails the loss of body heat, which is important in a cold environment. The circulatory system of the skin contains three major types of blood vessels that enable it to fulfill these two important functions. The first type are arteries, capillaries, and veins that serve mainly nutrition needs. The second type is the subcutaneous venous plexus that plays a major role in the conduction of heat, and contains a major fraction of the cutaneous blood volume. The third type are arteriovenous anastomoses which can be found in areas of the body especially exposed to maximal cooling like the hands, feet, nose, lips and ears. These areas are called apical structures and are richly innervated. The anastomoses connect cutaneous arterioles and venules directly, playing an important role in the reduction of blood flow in a cold environment (Rowell. 1993; Guyton. 1981; Rowell. 1974).
# Regulation of blood flow in the skin
Blood flow in the cutaneous resistance vessels and the subcutaneous venous plexus are both neurally and locally regulated. However, there are some important differences. One is, that cutaneous resistance vessels exhibit a basal tone independently of innervation in reaction to passive stretch induced by blood pressure (Rowell. 1974). This intrinsic basal tone is normally absent in cutaneous capacitance vessels .
Along with this basal tone, all resistance vessels in the skin receive a tonic outflow from sympathetic vasoconstrictor fibers. This tonic outflow is inversely associated with body temperature. Vasodilation therefore occurs passively in resistance vessels the (alpha-adrenergic) vasoconstrictor tone decreases. Furthermore, an active neurogenic vasodilation must be assumed in the human skin. However, it is not clear if this vasodilation is mediated by specific vasodilator nerve fibers or if neuro-humoral effects are involved that are associated with the sympathetic cholinergic activation of sweat glands (Rowell. 1993; Lembeck & Holzbauer. 1988). Although some experiments lead to the conclusion that sympathetic outflow is involved in facial vasodilation (Drummond & Lance. 1987), 40 years of research have not clarified the mechanism behind active vasodilation.
Cutaneous veins also are richly innervated with sympathetic vasoconstrictor fibers. The effect of activation of the outflow of these fibers is reduced by local cooling. In addition, cutaneous veins are temporarily reactive to various other stimuli. Each of the following can cause remarkably intense venoconstriction without obvious value to the organism: emotional stimuli (e.g. startle, apprehension, discomfort), hyperventilation, deep inspiration, and the Valsalva maneuver (Rowell. 1974).
In resistance vessels, increased pressure mainly increases flow per time unit. In the cutaneous venous plexus with its generally slow flow rate, pressure mainly influences volume. Because of its enormous volume variability and its large potential capacity the venous plexus is believed to determine skin color (Rowell. 1993; Mellander, Andersson, Afzelius, & Hellstrand. 1982; Rowell. 1974). Since pronounced blushing is also characterized by a deep reddening of the skin, vasodilation of the venous plexus is probably the physical mechanism underlying it. But why is emotional blushing only visible or apparent in a specific area called the blush region? That area is restricted to the face, ears, neck, and in some rare cases the upper body. Two main hypotheses to explain this regional restriction have been proposed. One is that vasodilation takes place throughout the entire skin of the body but is only visible in the blush region due to special anatomical structure of that region. The second is that a specific form of vasodilation takes place exclusively in the blush region. It is likely, that a combination of these two factors accounts for blushing.
# Physiology of blushing
There is evidence that the blushing region is anatomically different in structure. The facial skin, for example, has more capillary loops per square millimeter and generally more vessels per unit volume than other skin areas. In addition, blood vessels of the cheek are wider in diameter, are nearer the surface, and visibility is less diminished by tissue fluid. These specific characteristics of the architecture of the facial vessels led Wilkin in an overview of possible causes of facial flushing to the following conclusion: " increased capacity and greater visibility can account for the limited distribution of flushing" (Wilkin. 1988).
Evidence for special vasodilation mechanisms was reported by Mellander and his colleagues (Mellander, Andersson, Afzelius, & Hellstrand. 1982). They studied buccal segments of the human facial veins in vitro. Unlike veins from other areas of the skin, facial veins responded with an active myogenic contraction to passive stretch and were therefore able to develop an intrinsic basal tone. Additionally Mellander et al. showed that the veins in this specific area were also supplied with beta-adrenoceptors in addition to the common alpha-adrenoceptors. These beta-adrenoceptors could exert a dilator mechanism on the above-described basal tone of the facial cutaneous venous plexus. Mellander and his colleagues propose that this mechanism is involved in emotional blushing. Drummond has partially confirmed this effect by pharmacological blocking experiments (Drummond. 1997). In a number of trials, he blocked both alpha-adrenergic receptors (with phentolamine) and beta-adrenergic receptors (with propranolol introduced
transcutaneously by iontophoresis). Blushing was measured at the forehead using a dual channel laser Doppler flowmeter. Subjects were undergraduate students divided into frequent and infrequent blushers according to self-report. Their mean age was 22.9 years, which is especially favorable for assessing blushing, since young subjects are more likely to blush and blush more intensively. The subjects underwent several procedures, one of which was designed to produce blushing. Alpha-adrenergic blockade with phentolamine had no influence on the amount of blushing in frequent or in infrequent blushers, indicating that release of sympathetic vasoconstrictor tone does not substantially influence blushing. This result was expected since vasoconstrictor tone in the facial area is known to be generally low (van der Meer. 1985). Beta-adrenergic blockade with propranolol on the other hand decreased blushing in both frequent and infrequent blushers. However, despite complete blockade, blood flow still increased
substantially during the embarrassment and blushing inducing procedure. Additional vasodilator mechanisms must therefore be involved. So far, no specific mechanism has been suggested. | Blushing
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
To blush is to display redness in one's face; the term is seldom applied except when the redness is construed as a result of embarrassment, shame, or modesty. Blushing is generally distinguished, despite a close physiological relation, from flushing, which is more intensive and extends over more of the body, and seldom has a mental source.
If redness persists for abnormal amounts of time after blushing, then it may be considered an early sign of rosacea.
A medical condition known as Idiopathic craniofacial erythema exists, in which the sufferer blushes strongly with little or no provocation.
Erythrophobia (literally "fear of redness") refers to pathological blushing.
# Physiological anatomy of the cutaneous blood circulation in humans
The function of cutaneous blood flow is nutrition of the skin and regulation of body heat. The higher the cutaneous blood flow, the more heat radiates. Restriction of cutaneous blood flow curtails the loss of body heat, which is important in a cold environment. The circulatory system of the skin contains three major types of blood vessels that enable it to fulfill these two important functions. The first type are arteries, capillaries, and veins that serve mainly nutrition needs. The second type is the subcutaneous venous plexus that plays a major role in the conduction of heat, and contains a major fraction of the cutaneous blood volume. The third type are arteriovenous anastomoses which can be found in areas of the body especially exposed to maximal cooling like the hands, feet, nose, lips and ears. These areas are called apical structures and are richly innervated. The anastomoses connect cutaneous arterioles and venules directly, playing an important role in the reduction of blood flow in a cold environment (Rowell. 1993; Guyton. 1981; Rowell. 1974).
# Regulation of blood flow in the skin
Blood flow in the cutaneous resistance vessels and the subcutaneous venous plexus are both neurally and locally regulated. However, there are some important differences. One is, that cutaneous resistance vessels exhibit a basal tone independently of innervation in reaction to passive stretch induced by blood pressure (Rowell. 1974). This intrinsic basal tone is normally absent in cutaneous capacitance vessels .
Along with this basal tone, all resistance vessels in the skin receive a tonic outflow from sympathetic vasoconstrictor fibers. This tonic outflow is inversely associated with body temperature. Vasodilation therefore occurs passively in resistance vessels the (alpha-adrenergic) vasoconstrictor tone decreases. Furthermore, an active neurogenic vasodilation must be assumed in the human skin. However, it is not clear if this vasodilation is mediated by specific vasodilator nerve fibers or if neuro-humoral effects are involved that are associated with the sympathetic cholinergic activation of sweat glands (Rowell. 1993; Lembeck & Holzbauer. 1988). Although some experiments lead to the conclusion that sympathetic outflow is involved in facial vasodilation (Drummond & Lance. 1987), 40 years of research have not clarified the mechanism behind active vasodilation.
Cutaneous veins also are richly innervated with sympathetic vasoconstrictor fibers. The effect of activation of the outflow of these fibers is reduced by local cooling. In addition, cutaneous veins are temporarily reactive to various other stimuli. Each of the following can cause remarkably intense venoconstriction without obvious value to the organism: emotional stimuli (e.g. startle, apprehension, discomfort), hyperventilation, deep inspiration, and the Valsalva maneuver (Rowell. 1974).
In resistance vessels, increased pressure mainly increases flow per time unit. In the cutaneous venous plexus with its generally slow flow rate, pressure mainly influences volume. Because of its enormous volume variability and its large potential capacity the venous plexus is believed to determine skin color (Rowell. 1993; Mellander, Andersson, Afzelius, & Hellstrand. 1982; Rowell. 1974). Since pronounced blushing is also characterized by a deep reddening of the skin, vasodilation of the venous plexus is probably the physical mechanism underlying it. But why is emotional blushing only visible or apparent in a specific area called the blush region? That area is restricted to the face, ears, neck, and in some rare cases the upper body. Two main hypotheses to explain this regional restriction have been proposed. One is that vasodilation takes place throughout the entire skin of the body but is only visible in the blush region due to special anatomical structure of that region. The second is that a specific form of vasodilation takes place exclusively in the blush region. It is likely, that a combination of these two factors accounts for blushing.
# Physiology of blushing
There is evidence that the blushing region is anatomically different in structure. The facial skin, for example, has more capillary loops per square millimeter and generally more vessels per unit volume than other skin areas. In addition, blood vessels of the cheek are wider in diameter, are nearer the surface, and visibility is less diminished by tissue fluid. These specific characteristics of the architecture of the facial vessels led Wilkin in an overview of possible causes of facial flushing to the following conclusion: "[...] increased capacity and greater visibility can account for the limited distribution of flushing" (Wilkin. 1988).
Evidence for special vasodilation mechanisms was reported by Mellander and his colleagues (Mellander, Andersson, Afzelius, & Hellstrand. 1982). They studied buccal segments of the human facial veins in vitro. Unlike veins from other areas of the skin, facial veins responded with an active myogenic contraction to passive stretch and were therefore able to develop an intrinsic basal tone. Additionally Mellander et al. showed that the veins in this specific area were also supplied with beta-adrenoceptors in addition to the common alpha-adrenoceptors. These beta-adrenoceptors could exert a dilator mechanism on the above-described basal tone of the facial cutaneous venous plexus. Mellander and his colleagues propose that this mechanism is involved in emotional blushing. Drummond has partially confirmed this effect by pharmacological blocking experiments (Drummond. 1997). In a number of trials, he blocked both alpha-adrenergic receptors (with phentolamine) and beta-adrenergic receptors (with propranolol introduced
transcutaneously by iontophoresis). Blushing was measured at the forehead using a dual channel laser Doppler flowmeter. Subjects were undergraduate students divided into frequent and infrequent blushers according to self-report. Their mean age was 22.9 years, which is especially favorable for assessing blushing, since young subjects are more likely to blush and blush more intensively. The subjects underwent several procedures, one of which was designed to produce blushing. Alpha-adrenergic blockade with phentolamine had no influence on the amount of blushing in frequent or in infrequent blushers, indicating that release of sympathetic vasoconstrictor tone does not substantially influence blushing. This result was expected since vasoconstrictor tone in the facial area is known to be generally low (van der Meer. 1985). Beta-adrenergic blockade with propranolol on the other hand decreased blushing in both frequent and infrequent blushers. However, despite complete blockade, blood flow still increased
substantially during the embarrassment and blushing inducing procedure. Additional vasodilator mechanisms must therefore be involved. So far, no specific mechanism has been suggested. | https://www.wikidoc.org/index.php/Blushing | |
61aaa4584107b2273f3cef14dd001e32163015f2 | wikidoc | Body bag | Body bag
A body bag is a non-porous bag designed to contain a human body, used for the storage and transport of corpses. Body bags can also be used for the storage of corpses within morgues. Before purpose-made body bags were available, cotton mattress covers were sometimes used, particularly in combat zones during the Second World War. However, the subsequent rubber (and now plastic) body-bag designs are much superior, not least because they prevent leakage of body fluids, which often occurs after someone dies. The dimensions of a body-bag are generally around 36 inches by 90 inches.
In modern warfare, body bags have been used to contain the bodies of dead soldiers. Governments typically have reserves of body bags, both for anticipated wars and natural disasters. During the Cold War, vast reserves of body bags were built up in anticipation of millions of fatalities from nuclear war. This was the subject of Adrian Mitchell's haunting protest poem "Fifteen Million Plastic Bags".
Body bags are sometimes portrayed in films and television as being made of a heavy black plastic. Lightweight white body bags have since become popular because it is much easier to spot a piece of evidence that may have been jostled from the body in transit on a white background than on a black background. Even so black body-bags are still in general use, as the adjacent photo taken in 2008 shows. Other typical colours include orange, blue, or grey. Regardless of their colour, body bags are made of thick plastic and have a full-length zipper on them. Sometimes the zipper runs straight down the middle. Alternatively, the path of the zipper may be J-shaped or D-shaped. Depending on the design, there are sometimes handles (two on each side) to facilitate lifting. It is possible to write information on the plastic surface of a bodybag using a marker pen, and this often happens - either in situ (particularly when a large number of bodies are being collected) or at the mortuary, before being stored in refrigerated cabinets. Alternatively, some designs of body bag have transparent label pockets as an integral part of the design, into which a name-card can be inserted. In any case, a conventional toe tag can easily be tied to one of the lifting handles if required. Body bags are not designed to be washed and re-used, with good reason: aside from the obvious hygiene concerns, re-use of body bags could easily contaminate evidence in the case of a suspicious death. As a result, body bags are routinely discarded and incinerated after one use.
Although body bags are most often used for the transport of human remains from their place of discovery to a funeral home or mortuary, they can also be used for temporary burials such as in a combat zone. In such situations, proper funerals are impossible due to imminent enemy attack. This was the situation during the Falklands War of 1982, during which British casualties were placed in grey plastic bodybags and then laid in mass graves. Some months after the conflict ended, all remains were exhumed from their temporary graves to receive a conventional funeral service with full military honours.
The term body bag is sometimes used for fashion or other bags worn on the body (sling body bag or across body bag) and this sense has no connection with either of the two above senses. | Body bag
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A body bag is a non-porous bag designed to contain a human body, used for the storage and transport of corpses. Body bags can also be used for the storage of corpses within morgues. Before purpose-made body bags were available, cotton mattress covers were sometimes used, particularly in combat zones during the Second World War. However, the subsequent rubber (and now plastic) body-bag designs are much superior, not least because they prevent leakage of body fluids, which often occurs after someone dies. The dimensions of a body-bag are generally around 36 inches by 90 inches.
In modern warfare, body bags have been used to contain the bodies of dead soldiers. Governments typically have reserves of body bags, both for anticipated wars and natural disasters. During the Cold War, vast reserves of body bags were built up in anticipation of millions of fatalities from nuclear war[citation needed]. This was the subject of Adrian Mitchell's haunting protest poem "Fifteen Million Plastic Bags".
Body bags are sometimes portrayed in films and television as being made of a heavy black plastic. Lightweight white body bags have since become popular because it is much easier to spot a piece of evidence that may have been jostled from the body in transit on a white background than on a black background. Even so black body-bags are still in general use, as the adjacent photo taken in 2008 shows. Other typical colours include orange, blue, or grey. Regardless of their colour, body bags are made of thick plastic and have a full-length zipper on them. Sometimes the zipper runs straight down the middle. Alternatively, the path of the zipper may be J-shaped or D-shaped. Depending on the design, there are sometimes handles (two on each side) to facilitate lifting. It is possible to write information on the plastic surface of a bodybag using a marker pen, and this often happens - either in situ (particularly when a large number of bodies are being collected) or at the mortuary, before being stored in refrigerated cabinets. Alternatively, some designs of body bag have transparent label pockets as an integral part of the design, into which a name-card can be inserted. In any case, a conventional toe tag can easily be tied to one of the lifting handles if required. Body bags are not designed to be washed and re-used, with good reason: aside from the obvious hygiene concerns, re-use of body bags could easily contaminate evidence in the case of a suspicious death. As a result, body bags are routinely discarded and incinerated after one use.
Although body bags are most often used for the transport of human remains from their place of discovery to a funeral home or mortuary, they can also be used for temporary burials such as in a combat zone. In such situations, proper funerals are impossible due to imminent enemy attack. This was the situation during the Falklands War of 1982, during which British casualties were placed in grey plastic bodybags and then laid in mass graves. Some months after the conflict ended, all remains were exhumed from their temporary graves to receive a conventional funeral service with full military honours.
The term body bag is sometimes used for fashion or other bags worn on the body (sling body bag or across body bag) and this sense has no connection with either of the two above senses. | https://www.wikidoc.org/index.php/Body_bag | |
137066aea9653093bd17094ecd6c803da86f8a2b | wikidoc | Bone age | Bone age
# Overview
Bone age is a way of describing the degree of maturation of a child's bones. As a person grows from fetal life through childhood, puberty, and finishes growth as a young adult, the bones of the skeleton change in size and shape. These changes can be seen by x-ray. The "bone age" of a child is the average age at which children reach this stage of bone maturation. A child's current height and bone age can be used to predict adult height.
At birth, only the metaphyses of the "long bones" are present. The long bones are those that grow primarily by elongation at an epiphysis at one end of the growing bone. The long bones include the femurs, tibias, and fibulas of the lower limb, the humeri, radii, and ulnas of the upper limb (arm + forearm), and the phalanges of the fingers and toes. The long bones of the leg comprise nearly half of adult height. The other primary skeletal component of height is the spine and skull.
As a child grows the epiphyses become calcified and appear on the x-rays, as do the carpal and tarsal bones of the hands and feet, separated on the x-rays by a layer of invisible cartilage where most of the growth is occurring. As sex steroid levels rise during puberty, bone maturation accelerates. As growth nears conclusion and attainment of adult height, bones begin to approach the size and shape of adult bones. The remaining cartilaginous portions of the epiphyses become thinner. As these cartilaginous zones become obliterated, the epiphyses are said to be "closed" and no further lengthening of the bones will occur. A small amount of spinal growth concludes an adolescent's growth.
Pediatric endocrinologists are the physicians who most commonly order and interpret bone age x-rays and evaluate children for advanced or delayed growth and physical development.
# Methods
The most commonly used method is based on a single x-ray of the fingers, hand, and wrist. A hand is easily x-rayed with minimal radiation and shows many bones in a single view. The bones in the x-ray are compared to the bones of a standard atlas, usually Greulich and Pyle
Male
- 4y 6m
- 11y 6m
- 13y
- 13y 6m
- 14y
Female
- 2y 6m
- 3yImage:
- 4y 2m
- 4y 6m
- 5y
- 6y 12m
- 8y 10m
- 11y
- 12y
A more complex method also based on hand x-rays is the "TW2" method An atlas based on knee maturation has also been compiled.
The hands of infants do not change much in the first year of life and if precise bone age assessment is desired, an x-ray of approximately half of the skeleton (a "hemiskeleton" view) may be obtained to assess some of the areas such as shoulders and pelvis which change more in infancy.
# Height prediction
Statistics have been compiled to indicate the percentage of height growth remaining at a given bone age. By simple arithmetic, a predicted adult height can be computed from a child's height and bone age. Separate tables are used for boys and girls because of the sex difference in timing of puberty, and slightly different percentages are used for children with unusually advanced or delayed bone maturation. These tables, the Bayley-Pinneau tables, are included as an appendix in the Greulich and Pyle atlas.
In a number of conditions involving atypical growth, bone age height predictions are less accurate. For example, in children born small for gestational age who remain short after birth, the bone age is a poor predictor of adult height.
# Clinical application of bone age readings
An advanced or delayed bone age does not always indicate disease or "pathologic" growth. Conversely, the bone age may be normal in some conditions of abnormal growth. Children do not mature at exactly the same tempo. Just as there is wide variation among the normal population in age of losing teeth or experiencing the first menstrual period, the bone age of a healthy child may be a year or two advanced or delayed.
An advanced bone age is common when a child has had prolonged elevation of sex steroid levels, as in precocious puberty or congenital adrenal hyperplasia. The bone age is often marginally advanced with premature adrenarche, when a child is overweight from a young age or when a child has lipodystrophy. Bone age may be significantly advanced in genetic overgrowth syndromes, such as Sotos syndrome, Beckwith-Wiedemann syndrome and Marshall-Smith syndrome.
Bone maturation is delayed with the variation of normal development termed constitutional delay of growth and puberty, but delay also accompanies growth failure due to growth hormone deficiency and hypothyroidism. | Bone age
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bone age is a way of describing the degree of maturation of a child's bones. As a person grows from fetal life through childhood, puberty, and finishes growth as a young adult, the bones of the skeleton change in size and shape. These changes can be seen by x-ray. The "bone age" of a child is the average age at which children reach this stage of bone maturation. A child's current height and bone age can be used to predict adult height.
At birth, only the metaphyses of the "long bones" are present. The long bones are those that grow primarily by elongation at an epiphysis at one end of the growing bone. The long bones include the femurs, tibias, and fibulas of the lower limb, the humeri, radii, and ulnas of the upper limb (arm + forearm), and the phalanges of the fingers and toes. The long bones of the leg comprise nearly half of adult height. The other primary skeletal component of height is the spine and skull.
As a child grows the epiphyses become calcified and appear on the x-rays, as do the carpal and tarsal bones of the hands and feet, separated on the x-rays by a layer of invisible cartilage where most of the growth is occurring. As sex steroid levels rise during puberty, bone maturation accelerates. As growth nears conclusion and attainment of adult height, bones begin to approach the size and shape of adult bones. The remaining cartilaginous portions of the epiphyses become thinner. As these cartilaginous zones become obliterated, the epiphyses are said to be "closed" and no further lengthening of the bones will occur. A small amount of spinal growth concludes an adolescent's growth.
Pediatric endocrinologists are the physicians who most commonly order and interpret bone age x-rays and evaluate children for advanced or delayed growth and physical development.
# Methods
The most commonly used method is based on a single x-ray of the fingers, hand, and wrist. A hand is easily x-rayed with minimal radiation and shows many bones in a single view. The bones in the x-ray are compared to the bones of a standard atlas, usually Greulich and Pyle [1]
Male
- 4y 6m
- 11y 6m
- 13y
- 13y 6m
- 14y
Female
- 2y 6m
- 3yImage:
- 4y 2m
- 4y 6m
- 5y
- 6y 12m
- 8y 10m
- 11y
- 12y
A more complex method also based on hand x-rays is the "TW2" method [2] An atlas based on knee maturation has also been compiled.
The hands of infants do not change much in the first year of life and if precise bone age assessment is desired, an x-ray of approximately half of the skeleton (a "hemiskeleton" view) may be obtained to assess some of the areas such as shoulders and pelvis which change more in infancy.
# Height prediction
Statistics have been compiled to indicate the percentage of height growth remaining at a given bone age. By simple arithmetic, a predicted adult height can be computed from a child's height and bone age. Separate tables are used for boys and girls because of the sex difference in timing of puberty, and slightly different percentages are used for children with unusually advanced or delayed bone maturation. These tables, the Bayley-Pinneau tables, are included as an appendix in the Greulich and Pyle atlas.
In a number of conditions involving atypical growth, bone age height predictions are less accurate. For example, in children born small for gestational age who remain short after birth, the bone age is a poor predictor of adult height.
# Clinical application of bone age readings
An advanced or delayed bone age does not always indicate disease or "pathologic" growth. Conversely, the bone age may be normal in some conditions of abnormal growth. Children do not mature at exactly the same tempo. Just as there is wide variation among the normal population in age of losing teeth or experiencing the first menstrual period, the bone age of a healthy child may be a year or two advanced or delayed.
An advanced bone age is common when a child has had prolonged elevation of sex steroid levels, as in precocious puberty or congenital adrenal hyperplasia. The bone age is often marginally advanced with premature adrenarche, when a child is overweight from a young age or when a child has lipodystrophy. Bone age may be significantly advanced in genetic overgrowth syndromes, such as Sotos syndrome, Beckwith-Wiedemann syndrome and Marshall-Smith syndrome.
Bone maturation is delayed with the variation of normal development termed constitutional delay of growth and puberty, but delay also accompanies growth failure due to growth hormone deficiency and hypothyroidism. | https://www.wikidoc.org/index.php/Bone_age | |
99f03f85c199b1cd2464ddb320578bca663a8fd8 | wikidoc | Bone wax | Bone wax
Bone wax is made of beeswax containing a softening agent such as paraffin. Bone wax is used to mechanically stop bone bleeding during surgical procedures. The bone wax is smeared across the bleeding edge of the bone, blocking the holes and causing immediate bone hemostasis through a tamponade effect. Bone wax is supplied in sterile sticks, and most often requires softening before it can be applied. Once applied, it essentially never goes away. Although inexpensive, easy to use and immediate, bone wax has a number of adverse reactions associated with it.
Bone wax inhibits formation of new bone osteogenesis and acts as a physical barrier preventing bone union.
In the presence of bone wax, osteoblasts will be absent in a bone defect. In defects where bone wax was applied and removed after 10 minutes, there was complete inhibition of bone regeneration. For this reason bone wax is almost never used in areas where bone fusion is critical.
Bone wax increases infection rates and impairs the ability of bone to clear bacteria. In the presence of bone wax, the number of bacteria needed to produce osteomyelitis is reduced by a factor of 10,007. In a recent study of infection rates following spinal surgery, surgical site infections occurred in 6 of 42 cases in which bone wax was used, and in only 1 of 72 cases in which it was not used.
Infection and non-union are a particularly important problem in cardiac surgery. According to the American Heart Association, the incidence of deep sternal wound infections is 1% to 5% of patients undergoing coronary artery bypass surgery, with a mortality rate of about 25%.
Bone wax remains as a foreign body for many years, and can cause a giant cell reaction and local inflammation. In skull base surgery, bone wax has been reported to cause granuloma formation and CSF fluid leaks.
The FDA has recently approved a new water soluble bone hemostasis material designed to look and feel like bone wax. This material comprises a sterile mixture of water-soluble alkylene oxide copolymers, derived from ethylene oxide and propylene oxide. These copolymers have a long history in the medical and pharmaceutical fields, and they are considered inert. These compounds are not metabolized, but eliminated from the body unchanged.
It is anticipated that with the introduction of these new hemostatic materials, the incidence of surgical bone infections, non-union and inflammatory complications will decrease with time.
The alternative to bone wax is called Ostene. It does not have any of the complications known to occur with the use of traditional bone wax. | Bone wax
Bone wax is made of beeswax containing a softening agent such as paraffin. Bone wax is used to mechanically stop bone bleeding during surgical procedures. The bone wax is smeared across the bleeding edge of the bone, blocking the holes and causing immediate bone hemostasis through a tamponade effect. Bone wax is supplied in sterile sticks, and most often requires softening before it can be applied. Once applied, it essentially never goes away. Although inexpensive, easy to use and immediate, bone wax has a number of adverse reactions associated with it.
Bone wax inhibits formation of new bone osteogenesis and acts as a physical barrier preventing bone union.[1][2]
In the presence of bone wax, osteoblasts will be absent in a bone defect.[3] In defects where bone wax was applied and removed after 10 minutes, there was complete inhibition of bone regeneration.[4] For this reason bone wax is almost never used in areas where bone fusion is critical.[5]
Bone wax increases infection rates and impairs the ability of bone to clear bacteria.[6] In the presence of bone wax, the number of bacteria needed to produce osteomyelitis is reduced by a factor of 10,007. In a recent study of infection rates following spinal surgery, surgical site infections occurred in 6 of 42 cases in which bone wax was used, and in only 1 of 72 cases in which it was not used.[7]
Infection and non-union are a particularly important problem in cardiac surgery.[8] According to the American Heart Association, the incidence of deep sternal wound infections is 1% to 5% of patients undergoing coronary artery bypass surgery, with a mortality rate of about 25%.[9]
Bone wax remains as a foreign body for many years, and can cause a giant cell reaction and local inflammation.[10] In skull base surgery, bone wax has been reported to cause granuloma formation and CSF fluid leaks.[11][12]
The FDA has recently approved a new water soluble bone hemostasis material designed to look and feel like bone wax.[13] This material comprises a sterile mixture of water-soluble alkylene oxide copolymers, derived from ethylene oxide and propylene oxide. These copolymers have a long history in the medical and pharmaceutical fields, and they are considered inert. These compounds are not metabolized, but eliminated from the body unchanged.
It is anticipated that with the introduction of these new hemostatic materials, the incidence of surgical bone infections, non-union and inflammatory complications will decrease with time.
The alternative to bone wax is called Ostene. It does not have any of the complications known to occur with the use of traditional bone wax. | https://www.wikidoc.org/index.php/Bone_wax | |
7a6f9d1f77de87b97aa86f606f2dc42fe1b23f14 | wikidoc | Boosting | Boosting
Boosting is a machine learning meta-algorithm for performing supervised learning. Boosting is based on the question posed by Kearns: can a set of weak learners create a single strong learner? A weak learner is defined to be a classifier which is only slightly correlated with the true classification. In contrast, a strong learner is a classifier that is arbitrarily well-correlated with the true classification.
The affirmative answer to Kearns question has significant ramifications in machine learning and statistics.
# Boosting Algorithms
While boosting is not algorithmically constrained, most boosting algorithms follow a template. Typically boosting occurs in iterations, by incrementally adding weak learners to a final strong learner. At every iteration, a weak learner learns the training data with respect to a distribution. The weak learner is then added to the final strong learner. This is typically done by weighting the weak learner in some manner, which is typically related to the weak learner's accuracy. After the weak learner is added to the final strong learner, the data is reweighted: examples that are misclassified gain weight and examples that are classified correctly lose weight (some boosting algorithms will actually decrease the weight of repeatedly misclassified examples, e.g. boost by majority and BrownBoost). Thus, future weak learners will focus more on the examples that previous weak learners misclassified.
There are many boosting algorithms. The original algorithms proposed by Rob Schapire (a recursive majority gate formulation ) and Yoav Freund (boost by majority ) were not adaptive and could not take full advantage of the weak learners.
Some algorithms refer to themselves as "boosting algorithms," and these algorithms can be quite effective. However, in the probably approximately correct learning (PAC) model, only provable boosting algorithms should adopt the title "boosting." Algorithms that are similar to boosting in spirit, but not provably PAC-boosters, are sometimes called "leveraging algorithms." These can be quite effective machine learning algorithms .
# Examples of Boosting Algorithms
The main variation between many boosting algorithms is their method of weighting training data points and hypotheses. AdaBoost is very popular and perhaps the most significant historically as it was the first algorithm that could adapt to the weak learners. However, there are many more recent algorithms such as LPBoost, TotalBoost, BrownBoost,MadaBoost, LogitBoost, and others. Many boosting algorithms fit into the AnyBoost framework, which shows that boosting performs gradient descent in function space using a convex cost function. | Boosting
Template:Other
Boosting is a machine learning meta-algorithm for performing supervised learning. Boosting is based on the question posed by Kearns[1]: can a set of weak learners create a single strong learner? A weak learner is defined to be a classifier which is only slightly correlated with the true classification. In contrast, a strong learner is a classifier that is arbitrarily well-correlated with the true classification.
The affirmative answer to Kearns question has significant ramifications in machine learning and statistics.
# Boosting Algorithms
While boosting is not algorithmically constrained, most boosting algorithms follow a template. Typically boosting occurs in iterations, by incrementally adding weak learners to a final strong learner. At every iteration, a weak learner learns the training data with respect to a distribution. The weak learner is then added to the final strong learner. This is typically done by weighting the weak learner in some manner, which is typically related to the weak learner's accuracy. After the weak learner is added to the final strong learner, the data is reweighted: examples that are misclassified gain weight and examples that are classified correctly lose weight (some boosting algorithms will actually decrease the weight of repeatedly misclassified examples, e.g. boost by majority and BrownBoost). Thus, future weak learners will focus more on the examples that previous weak learners misclassified.
There are many boosting algorithms. The original algorithms proposed by Rob Schapire (a recursive majority gate formulation [2]) and Yoav Freund (boost by majority [3]) were not adaptive and could not take full advantage of the weak learners.
Some algorithms refer to themselves as "boosting algorithms," and these algorithms can be quite effective. However, in the probably approximately correct learning (PAC) model, only provable boosting algorithms should adopt the title "boosting." Algorithms that are similar to boosting in spirit, but not provably PAC-boosters, are sometimes called "leveraging algorithms." These can be quite effective machine learning algorithms [4].
# Examples of Boosting Algorithms
The main variation between many boosting algorithms is their method of weighting training data points and hypotheses. AdaBoost is very popular and perhaps the most significant historically as it was the first algorithm that could adapt to the weak learners. However, there are many more recent algorithms such as LPBoost, TotalBoost, BrownBoost,MadaBoost, LogitBoost, and others. Many boosting algorithms fit into the AnyBoost framework[5], which shows that boosting performs gradient descent in function space using a convex cost function. | https://www.wikidoc.org/index.php/Boosting | |
afc531538693936e018d6368bccfdcffd3d75f5d | wikidoc | Borazine | Borazine
Borazine is an inorganic compound composed of the elements boron, nitrogen and hydrogen. In this cyclic compound three hydroborane (BH) units and three amino units (NH) alternate.
The compound was synthesised in 1926 by the chemists Alfred Stock and Pohland by a reaction of diborane with ammonia. The structure is isoelectronic and isostructural with benzene and for this reason borazine is called inorganic benzene by a proposal of Nils Wiberg and the compound also goes by the name of borazol from the German name for benzene which is benzol.
# Synthesis
Borazine is synthesized from diborane and ammonia in a 1:2 ratio at 250 - 300 °C with a conversion of 50%.
An alternative more efficient route begins with lithium borohydride and ammonium chloride with improved chemical yield:
In a two-step process to borazine, boron trichloride is first converted to trichloroborazine:
The B-Cl bonds are subsequently converted to B-H bonds:
# Properties
Borazine is a colourless liquid with an aromatic smell. In water it decomposes to boric acid, ammonia, and hydrogen. Borazine, with a standard enthalpy change of formation ΔHf of -531 kJ/mol, is thermally very stable.
## Structure
Borazine is isostructural with benzene and bond lengths are identical just as in benzene. The distance between boron and nitrogen in the ring is 0.1436 nm, the carbon carbon bond in benzene has a length of 0.1397 nm. The boron nitrogen bond is between that of the boron nitrogen single bond with 0.151 nm and the boron nitrogen double bond which is 0.131 nm. This suggests partial delocalisation of nitrogen lone pair electrons.
## Mesomers
The electronegativity of boron (2.04 on the Pauling scale) compared to that of nitrogen (3.04) and also the electron deficiency on the boron atom and the lone pair on nitrogen favor alternative mesomer structures for borazine.
Boron is the Lewis acid and nitrogen is the Lewis base.
# Reactions
Borazine is more reactive than benzene. It reacts with hydrogen chloride in an addition reaction. If borazine were truly aromatic like benzene this reaction would not occur without a Lewis acid catalyst.
The addition reaction with bromine takes place without catalyst. Borazines interact with nucleophilic attack at boron and electrophilic attack at nitrogen. Heating borazine at 70 °C expulses hydrogen with formation of a borazinyl polymer or polyborazylene in which the monomer units are coupled in a para fashion by new boron - nitrogen bonds.
# Applications
Borazine and borazine derivatives are potential precursors to boron nitride ceramics. Boron nitride can be prepared by heating polyborazylene to 1000 °C. Borazines are also starting materials for other potential ceramics such as boron carbonitrides: | Borazine
Template:Chembox new
Borazine is an inorganic compound composed of the elements boron, nitrogen and hydrogen. In this cyclic compound three hydroborane (BH) units and three amino units (NH) alternate.
The compound was synthesised in 1926 by the chemists Alfred Stock and Pohland by a reaction of diborane with ammonia. [1] The structure is isoelectronic and isostructural with benzene and for this reason borazine is called inorganic benzene by a proposal of Nils Wiberg and the compound also goes by the name of borazol from the German name for benzene which is benzol.
# Synthesis
Borazine is synthesized from diborane and ammonia in a 1:2 ratio at 250 - 300 °C with a conversion of 50%.
An alternative more efficient route begins with lithium borohydride and ammonium chloride with improved chemical yield:
In a two-step process to borazine, boron trichloride is first converted to trichloroborazine:
The B-Cl bonds are subsequently converted to B-H bonds:
# Properties
Borazine is a colourless liquid with an aromatic smell. In water it decomposes to boric acid, ammonia, and hydrogen. Borazine, with a standard enthalpy change of formation ΔHf of -531 kJ/mol, is thermally very stable.
## Structure
Borazine is isostructural with benzene and bond lengths are identical just as in benzene. The distance between boron and nitrogen in the ring is 0.1436 nm, the carbon carbon bond in benzene has a length of 0.1397 nm. The boron nitrogen bond is between that of the boron nitrogen single bond with 0.151 nm and the boron nitrogen double bond which is 0.131 nm. This suggests partial delocalisation of nitrogen lone pair electrons.
## Mesomers
The electronegativity of boron (2.04 on the Pauling scale) compared to that of nitrogen (3.04) and also the electron deficiency on the boron atom and the lone pair on nitrogen favor alternative mesomer structures for borazine.
Boron is the Lewis acid and nitrogen is the Lewis base.
# Reactions
Borazine is more reactive than benzene. It reacts with hydrogen chloride in an addition reaction. If borazine were truly aromatic like benzene this reaction would not occur without a Lewis acid catalyst.
The addition reaction with bromine takes place without catalyst. Borazines interact with nucleophilic attack at boron and electrophilic attack at nitrogen. Heating borazine at 70 °C expulses hydrogen with formation of a borazinyl polymer or polyborazylene in which the monomer units are coupled in a para fashion by new boron - nitrogen bonds.
# Applications
Borazine and borazine derivatives are potential precursors to boron nitride ceramics. Boron nitride can be prepared by heating polyborazylene to 1000 °C. Borazines are also starting materials for other potential ceramics such as boron carbonitrides:
# External links
- Borazines at Tennessee Tech University Powerpoint
- National Pollutant Inventory - Boron and compounds | https://www.wikidoc.org/index.php/Borazine | |
96208693ba1df0c783a9dcefc5126f8ac2a39242 | wikidoc | Borrelia | Borrelia
# Overview
Borrelia is a genus of bacteria of the spirochete class. It is a zoonotic, vector-borne disease transmitted primarily by ticks and some by lice, depending on the species. There are 37 known species of Borrelia.
# Borreliosis (Lyme disease)
Of the 37 known species of Borrelia, 12 of these species are known to cause Lyme disease or borreliosis and are transmitted by ticks. The major Borrelia species causing Lyme disease are Borrelia burgdorferi, Borrelia afzelii, Borrelia garinii and Borrelia valaisiana.
# Species and Strains
Until recently it was thought that only three genospecies caused Lyme disease (borreliosis): B. burgdorferi sensu stricto ( the predominant species in North America, but also present in Europe); B. afzelii; and B. garinii (both predominant in Eurasia). To date the complete genome of B. burgdorferi sensu stricto strain B31, B. afzelii strain PKo and B. garinii strain PBi is known. B. burgdorferi strain B31 was derived by limited dilutional cloning from the original Lyme-disease tick isolate derived by Alan Barbour. There are over 300 species or strains of Borrelia world wide with apx 100 in the U.S. and it is unknown how many cause lyme like sickness, but many of them may.
At present, diagnostic tests are based only on B. burgdorferi sensu stricto (the only species used in the U.S.), B. afzelii, and B. garinii.
## Emerging Genospecies
- B. valaisiana was identified as a genomic species from Strain VS116, and named B. valaisiana in 1997. It was later detected by Polymerase chain reaction (PCR) in human cerebral spinal fluid (CSF) in Greece. B. valaisiana has been isolated throughout Europe, as well east Asia.
Newly discovered genospecies have also been found to cause disease in humans:
- B. lusitaniae in Europe (especially Portugal), North Africa and Asia.
- B. bissettii in the U.S. and Europe.
- B. spielmanii in Europe.
Additional B. burgdorferi sensu lato genospecies suspected of causing illness, but not confirmed by culture, include B. japonica, B. tanukii and B. turdae (Japan); B. sinica (China); and B. andersonii (U.S.). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease.
The B. miyamotoi spirochete, related to the relapsing fever group of spirochetes, is also suspected of causing illness in Japan. Spirochetes similar to B. miyamotoi have recently been found in both I. ricinus ticks in Sweden and I. scapularis ticks in the U.S.
## B. lonestari
Apart from this group of closely related genospecies, additional Borrelia species of interest include B. lonestari, a spirochete recently detected in the Amblyomma americanum tick (Lone Star tick) in the U.S. B. lonestari is suspected of causing STARI (Southern Tick-Associated Rash Illness), also known as Masters disease in honor of its discoverer Ed Masters. The illness follows a Lone Star tick bite and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.
# Relapsing fever
Other Borrelia species cause relapsing fever such as Borrelia recurrentis, caused by the human body louse. No animal reservoir of B. recurrentis exists. Lice that feed on infected humans acquire the Borrelia organisms that then multiply in the gut of the louse. When an infected louse feeds on an uninfected human, the organism gains access when the victim crushes the louse or scratches the area where the louse is feeding. B. recurrentis infects the person via mucous membranes and then invades the bloodstream.
Other tick-borne relapsing infections are acquired from other species, such as Borrelia hermsii or Borrelia Parkeri, which can be spread from rodents, and serve as a reservoir for the infection, via a tick vector. Borelia hermsii and Borrelia recurrentis cause very similar diseases although the disease associated with Borrelia hermsii has more relapses and is responsible for more fatalities, while the disease caused by B. recurrentis has longer febrile and afebrile intervals and a longer incubation period.
# Gallery
- "Black-legged ticks", Ixodes scapularis, also referred to as I. dammini, are found on a wide rage of hosts. From Public Health Image Library (PHIL).
- Female “Lone star tick” From Public Health Image Library (PHIL).
- Dorsal view of the “soft tick” Carios kelleyi. From Public Health Image Library (PHIL).
- Dorsal view of the “soft tick” Carios kelleyi. From Public Health Image Library (PHIL).
- White tail deer during a Lyme disease field investigation. From Public Health Image Library (PHIL).
- White-footed mouse, Peromyscus leucopus, which is a host of ticks thatare known to carry the bacteria, Borrelia burgdorferi, responsible for Lyme disease. From Public Health Image Library (PHIL). | Borrelia
Template:Seealso
Template:Seealso
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Borrelia is a genus of bacteria of the spirochete class. It is a zoonotic, vector-borne disease transmitted primarily by ticks and some by lice, depending on the species. There are 37 known species of Borrelia.
# Borreliosis (Lyme disease)
Of the 37 known species of Borrelia, 12 of these species are known to cause Lyme disease or borreliosis and are transmitted by ticks. The major Borrelia species causing Lyme disease are Borrelia burgdorferi, Borrelia afzelii, Borrelia garinii and Borrelia valaisiana.
# Species and Strains
Until recently it was thought that only three genospecies caused Lyme disease (borreliosis): B. burgdorferi sensu stricto ( the predominant species in North America, but also present in Europe); B. afzelii; and B. garinii (both predominant in Eurasia). To date the complete genome of B. burgdorferi sensu stricto strain B31, B. afzelii strain PKo and B. garinii strain PBi is known. B. burgdorferi strain B31 was derived by limited dilutional cloning from the original Lyme-disease tick isolate derived by Alan Barbour. There are over 300 species or strains of Borrelia world wide with apx 100 in the U.S. and it is unknown how many cause lyme like sickness, but many of them may.
At present, diagnostic tests are based only on B. burgdorferi sensu stricto (the only species used in the U.S.), B. afzelii, and B. garinii.
## Emerging Genospecies
- B. valaisiana was identified as a genomic species from Strain VS116, and named B. valaisiana in 1997.[1] It was later detected by Polymerase chain reaction (PCR) in human cerebral spinal fluid (CSF) in Greece.[2] B. valaisiana has been isolated throughout Europe, as well east Asia.[3]
Newly discovered genospecies have also been found to cause disease in humans:
- B. lusitaniae [4] in Europe (especially Portugal), North Africa and Asia.
- B. bissettii [5][6] in the U.S. and Europe.
- B. spielmanii [7][8] in Europe.
Additional B. burgdorferi sensu lato genospecies suspected of causing illness, but not confirmed by culture, include B. japonica, B. tanukii and B. turdae (Japan); B. sinica (China); and B. andersonii (U.S.). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease.
The B. miyamotoi spirochete, related to the relapsing fever group of spirochetes, is also suspected of causing illness in Japan. Spirochetes similar to B. miyamotoi have recently been found in both I. ricinus ticks in Sweden and I. scapularis ticks in the U.S.[9][10]
## B. lonestari
Apart from this group of closely related genospecies, additional Borrelia species of interest include B. lonestari, a spirochete recently detected in the Amblyomma americanum tick (Lone Star tick) in the U.S.[11] B. lonestari is suspected of causing STARI (Southern Tick-Associated Rash Illness), also known as Masters disease in honor of its discoverer Ed Masters. The illness follows a Lone Star tick bite and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.[12]There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.
# Relapsing fever
Other Borrelia species cause relapsing fever such as Borrelia recurrentis, caused by the human body louse. No animal reservoir of B. recurrentis exists. Lice that feed on infected humans acquire the Borrelia organisms that then multiply in the gut of the louse. When an infected louse feeds on an uninfected human, the organism gains access when the victim crushes the louse or scratches the area where the louse is feeding. B. recurrentis infects the person via mucous membranes and then invades the bloodstream.
Other tick-borne relapsing infections are acquired from other species, such as Borrelia hermsii or Borrelia Parkeri, which can be spread from rodents, and serve as a reservoir for the infection, via a tick vector. Borelia hermsii and Borrelia recurrentis cause very similar diseases although the disease associated with Borrelia hermsii has more relapses and is responsible for more fatalities, while the disease caused by B. recurrentis has longer febrile and afebrile intervals and a longer incubation period.
# Gallery
- "Black-legged ticks", Ixodes scapularis, also referred to as I. dammini, are found on a wide rage of hosts. From Public Health Image Library (PHIL). [13]
- Female “Lone star tick” From Public Health Image Library (PHIL). [13]
- Dorsal view of the “soft tick” Carios kelleyi. From Public Health Image Library (PHIL). [13]
- Dorsal view of the “soft tick” Carios kelleyi. From Public Health Image Library (PHIL). [13]
- White tail deer during a Lyme disease field investigation. From Public Health Image Library (PHIL). [13]
- White-footed mouse, Peromyscus leucopus, which is a host of ticks thatare known to carry the bacteria, Borrelia burgdorferi, responsible for Lyme disease. From Public Health Image Library (PHIL). [13]
# External links
- Borrelia Microbe Wiki Page
- NCBI Borrelia Taxonomy Browser
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Borrelia | |
9cf6ec90147b981b34bfb10370ec1d5201182148 | wikidoc | Bosentan | Bosentan
# 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
Bosentan is an endothelin receptor antagonist that is FDA approved for the {{{indicationType}}} of pulmonary arterial hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, hypotension, palpitations, flushing, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tracleer® is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%).
- Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of hepatotoxicity in WHO Class II patients, which may preclude future use as their disease progresses.
- Healthcare professionals who prescribe Tracleer must enroll in the Tracleer Access Program (T.A.P.) and must comply with the required monitoring to minimize the risks associated with Tracleer.
- Dosing Information
- Initiate treatment at 62.5 mg twice daily for 4 weeks and then increase to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity.
- Tracleer should be administered in the morning and evening with or without food.
- Measure liver aminotransferase levels prior to initiation of treatment and then monthly. If aminotransferase levels increase, revise the monitoring and treatment plan. The table below summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations >3 × ULN during therapy with Tracleer. Discontinue Tracleer if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN. There is no experience with the reintroduction of Tracleer in these circumstances. Information.
- In patients with a body weight below 40 kg but who are over 12 years of age, the recommended initial and maintenance dose is 62.5 mg twice daily. There is limited information about the safety and efficacy of Tracleer in children between the ages of 12 and 18 years.
- Coadministration of Tracleer in Patients on Ritonavir
- In patients who have been receiving ritonavir for at least 10 days, start Tracleer at 62.5 mg once daily or every other day based upon individual tolerability.
- Coadministration of Ritonavir in Patients on Tracleer
- Discontinue use of Tracleer at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume Tracleer at 62.5 mg once daily or every other day based upon individual tolerability.
- Tracleer should generally be avoided in patients with moderate or severe liver impairment. Initiation of Tracleer should generally be avoided in patients with elevated aminotransferases >3 × ULN. No dose adjustment is required in patients with mildly impaired liver function.
- There is limited experience with abrupt discontinuation of Tracleer. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bosentan in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 62.5 mg orally twice daily for 4 weeks, followed by 125 mg twice daily or 62.5 mg twice daily in patients weighing less than 40 kilograms.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bosentan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bosentan in pediatric patients.
# Contraindications
- Pregnancy
- Use of Tracleer is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of childbearing potential must use two reliable forms of contraception during treatment and for one month after stopping Tracleer.
- Use with Cyclosporine A
- Coadministration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of Tracleer and cyclosporine A is contraindicated.
- Use with Glyburide
- An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore coadministration of glyburide and Tracleer is contraindicated.
- Hypersensitivity
- Tracleer is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include rash and angioedema.
# Warnings
- Hepatotoxicity
- Elevations in ALT or AST by more than 3 × ULN were observed in 11% of Tracleer-treated patients (n = 658) compared to 2% of placebo-treated patients (n = 280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥3 × ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with Tracleer. The combination of hepatocellular injury (increases in aminotransferases of > 3 × ULN) and increases in total bilirubin (≥ 2× ULN) is a marker for potential serious hepatotoxicity.
- Elevations of AST or ALT associated with Tracleer are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with Tracleer.
- Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly. Discontinue Tracleer if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN.
- Prescribing and Distribution Program for Tracleer
- Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a restricted program called the Tracleer Access Program (T.A.P.) As a component of the Tracleer REMS, prescribers, patients, and pharmacies must enroll in the program.
- Required components of the Tracleer REMS are:
- Healthcare professionals who prescribe Tracleer must review the prescriber educational materials, enroll in T.A.P. and comply with its requirements.
- Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) for females of childbearing potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly.
- To receive Tracleer, all patients must understand the risks and benefits, complete a patient enrollment form, and be re-enrolled annually by their prescriber.
- Pharmacies that dispense Tracleer must enroll in the program and agree to comply with the T.A.P. requirements.
- Further information about Tracleer and T.A.P. is available at www.tracleerrems.com or 1-866-228-3546.
- Patients with Pre-existing Hepatic Impairment
- Tracleer is not recommended in patients with moderate or severe liver impairment. In addition, initiation of Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult.
- Fluid Retention
- Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of Tracleer and other endothelin receptor antagonists. In PAH clinical trials with Tracleer, combined adverse events of fluid retention or edema were reported in 1.7 percent (placebo-corrected) of patients
- In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting Tracleer. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.
- If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as Tracleer or underlying heart failure, and the possible need for treatment or discontinuation of Tracleer.
- Pulmonary Veno-Occlusive Disease
- Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether Tracleer should be discontinued.
- Decreased Sperm Counts
- Decreased sperm counts have been observed in patients receiving Tracleer. Preclinical data also suggest that Tracleer, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.
- Decreases in Hemoglobin and Hematocrit
- Treatment with Tracleer can cause a dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.
# 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.
- Safety data on Tracleer were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 patients with pulmonary arterial hypertension and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to Tracleer in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years and n=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (n=328) to Tracleer ranged from 1 day to 1.7 years (n=174 more than 6 months and n=28 more than 12 months).
- Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension were more frequent on Tracleer (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and occurring more often on Tracleer was abnormal liver function.
- The adverse drug events that occurred in ≥3% of the Tracleer-treated patients and were more common on Tracleer in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg twice daily are shown in Table 2:
- An open-label, single arm, multicenter, safety study evaluated the effect on testicular function of Tracleer 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with Tracleer. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Tracleer was discontinued and after 2 months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Tracleer have an adverse effect on spermatogenesis.
- Treatment with Tracleer can cause a dose-related decrease in hemoglobin and hematocrit. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.
- The overall mean decrease in hemoglobin concentration for Tracleer-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of Tracleer treatment and hemoglobin levels stabilized by 4–12 weeks of Tracleer treatment. In placebo-controlled studies of all uses of Tracleer, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of Tracleer-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients.
- A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of Tracleer-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of Tracleer treatment.
- During the course of treatment the hemoglobin concentration remained within normal limits in 68% of Tracleer-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis.
## Postmarketing Experience
- There have been several postmarketing reports of angioedema associated with the use of Tracleer. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing Tracleer.
- The following additional adverse reactions have been reported during the postapproval use of Tracleer. Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Tracleer exposure:
- Unexplained hepatic cirrhosis
- Liver failure
- Hypersensitivity
- Thrombocytopenia
- Rash
- Jaundice
- Anemia requiring transfusion
- Neutropenia and leukopenia
# Drug Interactions
- Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan (see ketoconazole). Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with Tracleer will likely lead to large increases in plasma concentrations of bosentan. Coadministration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with Tracleer is not recommended.
- Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when Tracleer is coadministered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, Tracleer is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.
- Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Tracleer is coadministered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Tracleer.
- An interaction study demonstrated that coadministration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects.
- The concomitant administration of Tracleer and cyclosporine A is contraindicated.
- During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. Coadministration of bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A substrate) by approximately 50%.
- An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of Tracleer and glyburide is contraindicated, and alternative hypoglycemic agents should be considered.
- Coadministration of bosentan decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Tracleer is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A. The possibility of worsened glucose control in patients using these agents should be considered.
- In vitro data indicate that bosentan is a substrate of the Organic Anion Transport Protein (OATP), CYP3A and CYP2C9. Ritonavir inhibits OATP and inhibits and induces CYP3A. However, the impact of ritonavir on the pharmacokinetics of bosentan may largely result from its effect on OATP.
- In normal volunteers, coadministration of Tracleer 125 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily increased the trough concentrations of bosentan on Days 4 and 10 approximately 48-fold and 5-fold, respectively, compared with those measured after Tracleer administered alone. Therefore, adjust the dose of Tracleer when initiating lopinavir/ritonavir.
- Coadministration of bosentan 125 mg twice daily had no substantial impact on the pharmacokinetics of lopinavir/ritonavir 400/100 mg twice daily.
- Coadministration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A substrate), and its active β-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Tracleer is also expected to reduce plasma concentrations of other statins that are significantly metabolized by CYP3A, such as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A-metabolized statins should have cholesterol levels monitored after Tracleer is initiated to see whether the statin dose needs adjustment.
- Coadministration of bosentan and rifampin in normal volunteers resulted in a mean 6-fold increase in bosentan trough levels after the first concomitant dose (likely due to inhibition of OATP by rifampin), but about a 60% decrease in bosentan levels at steady-state. The effect of Tracleer on rifampin levels has not been assessed. When consideration of the potential benefits, and known and unknown risks leads to concomitant use, measure serum aminotransferases weekly for the first 4 weeks before reverting to normal monitoring.
- Coadministration of tacrolimus and Tracleer has not been studied in humans. Coadministration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and Tracleer are used together.
- Coadministration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold in normal volunteers. No dose adjustment of Tracleer is necessary, but increased effects of Tracleer should be considered.
- Coadministration of bosentan 500 mg twice daily for 6 days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of Tracleer and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among Tracleer- and placebo-treated patients.
- Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan.
- In normal volunteers, coadministration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of pulmonary arterial hypertension or erectile dysfunction.
- In a small, randomized, double-blind, placebo-controlled study, 34 patients treated with bosentan 125 mg twice daily for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Use of Tracleer is contraindicated in females who are or may become pregnant. While there are no adequate and well-controlled studies in pregnant females, animal studies show that Tracleer is likely to cause major birth defects when administered during pregnancy. Bosentan caused teratogenic effects in animals including malformations of the head, mouth, face, and large blood vessels. If Tracleer is used during pregnancy or if a patient becomes pregnant while taking Tracleer, the patient should be apprised of the potential hazard to the fetus.
- Females of childbearing potential should have a negative pregnancy test before starting treatment with Tracleer. The prescriber should not dispense a prescription for Tracleer without documenting a negative urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse. Follow-up urine or serum pregnancy tests should be obtained monthly in females of childbearing potential taking Tracleer. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus.
- Drug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using Tracleer and should not be used as a patient's only contraceptive method. Females of childbearing potential using Tracleer must use two reliable forms of contraception unless she has a tubal sterilization or has a Copper T 380A IUD or LNg 20 IUS. In these cases, no additional contraception is needed. Contraception should be continued until one month after completing Tracleer therapy. Females of childbearing potential using Tracleer should seek contraception counseling from a gynecologist or other expert as needed.
- Bosentan was teratogenic in rats given oral doses two times the maximum recommended human dose (on a mg/ m2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the MRHD (on a mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bosentan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Bosentan during labor and delivery.
### Nursing Mothers
- It is not known whether bosentan is excreted into human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from bosentan, a decision should be made to discontinue nursing or to discontinue Tracleer, taking into account the importance of Tracleer to the mother.
### Pediatric Use
- Safety and efficacy in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of Tracleer did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Bosentan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Bosentan with respect to specific racial populations.
### Renal Impairment
- The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment.
### Hepatic Impairment
- Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (Cmax and AUC) of bosentan. The pharmacokinetics of Tracleer has not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. Tracleer should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan was not altered in patients with mild impairment of hepatic function (Child-Pugh Class A).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bosentan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Bosentan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Reduce the dose and closely monitor patients developing aminotransferase elevations >3 × ULN.
- Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter.
- Rifampin alters bosentan exposure. Monitor hepatic function weekly for 4 weeks, followed by normal monitoring.
# IV Compatibility
There is limited information regarding IV Compatibility of Bosentan in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.
- In the postmarketing period, there was one reported overdose of 10,000 mg of Tracleer taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support.
### Management
- Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Bosentan in the drug label.
# Pharmacology
## Mechanism of Action
- Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown.
- Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease.
## Structure
- Tracleer is the proprietary name for bosentan, an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N--bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula:
- Bosentan has a molecular weight of 569.64 and a molecular formula of C27H29N5O6SH2O. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive.
- Tracleer is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, and ethylcellulose. Each Tracleer 62.5 mg tablet contains 64.541 mg of bosentan, equivalent to 62.5 mg of anhydrous bosentan. Each Tracleer 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Bosentan in the drug label.
## Pharmacokinetics
- After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 hours and the terminal elimination half-life (t1/2) is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about 2-fold greater in adult patients with pulmonary arterial hypertension than in healthy adult subjects.
- The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food. The volume of distribution is about 18 L. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.
- Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10%–20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Total clearance after a single intravenous dose is about 4 L/hr in patients with pulmonary arterial hypertension. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days. Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine.
- It is not known whether bosentan's pharmacokinetics is influenced by gender, race, or age.
- In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure of bosentan. In a study comparing 8 patients with mild liver impairment (Child-Pugh Class A) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan was not altered in patients with mild hepatic impairment.
- In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and pulmonary arterial hypertension associated with portal hypertension than in 3 patients with normal liver function and pulmonary arterial hypertension of other etiologies.
- The pharmacokinetics of Tracleer has not been evaluated in patients with severe liver impairment (Child-Pugh Class C).
- In patients with severe renal impairment (creatinine clearance 15–30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to people with normal renal function. These differences do not appear to be clinically important.
## Nonclinical Toxicology
- Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose of 125 mg twice daily, on a mg/m2 basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan.
- Bosentan was teratogenic in rats given oral doses ≥60 mg/kg/day. In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 and 300 mg/kg/day. Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs.
- The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents.
- Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4-6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD).
# Clinical Studies
- Two randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared 2 doses (125 mg twice daily and 250 mg twice daily) of Tracleer with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo. Patients had severe (WHO functional Class III–IV) pulmonary arterial hypertension: idiopathic or heritable pulmonary arterial hypertension (72%) or pulmonary arterial hypertension associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with pulmonary arterial hypertension associated with other conditions such as HIV disease or recurrent pulmonary emboli.
- In both studies, Tracleer or placebo was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g., calcium channel blockers, ACE inhibitors), but not epoprostenol. Tracleer was given at a dose of 62.5 mg twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351.
- The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years.
- Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 3.
- In both trials, treatment with Tracleer resulted in a significant increase in exercise ability. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (Figure 1). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, but the potential for increased hepatotoxicity causes this dose not to be recommended. There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences.
- Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined Tracleer (125 mg twice daily and 250 mg twice daily) groups. Values are expressed as mean ± standard error of the mean.
- Invasive hemodynamic parameters were assessed in Study 351. Treatment with Tracleer led to a significant increase in cardiac index (CI) associated with a significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 4).
- The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown.
- Symptoms of pulmonary arterial hypertension were assessed by Borg dyspnea score, WHO functional class, and rate of "clinical worsening." Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in Tracleer-treated patients. There was a significant reduction in the rate of clinical worsening (Table 5 and Figure 2). Figure 2 shows the log-rank test reflecting clinical worsening over 28 weeks.
- In a randomized, double-blind, multicenter, placebo-controlled trial, 185 mildly symptomatic PAH patients with WHO Functional Class II (mean baseline 6-minute walk distance of 443 meters) received Tracleer 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n = 93), or placebo (n = 92) for 6 months. Enrolled patients were treatment-naïve (n = 156) or on a stable dose of sildenafil (n = 29). The coprimary endpoints were change from baseline to month 6 in PVR and 6-minute walk distance. Time to clinical worsening (assessed as the sum of death, hospitalization due to PAH complications, or symptomatic progression of PAH), Borg dyspnea index, change in WHO functional class and hemodynamics were assessed as secondary endpoints.
- Compared with placebo, Tracleer treatment was associated with a reduced incidence of worsening of at least one functional class (3% Tracleer vs. 13% placebo, p = 0.03), and improvement in hemodynamic variables (PVR, mPAP, TPR, cardiac index, and SVO2; p < 0.05). The + 19 m mean (+14 m median) increase in 6-minute walk distance with Tracleer vs. placebo was not significant (p = 0.08). There was a significant delay in time to clinical worsening (first seen primarily as symptomatic progression of PAH) with Tracleer compared with placebo (hazard ratio 0.2, p = 0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline.
- Long-term follow-up of patients with Class III and IV PAH who were treated with Tracleer in open-label extensions of trials (N=235) showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment.
- These uncontrolled observations do not allow comparison with a group not given Tracleer and cannot be used to determine the long-term effect of Tracleer on mortality.
- A small study (N=54) and its open label extension (N=37) of up to 40 weeks with patients with Eisenmenger physiology demonstrated effects of Tracleer on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1).
- Tracleer is not effective in the treatment of congestive heart failure with left ventricular dysfunction. In a pair of studies, 1613 subjects with NYHA Class III-IV heart failure, left ventricular ejection fraction <35%, on diuretics, ACE inhibitor, and other therapies, were randomized to placebo or Tracleer (62.5 mg twice daily titrated as tolerated to 125 mg twice daily) and followed for up to 70 weeks. Use of Tracleer was associated with no benefit on patient global assessment (the primary end point) or mortality. However, hospitalizations for heart failure were more common during the first 4 to 8 weeks after Tracleer was initiated. In a placebo-controlled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4-8 weeks of treatment with Tracleer. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.
# How Supplied
- 62.5 mg film-coated, round, biconvex, orange-white tablets, embossed with identification marking "62,5", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.
- 125 mg film-coated, oval, biconvex, orange-white tablets, embossed with identification marking "125", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.
- Store at 20°C – 25°C (68°F – 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F).
## Storage
There is limited information regarding Bosentan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Bosentan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tracleer®
# Look-Alike Drug Names
- Tracleer® — Tricor®
# Drug Shortage Status
# Price | Bosentan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Black Box Warning
# Overview
Bosentan is an endothelin receptor antagonist that is FDA approved for the {{{indicationType}}} of pulmonary arterial hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, hypotension, palpitations, flushing, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tracleer® is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%).
- Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of hepatotoxicity in WHO Class II patients, which may preclude future use as their disease progresses.
- Healthcare professionals who prescribe Tracleer must enroll in the Tracleer Access Program (T.A.P.) and must comply with the required monitoring to minimize the risks associated with Tracleer.
- Dosing Information
- Initiate treatment at 62.5 mg twice daily for 4 weeks and then increase to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity.
- Tracleer should be administered in the morning and evening with or without food.
- Measure liver aminotransferase levels prior to initiation of treatment and then monthly. If aminotransferase levels increase, revise the monitoring and treatment plan. The table below summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations >3 × ULN during therapy with Tracleer. Discontinue Tracleer if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN. There is no experience with the reintroduction of Tracleer in these circumstances. Information.
- In patients with a body weight below 40 kg but who are over 12 years of age, the recommended initial and maintenance dose is 62.5 mg twice daily. There is limited information about the safety and efficacy of Tracleer in children between the ages of 12 and 18 years.
- Coadministration of Tracleer in Patients on Ritonavir
- In patients who have been receiving ritonavir for at least 10 days, start Tracleer at 62.5 mg once daily or every other day based upon individual tolerability.
- Coadministration of Ritonavir in Patients on Tracleer
- Discontinue use of Tracleer at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume Tracleer at 62.5 mg once daily or every other day based upon individual tolerability.
- Tracleer should generally be avoided in patients with moderate or severe liver impairment. Initiation of Tracleer should generally be avoided in patients with elevated aminotransferases >3 × ULN. No dose adjustment is required in patients with mildly impaired liver function.
- There is limited experience with abrupt discontinuation of Tracleer. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bosentan in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 62.5 mg orally twice daily for 4 weeks, followed by 125 mg twice daily or 62.5 mg twice daily in patients weighing less than 40 kilograms.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bosentan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bosentan in pediatric patients.
# Contraindications
- Pregnancy
- Use of Tracleer is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of childbearing potential must use two reliable forms of contraception during treatment and for one month after stopping Tracleer.
- Use with Cyclosporine A
- Coadministration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of Tracleer and cyclosporine A is contraindicated.
- Use with Glyburide
- An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore coadministration of glyburide and Tracleer is contraindicated.
- Hypersensitivity
- Tracleer is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include rash and angioedema.
# Warnings
- Hepatotoxicity
- Elevations in ALT or AST by more than 3 × ULN were observed in 11% of Tracleer-treated patients (n = 658) compared to 2% of placebo-treated patients (n = 280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥3 × ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with Tracleer. The combination of hepatocellular injury (increases in aminotransferases of > 3 × ULN) and increases in total bilirubin (≥ 2× ULN) is a marker for potential serious hepatotoxicity.
- Elevations of AST or ALT associated with Tracleer are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with Tracleer.
- Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly. Discontinue Tracleer if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN.
- Prescribing and Distribution Program for Tracleer
- Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a restricted program called the Tracleer Access Program (T.A.P.) As a component of the Tracleer REMS, prescribers, patients, and pharmacies must enroll in the program.
- Required components of the Tracleer REMS are:
- Healthcare professionals who prescribe Tracleer must review the prescriber educational materials, enroll in T.A.P. and comply with its requirements.
- Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) for females of childbearing potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly.
- To receive Tracleer, all patients must understand the risks and benefits, complete a patient enrollment form, and be re-enrolled annually by their prescriber.
- Pharmacies that dispense Tracleer must enroll in the program and agree to comply with the T.A.P. requirements.
- Further information about Tracleer and T.A.P. is available at www.tracleerrems.com or 1-866-228-3546.
- Patients with Pre-existing Hepatic Impairment
- Tracleer is not recommended in patients with moderate or severe liver impairment. In addition, initiation of Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult.
- Fluid Retention
- Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of Tracleer and other endothelin receptor antagonists. In PAH clinical trials with Tracleer, combined adverse events of fluid retention or edema were reported in 1.7 percent (placebo-corrected) of patients
- In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting Tracleer. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.
- If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as Tracleer or underlying heart failure, and the possible need for treatment or discontinuation of Tracleer.
- Pulmonary Veno-Occlusive Disease
- Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether Tracleer should be discontinued.
- Decreased Sperm Counts
- Decreased sperm counts have been observed in patients receiving Tracleer. Preclinical data also suggest that Tracleer, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.
- Decreases in Hemoglobin and Hematocrit
- Treatment with Tracleer can cause a dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.
# 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.
- Safety data on Tracleer were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 patients with pulmonary arterial hypertension and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to Tracleer in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years and n=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (n=328) to Tracleer ranged from 1 day to 1.7 years (n=174 more than 6 months and n=28 more than 12 months).
- Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension were more frequent on Tracleer (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and occurring more often on Tracleer was abnormal liver function.
- The adverse drug events that occurred in ≥3% of the Tracleer-treated patients and were more common on Tracleer in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg twice daily are shown in Table 2:
- An open-label, single arm, multicenter, safety study evaluated the effect on testicular function of Tracleer 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with Tracleer. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Tracleer was discontinued and after 2 months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Tracleer have an adverse effect on spermatogenesis.
- Treatment with Tracleer can cause a dose-related decrease in hemoglobin and hematocrit. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.
- The overall mean decrease in hemoglobin concentration for Tracleer-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of Tracleer treatment and hemoglobin levels stabilized by 4–12 weeks of Tracleer treatment. In placebo-controlled studies of all uses of Tracleer, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of Tracleer-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients.
- A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of Tracleer-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of Tracleer treatment.
- During the course of treatment the hemoglobin concentration remained within normal limits in 68% of Tracleer-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis.
## Postmarketing Experience
- There have been several postmarketing reports of angioedema associated with the use of Tracleer. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing Tracleer.
- The following additional adverse reactions have been reported during the postapproval use of Tracleer. Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Tracleer exposure:
- Unexplained hepatic cirrhosis
- Liver failure
- Hypersensitivity
- Thrombocytopenia
- Rash
- Jaundice
- Anemia requiring transfusion
- Neutropenia and leukopenia
# Drug Interactions
- Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan (see ketoconazole). Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with Tracleer will likely lead to large increases in plasma concentrations of bosentan. Coadministration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with Tracleer is not recommended.
- Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when Tracleer is coadministered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, Tracleer is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.
- Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Tracleer is coadministered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Tracleer.
- An interaction study demonstrated that coadministration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects.
- The concomitant administration of Tracleer and cyclosporine A is contraindicated.
- During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. Coadministration of bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A substrate) by approximately 50%.
- An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of Tracleer and glyburide is contraindicated, and alternative hypoglycemic agents should be considered.
- Coadministration of bosentan decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Tracleer is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A. The possibility of worsened glucose control in patients using these agents should be considered.
- In vitro data indicate that bosentan is a substrate of the Organic Anion Transport Protein (OATP), CYP3A and CYP2C9. Ritonavir inhibits OATP and inhibits and induces CYP3A. However, the impact of ritonavir on the pharmacokinetics of bosentan may largely result from its effect on OATP.
- In normal volunteers, coadministration of Tracleer 125 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily increased the trough concentrations of bosentan on Days 4 and 10 approximately 48-fold and 5-fold, respectively, compared with those measured after Tracleer administered alone. Therefore, adjust the dose of Tracleer when initiating lopinavir/ritonavir.
- Coadministration of bosentan 125 mg twice daily had no substantial impact on the pharmacokinetics of lopinavir/ritonavir 400/100 mg twice daily.
- Coadministration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A substrate), and its active β-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Tracleer is also expected to reduce plasma concentrations of other statins that are significantly metabolized by CYP3A, such as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A-metabolized statins should have cholesterol levels monitored after Tracleer is initiated to see whether the statin dose needs adjustment.
- Coadministration of bosentan and rifampin in normal volunteers resulted in a mean 6-fold increase in bosentan trough levels after the first concomitant dose (likely due to inhibition of OATP by rifampin), but about a 60% decrease in bosentan levels at steady-state. The effect of Tracleer on rifampin levels has not been assessed. When consideration of the potential benefits, and known and unknown risks leads to concomitant use, measure serum aminotransferases weekly for the first 4 weeks before reverting to normal monitoring.
- Coadministration of tacrolimus and Tracleer has not been studied in humans. Coadministration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and Tracleer are used together.
- Coadministration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold in normal volunteers. No dose adjustment of Tracleer is necessary, but increased effects of Tracleer should be considered.
- Coadministration of bosentan 500 mg twice daily for 6 days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of Tracleer and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among Tracleer- and placebo-treated patients.
- Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan.
- In normal volunteers, coadministration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of pulmonary arterial hypertension or erectile dysfunction.
- In a small, randomized, double-blind, placebo-controlled study, 34 patients treated with bosentan 125 mg twice daily for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Use of Tracleer is contraindicated in females who are or may become pregnant. While there are no adequate and well-controlled studies in pregnant females, animal studies show that Tracleer is likely to cause major birth defects when administered during pregnancy. Bosentan caused teratogenic effects in animals including malformations of the head, mouth, face, and large blood vessels. If Tracleer is used during pregnancy or if a patient becomes pregnant while taking Tracleer, the patient should be apprised of the potential hazard to the fetus.
- Females of childbearing potential should have a negative pregnancy test before starting treatment with Tracleer. The prescriber should not dispense a prescription for Tracleer without documenting a negative urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse. Follow-up urine or serum pregnancy tests should be obtained monthly in females of childbearing potential taking Tracleer. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus.
- Drug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using Tracleer and should not be used as a patient's only contraceptive method. Females of childbearing potential using Tracleer must use two reliable forms of contraception unless she has a tubal sterilization or has a Copper T 380A IUD or LNg 20 IUS. In these cases, no additional contraception is needed. Contraception should be continued until one month after completing Tracleer therapy. Females of childbearing potential using Tracleer should seek contraception counseling from a gynecologist or other expert as needed.
- Bosentan was teratogenic in rats given oral doses two times the maximum recommended human dose [MRHD] (on a mg/ m2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the MRHD (on a mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bosentan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Bosentan during labor and delivery.
### Nursing Mothers
- It is not known whether bosentan is excreted into human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from bosentan, a decision should be made to discontinue nursing or to discontinue Tracleer, taking into account the importance of Tracleer to the mother.
### Pediatric Use
- Safety and efficacy in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of Tracleer did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Bosentan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Bosentan with respect to specific racial populations.
### Renal Impairment
- The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment.
### Hepatic Impairment
- Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (Cmax and AUC) of bosentan. The pharmacokinetics of Tracleer has not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. Tracleer should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan was not altered in patients with mild impairment of hepatic function (Child-Pugh Class A).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bosentan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Bosentan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Reduce the dose and closely monitor patients developing aminotransferase elevations >3 × ULN.
- Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter.
- Rifampin alters bosentan exposure. Monitor hepatic function weekly for 4 weeks, followed by normal monitoring.
# IV Compatibility
There is limited information regarding IV Compatibility of Bosentan in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.
- In the postmarketing period, there was one reported overdose of 10,000 mg of Tracleer taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support.
### Management
- Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Bosentan in the drug label.
# Pharmacology
## Mechanism of Action
- Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown.
- Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease.
## Structure
- Tracleer is the proprietary name for bosentan, an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2´]-bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula:
- Bosentan has a molecular weight of 569.64 and a molecular formula of C27H29N5O6S•H2O. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive.
- Tracleer is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, and ethylcellulose. Each Tracleer 62.5 mg tablet contains 64.541 mg of bosentan, equivalent to 62.5 mg of anhydrous bosentan. Each Tracleer 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Bosentan in the drug label.
## Pharmacokinetics
- After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 hours and the terminal elimination half-life (t1/2) is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about 2-fold greater in adult patients with pulmonary arterial hypertension than in healthy adult subjects.
- The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food. The volume of distribution is about 18 L. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.
- Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10%–20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Total clearance after a single intravenous dose is about 4 L/hr in patients with pulmonary arterial hypertension. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days. Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine.
- It is not known whether bosentan's pharmacokinetics is influenced by gender, race, or age.
- In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure of bosentan. In a study comparing 8 patients with mild liver impairment (Child-Pugh Class A) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan was not altered in patients with mild hepatic impairment.
- In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and pulmonary arterial hypertension associated with portal hypertension than in 3 patients with normal liver function and pulmonary arterial hypertension of other etiologies.
- The pharmacokinetics of Tracleer has not been evaluated in patients with severe liver impairment (Child-Pugh Class C).
- In patients with severe renal impairment (creatinine clearance 15–30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to people with normal renal function. These differences do not appear to be clinically important.
## Nonclinical Toxicology
- Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 125 mg twice daily, on a mg/m2 basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan.
- Bosentan was teratogenic in rats given oral doses ≥60 mg/kg/day. In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 and 300 mg/kg/day. Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs.
- The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents.
- Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4-6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD).
# Clinical Studies
- Two randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared 2 doses (125 mg twice daily and 250 mg twice daily) of Tracleer with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo. Patients had severe (WHO functional Class III–IV) pulmonary arterial hypertension: idiopathic or heritable pulmonary arterial hypertension (72%) or pulmonary arterial hypertension associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with pulmonary arterial hypertension associated with other conditions such as HIV disease or recurrent pulmonary emboli.
- In both studies, Tracleer or placebo was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g., calcium channel blockers, ACE inhibitors), but not epoprostenol. Tracleer was given at a dose of 62.5 mg twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351.
- The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years.
- Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 3.
- In both trials, treatment with Tracleer resulted in a significant increase in exercise ability. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (Figure 1). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, but the potential for increased hepatotoxicity causes this dose not to be recommended. There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences.
- Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined Tracleer (125 mg twice daily and 250 mg twice daily) groups. Values are expressed as mean ± standard error of the mean.
- Invasive hemodynamic parameters were assessed in Study 351. Treatment with Tracleer led to a significant increase in cardiac index (CI) associated with a significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 4).
- The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown.
- Symptoms of pulmonary arterial hypertension were assessed by Borg dyspnea score, WHO functional class, and rate of "clinical worsening." Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in Tracleer-treated patients. There was a significant reduction in the rate of clinical worsening (Table 5 and Figure 2). Figure 2 shows the log-rank test reflecting clinical worsening over 28 weeks.
- In a randomized, double-blind, multicenter, placebo-controlled trial, 185 mildly symptomatic PAH patients with WHO Functional Class II (mean baseline 6-minute walk distance of 443 meters) received Tracleer 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n = 93), or placebo (n = 92) for 6 months. Enrolled patients were treatment-naïve (n = 156) or on a stable dose of sildenafil (n = 29). The coprimary endpoints were change from baseline to month 6 in PVR and 6-minute walk distance. Time to clinical worsening (assessed as the sum of death, hospitalization due to PAH complications, or symptomatic progression of PAH), Borg dyspnea index, change in WHO functional class and hemodynamics were assessed as secondary endpoints.
- Compared with placebo, Tracleer treatment was associated with a reduced incidence of worsening of at least one functional class (3% Tracleer vs. 13% placebo, p = 0.03), and improvement in hemodynamic variables (PVR, mPAP, TPR, cardiac index, and SVO2; p < 0.05). The + 19 m mean (+14 m median) increase in 6-minute walk distance with Tracleer vs. placebo was not significant (p = 0.08). There was a significant delay in time to clinical worsening (first seen primarily as symptomatic progression of PAH) with Tracleer compared with placebo (hazard ratio 0.2, p = 0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline.
- Long-term follow-up of patients with Class III and IV PAH who were treated with Tracleer in open-label extensions of trials (N=235) showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment.
- These uncontrolled observations do not allow comparison with a group not given Tracleer and cannot be used to determine the long-term effect of Tracleer on mortality.
- A small study (N=54) and its open label extension (N=37) of up to 40 weeks with patients with Eisenmenger physiology demonstrated effects of Tracleer on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1).
- Tracleer is not effective in the treatment of congestive heart failure with left ventricular dysfunction. In a pair of studies, 1613 subjects with NYHA Class III-IV heart failure, left ventricular ejection fraction <35%, on diuretics, ACE inhibitor, and other therapies, were randomized to placebo or Tracleer (62.5 mg twice daily titrated as tolerated to 125 mg twice daily) and followed for up to 70 weeks. Use of Tracleer was associated with no benefit on patient global assessment (the primary end point) or mortality. However, hospitalizations for heart failure were more common during the first 4 to 8 weeks after Tracleer was initiated. In a placebo-controlled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4-8 weeks of treatment with Tracleer. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.
# How Supplied
- 62.5 mg film-coated, round, biconvex, orange-white tablets, embossed with identification marking "62,5", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.
- 125 mg film-coated, oval, biconvex, orange-white tablets, embossed with identification marking "125", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.
- Store at 20°C – 25°C (68°F – 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F).
## Storage
There is limited information regarding Bosentan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Bosentan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tracleer®[2]
# Look-Alike Drug Names
- Tracleer® — Tricor®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Bosentan | |
09e90dbffdd224705302912e818f298c663b9d58 | wikidoc | Bothrops | Bothrops
Bothrops is a genus of venomous pitvipers found in Central America, South America. Currently, 32 species are recognized. The generic name is derived from the Greek words bothros and ops that mean "pit" and "eye" or "face"; an allusion to the heat-sensitive loreal pit organs. Members of this genus are responsible for more human deaths in the Americas than any other group of venomous snakes.
# Description
These snakes range from small, never growing to more than 50-70 cm, to large at over 200 cm in length. Most are characterized by having a sharp canthus rostralis and an unelevated snout.
The arrangement of the scales on top of the head is extremely variable; the number of intrasupraoculars may be anything from 3 to 14. Usually there are 7-9 supralabials and 9-11 sublabials. There are 21-29 midbody dorsal scales, 139-240 ventral scales and 30-86 subcaudals, which are generally divided.
# Geographic range
Found in northeastern Mexico (Tamaulipas) southward through Central and South America to Argentina. Also occurs on the islands of Saint Lucia and Martinique in the Lesser Antilles, as well as on Ilha da Queimada Grande off the coast of Brazil.
# Behavior
Most species are nocturnal, although a few that are found at higher altitudes are active during the day. Otherwise they may be seen on cloudy days or during periods of rain. Most are terrestrial, even though all are capable of climbing. One in particular, B. insularis, has a reputation for often being found in trees.
# Venom
Members of this genus are responsible for more fatalities in the Americas than any other group of venomous snakes. In this regard, the most important species are B. asper, B. atrox and B. jararaca. Without treatment, the fatality rate is estimated to be about 7%, but with treatment this is reduced to 0.5-3%.
Typical symptoms of bothropic envenomation include immediate burning pain, dizziness, nausea, vomiting, sweating, headache, massive swelling of the bitten extremity, hemorrhagic blebs, local necrosis, bleeding from the nose and gums, ecchymosis, erythemia, hypotension, tachycardia, coagulopathy with hypofibrinogenemia and thrombocytopenia, hematemesis, melena, epistaxis, hematuria, intracerebral hemorrhage and renal failure secondary to hypotension and bilateral cortical necrosis. There is usually some discoloration around the bite site and rashes may develop on the torso or the extremities.
In general, death results from hypotension secondary to hypovolemia, renal failure and intracranial hemorrhage. Common complications include necrosis and renal failure secondary to hypovolemic shock and the toxic effects of the venom.
# Species
*) Not including the nominate subspecies (typical form).
T) Type species.
# Taxonomy
Other (new) species may be encountered in literature, such as:
- B. alcatraz - Marques, Martins & Sazima, 2002. Range: Brazil (São Paulo). Common name: jararaca-de-Alcatrazes.
- B. muriciensis - Ferrarezzi & Freire, 2001. Range: northeastern Brazil (Alagoas). Common name: Murici lancehead. | Bothrops
Bothrops is a genus of venomous pitvipers found in Central America, South America.[1] Currently, 32 species are recognized.[4] The generic name is derived from the Greek words bothros and ops that mean "pit" and "eye" or "face"; an allusion to the heat-sensitive loreal pit organs. Members of this genus are responsible for more human deaths in the Americas than any other group of venomous snakes.[2]
# Description
These snakes range from small, never growing to more than 50-70 cm, to large at over 200 cm in length. Most are characterized by having a sharp canthus rostralis and an unelevated snout.[2]
The arrangement of the scales on top of the head is extremely variable; the number of intrasupraoculars may be anything from 3 to 14. Usually there are 7-9 supralabials and 9-11 sublabials. There are 21-29 midbody dorsal scales, 139-240 ventral scales and 30-86 subcaudals, which are generally divided.[2]
# Geographic range
Found in northeastern Mexico (Tamaulipas) southward through Central and South America to Argentina. Also occurs on the islands of Saint Lucia and Martinique in the Lesser Antilles, as well as on Ilha da Queimada Grande off the coast of Brazil.[1]
# Behavior
Most species are nocturnal, although a few that are found at higher altitudes are active during the day. Otherwise they may be seen on cloudy days or during periods of rain. Most are terrestrial, even though all are capable of climbing. One in particular, B. insularis, has a reputation for often being found in trees.[2]
# Venom
Members of this genus are responsible for more fatalities in the Americas than any other group of venomous snakes. In this regard, the most important species are B. asper, B. atrox and B. jararaca. Without treatment, the fatality rate is estimated to be about 7%, but with treatment this is reduced to 0.5-3%.[2]
Typical symptoms of bothropic envenomation include immediate burning pain, dizziness, nausea, vomiting, sweating, headache, massive swelling of the bitten extremity, hemorrhagic blebs, local necrosis, bleeding from the nose and gums, ecchymosis, erythemia, hypotension, tachycardia, coagulopathy with hypofibrinogenemia and thrombocytopenia, hematemesis, melena, epistaxis, hematuria, intracerebral hemorrhage and renal failure secondary to hypotension and bilateral cortical necrosis. There is usually some discoloration around the bite site and rashes may develop on the torso or the extremities.[2]
In general, death results from hypotension secondary to hypovolemia, renal failure and intracranial hemorrhage. Common complications include necrosis and renal failure secondary to hypovolemic shock and the toxic effects of the venom.[2]
# Species
*) Not including the nominate subspecies (typical form).
T) Type species.[1]
# Taxonomy
Other (new) species may be encountered in literature, such as:
- B. alcatraz - Marques, Martins & Sazima, 2002. Range: Brazil (São Paulo). Common name: jararaca-de-Alcatrazes.
- B. muriciensis - Ferrarezzi & Freire, 2001. Range: northeastern Brazil (Alagoas). Common name: Murici lancehead. | https://www.wikidoc.org/index.php/Bothrops | |
aa5ceb055c20ee875483cf7edffbc93d05c8df4a | wikidoc | Box plot | Box plot
# Overview
In descriptive statistics, a boxplot (also known as a box-and-whisker diagram or plot or candlestick chart) is a convenient way of graphically depicting groups of numerical data through their five-number summaries (the smallest observation, lower quartile (Q1), median, upper quartile (Q3), and largest observation). A boxplot also indicates which observations, if any, might be considered outliers. The boxplot was invented in 1977 by the American statistician John Tukey.
Boxplots are able to visually show different types of populations, without making any assumptions of the underlying statistical distribution. The spacings between the different parts of the box help indicate variance, skewness and identify outliers. Boxplots can be drawn either horizontally or vertically.
# Construction
For a data set, one constructs a horizontal box plot in the following manner:
- Calculate the first quartile (x.25), the median (x.50) and third quartile (x.75)
- Calculate the interquartile range (IQR) by subtracting the first quartile from the third quartile. (x.75-x.25)
- Construct a box above the number line bounded on the left by the first quartile (x.25) and on the right by the third quartile (x.75). The box may be as tall as one likes, although reasonably proportioned boxplots are customary.
- Indicate where the median lies inside of the box with the presence of a symbol or a line dividing the box at the median value.
- The mean value of the data can also be labeled with a point.
- Any data observation which lies more than 1.5*IQR lower than the first quartile or 1.5*IQR higher than the third quartile is considered an outlier. Indicate where the smallest value that is not an outlier is by a vertical tic mark or "whisker", and connect the whisker to the box via a horizontal line. Likewise, indicate where the largest value that is not an outlier is by a "whisker", and connect that whisker to the box via another horizontal line.
- Indicate outliers by open and closed dots. "Extreme" outliers, or those which lie more than three times the IQR to the left and right from the first and third quartiles, respectively, are indicated by the presence of an open dot. "Mild" outliers - that is, those observations which lie more than 1.5 times the IQR from the first and third quartile but are not also extreme outliers are indicated by the presence of a closed dot.
- Add an appropriate label to the number line and title the boxplot.
- A boxplot may be constructed in a similar manner vertically as opposed to horizontally by merely interchanging "bottom" for "left" and "top" for "right" in the above description.
# Example
A plain-text version might look like this:
For this data set:
- smallest non-outlier observation = 5 (left "whisker")
- lower (first) quartile (Q1, x.25) = 7
- median (second quartile) (Med, x.5) = 8.5
- upper (third) quartile (Q3, x.75) = 9
- largest non-outlier observation = 10
- interquartile range, IQR = Q3-Q1 = 2
- the value 3.5 is a "mild" outlier, between 1.5*(IQR) and 3*(IQR) below Q1
- the value 0.5 is an "extreme" outlier, more than 3*(IQR) below Q1
- the data is skewed to the left (negatively skewed)
The horizontal lines (the "whiskers") extend to at most 1.5 times the box width (the interquartile range) from either or both ends of the box. They must end at an observed value, thus connecting all the values outside the box that are not more than 1.5 times the box width away from the box. Three times the box width marks the boundary between "mild" and "extreme" outliers. In this boxplot, "mild" and "extreme" outliers are differentiated by closed and open dots, respectively.
There are alternative implementations of this detail of the box plot in various software packages, such as the whiskers extending to at most the 5th and 95th (or some more extreme) percentiles. Such approaches do not conform to Tukey's definition, with its emphasis on the median in particular and counting methods in general, and they tend to produce "outliers" for all data sets larger than ten, no matter what the shape of the distribution.
# Visualization
The boxplot is a quick graphic approach for examining one or more sets of data. Boxplots may seem more primitive than a histogram or probability density function (pdf) but they do have some advantages. Besides saving space on paper, boxplots are quicker to generate by hand. Histograms and probability density functions require assumptions of the statistical distribution. This assumption can be a major barrier because binning techniques can heavily influence the histogram and incorrect variance calculations will heavily affect the probability density function.
Because looking at a statistical distribution is more intuitive than looking at a boxplot, comparing the boxplot against the probability density function (theoretical histogram) for a normal N(0,1σ2) distribution may be a useful tool for understanding the boxplot (Figure 2). | Box plot
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In descriptive statistics, a boxplot (also known as a box-and-whisker diagram or plot or candlestick chart) is a convenient way of graphically depicting groups of numerical data through their five-number summaries (the smallest observation, lower quartile (Q1), median, upper quartile (Q3), and largest observation). A boxplot also indicates which observations, if any, might be considered outliers. The boxplot was invented in 1977 by the American statistician John Tukey.
Boxplots are able to visually show different types of populations, without making any assumptions of the underlying statistical distribution. The spacings between the different parts of the box help indicate variance, skewness and identify outliers. Boxplots can be drawn either horizontally or vertically.
# Construction
For a data set, one constructs a horizontal box plot in the following manner:
- Calculate the first quartile (x.25), the median (x.50) and third quartile (x.75)
- Calculate the interquartile range (IQR) by subtracting the first quartile from the third quartile. (x.75-x.25)
- Construct a box above the number line bounded on the left by the first quartile (x.25) and on the right by the third quartile (x.75). The box may be as tall as one likes, although reasonably proportioned boxplots are customary.
- Indicate where the median lies inside of the box with the presence of a symbol or a line dividing the box at the median value.
- The mean value of the data can also be labeled with a point.
- Any data observation which lies more than 1.5*IQR lower than the first quartile or 1.5*IQR higher than the third quartile is considered an outlier. Indicate where the smallest value that is not an outlier is by a vertical tic mark or "whisker", and connect the whisker to the box via a horizontal line. Likewise, indicate where the largest value that is not an outlier is by a "whisker", and connect that whisker to the box via another horizontal line.
- Indicate outliers by open and closed dots. "Extreme" outliers, or those which lie more than three times the IQR to the left and right from the first and third quartiles, respectively, are indicated by the presence of an open dot. "Mild" outliers - that is, those observations which lie more than 1.5 times the IQR from the first and third quartile but are not also extreme outliers are indicated by the presence of a closed dot.
- Add an appropriate label to the number line and title the boxplot.
- A boxplot may be constructed in a similar manner vertically as opposed to horizontally by merely interchanging "bottom" for "left" and "top" for "right" in the above description.
# Example
A plain-text version might look like this:
For this data set:
- smallest non-outlier observation = 5 (left "whisker")
- lower (first) quartile (Q1, x.25) = 7
- median (second quartile) (Med, x.5) = 8.5
- upper (third) quartile (Q3, x.75) = 9
- largest non-outlier observation = 10
- interquartile range, IQR = <math>Q3-Q1</math> = 2
- the value 3.5 is a "mild" outlier, between 1.5*(IQR) and 3*(IQR) below Q1
- the value 0.5 is an "extreme" outlier, more than 3*(IQR) below Q1
- the data is skewed to the left (negatively skewed)
The horizontal lines (the "whiskers") extend to at most 1.5 times the box width (the interquartile range) from either or both ends of the box. They must end at an observed value, thus connecting all the values outside the box that are not more than 1.5 times the box width away from the box. Three times the box width marks the boundary between "mild" and "extreme" outliers. In this boxplot, "mild" and "extreme" outliers are differentiated by closed and open dots, respectively.
There are alternative implementations of this detail of the box plot in various software packages, such as the whiskers extending to at most the 5th and 95th (or some more extreme) percentiles. Such approaches do not conform to Tukey's definition, with its emphasis on the median in particular and counting methods in general, and they tend to produce "outliers" for all data sets larger than ten, no matter what the shape of the distribution.
# Visualization
The boxplot is a quick graphic approach for examining one or more sets of data. Boxplots may seem more primitive than a histogram or probability density function (pdf) but they do have some advantages. Besides saving space on paper, boxplots are quicker to generate by hand. Histograms and probability density functions require assumptions of the statistical distribution. This assumption can be a major barrier because binning techniques can heavily influence the histogram and incorrect variance calculations will heavily affect the probability density function.
Because looking at a statistical distribution is more intuitive than looking at a boxplot, comparing the boxplot against the probability density function (theoretical histogram) for a normal N(0,1σ2) distribution may be a useful tool for understanding the boxplot (Figure 2). | https://www.wikidoc.org/index.php/Box_plot | |
2df44335791e9105a6c2d4c26208bddc1f02c609 | wikidoc | Boxthorn | Boxthorn
Boxthorn (Lycium) is a genus (tribe Lycieae, family Solanaceae) of about 90 species of plants native throughout much of the subtropical zones of the world, mostly found in dry, semi-saline environments.
Common names include wolfberry, desert-thorn, Christmas berry, Matrimony vine, and the confusing "Tea-tree" (it is not related to tea, and with the foliage being toxic, should not be used as such). Goji is a common English name made popular by several American-made juices and dried berries sometimes branded as "Tibetan" or "Himalayan" goji berries, although these terms do not geographically represent where the berries actually originate.
There are ~20 species in North America, ~30 species in South America, ~30 species in Africa, ~10 species in Eurasia, and one species in Australia. Grabowskia and Phrodus join Lycium in tribe Lycieae, and are the genera most closely related to Lycium.
They are long-lived, perennial, thorny shrubs, with deciduous alternate, simple leaves 1-8 cm long. The flowers are solitary or in small clusters, 6-25 mm diameter, with a corolla of five purple, white or greenish-white petals joined together at their bases. The fruit is fleshy, multiseeded berry 8-20 mm diameter that may be red, yellow, orange, purple or black. These fruit resemble nightshade and bittersweet berries. In some species, notably L. barbarum (Wolfberry), the fruit is edible (see that species for further detail).
Most species of Lycium are cosexual (all flowers have both male and female function), however, several species exhibit gender dimorphism. Evidence suggests that sexual dimorphism has evolved more than once in the Lycium genus. There are species that have both monecious and dioceous populations, most notably L. californicum.
The plant has been known to European herbalists since ancient times. In his Naturalis historia, Pliny the Elder describes Lycium as a medicinal plant (recommended as a treatment for sore eyes and inflammation), as does Pedanius Dioscorides in his P. Dioscoridae pharmacorum simplicium reique medicae (Hitchcock 1932). In his 1753 publication Species Plantarum, Linnaeus describes three Lycium species: L. afrum, L. barbarum, and L. europaeum (Hitchcock 1932).
## Uses
The fruit, leaves, and bark of certain species have been used in China throughout more than 2,000 years of recorded history. The fruit is known in China as gouqizi (枸杞子, wolfberry, Lycium barbarum), where it is used in herbal teas, soups, juices, and alcoholic beverages.
The berries may also be eaten whole and are used in this way for a variety of purposes in traditional Chinese medicine, as well as traditional Korean medicine, traditional Japanese medicine, and traditional Tibetan medicine.
The berry has a complex, rich nutrient and phytochemical profile among which its active ingredients include multiple essential vitamins, minerals, sources of dietary fiber, protein and numerous carotenoids, polyphenols, and polysaccharides (Gross et al., 2006).
Lycium species are used as food plants by the larvae of some Lepidoptera species including Coleophora vigilis (recorded on L. ferocissimum).
# Gallery
- African Boxthorn flower
African Boxthorn flower
- African Boxthorn shrub
African Boxthorn shrub
- Lycium intricatum
Lycium intricatum
- Lycium barbarum flower
Lycium barbarum flower | Boxthorn
Boxthorn (Lycium) is a genus (tribe Lycieae, family Solanaceae) of about 90 species of plants native throughout much of the subtropical zones of the world, mostly found in dry, semi-saline environments.
Common names include wolfberry, desert-thorn, Christmas berry, Matrimony vine, and the confusing "Tea-tree" (it is not related to tea, and with the foliage being toxic, should not be used as such). Goji is a common English name made popular by several American-made juices and dried berries sometimes branded as "Tibetan" or "Himalayan" goji berries, although these terms do not geographically represent where the berries actually originate[1].
There are ~20 species in North America, ~30 species in South America, ~30 species in Africa, ~10 species in Eurasia, and one species in Australia. Grabowskia and Phrodus join Lycium in tribe Lycieae, and are the genera most closely related to Lycium.
They are long-lived, perennial, thorny shrubs, with deciduous alternate, simple leaves 1-8 cm long. The flowers are solitary or in small clusters, 6-25 mm diameter, with a corolla of five purple, white or greenish-white petals joined together at their bases. The fruit is fleshy, multiseeded berry 8-20 mm diameter that may be red, yellow, orange, purple or black. These fruit resemble nightshade and bittersweet berries. In some species, notably L. barbarum (Wolfberry), the fruit is edible (see that species for further detail).
Most species of Lycium are cosexual (all flowers have both male and female function), however, several species exhibit gender dimorphism. Evidence suggests that sexual dimorphism has evolved more than once in the Lycium genus. There are species that have both monecious and dioceous populations, most notably L. californicum.
The plant has been known to European herbalists since ancient times. In his Naturalis historia, Pliny the Elder describes Lycium as a medicinal plant (recommended as a treatment for sore eyes and inflammation), as does Pedanius Dioscorides in his P. Dioscoridae pharmacorum simplicium reique medicae (Hitchcock 1932). In his 1753 publication Species Plantarum, Linnaeus describes three Lycium species: L. afrum, L. barbarum, and L. europaeum (Hitchcock 1932).
## Uses
The fruit, leaves, and bark of certain species have been used in China throughout more than 2,000 years of recorded history. The fruit is known in China as gouqizi (枸杞子, wolfberry, Lycium barbarum), where it is used in herbal teas, soups, juices, and alcoholic beverages.
The berries may also be eaten whole and are used in this way for a variety of purposes in traditional Chinese medicine, as well as traditional Korean medicine, traditional Japanese medicine, and traditional Tibetan medicine.
The berry has a complex, rich nutrient and phytochemical profile among which its active ingredients include multiple essential vitamins, minerals, sources of dietary fiber, protein and numerous carotenoids, polyphenols, and polysaccharides (Gross et al., 2006).
Lycium species are used as food plants by the larvae of some Lepidoptera species including Coleophora vigilis (recorded on L. ferocissimum).
# Gallery
- African Boxthorn flower
African Boxthorn flower
- African Boxthorn shrub
African Boxthorn shrub
- Lycium intricatum
Lycium intricatum
- Lycium barbarum flower
Lycium barbarum flower | https://www.wikidoc.org/index.php/Box_thorn_poisoning | |
47eb4628a8f2edc5c49bce07ea375704d99aa53f | wikidoc | Brassica | Brassica
Brassica (Brás-si-ca) is a genus of plants in the mustard family (Brassicaceae). The members of the genus may be collectively known either as cabbages, or as mustards. Crops from this genus are sometimes called cole crops.
This genus is remarkable for containing more important agricultural and horticultural crops than any other genus. It also includes a number of weeds, both wild taxa and escapees from cultivation. It includes over 30 wild species and hybrids, and numerous additional cultivars and hybrids of cultivated origin. Most are annuals or biennials, but some are small shrubs.
The genus is native in the wild in western Europe, the Mediterranean and temperate regions of Asia. In addition to the cultivated species, which are grown worldwide, many of the wild species grow as weeds, especially in North America, South America, and Australia.
Almost all parts of some species or other have been developed for food, including the root (swedes, turnips), stems (kohlrabi), leaves (cabbage, brussels sprouts), flowers (cauliflower, broccoli), and seeds (many, including mustard seed, oilseed rape). Some forms with white or purple foliage or flowerheads, are also sometimes grown for ornament.
Brassica species are sometimes used as food plants by the larvae of a number of Lepidoptera species - see List of Lepidoptera that feed on Brassica.
Due to their agricultural importance, Brassica plants have been the subject of much scientific interest. The close relationship between 6 particularly important species (Brassica carinata, B. juncea, B. oleracea, B. napus, B. nigra and B. rapa) is described by the Triangle of U theory.
Brassica vegetables are highly regarded for their nutritional value. They provide high amounts of vitamin C and soluble fiber and contain multiple nutrients with potent anti-cancer properties: 3,3'-Diindolylmethane, sulforaphane and selenium.
Researchers at the University of California at Berkeley have recently discovered that 3,3'-Diindolylmethane in Brassica vegetables is a potent modulator of the innate immune response system with potent anti-viral, anti-bacterial and anti-cancer activity.
# Species
There is some disagreement among botanists on the classification and status of Brassica species and subspecies. The following is an abbreviated list, with an emphasis on economically important species.
- B. carinata - Abyssinian Mustard or Abyssinian Cabbage, used to produce biodiesel.
- B. elongata - Elongated Mustard
- B. fruticulosa - Mediterranean Cabbage
- B. juncea - Indian Mustard, Brown and leaf mustards, Sarepta Mustard.
- B. napus - Rapeseed, Canola, Rutabaga (Swede Turnip), Nabicol
- B. narinosa - Broadbeaked Mustard
- B. nigra - Black Mustard
- B. oleracea - Kale, Cabbage, Broccoli, Cauliflower, Kai-lan, Brussels sprouts
- B. perviridis - Tender Green, Mustard Spinach
- B. rapa (syn B. campestris) - Chinese cabbage, Turnip, Rapini, Mustard, Komatsuna
- B. rupestris - Brown Mustard
- B. septiceps - Seventop Turnip
- B. tournefortii - Asian Mustard
## Deprecated species names
- B. kaber (Wild Mustard or Charlock) - see Sinapis arvensis
- B. alba or B. hirta (White or Yellow mustard) - see Sinapis alba
# Genome sequencing and genetics
The B. rapa genome is currently being sequenced by an international consortium. This also represents the A genome component of the amphidiploid crop species B. napus and B. juncea | Brassica
Brassica (Brás-si-ca) is a genus of plants in the mustard family (Brassicaceae). The members of the genus may be collectively known either as cabbages, or as mustards. Crops from this genus are sometimes called cole crops.[1]
This genus is remarkable for containing more important agricultural and horticultural crops than any other genus. It also includes a number of weeds, both wild taxa and escapees from cultivation. It includes over 30 wild species and hybrids, and numerous additional cultivars and hybrids of cultivated origin. Most are annuals or biennials, but some are small shrubs.
The genus is native in the wild in western Europe, the Mediterranean and temperate regions of Asia. In addition to the cultivated species, which are grown worldwide, many of the wild species grow as weeds, especially in North America, South America, and Australia.
Almost all parts of some species or other have been developed for food, including the root (swedes, turnips), stems (kohlrabi), leaves (cabbage, brussels sprouts), flowers (cauliflower, broccoli), and seeds (many, including mustard seed, oilseed rape). Some forms with white or purple foliage or flowerheads, are also sometimes grown for ornament.
Brassica species are sometimes used as food plants by the larvae of a number of Lepidoptera species - see List of Lepidoptera that feed on Brassica.
Due to their agricultural importance, Brassica plants have been the subject of much scientific interest. The close relationship between 6 particularly important species (Brassica carinata, B. juncea, B. oleracea, B. napus, B. nigra and B. rapa) is described by the Triangle of U theory.
Brassica vegetables are highly regarded for their nutritional value. They provide high amounts of vitamin C and soluble fiber and contain multiple nutrients with potent anti-cancer properties: 3,3'-Diindolylmethane, sulforaphane and selenium.
Researchers at the University of California at Berkeley have recently discovered that 3,3'-Diindolylmethane in Brassica vegetables is a potent modulator of the innate immune response system with potent anti-viral, anti-bacterial and anti-cancer activity.
# Species
There is some disagreement among botanists on the classification and status of Brassica species and subspecies. The following is an abbreviated list, with an emphasis on economically important species.
- B. carinata - Abyssinian Mustard or Abyssinian Cabbage, used to produce biodiesel.
- B. elongata - Elongated Mustard
- B. fruticulosa - Mediterranean Cabbage
- B. juncea - Indian Mustard, Brown and leaf mustards, Sarepta Mustard.
- B. napus - Rapeseed, Canola, Rutabaga (Swede Turnip), Nabicol
- B. narinosa - Broadbeaked Mustard
- B. nigra - Black Mustard
- B. oleracea - Kale, Cabbage, Broccoli, Cauliflower, Kai-lan, Brussels sprouts
- B. perviridis - Tender Green, Mustard Spinach
- B. rapa (syn B. campestris) - Chinese cabbage, Turnip, Rapini, Mustard, Komatsuna
- B. rupestris - Brown Mustard
- B. septiceps - Seventop Turnip
- B. tournefortii - Asian Mustard
## Deprecated species names
- B. kaber (Wild Mustard or Charlock) - see Sinapis arvensis
- B. alba or B. hirta (White or Yellow mustard) - see Sinapis alba
# Genome sequencing and genetics
The B. rapa genome is currently being sequenced by an international consortium. This also represents the A genome component of the amphidiploid crop species B. napus and B. juncea
.[2] | https://www.wikidoc.org/index.php/Brassica | |
13c32de31c3a9eed803e49b261de59b22504bc9c | wikidoc | Broccoli | Broccoli
Broccoli is a plant of the Cabbage family, Brassicaceae (formerly Cruciferae). It is classified as the Italica Cultivar Group of the species Brassica oleracea. Broccoli possesses abundant fleshy flower heads, usually green in color, arranged in a tree-like fashion on branches sprouting from a thick, edible stalk. The large mass of flower heads is surrounded by leaves. Broccoli most closely resembles cauliflower, which is a different cultivar group of the same species, but broccoli is green rather than white. In the United States, the term refers exclusively to the form with a single large head. This form is sometimes called "Calabrese" in the United Kingdom, where sprouting (non-heading) types and those with underdeveloped flower buds are also sold as broccoli.
# History
The word broccoli comes from the Latin broccolo, diminunitive of the term for a sprout. Broccoli is a cultivar of wild cabbage, remaining exactly the same species. Wild cabbage originated along the northern and western coasts of the Mediterranean, where it was apparently domesticated thousands of years ago. That domesticated cabbage was eventually bred into widely varying forms, including broccoli, cauliflower, cabbage, kale, kohlrabi, and brussels sprouts, all of which remain the same species.
Roman references to a cabbage-family vegetable that may have been broccoli are less than perfectly clear: the Roman natural history writer, Pliny the Elder, wrote about a vegetable that fit the description of broccoli. This would imply that the Romans grew their own broccoli for culinary uses during the 1st century. Some vegetable scholars recognize broccoli in the cookbook of Apicius.
Broccoli was an Italian vegetable, as its name suggests, long before it was eaten elsewhere. At that time it was a sprouting type, not the single large head that is seen today. It is first mentioned in France in 1560, but in 1724 broccoli was still so unfamiliar in England that Philip Miller's Gardener's Dictionary (1724 edition) referred to it as a stranger in England and explained it as "sprout colli-flower" or "Italian asparagus." In the American colonies, Thomas Jefferson was also an experimenting gardener with a wide circle of European correspondents, from whom he got packets of seeds for rare vegetables such as tomatoes. He noted the planting of broccoli at Monticello along with radishes, lettuce, and cauliflower on May 27 1767. Nevertheless, broccoli remained exotic in American gardens. In 1775, John Randolph, in A Treatise on Gardening by a Citizen of Virginia, felt he had to explain about broccoli: "The stems will eat like Asparagus, and the heads like cauliflower."
Italians brought broccoli to North America by 1806, but it did not become popular until the 1920s. Commercial cultivation of broccoli in the United States can be traced to the D'Arrigo brothers, Stephano and Andrea, Italian immigrants from Messina, whose company made some tentative plantings in San Jose, California, in 1922. A few crates were initially shipped to Boston, where there was a thriving Italian immigrant culture in the North End. The broccoli business boomed, with the D'Arrigo's brand name "Andy Boy" named after Stephano's two-year-old son, Andrew, and backed with advertisements on the radio.
# Varieties
There are three commonly grown types of broccoli. The most familiar is sometimes called Calabrese in Great Britain and simply 'broccoli' in North America. It has large (10 - 20 cm) green heads and thick stalks, and is named after Calabria in Italy where it was first cultivated. It is a cool season annual crop.
Sprouting broccoli has a larger number of heads with many thin stalks. It is planted in May to be harvested during the winter or early the following year in temperate climates.
Romanesco broccoli has a distinctive fractal appearance of its heads, and is yellow-green in colour. It is technically in the Botrytis (cauliflower) cultivar group
Purple cauliflower is a type of broccoli sold in southern Italy, Spain and the United Kingdom. It has a head shaped like cauliflower, but consisting of tiny flower buds. It sometimes, but not always, has a purple cast to the tips of the flower buds.
# Cultivation, preparation and nutritional value
Broccoli is a cool-weather crop that does poorly in hot summer weather. Other cultivar groups of Brassica oleracea include: cabbage (Capitata Group), cauliflower (Botrytis Group), kale and collard greens (Acephala Group), kohlrabi (Gongylodes Group), and Brussels sprouts (Gemmifera Group). Chinese broccoli (Alboglabra Group) is also a cultivar group of Brassica oleracea. It is usually boiled or steamed, but may be eaten raw and has become popular as a raw vegetable in hors-d'oeuvre trays.
Broccoli is high in vitamin C and soluble fiber and contains multiple nutrients with potent anti-cancer properties including diindolylmethane and selenium. The 3,3'-Diindolylmethane found in broccoli is a potent modulator of the innate immune response system with anti-viral, anti-bacterial and anti-cancer activity. Broccoli also contains the compound glucoraphanin, which can be processed into an anticancer compound sulforaphane, though the benefits of broccoli are reduced if the vegetable is boiled. A high intake of broccoli has been found to reduce the risk of aggressive prostate cancer. Broccoli leaf is also edible and contains far more betacarotene than the florets.
# In popular culture
In 1928, when broccoli was still something of a novelty in the United States, a cartoon appeared in the New Yorker magazine. A mother and child are seated at the table, and the mother says, "It's broccoli, dear." The child replies, "I say it's spinach, and I say the hell with it."
# In politics
United States President George H. W. Bush was known to have an active disdain for broccoli, having actually said so in an offhand remark during his presidency. In response, a powerful broccoli agriculture lobby sent several tons of it to the White House. This broccoli was promptly donated to the Capital Area Food Bank. His son, President George W. Bush, mentioned during a 2004 question-and-answer session that he doesn't mind broccoli, but does prefer the florets to the stalk.
# Gallery
- Extreme close-up of broccoli florets.
Extreme close-up of broccoli florets.
- Broccoli flowers.
Broccoli flowers.
- Two broccoli heads.
Two broccoli heads.
- Romanesco broccoli, showing fractal forms
Romanesco broccoli, showing fractal forms
- Steamed broccoli
Steamed broccoli
- Sicilian Purple Broccoli
Sicilian Purple Broccoli | Broccoli
Template:Infobox Cultivar
Broccoli is a plant of the Cabbage family, Brassicaceae (formerly Cruciferae). It is classified as the Italica Cultivar Group of the species Brassica oleracea. Broccoli possesses abundant fleshy flower heads, usually green in color, arranged in a tree-like fashion on branches sprouting from a thick, edible stalk. The large mass of flower heads is surrounded by leaves. Broccoli most closely resembles cauliflower, which is a different cultivar group of the same species, but broccoli is green rather than white. In the United States, the term refers exclusively to the form with a single large head. This form is sometimes called "Calabrese" in the United Kingdom, where sprouting (non-heading) types and those with underdeveloped flower buds are also sold as broccoli.
# History
The word broccoli comes from the Latin broccolo, diminunitive of the term for a sprout.[1] Broccoli is a cultivar of wild cabbage, remaining exactly the same species. Wild cabbage originated along the northern and western coasts of the Mediterranean, where it was apparently domesticated thousands of years ago.[2][3] That domesticated cabbage was eventually bred into widely varying forms, including broccoli, cauliflower, cabbage, kale, kohlrabi, and brussels sprouts, all of which remain the same species.
Roman references to a cabbage-family vegetable that may have been broccoli are less than perfectly clear: the Roman natural history writer, Pliny the Elder, wrote about a vegetable that fit the description of broccoli. This would imply that the Romans grew their own broccoli for culinary uses during the 1st century[4]. Some vegetable scholars recognize broccoli in the cookbook of Apicius.
Broccoli was an Italian vegetable, as its name suggests, long before it was eaten elsewhere. At that time it was a sprouting type, not the single large head that is seen today. It is first mentioned in France in 1560, but in 1724 broccoli was still so unfamiliar in England that Philip Miller's Gardener's Dictionary (1724 edition) referred to it as a stranger in England and explained it as "sprout colli-flower" or "Italian asparagus." In the American colonies, Thomas Jefferson was also an experimenting gardener with a wide circle of European correspondents, from whom he got packets of seeds for rare vegetables such as tomatoes. He noted the planting of broccoli at Monticello along with radishes, lettuce, and cauliflower on May 27 1767. Nevertheless, broccoli remained exotic in American gardens. In 1775, John Randolph, in A Treatise on Gardening by a Citizen of Virginia, felt he had to explain about broccoli: "The stems will eat like Asparagus, and the heads like cauliflower."
Italians brought broccoli to North America by 1806[5], but it did not become popular until the 1920s. Commercial cultivation of broccoli in the United States can be traced to the D'Arrigo brothers, Stephano and Andrea, Italian immigrants from Messina, whose company made some tentative plantings in San Jose, California, in 1922. A few crates were initially shipped to Boston, where there was a thriving Italian immigrant culture in the North End. The broccoli business boomed, with the D'Arrigo's brand name "Andy Boy" named after Stephano's two-year-old son, Andrew, and backed with advertisements on the radio.
# Varieties
There are three commonly grown types of broccoli. The most familiar is sometimes called Calabrese in Great Britain and simply 'broccoli' in North America. It has large (10 - 20 cm) green heads and thick stalks, and is named after Calabria in Italy where it was first cultivated. It is a cool season annual crop.
Sprouting broccoli has a larger number of heads with many thin stalks. It is planted in May to be harvested during the winter or early the following year in temperate climates.
Romanesco broccoli has a distinctive fractal appearance of its heads, and is yellow-green in colour. It is technically in the Botrytis (cauliflower) cultivar group
Purple cauliflower is a type of broccoli sold in southern Italy, Spain and the United Kingdom. It has a head shaped like cauliflower, but consisting of tiny flower buds. It sometimes, but not always, has a purple cast to the tips of the flower buds.
# Cultivation, preparation and nutritional value
Template:Nutritionalvalue
Broccoli is a cool-weather crop that does poorly in hot summer weather. Other cultivar groups of Brassica oleracea include: cabbage (Capitata Group), cauliflower (Botrytis Group), kale and collard greens (Acephala Group), kohlrabi (Gongylodes Group), and Brussels sprouts (Gemmifera Group). Chinese broccoli (Alboglabra Group) is also a cultivar group of Brassica oleracea. It is usually boiled or steamed, but may be eaten raw and has become popular as a raw vegetable in hors-d'oeuvre trays.
Broccoli is high in vitamin C and soluble fiber and contains multiple nutrients with potent anti-cancer properties including diindolylmethane and selenium. The 3,3'-Diindolylmethane found in broccoli is a potent modulator of the innate immune response system with anti-viral, anti-bacterial and anti-cancer activity.[6] [7] Broccoli also contains the compound glucoraphanin, which can be processed into an anticancer compound sulforaphane, though the benefits of broccoli are reduced if the vegetable is boiled.[8] A high intake of broccoli has been found to reduce the risk of aggressive prostate cancer.[9] Broccoli leaf is also edible and contains far more betacarotene than the florets.
# In popular culture
In 1928, when broccoli was still something of a novelty in the United States, a cartoon appeared in the New Yorker magazine. A mother and child are seated at the table, and the mother says, "It's broccoli, dear." The child replies, "I say it's spinach, and I say the hell with it."[10]
# In politics
United States President George H. W. Bush was known to have an active disdain for broccoli, having actually said so in an offhand remark during his presidency.[11] In response, a powerful broccoli agriculture lobby sent several tons of it to the White House. This broccoli was promptly donated to the Capital Area Food Bank.[12] His son, President George W. Bush, mentioned during a 2004 question-and-answer session that he doesn't mind broccoli, but does prefer the florets to the stalk.[13]
# Gallery
- Extreme close-up of broccoli florets.
Extreme close-up of broccoli florets.
- Broccoli flowers.
Broccoli flowers.
- Two broccoli heads.
Two broccoli heads.
- Romanesco broccoli, showing fractal forms
Romanesco broccoli, showing fractal forms
- Steamed broccoli
Steamed broccoli
- Sicilian Purple Broccoli
Sicilian Purple Broccoli | https://www.wikidoc.org/index.php/Broccoli | |
10d7763cc04073799277160b36ad267066191b76 | wikidoc | Brodmann | Brodmann
# Overview
Korbinian Brodmann (November 17, 1868 - August 22, 1918) was a German neurologist who became famous for his definition of the cerebral cortex into 52 distinct regions from their cytoarchitectonic (histological) characteristics. These areas are now usually referred to as Brodmann areas. Some of these areas were later associated to nervous functions, such as areas 41 and 42 in the temporal lobe (related to hearing), areas 1, 2 and 3 in the postcentral gyrus of the parietal lobe (the somatosensory region), and the areas 17 and 18 in the occipital lobe (the primary visual areas).
# Historical Perspective
Brodmann studied medicine in Munich, Würzburg, Berlin and Freiburg, where he received his medical diploma in 1895. Subsequently he studied at the Medical School in the University of Lausanne in Switzerland, and then worked in the University Clinic in Munich. He got a doctor of medicine degree from the University of Leipzig in 1898, with a thesis on chronical ependymal sclerosis. He worked also in the Psychiatric Clinic in the University of Jena, with Ludwig Binswanger, and in the Municipal Mental Asylum in Frankfurt, from 1900 to 1901. There, he met Alois Alzheimer, who was influential in his decision to pursue neuroscientific basic research.
Following this, Brodmann started to work in 1901 with Cécile and Oskar Vogt at the private institute "Neurobiologischen Zentralstation" in Berlin, and in 1902 in the Neurobiological Laboratory of the University of Berlin. In 1915 he joined the Kaiser-Wilhelm-Institut für Hirnforschung (Institute for Brain Research).
In 1909 he published his original research on cortical cytoarchitectonics in "Vergleichende Lokalisationslehre der Großhirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues" (Comparative Localization Studies in the Brain Cortex, its Fundamentals Represented on the Basis of its Cellular Architecture).
In the following years he worked at the University of Tübingen, where he was habilitated and made a full professor in 1913, and from 1910 to 1916 as physician and chairman of the Anatomical Laboratory at the University Psychiatric Clinic. In 1916 he moved to Halle in order to work in the Nietleben Municipal Hospital. Finally, in 1918, he accepted an invitation from the University of Munich to direct the group of histology at Psychiatric Research Center.
He died in Munich rather suddenly of a generalized septic infection following a pneumonia, barely under 50 years of age on August 22, 1918. | Brodmann
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Korbinian Brodmann (November 17, 1868 - August 22, 1918) was a German neurologist who became famous for his definition of the cerebral cortex into 52 distinct regions from their cytoarchitectonic (histological) characteristics. These areas are now usually referred to as Brodmann areas. Some of these areas were later associated to nervous functions, such as areas 41 and 42 in the temporal lobe (related to hearing), areas 1, 2 and 3 in the postcentral gyrus of the parietal lobe (the somatosensory region), and the areas 17 and 18 in the occipital lobe (the primary visual areas).
# Historical Perspective
Brodmann studied medicine in Munich, Würzburg, Berlin and Freiburg, where he received his medical diploma in 1895. Subsequently he studied at the Medical School in the University of Lausanne in Switzerland, and then worked in the University Clinic in Munich. He got a doctor of medicine degree from the University of Leipzig in 1898, with a thesis on chronical ependymal sclerosis. He worked also in the Psychiatric Clinic in the University of Jena, with Ludwig Binswanger, and in the Municipal Mental Asylum in Frankfurt, from 1900 to 1901. There, he met Alois Alzheimer, who was influential in his decision to pursue neuroscientific basic research.
Following this, Brodmann started to work in 1901 with Cécile and Oskar Vogt at the private institute "Neurobiologischen Zentralstation" in Berlin, and in 1902 in the Neurobiological Laboratory of the University of Berlin. In 1915 he joined the Kaiser-Wilhelm-Institut für Hirnforschung (Institute for Brain Research).
In 1909 he published his original research on cortical cytoarchitectonics in "Vergleichende Lokalisationslehre der Großhirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues" (Comparative Localization Studies in the Brain Cortex, its Fundamentals Represented on the Basis of its Cellular Architecture).
In the following years he worked at the University of Tübingen, where he was habilitated and made a full professor in 1913, and from 1910 to 1916 as physician and chairman of the Anatomical Laboratory at the University Psychiatric Clinic. In 1916 he moved to Halle in order to work in the Nietleben Municipal Hospital. Finally, in 1918, he accepted an invitation from the University of Munich to direct the group of histology at Psychiatric Research Center.
He died in Munich rather suddenly of a generalized septic infection following a pneumonia, barely under 50 years of age on August 22, 1918. | https://www.wikidoc.org/index.php/Brodmann | |
460871a1efbfc21faea4b7c93b28131935a8bc55 | wikidoc | Bronchus | Bronchus
# Overview
A bronchus (plural bronchi, adjective bronchial) is a caliber of airway in the respiratory tract that conducts air into the lungs. No gas exchange takes place in this part of the lungs.
# Anatomy
The trachea (windpipe) divides into two main bronchi (also mainstem bronchi), the left and the right, at the level of the sternal angle. The right main bronchus is wider, shorter, and more vertical than the left main bronchus. The right main bronchus subdivides into three segmental bronchi while the left main bronchus divides into two. The lobar bronchi divide into tertiary bronchi. Each of the segmental bronchi supplies a bronchopulmonary segment. A bronchopulmonary segment is a division of a lung that is separated from the rest of the lung by a connective tissue septum. This property allows a bronchopulmonary segment to be surgically removed without affecting other segments. There are ten segments per lung, but due to anatomic development, several segmental bronchi in the left lung fuse, giving rise to eight. The segmental bronchi divide into many primary bronchioles which divide into terminal bronchioles, each of which then gives rise to several respiratory bronchioles, which go on to divide into 2 to 11 alveolar ducts. There are 5 or 6 alveolar sacs associated with each alveolar duct. The alveolus is the basic anatomical unit of gas exchange in the lung.
There is hyaline cartilage present in the bronchi, present as irregular rings in the larger bronchi (and not as regular as in the trachea), and as small plates and islands in the smaller bronchi. Smooth muscle is present continuously around the bronchi.
In the mediastinum, at the level of the fifth thoracic vertebra, the trachea divides into the right and left primary bronchi. The bronchi branch into smaller and smaller passageways until they terminate in tiny air sacs called alveoli.
The cartilage and mucous membrane of the primary bronchi are similar to that in the trachea. As the branching continues through the bronchial tree, the amount of hyaline cartilage in the walls decreases until it is absent in the smallest bronchioles. As the cartilage decreases, the amount of smooth muscle increases. The mucous membrane also undergoes a transition from ciliated pseudostratified columnar epithelium to simple cuboidal epithelium to simple squamous epithelium.
The alveolar ducts and alveoli consist primarily of simple squamous epithelium, which permits rapid diffusion of oxygen and carbon dioxide. Exchange of gases between the air in the lungs and the blood in the capillaries occurs across the walls of the alveolar ducts and alveoli.
# Role in disease
Bronchitis is defined as inflammation of the bronchi. There are two main types: acute and chronic. Acute bronchitis is usually caused by viral or bacterial infections. Chronic bronchitis is a form of COPD, usually associated with smoking or long-term exposure to irritants.
Asthma is hyperreactivity of the bronchi with an inflammatory component, often in response to allergens.
While the left mainstem bronchus departs from the trachea at an angle, the right mainstem bronchus is almost a vertical continuation of the trachea. This anatomy predisposes the right lung to several problems:
- If food, liquids, or foreign bodies are aspirated, they often will lodge in the right mainstem bronchus. Aspiration pneumonia may result.
- If the endotracheal tube used for intubation is inserted too far, it usually lodges in the right mainstem bronchus. This allows ventilation of the right lung, but leaves the left lung useless.
- Patients with inadequate cough reflexes may develop chronic right middle lobe lung infections such as the Lady Windermere Syndrome.
# Additional images
- Cross sectional cut of a human secondary bronchus
- Transverse section of thorax, showing relations of pulmonary artery. | Bronchus
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A bronchus (plural bronchi, adjective bronchial) is a caliber of airway in the respiratory tract that conducts air into the lungs. No gas exchange takes place in this part of the lungs.
# Anatomy
The trachea (windpipe) divides into two main bronchi (also mainstem bronchi), the left and the right, at the level of the sternal angle. The right main bronchus is wider, shorter, and more vertical than the left main bronchus. The right main bronchus subdivides into three segmental bronchi while the left main bronchus divides into two. The lobar bronchi divide into tertiary bronchi. Each of the segmental bronchi supplies a bronchopulmonary segment. A bronchopulmonary segment is a division of a lung that is separated from the rest of the lung by a connective tissue septum. This property allows a bronchopulmonary segment to be surgically removed without affecting other segments. There are ten segments per lung, but due to anatomic development, several segmental bronchi in the left lung fuse, giving rise to eight. The segmental bronchi divide into many primary bronchioles which divide into terminal bronchioles, each of which then gives rise to several respiratory bronchioles, which go on to divide into 2 to 11 alveolar ducts. There are 5 or 6 alveolar sacs associated with each alveolar duct. The alveolus is the basic anatomical unit of gas exchange in the lung.
There is hyaline cartilage present in the bronchi, present as irregular rings in the larger bronchi (and not as regular as in the trachea), and as small plates and islands in the smaller bronchi. Smooth muscle is present continuously around the bronchi.
In the mediastinum, at the level of the fifth thoracic vertebra, the trachea divides into the right and left primary bronchi. The bronchi branch into smaller and smaller passageways until they terminate in tiny air sacs called alveoli.
The cartilage and mucous membrane of the primary bronchi are similar to that in the trachea. As the branching continues through the bronchial tree, the amount of hyaline cartilage in the walls decreases until it is absent in the smallest bronchioles. As the cartilage decreases, the amount of smooth muscle increases. The mucous membrane also undergoes a transition from ciliated pseudostratified columnar epithelium to simple cuboidal epithelium to simple squamous epithelium.
The alveolar ducts and alveoli consist primarily of simple squamous epithelium, which permits rapid diffusion of oxygen and carbon dioxide. Exchange of gases between the air in the lungs and the blood in the capillaries occurs across the walls of the alveolar ducts and alveoli.
# Role in disease
Bronchitis is defined as inflammation of the bronchi. There are two main types: acute and chronic. Acute bronchitis is usually caused by viral or bacterial infections. Chronic bronchitis is a form of COPD, usually associated with smoking or long-term exposure to irritants.
Asthma is hyperreactivity of the bronchi with an inflammatory component, often in response to allergens.
While the left mainstem bronchus departs from the trachea at an angle, the right mainstem bronchus is almost a vertical continuation of the trachea. This anatomy predisposes the right lung to several problems:
- If food, liquids, or foreign bodies are aspirated, they often will lodge in the right mainstem bronchus. Aspiration pneumonia may result.
- If the endotracheal tube used for intubation is inserted too far, it usually lodges in the right mainstem bronchus. This allows ventilation of the right lung, but leaves the left lung useless.
- Patients with inadequate cough reflexes may develop chronic right middle lobe lung infections such as the Lady Windermere Syndrome.
# Additional images
- Cross sectional cut of a human secondary bronchus
- Transverse section of thorax, showing relations of pulmonary artery. | https://www.wikidoc.org/index.php/Bronchi | |
4a32f775aa21ed180b42ddf1e76ae08db94fc5c0 | wikidoc | Bronopol | Bronopol
# Overview
Bronopol (INN) is a highly active antimicrobial chemical compound whose chemical formula is 2-bromo-2-nitropropane-1,3-diol.
Bronopol was invented by The Boots Company PLC, Nottingham, England in the early 1960s and first applications were as a preservative for pharmaceuticals. Bronopol's low mammalian toxicity (at in-use levels) and exceptional activity against bacteria (especially the troublesome Gram-negative species) ensured that it became popular as a preservative in many consumer products such as shampoos and cosmetics.
Bronopol was subsequently taken up as an effective antimicrobial in many industrial environments such as paper mills, oil exploration and production facilities, as well as cooling water disinfection plants.
World production soared from the tens of tonnes in the late 1970s to current estimates in excess of 5,000 tonnes. This is quite something considering the effective use-concentration which can be as low as 0.0025% (25 parts per million). Manufacturing today is the business of low cost producers, mainly in China.
Pharmaceutical products containing Bronopol are registered in a number of countries and Bronopol is the subject of a specific monograph in the British Pharmacopoeia 1998.
# Applications
Today, Bronopol is used in consumer products as an effective preservative agent, as well as a wide variety of industrial applications (almost any industrial water system is a potential environment for bacterial growth, leading to slime and corrosion problems - in many of these systems Bronopol can be a highly effective treatment).
It is also used as a substitute for Formaldehyde in chemical toilets.
The use of Bronopol in personal care products (cosmetics, toiletries) has declined since the late 1980s due to the recognized potential for nitrosamine formation.
## The Nitrosamine Problem
Although fairly ubiquitous in our diet and the environment, and even produced within the stomach from various foodstuffs, many nitrosamines are known or suspect carcinogens and therefore should be avoided in manufactured goods.
Nitrosamines are relatively easily produced from secondary amines and amides in the presence of nitrite ions (this is why they are formed in-vivo from foodstuffs).
While Bronopol is not in itself a nitrosating agent, under conditions where it decomposes (alkaline solution and/or elevated temperatures) it can liberate nitrite and low levels of formaldehyde and these decomposition products can react with any contaminant secondary amines or amides in a personal care formulation to produce significant levels of nitrosamines (due to the toxicity of thes substances, the term 'significant' means levels as low as 10s of parts per billion).
Manufacturers of personal care products are therefore instructed by regulatory authorities to 'avoid the formation of nitrosamines' which might mean removing amines or amides from the formulation, removing Bronopol from a formulation, or using nitrosamine inhibitors.
# Physical and chemical properties
## Appearance
Bronopol is supplied as crystals or crystalline powder, which may vary from white to pale yellow in colour depending on the grade of material being offered.
## Melting point
As a pure material, Bronopol has a melting point of about 130°C. However due to its polymorphic characteristics, Bronopol undergoes a lattice rearrangement at 100 to 105°C and this can often be wrongly interpreted as the melting point.
At temperatures above 140°C Bronopol will decompose exothermically releasing Hydrogen bromide and oxides of Nitrogen.
## Solubility
Bronopol is readily soluble in water although the dissolution process is endothermic. Solutions containing up to 28% w/v are possible at ambient temperature.
Bronopol is poorly soluble in non-polar solvents but shows a high affinity for polar organic solvents.
## Partition coefficient
Study of the solubility data clearly shows that Bronopol has a high affinity for polar rather than non-polar environments. In two phase systems, Bronopol partitions preferentially into the polar (usually aqueous) phase.
## Stability in aqueous solution
In aqueous solutions, Bronopol is most stable when the pH of the system is on the acid side of neutral. Temperature also has a significant effect on stability in alkaline systems.
## Degradation
When conditions are such that Bronopol decomposes in aqueous solution, very low levels of formaldehyde are produced. Liberated formaldehyde is not responsible for the biological activity associated with Bronopol.
Amongst other decomposition products detected after Bronopol breakdown are, bromide ion, nitrite ion, Bromonitroethanol and 2-Hydroxymethyl-2-nitropropane-1,3-diol. | Bronopol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bronopol (INN) is a highly active antimicrobial chemical compound whose chemical formula is 2-bromo-2-nitropropane-1,3-diol.
Bronopol was invented by The Boots Company PLC, Nottingham, England in the early 1960s and first applications were as a preservative for pharmaceuticals. Bronopol's low mammalian toxicity (at in-use levels) and exceptional activity against bacteria (especially the troublesome Gram-negative species) ensured that it became popular as a preservative in many consumer products such as shampoos and cosmetics.
Bronopol was subsequently taken up as an effective antimicrobial in many industrial environments such as paper mills, oil exploration and production facilities, as well as cooling water disinfection plants.
World production soared from the tens of tonnes in the late 1970s to current estimates in excess of 5,000 tonnes. This is quite something considering the effective use-concentration which can be as low as 0.0025% (25 parts per million). Manufacturing today is the business of low cost producers, mainly in China.
Pharmaceutical products containing Bronopol are registered in a number of countries and Bronopol is the subject of a specific monograph in the British Pharmacopoeia 1998.
# Applications
Today, Bronopol is used in consumer products as an effective preservative agent, as well as a wide variety of industrial applications (almost any industrial water system is a potential environment for bacterial growth, leading to slime and corrosion problems - in many of these systems Bronopol can be a highly effective treatment).
It is also used as a substitute for Formaldehyde in chemical toilets.
The use of Bronopol in personal care products (cosmetics, toiletries) has declined since the late 1980s due to the recognized potential for nitrosamine formation.
## The Nitrosamine Problem
Although fairly ubiquitous in our diet and the environment, and even produced within the stomach from various foodstuffs, many nitrosamines are known or suspect carcinogens and therefore should be avoided in manufactured goods.
Nitrosamines are relatively easily produced from secondary amines and amides in the presence of nitrite ions (this is why they are formed in-vivo from foodstuffs).
While Bronopol is not in itself a nitrosating agent, under conditions where it decomposes (alkaline solution and/or elevated temperatures) it can liberate nitrite and low levels of formaldehyde and these decomposition products can react with any contaminant secondary amines or amides in a personal care formulation to produce significant levels of nitrosamines (due to the toxicity of thes substances, the term 'significant' means levels as low as 10s of parts per billion).
Manufacturers of personal care products are therefore instructed by regulatory authorities to 'avoid the formation of nitrosamines' which might mean removing amines or amides from the formulation, removing Bronopol from a formulation, or using nitrosamine inhibitors.
# Physical and chemical properties
## Appearance
Bronopol is supplied as crystals or crystalline powder, which may vary from white to pale yellow in colour depending on the grade of material being offered.
## Melting point
As a pure material, Bronopol has a melting point of about 130°C. However due to its polymorphic characteristics, Bronopol undergoes a lattice rearrangement at 100 to 105°C and this can often be wrongly interpreted as the melting point.
At temperatures above 140°C Bronopol will decompose exothermically releasing Hydrogen bromide and oxides of Nitrogen.
## Solubility
Bronopol is readily soluble in water although the dissolution process is endothermic. Solutions containing up to 28% w/v are possible at ambient temperature.
Bronopol is poorly soluble in non-polar solvents but shows a high affinity for polar organic solvents.
## Partition coefficient
Study of the solubility data clearly shows that Bronopol has a high affinity for polar rather than non-polar environments. In two phase systems, Bronopol partitions preferentially into the polar (usually aqueous) phase.
## Stability in aqueous solution
In aqueous solutions, Bronopol is most stable when the pH of the system is on the acid side of neutral. Temperature also has a significant effect on stability in alkaline systems.
## Degradation
When conditions are such that Bronopol decomposes in aqueous solution, very low levels of formaldehyde are produced. Liberated formaldehyde is not responsible for the biological activity associated with Bronopol.
Amongst other decomposition products detected after Bronopol breakdown are, bromide ion, nitrite ion, Bromonitroethanol and 2-Hydroxymethyl-2-nitropropane-1,3-diol. | https://www.wikidoc.org/index.php/Bronopol | |
efeccc7649f7c291d8e391a88bdd224f8ec2d0f8 | wikidoc | Brucella | Brucella
# Overview
Human brucellosis is caused by four Brucellae species: B. abortus, B. canis, B. melitensis, and B. suis.
# Causes
- Brucella is a genus of gram-negative bacteria.They are small (0.5 to 0.7 by 0.6 to 1.5 µm), non-motile and encapsulated coccobacilli.
## Brucella species
Brucella species have been found primarily in mammals. Brucellla species, with their host and degree of virulence is described below:
## Tests to differentiate brucella species
Following tests may be used to differentiate between the different species of brucella. | Brucella
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Danitza Lukac, Vishal Devarkonda, M.B.B.S[2]
# Overview
Human brucellosis is caused by four Brucellae species: B. abortus, B. canis, B. melitensis, and B. suis.[1]
# Causes
- Brucella is a genus of gram-negative bacteria.[2]They are small (0.5 to 0.7 by 0.6 to 1.5 µm), non-motile and encapsulated coccobacilli.
## Brucella species
Brucella species have been found primarily in mammals. [3] Brucellla species, with their host and degree of virulence is described below:[4]
## Tests to differentiate brucella species
Following tests may be used to differentiate between the different species of brucella.[5] | https://www.wikidoc.org/index.php/Brucella | |
ce66dda071beb8bd6b8251f34f2d5693fb3c7e00 | wikidoc | Buformin | Buformin
# Overview
Buformin (1-butylbiguanide) is an oral antidiabetic drug of the biguanide class, chemically related to metformin and phenformin. Buformin was marketed by German pharmaceutical company Grünenthal as Silubin.
# Chemistry and animal toxicology
Buformin hydrochloride is a fine, white to slightly yellow, crystalline, odorless powder, with a weakly acidic bitter taste. Its melting point is 174 to 177 °C, it is a strong base, and is freely soluble in water, methanol and ethanol, but insoluble in chloroform and ether. Toxicity: guinea pig LD50 subcutaneous 18 mg/kg; mouse LD50 intraperitoneal 140 mg/kg and 300 mg/kg oral. The partition coefficient (log P in octanol-water) is -1.20E+00; its water solubility is 7.46E+05 mg/l at 25 °C. Vapor pressure is 1.64E-04 mm Hg at 25 °C (EST); Henry's law constant is 8.14E-16 atm-m3/mole at 25 °C (EST). Its Atmospheric -OH rate constant is 1.60E-10 cm3/molecule-sec at 25 °C.
# Mechanism of action
Buformin delays absorption of glucose from the gastrointestinal tract, increases insulin sensitivity and glucose uptake into cells, and inhibits synthesis of glucose by the liver. Buformin and the other biguanides are not hypoglycemic, but rather antihyperglycemic agents. They do not produce hypoglycemia; instead, they reduce basal and postprandial hyperglycemia in diabetics. Biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.
# Pharmacokinetics
After oral administration of 50 mg of buformin to volunteers, almost 90% of the applied quantity was recovered in the urine; the rate constant of elimination was found to be 0.38 per hr. Buformin is a strong base (pKa = 11.3) and not absorbed in the stomach. After intravenous injection of about 1 mg/kg buformin-14-C, the initial serum concentration is 0.2-0.4 µg/ml. Serum level and urinary elimination rate are linearly correlated. In man, after oral administration of 50 mg 14-C-buformin, the maximum serum concentration was 0.26-0.41 µg/ml. The buformin was eliminated with an average half-life of 2 h. About 84% of the dose administered was found excreted unchanged in the urine. Buformin is not metabolized in humans. The bioavailability of oral buformin and other biguanides is 40%-60%. Binding to plasma proteins is absent or very low.
# Dosage
The daily dose of buformin is 150–300 mg by mouth. Buformin has also been available in a sustained release preparation, Silubin Retard, which is still sold in Romania.
# Side effects and cotraindications
The side effect encountered are anorexia, nausea, diarrhea, metallic taste, and weight loss. Its use is contrindicated by
diabetic coma, ketoacidosis, severe infection, trauma, other severe infections where buformin is unlikely to control the hyperglycemia, renal or hepatic impairment, heart failure, recent myocardial infarct, dehydration, alcoholism, and conditions likely to predispose to lactic acidosis.
# Toxicity
Buformin was withdrawn from the market in many countries due to an elevated risk of causing lactic acidosis (although not the US, where it was never sold). Buformin is still available and prescribed in Romania (timed release Silubin Retard is sold by Zentiva), Hungary, Taiwan and Japan. The lactic acidosis occurred only in patients with a buformin plasma level of greater than 0.60 µg/ml and was rare in patients with normal renal function.
In one report, the toxic oral dose was 329 ± 30 mg/day in 24 patients who developed lactic acidosis on buformin. Another group of 24 patients on 258 ± 25 mg/day did not develop lactic acidosis on buformin.
# Anticancer properties
Buformin, along with phenformin and metformin, inhibits the growth and development of cancer. The anticancer property of these drugs is due to their ability to disrupt the Warburg effect and revert the cytosolic glycolysis characteristic of cancer cells to normal oxidation of pyruvate by the mitochondria. Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.
# History
Buformin was synthesized as an oral antidiabetic in 1957. | Buformin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Buformin (1-butylbiguanide) is an oral antidiabetic drug of the biguanide class, chemically related to metformin and phenformin. Buformin was marketed by German pharmaceutical company Grünenthal as Silubin.
# Chemistry and animal toxicology
Buformin hydrochloride is a fine, white to slightly yellow, crystalline, odorless powder, with a weakly acidic bitter taste. Its melting point is 174 to 177 °C, it is a strong base, and is freely soluble in water, methanol and ethanol, but insoluble in chloroform and ether.[1][2] Toxicity: guinea pig LD50 subcutaneous 18 mg/kg; mouse LD50 intraperitoneal 140 mg/kg and 300 mg/kg oral.[3] The partition coefficient (log P in octanol-water) is -1.20E+00; its water solubility is 7.46E+05 mg/l at 25 °C. Vapor pressure is 1.64E-04 mm Hg at 25 °C (EST); Henry's law constant is 8.14E-16 atm-m3/mole at 25 °C (EST). Its Atmospheric -OH rate constant is 1.60E-10 cm3/molecule-sec at 25 °C.[4]
# Mechanism of action
Buformin delays absorption of glucose from the gastrointestinal tract, increases insulin sensitivity and glucose uptake into cells, and inhibits synthesis of glucose by the liver. Buformin and the other biguanides are not hypoglycemic, but rather antihyperglycemic agents. They do not produce hypoglycemia; instead, they reduce basal and postprandial hyperglycemia in diabetics.[5] Biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.[6]
# Pharmacokinetics
After oral administration of 50 mg of buformin to volunteers, almost 90% of the applied quantity was recovered in the urine; the rate constant of elimination was found to be 0.38 per hr. Buformin is a strong base (pKa = 11.3) and not absorbed in the stomach. After intravenous injection of about 1 mg/kg buformin-14-C, the initial serum concentration is 0.2-0.4 µg/ml. Serum level and urinary elimination rate are linearly correlated.[7] In man, after oral administration of 50 mg 14-C-buformin, the maximum serum concentration was 0.26-0.41 µg/ml. The buformin was eliminated with an average half-life of 2 h. About 84% of the dose administered was found excreted unchanged in the urine.[8] Buformin is not metabolized in humans. The bioavailability of oral buformin and other biguanides is 40%-60%. Binding to plasma proteins is absent or very low.[9][10][11]
# Dosage
The daily dose of buformin is 150–300 mg by mouth.[12] Buformin has also been available in a sustained release preparation, Silubin Retard, which is still sold in Romania.
# Side effects and cotraindications
The side effect encountered are anorexia, nausea, diarrhea, metallic taste, and weight loss. Its use is contrindicated by
diabetic coma, ketoacidosis, severe infection, trauma, other severe infections where buformin is unlikely to control the hyperglycemia, renal or hepatic impairment, heart failure, recent myocardial infarct, dehydration, alcoholism, and conditions likely to predispose to lactic acidosis.
# Toxicity
Buformin was withdrawn from the market in many countries due to an elevated risk of causing lactic acidosis (although not the US, where it was never sold). Buformin is still available and prescribed in Romania (timed release Silubin Retard is sold by Zentiva), Hungary,[13][14][15][16] Taiwan[17] and Japan.[18] The lactic acidosis occurred only in patients with a buformin plasma level of greater than 0.60 µg/ml and was rare in patients with normal renal function.[19][20][21]
In one report, the toxic oral dose was 329 ± 30 mg/day in 24 patients who developed lactic acidosis on buformin. Another group of 24 patients on 258 ± 25 mg/day did not develop lactic acidosis on buformin.[22]
# Anticancer properties
Buformin, along with phenformin and metformin, inhibits the growth and development of cancer.[23][24][25][26][27] The anticancer property of these drugs is due to their ability to disrupt the Warburg effect and revert the cytosolic glycolysis characteristic of cancer cells to normal oxidation of pyruvate by the mitochondria.[28] Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.[29]
# History
Buformin was synthesized as an oral antidiabetic in 1957.[30] | https://www.wikidoc.org/index.php/Buformin | |
5dc57fa24c728149a18514555d84351aaf6e1af7 | wikidoc | Paranoia | Paranoia
# Overview
Paranoia is a disturbed thought process characterized by excessive anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs concerning a perceived threat. In the original Greek, παράνοια (paranoia) simply means madness (para = outside; nous = mind) and, historically, this characterization was used to describe any delusional state.
# Use in psychiatry
More recently, the clinical use of the term has been used to describe delusions where the affected person believes they are being persecuted. Specifically, they have been defined as containing two central elements:
- The individual thinks that harm is occurring, or is going to occur, to him or her.
- The individual thinks that the persecutor has the intention to cause harm.
Paranoia is often associated with psychotic illnesses, particularly schizophrenia, although attenuated features may be present in other primarily non-psychotic diagnoses, such as paranoid personality disorder. Paranoia can also be a side effect of medication or recreational drugs such as marijuana and particularly stimulants such as methamphetamine.
In the unrestricted use of the term, common paranoid delusions can include the belief that the person is being followed, poisoned or loved at a distance (often by a media figure or important person, a delusion known as erotomania or de Clerambault syndrome).
Other common paranoid delusions include the belief that the person has an imaginary disease or parasitic infection (delusional parasitosis); that the person is on a special quest or has been chosen by God; that the person has had thoughts inserted or removed from conscious thought; or that the person's actions are being controlled by an external force.
Therefore, in common usage, the term paranoid addresses a range of
mental conditions, assumed by the use of the term to be of psychiatric origin, in which the subject is seen to generalise or project fears and anxieties onto the external world, particularly in the form of organised behaviour focused on them. The syndrome is applied equally to powerful people like executives obsessed with takeover bids or political leaders convinced of plots against them, and to insignificant people who believe for instance that shadowy agencies are operating against them.
# History
The term paranoia was used by Emil Kraepelin to describe a mental illness in which a delusional belief is the sole or most prominent feature. In his original attempt at classifying different forms of mental illness, Kraepelin used the term pure paranoia to describe a condition where a delusion was present, but without any apparent deterioration in intellectual abilities and without any of the other features of dementia praecox, the condition later renamed schizophrenia. Notably, in his definition, the belief does not have to be persecutory to be classified as paranoid, so any number of delusional beliefs can be classified as paranoia. For example, a person who has the sole delusional belief that he is an important religious figure would be classified by Kraepelin as having 'pure paranoia'.
# Causes
## Common Causes
- Schizophrenia
- Paranoid personality disorder
- Drug abuse
- Poisoning
## Causes by Organ System
## Causes in Alphabetical Order
- Bilateral mesencephalo-thalamic ischaemia
- Acute intermittent porphyria
- Alcohol Withdrawal
- Alcoholism
- Amphetamine Sulfate
- Binswanger's disease
- Brain tumor
- Cannabis intoxication
- Cannabis
- Carbidopa
- Cathinone poisoning
- ChildhoodOnset Schizophrenia
- Chromosome 22q11 Deletion Spectrum
- Cocaine addiction
- Crystal meth addiction
- Delusional disorders
- Dopar
- Down's Syndrome associated Alzheimer's disease
- Dronabinol
- Ecstasy addiction
- Ecstasy withdrawal
- Ecstasy
- Efavirenz
- Frontotempoal atrophy
- GHB withdrawal
- Hawaiian Baby Woodrose poisoning
- Heroin dependence
- ICU psychosis
- Levodopa
- LSD addiction
- Lupus
- Marijuana abuse
- Marijuana addiction
- Marijuana intoxication
- Marijuana overdose
- Marijuana
- Marinol
- Mazindol
- Methyldopa
- Methyphenidate
- Mulitiple sclerosis
- Narcotic addiction
- Opioid addiction
- Oxycontin addiction
- Panic attacks
- Paranoid Personality Disorder
- Parkinson disease
- Pergolide
- Prolintane
- Psychosis
- PTSD
- Right parietal lobe syndrome
- Ritalin
- Schizoaffective disorder
- Schizoid personality disorder
- Schizophrenia
- Shprintzen syndorme
- Social phobia
- Sodium oxybate
- Steroid abuse
- Substance Withdrawal Syndrome
- Thioridazine Hydrochloride
- Tranquilizer addiction
- Wolfram's disease
- Wormwood poisoning | Paranoia
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-In-Chief:Aditya Govindavarjhulla, M.B.B.S. [2]
# Overview
Paranoia is a disturbed thought process characterized by excessive anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs concerning a perceived threat. In the original Greek, παράνοια (paranoia) simply means madness (para = outside; nous = mind) and, historically, this characterization was used to describe any delusional state.
# Use in psychiatry
More recently, the clinical use of the term has been used to describe delusions where the affected person believes they are being persecuted. Specifically, they have been defined as containing two central elements:
- The individual thinks that harm is occurring, or is going to occur, to him or her.
- The individual thinks that the persecutor has the intention to cause harm.
Paranoia is often associated with psychotic illnesses, particularly schizophrenia, although attenuated features may be present in other primarily non-psychotic diagnoses, such as paranoid personality disorder. Paranoia can also be a side effect of medication or recreational drugs such as marijuana and particularly stimulants such as methamphetamine.
In the unrestricted use of the term, common paranoid delusions can include the belief that the person is being followed, poisoned or loved at a distance (often by a media figure or important person, a delusion known as erotomania or de Clerambault syndrome).
Other common paranoid delusions include the belief that the person has an imaginary disease or parasitic infection (delusional parasitosis); that the person is on a special quest or has been chosen by God; that the person has had thoughts inserted or removed from conscious thought; or that the person's actions are being controlled by an external force.
Therefore, in common usage, the term paranoid addresses a range of
mental conditions, assumed by the use of the term to be of psychiatric origin, in which the subject is seen to generalise or project fears and anxieties onto the external world, particularly in the form of organised behaviour focused on them. The syndrome is applied equally to powerful people like executives obsessed with takeover bids or political leaders convinced of plots against them, and to insignificant people who believe for instance that shadowy agencies are operating against them.
# History
The term paranoia was used by Emil Kraepelin to describe a mental illness in which a delusional belief is the sole or most prominent feature. In his original attempt at classifying different forms of mental illness, Kraepelin used the term pure paranoia to describe a condition where a delusion was present, but without any apparent deterioration in intellectual abilities and without any of the other features of dementia praecox, the condition later renamed schizophrenia. Notably, in his definition, the belief does not have to be persecutory to be classified as paranoid, so any number of delusional beliefs can be classified as paranoia. For example, a person who has the sole delusional belief that he is an important religious figure would be classified by Kraepelin as having 'pure paranoia'.
# Causes
## Common Causes
- Schizophrenia
- Paranoid personality disorder
- Drug abuse
- Poisoning
## Causes by Organ System
## Causes in Alphabetical Order
- Bilateral mesencephalo-thalamic ischaemia[1]
- Acute intermittent porphyria
- Alcohol Withdrawal
- Alcoholism
- Amphetamine Sulfate
- Binswanger's disease
- Brain tumor
- Cannabis intoxication
- Cannabis
- Carbidopa
- Cathinone poisoning
- ChildhoodOnset Schizophrenia
- Chromosome 22q11 Deletion Spectrum
- Cocaine addiction
- Crystal meth addiction
- Delusional disorders
- Dopar
- Down's Syndrome associated Alzheimer's disease
- Dronabinol
- Ecstasy addiction
- Ecstasy withdrawal
- Ecstasy
- Efavirenz
- Frontotempoal atrophy
- GHB withdrawal [2]
- Hawaiian Baby Woodrose poisoning
- Heroin dependence
- ICU psychosis
- Levodopa
- LSD addiction
- Lupus
- Marijuana abuse
- Marijuana addiction
- Marijuana intoxication
- Marijuana overdose
- Marijuana
- Marinol
- Mazindol
- Methyldopa
- Methyphenidate
- Mulitiple sclerosis
- Narcotic addiction
- Opioid addiction
- Oxycontin addiction
- Panic attacks
- Paranoid Personality Disorder
- Parkinson disease
- Pergolide
- Prolintane
- Psychosis
- PTSD
- Right parietal lobe syndrome
- Ritalin
- Schizoaffective disorder
- Schizoid personality disorder
- Schizophrenia
- Shprintzen syndorme [3]
- Social phobia
- Sodium oxybate
- Steroid abuse
- Substance Withdrawal Syndrome
- Thioridazine Hydrochloride
- Tranquilizer addiction
- Wolfram's disease
- Wormwood poisoning | https://www.wikidoc.org/index.php/Burn_syndrome | |
97e6c9a45a5dc4de29196fa5ab4eaf0a35a8da3e | wikidoc | Buttocks | Buttocks
The buttocks (singular: buttock) are rounded portions of the anatomy located on the posterior of the pelvic region of the apes, including humans and many other bipeds or quadrupeds.
# Anatomy
The buttocks are formed by the masses of the gluteal muscles or 'glutes' (the gluteus maximus and the gluteus medius) superimposed by a layer of fat. The superior aspect of the buttock ends at the iliac crest, and the lower aspect is outlined by the horizontal gluteal crease. The gluteus maximus has two insertion points: 1/3 superior portion of the linea aspera of the femur, and the superior portion of the iliotibial tractus. The masses of the gluteus maximus muscle are separated by an intermediate gluteal cleft or "crack" in which the anus is situated.
The buttocks allow primates to sit upright without needing to rest their weight on their feet as four-legged animals do.
Some baboons and all gibbons, though otherwise fur-covered, have characteristic naked callosities on their buttocks. While girls and boys generally have smooth, so-called 'baby-bottoms', mature males and females have varying degrees of hairgrowth, as on other parts of their body. Females generally have hair growth in the crack (particularly around the anus), often extending laterally onto the lower aspect of the cheeks. In addition to such areas, males often have hair growth over the most of (or the entire) the buttocks.
# Connotations
The English word of Greek origin "callipygian" indicates someone who has beautiful buttocks. However, the qualities that make buttocks "beautiful" or "well-formed" are not fixed, as sexual aesthetics of the buttocks vary considerably from culture to culture, from one period of fashion to another and even from person to person.
In ancient astrology, various parts of the body were associated with signs of the zodiac - e.g. the buttocks to the Balance.
Depending on the context, exposure of the buttocks in non-intimate situations often causes feelings of shame, embarrassment or humiliation in a non-exhibitionist subject, and embarrassment or amusement in a non-voyeurist audience (see "pantsing"). Expressions such as being "caught with one's pants/ trousers down" or more explicitly in Dutch, "met de billen bloot" ("with bared buttocks"), use the image as a metaphor for non-physical embarrassment as well.
Willfully exposing one's own bare buttocks as a protest, a provocation, or just for fun (especially but not exclusively practiced by youngsters such as North American frat boys) is called "mooning".
A "wedgie" is pulling someone's undergarments or swimming trunks up through their buttock "crack" to be hauled over the top of the victim's trousers, sometimes partially baring the victim's buttocks.
It is no coincidence that the English verb to spank is the only one specifically meant for physical discipline of a specific part of the body, and various other languages have terms specifically referring to spanking; in many punitive traditions, the buttocks are the preferential target for painful lessons, from educational to judicial, as offering them for punishment (especially divested) adds a psychological dose of embarrassment and even sexual humiliation to the pain, which can be meted out with less risk of long-term corporal harm than elsewhere. There are, in various cultural traditions, expressions like "A black man's ears are in his buttocks" (e.g. in Uganda).
Many comedians, writers and others rely on the buttocks in these and other ways (such as flatulence and toilet humor) as a source of amusement, camaraderie and fun, despite (or in some cases for the sake of) the risk of being in dubious taste, if not censored.
Because in most cultures the buttocks are rarely shown naked, they are generally considered unsuitable for ornamental body markings and body modification, but may be preferential for discreet markings, such as secretive membership proof or to be shown in intimate company (e.g. amongst lovers).
In American English, phrases use the buttocks or synonyms (especially butt and arse/ass) as a pars pro toto for a whole person, but generally with a negative connotation. For example, terminating an employee may be described as "firing his ass". One might say "move your ass" or "haul ass" (or the polite, understood euphemisms "move it" or "haul it") as an exhortation to greater haste or urgency. Expressed as a function of punishment, defeat or assault becomes "kicking one's ass". Such phrases also may suggest a person's characteristics, e.g. difficult people are termed "hard asses" (polite euphemism: "hard nosed"). People deemed excessively puritanical or proper may be termed "tight asses". An annoying person or any source of frustration may be termed "a pain in the ass" (euphemism: "a pain in the neck", though some claim that this alleged euphemism actually appeared in English earlier than the former).
Certain physical dispositions of the buttocks — particularly size — are sometimes identified, controversially, as a racial characteristic (see race). The most famous intersection of racism and buttocks may be the case of Saartjie Baartman, the so-called Hottentot Venus.
# Synonyms
The anatomical Latin name for the buttocks is nates (Template:PronEng in English), which is plural; the singular, natis (buttock), is rarely used.
As buttocks are an object of both shame and fascination, it is not surprising that there are many colloquial terms, euphemistic, ironic or other, to refer to them. These include the following:
- backside, posterior, behind and its derivates (hind-quarters, hinder or the childish homophone heinie, strictly the whole body behind the hind leg-trunk attachment), rear or rear-end, derrière (French for "behind") - all strictly positional descriptions, as the inaccurate use of rump (as in 'rump roast', after a 'hot' spanking), thighs, upper legs; analogous are:
aft, stern and poop, naval in origin; in nautical jargon, buttocks also designates the aftermost portion of a hull above the water line and in front of the rudder, merging with the run below the water line
caboose, originally a ship's galley in wooden cabin on deck; also the "rear end" car of a freight train, considered a cute synonym suitable for any audience Nude cyclists with painted buttocks
bottom (and the shortening "bot" as well as childish diminutives "bottie" or "botty"), but the use of similar-sounding booty (slang for the female body since the 1920s) as famously by K.C. and the Sunshine Band's Shake Your Booty, is an 'artistic liberty'; equivalents in other languages include the Latino culo from Latin culus, 'bottom'
tail (strictly anatomically a zoomorphism, humans only have a tail-bone, yet the illogical tail feather was popularized by musicians; also used for the even more sensual phallus) and tail-end
Tush or tushy (from the Yiddish language "tuchis" or "tochis" meaning "under" or "beneath")
Dumper sometimes denotates the buttocks, especially when talking about a large butt.
trunk, in American English, particularly when describing large buttocks "junk in the trunk". This usage refers metaphorically to an automobile's trunk.
- aft, stern and poop, naval in origin; in nautical jargon, buttocks also designates the aftermost portion of a hull above the water line and in front of the rudder, merging with the run below the water line
- caboose, originally a ship's galley in wooden cabin on deck; also the "rear end" car of a freight train, considered a cute synonym suitable for any audience Nude cyclists with painted buttocks
- bottom (and the shortening "bot" as well as childish diminutives "bottie" or "botty"), but the use of similar-sounding booty (slang for the female body since the 1920s) as famously by K.C. and the Sunshine Band's Shake Your Booty, is an 'artistic liberty'; equivalents in other languages include the Latino culo from Latin culus, 'bottom'
- tail (strictly anatomically a zoomorphism, humans only have a tail-bone, yet the illogical tail feather was popularized by musicians; also used for the even more sensual phallus) and tail-end
- Tush or tushy (from the Yiddish language "tuchis" or "tochis" meaning "under" or "beneath")
- Dumper sometimes denotates the buttocks, especially when talking about a large butt.
- trunk, in American English, particularly when describing large buttocks "junk in the trunk". This usage refers metaphorically to an automobile's trunk.
- arse or ass, asshole, and (butt-)hole - a pars pro toto (strictly only the actual body cavity and directly adjoining anal region); also used as an insult for a person. The term is Anglo-Saxon dialect, and therefore dates back over a thousand years.
- fuck bucket or fuckbuck, fuck bucket, and (fuck-)bucket
- badonkadonk - onomatopoeic slang meaning the voluptuously bouncing, large yet firm buttocks of a woman
- breech, a metaphorical sense derived from on older form of the garment breeches (as the French culotte meaning pantoloons, via cul from Latin culus 'butt'), so 'bare breech' means without breeches, i.e. trouserless butt
- bum - in British English, used frequently in the United Kingdom, Ireland, Canada, Australia, New Zealand and many other English speaking Commonwealth countries, also historically in U.S., is a mild often humorous reference to buttocks, not necessarily in vulgar or sexual context: "I've a boil on my bum, thrice as large as my thumb" - The Judge With The Sore Rump, St. George Tucker. Also used in reference to anal intercourse, often as an insult, as in bum boy (for a homosexual). Also verb - to practise anal intercourse.
- buns, mounds (cfr. Butte, a geographical mound, known since 1805 in American English, from (Old) French butte "mound, knoll") and orbs - shape-metaphors, used mostly to describe male buttocks only
- bund - derived from Punjabi
- bunda - bottom, of Brazilian Portuguese origin.
- butt - the common term for a pair of buttocks (singular, as one body-part; cognate but neither its root nor an abbreviation) in the US, used in everyday speech. It is also acceptable in print.
- can (a container) had an unusual development: Slang meaning "toilet" is c. 1900, said to be a shortening of piss-can, meaning "buttocks" from c. 1910, verb meaning "fire an employee" (to flush=dump?) from 1905.
- cheeks, a shape-metaphor within human anatomy, but also used in the singular: left cheek and right cheek; sounds particularly naughty because of the homonym and the adjective cheeky, lending themselves to word puns
- culo - slang, usually meaning a voluptuous, round and firm buttocks of a woman. Put simply the Latino equivalent for a booty, although in Spanish it is considered vulgar and offensive (but less so in Spain than in Latin America).
- fanny - a socially acceptable term in print, in the United States at least, for many years before some of the bolder terms came along; and a subject of jokes, since "Fannie" can be a woman's name, diminutive of "Frances"; however, in British English fanny refers to the female genitals or vulva and is considered vulgar. The figure of a bare-bottomed lass named Fanny is ubiquitous in Provence (the south of France) wherever pétanque is played. There it is traditional that when a player loses 13 to 0 it is said that “il est fanny” (he's fanny), and that he has to kiss the bottom of a girl called Fanny. Since there is rarely an obliging Fanny, there is always a substitute picture, woodcarving or pottery so that Fanny’s bottom is always available.
- fourth point of contact: in military slang, because of the sequence of textbook parachute jump landing
- fundament (literally "foundation", not common in this general sense in English, but for the butt since 1297)
- Gand or Gaand - a Hindi derivate
- hams, like buttocks generally as a plural, after the meat cut from the analogous part of a hog ; pressed ham refers to mooning against a window; brawn, a singular derived from the Frankish for ham or roast, is also used for both a muscular body part (but either on arms or legs) or boar meat, especially roast
- moneymaker, a term coming from exotic dancers and other entertainers who use their buttocks (even clothed) to earn money. It is usually used in reference to females.
- hurdies - British, origin unknown, also applied to the whole rump
- moon was a common shape-metaphor for the butt in English since 1756, and the verb to moon meant 'to expose to (moon)light' since 1601, long before they were combined in US student slang in the verb (al expression) mooning "to flash the buttocks" in 1968.
- prat (British English, origin unknown; as in pratfall, a vaudeville term; also a term of abuse for a person)
- seat (of the trousers; or metaphorically) another long-standing socially acceptable term, referring to the use for sitting - but compare the sarcastic use of seat of wisdom and similar expressions, such as 'seat of learning', referring to use as target for an 'educational' spanking.
- sit-upon; has various independent counterparts in other languages, e.g. Dutch zitvlak ('sitting plain'), German Gesäß (~=guh|seys), Italian sedere
- six; in military terminology, particularly in the U.S. Navy, it refers to the term "six o'clock", i. e. a point directly behind the referenced person.
- ultimatum (Latin, literally 'the outer-most') was used in slang c.1820s.
# Related terms
- The word "callipygian" is sometimes used to describe someone with notably attractive buttocks. The term comes from the Greek kallipygos, (first used for the Venus Kallipygos) which literally means "beautiful buttocks"; the prefix is also a root of "calligraphy" ("beautiful writing") and "calliope" ("beautiful voice"); callimammapygian means having both beautiful breasts and - buttocks.
- Both the English (in) tails and the Dutch billentikker ('tapping the buttocks') are ironic terms for very formal coats with a significantly longer tail end as part of festive (especially wedding party) dress
- macropygia means 'heaving large buttocks, hindquarter', and occurs in biological species names,
- a pygopag(ous) (from the Greek pygè 'buttock' and pagein 'attached') was a monster in Ancient (Greek) mythology consisting of two bodies joint by common buttocks, now a medical term for 'Siamese' twins thus joint back-to-back
- pygophilia is sexual arousal or excitement caused by seeing, playing with or touching the woman's buttocks; people who have strong attraction to buttocks are called pygophilists.
- pygoscopia means observing someone's rear; pygoscopophobia a pathological fear to be its unwilling object
- pygalgia is soreness in the buttocks, i.e. a pain in the rump.
- Steatopygia is a marked accumulation of fat in and around the buttocks.
- uropygial in ornithology mean, situated on, belonging to, the uropygium, i.e. the rump of a bird
- "bubble butt" has at least two connotations, which are at odds with each other: either a small, round and firm pair of buttocks resembling a pair of soap bubbles next to each other, or a large rear end, seemingly about to burst from the strain. In both cases, the term implies an appealing shapeliness about the buttocks.
# Fashion
Because many cultures have a (partial) nudity taboo, which usually applies specifically to the buttocks (as usually to the most erogenous zones), mainstream garments generally cover the buttocks completely, even when it is not a practical requirement. Nevertheless male and female clothing is often designed in a way that reveals the shape of the buttocks under the clothing.
Some articles of clothing are designed to expose the buttocks. Such clothing is not generally worn in public situations; however, it is considered appropriate to wear such clothing at swimming facilities or at the beach.
Emphasis on one part or another of the body tends to shift with generations. The 1880s were well-known for the fashion trend among women called the bustle, which made even the smallest buttocks seemingly huge. The popularity of this fashion is shown in the famous Georges Seurat painting Sunday Afternoon on the Island of La Grande Jatte in the two women to the far left and right. Like long underwear with the ubiquitous 'butt flap' (used to allow baring only the bottom with a simple gesture, as for hygiene), this clothing style was acknowledged in popular media such as cartoons and comics for generations afterward.
More recently, the cleavage of the buttocks could be exposed by some women as fashion dictated trousers be worn lower. (known as a "coin slot", or "vertical smile").
An example of another attitude in an otherwise hardly exhibitionist culture is the Japanese fundoshi. | Buttocks
Template:Infobox Anatomy
The buttocks (singular: buttock) are rounded portions of the anatomy located on the posterior of the pelvic region of the apes, including humans and many other bipeds or quadrupeds.
# Anatomy
The buttocks are formed by the masses of the gluteal muscles or 'glutes' (the gluteus maximus and the gluteus medius) superimposed by a layer of fat. The superior aspect of the buttock ends at the iliac crest, and the lower aspect is outlined by the horizontal gluteal crease. The gluteus maximus has two insertion points: 1/3 superior portion of the linea aspera of the femur, and the superior portion of the iliotibial tractus. The masses of the gluteus maximus muscle are separated by an intermediate gluteal cleft or "crack" in which the anus is situated.
The buttocks allow primates to sit upright without needing to rest their weight on their feet as four-legged animals do.
Some baboons and all gibbons, though otherwise fur-covered, have characteristic naked callosities on their buttocks. While girls and boys generally have smooth, so-called 'baby-bottoms', mature males and females have varying degrees of hairgrowth, as on other parts of their body. Females generally have hair growth in the crack (particularly around the anus), often extending laterally onto the lower aspect of the cheeks. In addition to such areas, males often have hair growth over the most of (or the entire) the buttocks.
# Connotations
The English word of Greek origin "callipygian" indicates someone who has beautiful buttocks. However, the qualities that make buttocks "beautiful" or "well-formed" are not fixed, as sexual aesthetics of the buttocks vary considerably from culture to culture, from one period of fashion to another and even from person to person.
In ancient astrology, various parts of the body were associated with signs of the zodiac - e.g. the buttocks to the Balance.
Depending on the context, exposure of the buttocks in non-intimate situations often causes feelings of shame, embarrassment or humiliation in a non-exhibitionist subject, and embarrassment or amusement in a non-voyeurist audience (see "pantsing"). Expressions such as being "caught with one's pants/ trousers down" or more explicitly in Dutch, "met de billen bloot" ("with bared buttocks"), use the image as a metaphor for non-physical embarrassment as well.
Willfully exposing one's own bare buttocks as a protest, a provocation, or just for fun (especially but not exclusively practiced by youngsters such as North American frat boys) is called "mooning".
A "wedgie" is pulling someone's undergarments or swimming trunks up through their buttock "crack" to be hauled over the top of the victim's trousers, sometimes partially baring the victim's buttocks.
It is no coincidence that the English verb to spank is the only one specifically meant for physical discipline of a specific part of the body, and various other languages have terms specifically referring to spanking; in many punitive traditions, the buttocks are the preferential target for painful lessons, from educational to judicial, as offering them for punishment (especially divested) adds a psychological dose of embarrassment and even sexual humiliation to the pain, which can be meted out with less risk of long-term corporal harm than elsewhere. There are, in various cultural traditions, expressions like "A black man's ears are in his buttocks" (e.g. in Uganda).
Many comedians, writers and others rely on the buttocks in these and other ways (such as flatulence and toilet humor) as a source of amusement, camaraderie and fun, despite (or in some cases for the sake of) the risk of being in dubious taste, if not censored.
Because in most cultures the buttocks are rarely shown naked, they are generally considered unsuitable for ornamental body markings and body modification, but may be preferential for discreet markings, such as secretive membership proof or to be shown in intimate company (e.g. amongst lovers).
In American English, phrases use the buttocks or synonyms (especially butt and arse/ass) as a pars pro toto for a whole person, but generally with a negative connotation. For example, terminating an employee may be described as "firing his ass". One might say "move your ass" or "haul ass" (or the polite, understood euphemisms "move it" or "haul it") as an exhortation to greater haste or urgency. Expressed as a function of punishment, defeat or assault becomes "kicking one's ass". Such phrases also may suggest a person's characteristics, e.g. difficult people are termed "hard asses" (polite euphemism: "hard nosed"). People deemed excessively puritanical or proper may be termed "tight asses". An annoying person or any source of frustration may be termed "a pain in the ass" (euphemism: "a pain in the neck", though some claim that this alleged euphemism actually appeared in English earlier than the former).
Certain physical dispositions of the buttocks — particularly size — are sometimes identified, controversially, as a racial characteristic (see race). The most famous intersection of racism and buttocks may be the case of Saartjie Baartman, the so-called Hottentot Venus.
# Synonyms
Template:Wiktionarypar
The anatomical Latin name for the buttocks is nates (Template:PronEng in English), which is plural; the singular, natis (buttock), is rarely used.
As buttocks are an object of both shame and fascination, it is not surprising that there are many colloquial terms, euphemistic, ironic or other, to refer to them. These include the following:
- backside, posterior, behind and its derivates (hind-quarters, hinder or the childish homophone heinie, strictly the whole body behind the hind leg-trunk attachment), rear or rear-end, derrière (French for "behind") - all strictly positional descriptions, as the inaccurate use of rump (as in 'rump roast', after a 'hot' spanking), thighs, upper legs; analogous are:
aft, stern and poop, naval in origin; in nautical jargon, buttocks also designates the aftermost portion of a hull above the water line and in front of the rudder, merging with the run below the water line
caboose, originally a ship's galley in wooden cabin on deck; also the "rear end" car of a freight train, considered a cute synonym suitable for any audience Nude cyclists with painted buttocks
bottom (and the shortening "bot" as well as childish diminutives "bottie" or "botty"), but the use of similar-sounding booty (slang for the female body since the 1920s) as famously by K.C. and the Sunshine Band's Shake Your Booty, is an 'artistic liberty'; equivalents in other languages include the Latino culo from Latin culus, 'bottom'
tail (strictly anatomically a zoomorphism, humans only have a tail-bone, yet the illogical tail feather was popularized by musicians; also used for the even more sensual phallus) and tail-end
Tush or tushy (from the Yiddish language "tuchis" or "tochis" meaning "under" or "beneath")
Dumper sometimes denotates the buttocks, especially when talking about a large butt.
trunk, in American English, particularly when describing large buttocks "junk in the trunk". This usage refers metaphorically to an automobile's trunk.
- aft, stern and poop, naval in origin; in nautical jargon, buttocks also designates the aftermost portion of a hull above the water line and in front of the rudder, merging with the run below the water line
- caboose, originally a ship's galley in wooden cabin on deck; also the "rear end" car of a freight train, considered a cute synonym suitable for any audience Nude cyclists with painted buttocks
- bottom (and the shortening "bot" as well as childish diminutives "bottie" or "botty"), but the use of similar-sounding booty (slang for the female body since the 1920s) as famously by K.C. and the Sunshine Band's Shake Your Booty, is an 'artistic liberty'; equivalents in other languages include the Latino culo from Latin culus, 'bottom'
- tail (strictly anatomically a zoomorphism, humans only have a tail-bone, yet the illogical tail feather was popularized by musicians; also used for the even more sensual phallus) and tail-end
- Tush or tushy (from the Yiddish language "tuchis" or "tochis" meaning "under" or "beneath")
- Dumper sometimes denotates the buttocks, especially when talking about a large butt.
- trunk, in American English, particularly when describing large buttocks "junk in the trunk". This usage refers metaphorically to an automobile's trunk.
- arse or ass, asshole, and (butt-)hole - a pars pro toto (strictly only the actual body cavity and directly adjoining anal region); also used as an insult for a person. The term is Anglo-Saxon dialect, and therefore dates back over a thousand years.
- fuck bucket or fuckbuck, fuck bucket, and (fuck-)bucket
- badonkadonk - onomatopoeic slang meaning the voluptuously bouncing, large yet firm buttocks of a woman
- breech, a metaphorical sense derived from on older form of the garment breeches (as the French culotte meaning pantoloons, via cul from Latin culus 'butt'), so 'bare breech' means without breeches, i.e. trouserless butt
- bum - in British English, used frequently in the United Kingdom, Ireland, Canada, Australia, New Zealand and many other English speaking Commonwealth countries, also historically in U.S., is a mild often humorous reference to buttocks, not necessarily in vulgar or sexual context: "I've a boil on my bum, thrice as large as my thumb" - The Judge With The Sore Rump, St. George Tucker. Also used in reference to anal intercourse, often as an insult, as in bum boy (for a homosexual). Also verb - to practise anal intercourse.
- buns, mounds (cfr. Butte, a geographical mound, known since 1805 in American English, from (Old) French butte "mound, knoll") and orbs - shape-metaphors, used mostly to describe male buttocks only
- bund - derived from Punjabi
- bunda - bottom, of Brazilian Portuguese origin.
- butt - the common term for a pair of buttocks (singular, as one body-part; cognate but neither its root nor an abbreviation) in the US, used in everyday speech. It is also acceptable in print.
- can (a container) had an unusual development: Slang meaning "toilet" is c. 1900, said to be a shortening of piss-can, meaning "buttocks" from c. 1910, verb meaning "fire an employee" (to flush=dump?) from 1905.
- cheeks, a shape-metaphor within human anatomy, but also used in the singular: left cheek and right cheek; sounds particularly naughty because of the homonym and the adjective cheeky, lending themselves to word puns
- culo - slang, usually meaning a voluptuous, round and firm buttocks of a woman. Put simply the Latino equivalent for a booty, although in Spanish it is considered vulgar and offensive (but less so in Spain than in Latin America).
- fanny - a socially acceptable term in print, in the United States at least, for many years before some of the bolder terms came along; and a subject of jokes, since "Fannie" can be a woman's name, diminutive of "Frances"; however, in British English fanny refers to the female genitals or vulva and is considered vulgar. The figure of a bare-bottomed lass named Fanny is ubiquitous in Provence (the south of France) wherever pétanque is played. There it is traditional that when a player loses 13 to 0 it is said that “il est fanny” (he's fanny), and that he has to kiss the bottom of a girl called Fanny. Since there is rarely an obliging Fanny, there is always a substitute picture, woodcarving or pottery so that Fanny’s bottom is always available.[1]
- fourth point of contact: in military slang, because of the sequence of textbook parachute jump landing
- fundament (literally "foundation", not common in this general sense in English, but for the butt since 1297)
- Gand or Gaand - a Hindi derivate
- hams, like buttocks generally as a plural, after the meat cut from the analogous part of a hog ; pressed ham refers to mooning against a window; brawn, a singular derived from the Frankish for ham or roast, is also used for both a muscular body part (but either on arms or legs) or boar meat, especially roast
- moneymaker, a term coming from exotic dancers and other entertainers who use their buttocks (even clothed) to earn money. It is usually used in reference to females.
- hurdies - British, origin unknown, also applied to the whole rump
- moon was a common shape-metaphor for the butt in English since 1756, and the verb to moon meant 'to expose to (moon)light' since 1601, long before they were combined in US student slang in the verb (al expression) mooning "to flash the buttocks" in 1968.
- prat (British English, origin unknown; as in pratfall, a vaudeville term; also a term of abuse for a person)
- seat (of the trousers; or metaphorically) another long-standing socially acceptable term, referring to the use for sitting - but compare the sarcastic use of seat of wisdom and similar expressions, such as 'seat of learning', referring to use as target for an 'educational' spanking.
- sit-upon; has various independent counterparts in other languages, e.g. Dutch zitvlak ('sitting plain'), German Gesäß (~=guh|seys), Italian sedere
- six; in military terminology, particularly in the U.S. Navy, it refers to the term "six o'clock", i. e. a point directly behind the referenced person.
- ultimatum (Latin, literally 'the outer-most') was used in slang c.1820s.
# Related terms
- The word "callipygian" is sometimes used to describe someone with notably attractive buttocks. The term comes from the Greek kallipygos, (first used for the Venus Kallipygos) which literally means "beautiful buttocks"; the prefix is also a root of "calligraphy" ("beautiful writing") and "calliope" ("beautiful voice"); callimammapygian means having both beautiful breasts and - buttocks.
- Both the English (in) tails and the Dutch billentikker ('tapping the buttocks') are ironic terms for very formal coats with a significantly longer tail end as part of festive (especially wedding party) dress
- macropygia means 'heaving large buttocks, hindquarter', and occurs in biological species names,
- a pygopag(ous) (from the Greek pygè 'buttock' and pagein 'attached') was a monster in Ancient (Greek) mythology consisting of two bodies joint by common buttocks, now a medical term for 'Siamese' twins thus joint back-to-back
- pygophilia is sexual arousal or excitement caused by seeing, playing with or touching the woman's buttocks; people who have strong attraction to buttocks are called pygophilists.
- pygoscopia means observing someone's rear; pygoscopophobia a pathological fear to be its unwilling object
- pygalgia is soreness in the buttocks, i.e. a pain in the rump.
- Steatopygia is a marked accumulation of fat in and around the buttocks.
- uropygial in ornithology mean, situated on, belonging to, the uropygium, i.e. the rump of a bird
- "bubble butt" has at least two connotations, which are at odds with each other: either a small, round and firm pair of buttocks resembling a pair of soap bubbles next to each other, or a large rear end, seemingly about to burst from the strain. In both cases, the term implies an appealing shapeliness about the buttocks.
# Fashion
Because many cultures have a (partial) nudity taboo, which usually applies specifically to the buttocks (as usually to the most erogenous zones), mainstream garments generally cover the buttocks completely, even when it is not a practical requirement. Nevertheless male and female clothing is often designed in a way that reveals the shape of the buttocks under the clothing.
Some articles of clothing are designed to expose the buttocks. Such clothing is not generally worn in public situations; however, it is considered appropriate to wear such clothing at swimming facilities or at the beach.
Emphasis on one part or another of the body tends to shift with generations. The 1880s were well-known for the fashion trend among women called the bustle, which made even the smallest buttocks seemingly huge. The popularity of this fashion is shown in the famous Georges Seurat painting Sunday Afternoon on the Island of La Grande Jatte in the two women to the far left and right. Like long underwear with the ubiquitous 'butt flap' (used to allow baring only the bottom with a simple gesture, as for hygiene), this clothing style was acknowledged in popular media such as cartoons and comics for generations afterward.
More recently, the cleavage of the buttocks could be exposed by some women as fashion dictated trousers be worn lower. (known as a "coin slot", or "vertical smile").
An example of another attitude in an otherwise hardly exhibitionist culture is the Japanese fundoshi. | https://www.wikidoc.org/index.php/Buttock | |
46dff2ba1fcecd8267b27af6f27b21561e286861 | wikidoc | C10orf67 | C10orf67
Chromosome 10 open reading frame 67 (C10orf67), also known as C10orf115, LINC01552, and BA215C7.4, is an un-characterized human protein-coding gene. Several studies indicate a possible link between genetic polymorphisms of this and several other genes to chronic inflammatory barrier diseases such as Crohn’s Disease and sarcoidosis.
# Gene
The gene spans 142,366 base pairs and is located at the 10p12.2 locus on the minus (-) or sense strand of chromosome 10. It is flanked upstream by the gene ARMC3 and downstream by the gene KIAA1217. These genes are approximately 150,000 bp and 350,000 bp from C10orf67, respectively.
## Transcript
There are 23 alternatively spliced exons, which encode 13 transcript variants. The primary transcript, only 2943 bp, is not well conserved among orthologs, rather, the X2 variant, 3417 bp, has far greater identity with orthologous proteins. This X2 transcript variant contains 15 exons which yield a polypeptide of 551 amino acids.
# Protein
## General properties
*depending on post-translational modifications (PTMs)
From no PTMs - all possible PTMs
The isoelectric point is significantly greater than average for human proteins (6.81).
## Structure
Shown to the right is a predicted tertiary structure of the protein. It is marked by long alpha-helices with several coil regions and beta strands localized to the end of the protein opposite the N- and C- terminal ends.
## Expression
C10orf67 is moderately expressed (50-75%) in most tissues in the body. However, a study on NCBI GEO discussing the influence of interleukin-13 (IL-13) on gene expression found that protein expression dropped to zero in the presence of IL-13 in airway epithelia.
## Subcellular localization
The protein contains a mitochondrial signal peptide localizing it to the mitochondrial matrix. Analysis with subcellular localization software confirmed this finding. However, some orthologs were also predicted to localize in the nucleus. Though the high isoelectric point of the Human protein provides further evidence for the mitochondrial localization due to the high pH of the mitochondrial matrix.
## Post-translational modifications
### Cleavage sites
The protein is initially cleaved to remove the 36 amino acid N-terminal signal peptide after it is localized to the mitochondrion.
### Phosphorylation
There are a number of predicted phosphorylation sites, however there is one experimentally-confirmed phosphorylation site at threonine 69. The other phosphorylation sites are summarized in the protein diagram below.
### Sumoylation
There are five predicted sumoylation sites within C10orf67. These are summarized by the following table:
# Homology and evolution
## Evolution
C10orf67 has no known paralogs but has many orthologs within eukaryotes and retains significant identity with species as distantly related as invertebrates. Several select orthologs are listed below with some identifying information.
## Evolution
The rate of evolution of C10orf67 was compared to that of fibrinogen and cytochrome c, which represent fast and slow rates of evolution, respectively. The bolded species in the table were selected to represent the fibrinogen and cytochrome c orthologs to determine the rate of evolution of the respective proteins.
The rate of evolution of C10orf67 is very curious in that it follows a logarithmic trend rather than a linear trend, like most proteins.
# Clinical significance
## Sarcoidosis
While the function of C10orf67 is unknown, its interactions with IL-13 further suggest a role of C10orf67 in sarcoidosis as the disease is known to involve various interleukins.
## Cancer
While several NCBI GEO profiles examining various factors on gene expression show that C10orf67 is expressed in varying levels in different cancer tissues, the mitochondrial localization may yield some insight as to a clinical function. Mitochondria have been shown to have some influence in cell proliferation. Given the high energy demand from cell proliferation, there have been several hypotheses that the mitochondria may play a role in the cell cycle and that C10orf67, being localized to the mitochondria, may have a hand in this as well. | C10orf67
Chromosome 10 open reading frame 67 (C10orf67), also known as C10orf115, LINC01552, and BA215C7.4, is an un-characterized human protein-coding gene. Several studies indicate a possible link between genetic polymorphisms of this and several other genes to chronic inflammatory barrier diseases such as Crohn’s Disease and sarcoidosis.[1][2][3]
# Gene
The gene spans 142,366 base pairs and is located at the 10p12.2 locus on the minus (-) or sense strand of chromosome 10. It is flanked upstream by the gene ARMC3[4] and downstream by the gene KIAA1217.[5][6] These genes are approximately 150,000 bp and 350,000 bp from C10orf67, respectively.
## Transcript
There are 23 alternatively spliced exons, which encode 13 transcript variants. The primary transcript, only 2943 bp, is not well conserved among orthologs, rather, the X2 variant, 3417 bp, has far greater identity with orthologous proteins. This X2 transcript variant contains 15 exons which yield a polypeptide of 551 amino acids.[7][8]
# Protein
## General properties
*depending on post-translational modifications (PTMs)
**From no PTMs - all possible PTMs
The isoelectric point is significantly greater than average for human proteins (6.81).[9]
## Structure
Shown to the right is a predicted tertiary structure of the protein. It is marked by long alpha-helices with several coil regions and beta strands localized to the end of the protein opposite the N- and C- terminal ends.
## Expression
C10orf67 is moderately expressed (50-75%) in most tissues in the body.[11] However, a study on NCBI GEO discussing the influence of interleukin-13 (IL-13) on gene expression[12] found that protein expression dropped to zero in the presence of IL-13 in airway epithelia.
## Subcellular localization
The protein contains a mitochondrial signal peptide localizing it to the mitochondrial matrix.[13] Analysis with subcellular localization software[14][15] confirmed this finding. However, some orthologs were also predicted to localize in the nucleus. Though the high isoelectric point of the Human protein provides further evidence for the mitochondrial localization due to the high pH of the mitochondrial matrix.
## Post-translational modifications
### Cleavage sites
The protein is initially cleaved to remove the 36 amino acid N-terminal signal peptide after it is localized to the mitochondrion.[16]
### Phosphorylation
There are a number of predicted phosphorylation sites, however there is one experimentally-confirmed phosphorylation site at threonine 69.[17] The other phosphorylation sites are summarized in the protein diagram below.
### Sumoylation
There are five predicted sumoylation sites within C10orf67. These are summarized by the following table:
# Homology and evolution
## Evolution
C10orf67 has no known paralogs but has many orthologs within eukaryotes and retains significant identity with species as distantly related as invertebrates. Several select orthologs are listed below with some identifying information.
## Evolution
The rate of evolution of C10orf67 was compared to that of fibrinogen and cytochrome c, which represent fast and slow rates of evolution, respectively. The bolded species in the table were selected to represent the fibrinogen and cytochrome c orthologs to determine the rate of evolution of the respective proteins.
The rate of evolution of C10orf67 is very curious in that it follows a logarithmic trend rather than a linear trend, like most proteins.
# Clinical significance
## Sarcoidosis
While the function of C10orf67 is unknown, its interactions with IL-13 further suggest a role of C10orf67 in sarcoidosis as the disease is known to involve various interleukins.
## Cancer
While several NCBI GEO profiles examining various factors on gene expression show that C10orf67 is expressed in varying levels in different cancer tissues,[18][19] the mitochondrial localization may yield some insight as to a clinical function. Mitochondria have been shown to have some influence in cell proliferation. Given the high energy demand from cell proliferation, there have been several hypotheses that the mitochondria may play a role in the cell cycle and that C10orf67, being localized to the mitochondria, may have a hand in this as well. | https://www.wikidoc.org/index.php/C10orf67 | |
ab19d3ee6a20d2fd9bcb9631c53acebd66a69157 | wikidoc | C10orf71 | C10orf71
C10orf71 is a gene located on chromosome 10 open reading frame 71. It is primarily understood that this gene is moderately expressed in muscle tissue and cardiac tissue.
# Gene
The cytogenic locus is found at 10q11.23. C10orf71 encodes 28294 base pairs (bp) within chromosome 10 at 49299193-49327487 bp. It is located on the plus strand and is flanked by several other genes.
# mRNA
The mRNA sequence of C10orf71 has 3 exons and 10 stop codons in the favorable splice form. The two alternative splice forms had 47 and 75 stop codons interspersed throughout the sequence so they were not utilized to obtain further sequence information. The main splice form that was analyzed had the ten stop codons interspersed throughout the 5' and 3' UTR, which was why this splice form was utilized to further analyze. The mRNA of the Homo sapiens ortholog of C10orf71was 5286 bp in length.
The three alternative splice forms found of C10orf71 mRNA sequence and the locations stop codons, exons and the Kozak site found in Splice 1. Splice 1 was utilized to analyze and obtain information about as all of the stop codons found in this splice form were found in the 5' and 3' UTR regions of the sequence. There were three exons found in Splice 1 with a Kozak consensus sequence in the overall sequence as well.
# Protein
The mature C10orf71 protein of the Homo sapiens homolog is 1435 amino acids (aa) in length and weighs approximately 156.5 kDa. This homolog has an isoelectric point of 5.94. The range of pH values from Homo sapiens to the latest ortholog analyzed, Rhincodon types, ranged from 5.94-6.93, with it gradually increasing as it went later in the divergence of the ortholog.
Comparison of some of the orthologs analyzed when compared to Homo sapiens. The orthologs are arranged from species that are most closely related to the Homo sapiens ortholog to least closely related (top to bottom respectively).
## Composition of protein
C10orf71 is predicted to be a non-transmembrane, soluble protein. It is predicted to be a nuclear protein with 91.3% confidence with it being fairly confident to be a nuclear protein throughout the orthologs. There was one positive charge cluster found in C10orf71 protein sequence, that is located from amino acids 1165-1193. This cluster was moderately conserved throughout the orthologs analyzed. There was also a mixed charge cluster found in the Homo sapiens' sequence of this protein, located from amino acid 750-778, although this cluster was not highly conserved throughout the analyzed orthologs. There was one repeat sequence found as well, TASKPPA, located at amino acids 163-169 and 116-1172. This protein is Proline and Serine rich as well.
## Domains and motifs
One confirmed domain of unknown function (DUF) was found within the C10orf71 protein sequence, DUF4585. DUF4585 is located on the Homo sapiens protein sequence from amino acid 311-334. DUF4585 was highly conserved throughout the orthologs that were analyzed. There was also a small vacuolar targeting motif (VAC) found within the analyzed protein sequence spanning amino acids 543-546.
## Protein structure
The mature C10orf71 protein contains nuclear localization signals (NLS), pat4 (RKPK at aa 382, RPRK at aa 640, KRRK at aa 1190) and pat7 (PPWRKPK at aa 379 and PWRKPKT at aa 380) with an NLS score pf 0.94. A secondary structure was constructed with a 6.1% confidence level.
## Post-translational modifications
There were seven GlcNAc O-glycosylation sites predicted within the protein sequence found at amino acids 116, 120, 139, 165, 468, 470, and 844. There were also several phosphorylation sites found interspersed throughout the sequence. One propeptide cleavage site was predicted at amino acid 38. There were three predicted sumoylation sites found at amino acids 599, 890, and 1176.
## Expression
C10orf71 was found to be highly expressed in cardiac, muscle, and liver tissue (biology).
## Regulation of expression
There were 6 possible promoters found in the sequence. Promoter GXP_6729162 is 1403 bp in length. This promoter had several transcription factors of interest including those involved with myocytes.
## Function
There is little scientific information known about the function of C10orf71.
## Interacting proteins
There was a total of 25 proteins generated that were predicted to interact with C10orf71 (Homo sapiens ortholog). Most of the interactions predicted were physical interactions with C10orf71. These interactions were discovered through a variety of mechanisms including, but not limited to: affinity chromatography, microarray analysis, and tandem mass spectrometry among others. Refer to table for details about the interacting proteins of C10orf71.
Interacting proteins, their function if known, and any tissues they have been found or predicted to be expressed in and any diseases they have been associated with.
# Homologs
## Paralogs
There are currently no known paralogs to the C10orf71 gene.
## Orthologs
C10orf71 is known to have 68 orthologs in various species including primates (11 species), rodents (8 species), Laurasiatheria carnivores (14 species), Placental mammals (38 species), Sauropsida birds and reptiles (7 species), and fish (11 species). The highly conserved sequences are primarily from primates with the identity percentage of these species being >90%, whereas species such as reptiles, birds, and fish had an identity percentage ≤30%. Refer to table for additional information on dates of divergence, sequence length, and sequence identity and similarity for orthologs. C10orf71 is not present in prokaryotes, archaea, or fungi.
Ortholog table in descending order to latest ortholog diverged. This table compares the orthologs analyzed, their species names, common names, dates of divergence from Homo sapiens ortholog (MYA), length (aa), and percentage of similarity and identity.
## Phylogeny
A phylogenetic tree was constructed for the orthologs that were analyzed in comparison to Homo sapiens. With the species of latest divergence being Rhincodon types, or the whale shark.
## Evolutionary rate
C10orf71's rate of divergence was faster than that of fibrinogen or Cytochrome C.
# Clinical significance
There was a microarray experiment that also showed evidence that C10orf71's expression was lowered in skeletal muscle tissues that experienced sepsis. There was clinical significance found in the expression level of C10orf71 in an experiment looking at those with Myotonic dystrophy. One microarray analysis produced results that showed C10orf71's expression level decreased in those with prostate cancer as well. | C10orf71
C10orf71 is a gene located on chromosome 10 open reading frame 71.[1][2] It is primarily understood that this gene is moderately expressed in muscle tissue and cardiac tissue.[3][4]
# Gene
The cytogenic locus is found at 10q11.23.[1] C10orf71 encodes 28294 base pairs (bp) within chromosome 10 at 49299193-49327487 bp.[1] It is located on the plus strand and is flanked by several other genes.[1]
# mRNA
The mRNA sequence of C10orf71 has 3 exons and 10 stop codons in the favorable splice form.[1][6] The two alternative splice forms had 47 and 75 stop codons interspersed throughout the sequence so they were not utilized to obtain further sequence information. The main splice form that was analyzed had the ten stop codons interspersed throughout the 5' and 3' UTR, which was why this splice form was utilized to further analyze. The mRNA of the Homo sapiens ortholog of C10orf71was 5286 bp in length.[1][6]
The three alternative splice forms found of C10orf71 mRNA sequence and the locations stop codons, exons and the Kozak site found in Splice 1. Splice 1 was utilized to analyze and obtain information about as all of the stop codons found in this splice form were found in the 5' and 3' UTR regions of the sequence. There were three exons found in Splice 1 with a Kozak consensus sequence in the overall sequence as well.[1][6]
# Protein
The mature C10orf71 protein of the Homo sapiens homolog is 1435 amino acids (aa) in length and weighs approximately 156.5 kDa.[6] This homolog has an isoelectric point of 5.94.[6] The range of pH values from Homo sapiens to the latest ortholog analyzed, Rhincodon types, ranged from 5.94-6.93, with it gradually increasing as it went later in the divergence of the ortholog.[6]
Comparison of some of the orthologs analyzed when compared to Homo sapiens. The orthologs are arranged from species that are most closely related to the Homo sapiens ortholog to least closely related (top to bottom respectively).[6]
## Composition of protein
C10orf71 is predicted to be a non-transmembrane, soluble protein.[7] It is predicted to be a nuclear protein with 91.3% confidence with it being fairly confident to be a nuclear protein throughout the orthologs.[8] There was one positive charge cluster found in C10orf71 protein sequence, that is located from amino acids 1165-1193.[6] This cluster was moderately conserved throughout the orthologs analyzed. There was also a mixed charge cluster found in the Homo sapiens' sequence of this protein, located from amino acid 750-778, although this cluster was not highly conserved throughout the analyzed orthologs.[6] There was one repeat sequence found as well, TASKPPA, located at amino acids 163-169 and 116-1172. This protein is Proline and Serine rich as well.[6]
## Domains and motifs
One confirmed domain of unknown function (DUF) was found within the C10orf71 protein sequence, DUF4585.[1] DUF4585 is located on the Homo sapiens protein sequence from amino acid 311-334. DUF4585 was highly conserved throughout the orthologs that were analyzed. There was also a small vacuolar targeting motif (VAC) found within the analyzed protein sequence spanning amino acids 543-546.[8]
## Protein structure
The mature C10orf71 protein contains nuclear localization signals (NLS), pat4 (RKPK at aa 382, RPRK at aa 640, KRRK at aa 1190) and pat7 (PPWRKPK at aa 379 and PWRKPKT at aa 380) with an NLS score pf 0.94. A secondary structure was constructed with a 6.1% confidence level.[7]
## Post-translational modifications
There were seven GlcNAc O-glycosylation sites predicted within the protein sequence found at amino acids 116, 120, 139, 165, 468, 470, and 844.[7] There were also several phosphorylation sites found interspersed throughout the sequence. One propeptide cleavage site was predicted at amino acid 38.[7] There were three predicted sumoylation sites found at amino acids 599, 890, and 1176.
## Expression
C10orf71 was found to be highly expressed in cardiac, muscle, and liver tissue (biology).[1]
## Regulation of expression
There were 6 possible promoters found in the sequence. Promoter GXP_6729162 is 1403 bp in length.[10] This promoter had several transcription factors of interest including those involved with myocytes.[10]
## Function
There is little scientific information known about the function of C10orf71.
## Interacting proteins
There was a total of 25 proteins generated that were predicted to interact with C10orf71 (Homo sapiens ortholog).[11][12] Most of the interactions predicted were physical interactions with C10orf71.[11] These interactions were discovered through a variety of mechanisms including, but not limited to: affinity chromatography, microarray analysis, and tandem mass spectrometry among others.[11][12] Refer to table for details about the interacting proteins of C10orf71.[13]
Interacting proteins, their function if known, and any tissues they have been found or predicted to be expressed in and any diseases they have been associated with.[11][12][13]
# Homologs
## Paralogs
There are currently no known paralogs to the C10orf71 gene.
## Orthologs
C10orf71 is known to have 68 orthologs in various species including primates (11 species), rodents (8 species), Laurasiatheria carnivores (14 species), Placental mammals (38 species), Sauropsida birds and reptiles (7 species), and fish (11 species).[38] The highly conserved sequences are primarily from primates with the identity percentage of these species being >90%, whereas species such as reptiles, birds, and fish had an identity percentage ≤30%.[6] Refer to table for additional information on dates of divergence, sequence length, and sequence identity and similarity for orthologs. C10orf71 is not present in prokaryotes, archaea, or fungi.[38]
Ortholog table in descending order to latest ortholog diverged. This table compares the orthologs analyzed, their species names, common names, dates of divergence from Homo sapiens ortholog (MYA), length (aa), and percentage of similarity and identity.[1][6][8][38][39]
## Phylogeny
A phylogenetic tree was constructed for the orthologs that were analyzed in comparison to Homo sapiens. With the species of latest divergence being Rhincodon types, or the whale shark.[38][39]
## Evolutionary rate
C10orf71's rate of divergence was faster than that of fibrinogen or Cytochrome C.[38]
# Clinical significance
There was a microarray experiment that also showed evidence that C10orf71's expression was lowered in skeletal muscle tissues that experienced sepsis.[40] There was clinical significance found in the expression level of C10orf71 in an experiment looking at those with Myotonic dystrophy.[40] One microarray analysis produced results that showed C10orf71's expression level decreased in those with prostate cancer as well.[40] | https://www.wikidoc.org/index.php/C10orf71 | |
390c722fcd716c952f99f644f0344f1804296af8 | wikidoc | C10orf76 | C10orf76
C10orf76 or chromosome 10 open reading frame 76, also known as UPF0668, is a protein that in humans is encoded by the c10orf76 gene. Its function is not currently known, but experimental evidence has suggested that it may be involved in transcriptional regulation. The protein contains a conserved proline-rich motif, suggesting that it may participate in protein-protein interactions via an SH3-binding domain, although no such interactions have been experimentally verified. The well-conserved gene appears to have emerged in Fungi approximately 1.2 billion years ago. The locus is alternatively spliced and predicted to yield five protein variants, three of which contain a protein domain of unknown function, DUF1741.
# Function
The function of c10orf76 is not yet known. It has been found to contain a potential SH3-binding domain, which is known to participate in protein-protein binding interactions; however, no protein interactions have been experimentally verified with c10orf76. A 2007 gene expression study found c10orf76 expression to vary inversely with the expression of several other genes, including NFYB, CCR5, and NSBP1, suggesting that the protein may function as a transcriptional regulator.
# Homology
C10orf76 is well-conserved throughout Eumetazoans. Some weakly similar orthologs (approximately 35% sequence identity) were identified in Parazoa (i.e., A. queenslandica) and in Fungi, specifically Ascomycetes (i.e., A. oryzae).
The following table illustrates the sequence similarity between human c10orf76 protein and various orthologs. Similar sequences were identified with BLAST and BLAT tools.
# Gene
## Characteristics
In humans, the c10orf76 gene, also known by the alias FLJ13114, spans 210,577 base pairs on the reverse strand of the long arm of chromosome 10. Its 26 alternatively spliced exons encode 5 potential transcript variants, the largest of which being 4101 base pairs in length.
The human c10orf76 locus is flanked on the left and right sides by HPS6 and KCNIP2, respectively. HPS6 is a protein that may play a role in organelle biogenesis, and KCNIP2 is a voltage-gated potassium channel interacting protein. The same pattern is observed in the orthologous locus in mice, as well as most other vertebrates.
## Expression
The NCBI (GenBank) gene profile for c10orf76 labels the start of the first transcribed exon as the beginning of the gene. The primary promoter predicted by the El Dorado tool from Genomatix begins 519 base pairs upstream of this transcription start site. This promoter is predicted to be 658 base pairs in length and thus includes the first transcribed exon at its 3 prime end.
The c10orf76 locus is thought to be alternatively spliced into at least five unique isoforms, although it is unclear how this splicing is regulated. A second potential promoter, also predicted by El Dorado, likely drives expression of one of the shorter documented variants (positioned before exon 23).
# Protein
## Characteristics
The largest protein variant is 689 amino acids in length. It has a molecular mass of approximately 78.7kDa and is isoelectric at pH 6.13. It may be secreted via a non-classical pathway. NCBI identifies a protein domain of unknown function between amino acids Asp435 and Leu671, known as DUF1741 (Domain of Unknown Function 1741). This domain is not known to exist in any other proteins.
## Expression
A potential stem loop region at the 3 prime end of the first exon (and thus, the end of the promoter) was predicted by the Dotlet program from ExPASy. This could serve to regulate protein translation. Also, an Alu segment in the 3 prime untranslated region of the mature mRNA could serve as a potential translational regulatory mechanism.
The protein has been found to be differentially expressed in some medical conditions and in response to certain cellular signals. For example, decreased c10orf76 expression is observed in patients with chronic B-cell lymphocytic leukemia. Decreased expression is also observed in cells treated with vascular endothelial growth factor.
The protein is thought to be localized to the cytoplasm, although this is uncertain. It has also been predicted to be a 3-pass transmembrane protein. Also, a mitochondrial sorting signal was identified at the beginning of one of the protein isoforms using MitoProt II (located at Met416 of the largest protein variant).
## Structure
The structure of the c10orf76 protein has not been experimentally explored. The secondary structure is predicted to be completely helical in nature, with intervening regions of protein disorder. The potential SH3-binding domain is located on a predicted region of disorder, further supporting a protein-protein binding function for c10orf76. A helical region between amino acids 610-655 was predicted to be a coiled coil motif.
A PHYRE2 protein structure prediction suggested that the first 200 residues of c10orf76 may share strong structural similarities with Symplekin, a nuclear-localized protein that is thought to be a scaffold component of the polyadenylation complex.
## Predicted protein Interactions
The expression of c10orf76 mRNA has been found to be inversely correlated with expression of various other mRNAs, including NFYB, CCR5, and NSBP1. Although this study and the predicted SH3-binding domain suggest that c10orf76 partakes in protein-protein binding interactions, none have been experimentally verified. A short search using IntAct, MINT, and STRING also yielded zero predicted protein-protein interactions.
## Predicted posttranslational modifications
There is a potential that the protein is secreted via a non-classical pathway, which may underlie the functionality of some of the posttranslational modifications. There are ten conserved potential phosphorylation sites within the protein sequence. Also, there are nine residues that are confidently (>90%) predicted by NetOGlyc to undergo O-linked glycosylation, all residing within the low complexity region between Leu325 and Ser359.
## Regions of potential research interest
The protein coded by the largest mRNA variant of c10orf76 encodes a proline-rich motif containing two PxxP domains, where "P" represents a proline residue and "x" represents any other amino acid (highlighted in blue below). These domains have been shown to participate in protein-protein binding interactions, specifically via the SH3 protein binding domain. The potential SH3-binding domain exists within a low complexity region with an unusually high number of amino acids with oxygen-containing side-groups (highlighted in green below). An NetOGlyc analysis of the region suggests that these residues are likely to undergo O-linked glycosylation and thus may serve to regulate binding to the potential SH3-binding domain.
325 L V T T P V S P A P T T P V T P L G T T P P S S 359
An Alu element was identified in the 3`-UTR of the longest mRNA transcript variant It is unclear as to whether this sequence serves any functional or regulatory purpose, but there is existing evidence for Alu-mediated protein translation regulation, so this cannot be ruled out in c10orf76.
The N-terminus of a short transcript variant (exons 17-26) was predicted to have a mitochondrial sorting signal with 96% confidence using the MitoProt II tool. It is unclear as to whether this is a uniquely transcribed variant or it results from protein cleavage of the full-size protein. There are no predicted alternative promoters upstream of this variant's first exon.
# Model organisms
Model organisms have been used in the study of C10orf76 function. A conditional knockout mouse line called 9130011E15Riktm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping | C10orf76
C10orf76 or chromosome 10 open reading frame 76, also known as UPF0668, is a protein that in humans is encoded by the c10orf76 gene.[1] Its function is not currently known, but experimental evidence has suggested that it may be involved in transcriptional regulation.[2] The protein contains a conserved proline-rich motif,[1][3] suggesting that it may participate in protein-protein interactions via an SH3-binding domain,[4] although no such interactions have been experimentally verified. The well-conserved gene appears to have emerged in Fungi approximately 1.2 billion years ago.[3][5] The locus is alternatively spliced and predicted to yield five protein variants, three of which contain a protein domain of unknown function, DUF1741.[1][6]
# Function
The function of c10orf76 is not yet known. It has been found to contain a potential SH3-binding domain,[1][4] which is known to participate in protein-protein binding interactions; however, no protein interactions have been experimentally verified with c10orf76. A 2007 gene expression study found c10orf76 expression to vary inversely with the expression of several other genes, including NFYB, CCR5, and NSBP1, suggesting that the protein may function as a transcriptional regulator.[2]
# Homology
C10orf76 is well-conserved throughout Eumetazoans.[1][3] Some weakly similar orthologs (approximately 35% sequence identity) were identified in Parazoa (i.e., A. queenslandica) and in Fungi, specifically Ascomycetes (i.e., A. oryzae).[3]
The following table illustrates the sequence similarity between human c10orf76 protein and various orthologs. Similar sequences were identified with BLAST[3] and BLAT[7] tools.
# Gene
## Characteristics
In humans, the c10orf76 gene, also known by the alias FLJ13114, spans 210,577 base pairs on the reverse strand of the long arm of chromosome 10.[6] Its 26 alternatively spliced exons encode 5 potential transcript variants, the largest of which being 4101 base pairs in length.[6]
The human c10orf76 locus is flanked on the left and right sides by HPS6 and KCNIP2, respectively.[1] HPS6 is a protein that may play a role in organelle biogenesis,[8] and KCNIP2 is a voltage-gated potassium channel interacting protein.[9] The same pattern is observed in the orthologous locus in mice,[10] as well as most other vertebrates.
## Expression
The NCBI (GenBank) gene profile for c10orf76 labels the start of the first transcribed exon as the beginning of the gene.[1] The primary promoter predicted by the El Dorado tool from Genomatix begins 519 base pairs upstream of this transcription start site.[11] This promoter is predicted to be 658 base pairs in length and thus includes the first transcribed exon at its 3 prime end.[1]
The c10orf76 locus is thought to be alternatively spliced into at least five unique isoforms, although it is unclear how this splicing is regulated.[1] A second potential promoter, also predicted by El Dorado, likely drives expression of one of the shorter documented variants (positioned before exon 23).[6][11]
# Protein
## Characteristics
The largest protein variant is 689 amino acids in length.[1] It has a molecular mass of approximately 78.7kDa and is isoelectric at pH 6.13.[12] It may be secreted via a non-classical pathway.[13] NCBI identifies a protein domain of unknown function between amino acids Asp435 and Leu671, known as DUF1741 (Domain of Unknown Function 1741).[1] This domain is not known to exist in any other proteins.[3]
## Expression
A potential stem loop region at the 3 prime end of the first exon (and thus, the end of the promoter) was predicted by the Dotlet program from ExPASy.[14] This could serve to regulate protein translation.[15] Also, an Alu segment in the 3 prime untranslated region of the mature mRNA could serve as a potential translational regulatory mechanism.[16]
The protein has been found to be differentially expressed in some medical conditions and in response to certain cellular signals. For example, decreased c10orf76 expression is observed in patients with chronic B-cell lymphocytic leukemia.[17] Decreased expression is also observed in cells treated with vascular endothelial growth factor.[18]
The protein is thought to be localized to the cytoplasm,[19] although this is uncertain. It has also been predicted to be a 3-pass transmembrane protein.[12] Also, a mitochondrial sorting signal was identified at the beginning of one of the protein isoforms using MitoProt II (located at Met416 of the largest protein variant).[20]
## Structure
The structure of the c10orf76 protein has not been experimentally explored. The secondary structure is predicted to be completely helical in nature, with intervening regions of protein disorder.[22][23] The potential SH3-binding domain is located on a predicted region of disorder, further supporting a protein-protein binding function for c10orf76. A helical region between amino acids 610-655 was predicted to be a coiled coil motif.[24]
A PHYRE2[25] protein structure prediction suggested that the first 200 residues of c10orf76 may share strong structural similarities with Symplekin,[22] a nuclear-localized protein that is thought to be a scaffold component of the polyadenylation complex.[21]
## Predicted protein Interactions
The expression of c10orf76 mRNA has been found to be inversely correlated with expression of various other mRNAs, including NFYB, CCR5, and NSBP1.[2] Although this study and the predicted SH3-binding domain suggest that c10orf76 partakes in protein-protein binding interactions, none have been experimentally verified. A short search using IntAct,[26] MINT,[27] and STRING[28] also yielded zero predicted protein-protein interactions.
## Predicted posttranslational modifications
There is a potential that the protein is secreted via a non-classical pathway,[13] which may underlie the functionality of some of the posttranslational modifications. There are ten conserved potential phosphorylation sites within the protein sequence.[29] Also, there are nine residues that are confidently (>90%) predicted by NetOGlyc[30] to undergo O-linked glycosylation, all residing within the low complexity region between Leu325 and Ser359.
## Regions of potential research interest
The protein coded by the largest mRNA variant of c10orf76 encodes a proline-rich motif containing two PxxP domains, where "P" represents a proline residue and "x" represents any other amino acid[1] (highlighted in blue below). These domains have been shown to participate in protein-protein binding interactions, specifically via the SH3 protein binding domain.[4] The potential SH3-binding domain exists within a low complexity region with an unusually high number of amino acids with oxygen-containing side-groups (highlighted in green below). An NetOGlyc analysis[30] of the region suggests that these residues are likely to undergo O-linked glycosylation and thus may serve to regulate binding to the potential SH3-binding domain.[31]
325 L V T T P V S P A P T T P V T P L G T T P P S S 359
An Alu element was identified in the 3`-UTR of the longest mRNA transcript variant[1] It is unclear as to whether this sequence serves any functional or regulatory purpose, but there is existing evidence for Alu-mediated protein translation regulation, so this cannot be ruled out in c10orf76.[16]
The N-terminus of a short transcript variant (exons 17-26) was predicted to have a mitochondrial sorting signal with 96% confidence using the MitoProt II tool.[20] It is unclear as to whether this is a uniquely transcribed variant or it results from protein cleavage of the full-size protein. There are no predicted alternative promoters upstream of this variant's first exon.[11]
# Model organisms
Model organisms have been used in the study of C10orf76 function. A conditional knockout mouse line called 9130011E15Riktm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[32] Male and female animals underwent a standardized phenotypic screen[33] to determine the effects of deletion.[34][35][36][37] Additional screens performed: - In-depth immunological phenotyping[38] - in-depth bone and cartilage phenotyping[39] | https://www.wikidoc.org/index.php/C10orf76 | |
86f6338dc45b02c7d14ece7c196850861f2f8cec | wikidoc | C11orf16 | C11orf16
Gene C11orf16, chromosome 11 open reading frame 16, is a protein in humans that is encoded by the C11orf16 gene. It has 7 exons, and the size of 467 amino acids.
# Gene
## Location
The gene C11orf16 is located on chromosome 11(p15.4), starting at 8,920,076bp and ending at 8,933,006bp.
## Gene Neighborhood
Gene ASCL3 and AKIP1 are the neighbor genes of C11orf16 on Chromosome 11.
## Expression
### Human
The gene does not have high expression throughout the body tissues. The percentile rank within the sample are higher in pancreas, ovary, and appendix.
### Mouse Brain
Even though the gene does not have a significant high expression in the mouse brain, it is most expressed in midbrain, isocortex, olfactory areas, and medulla.
## Transcription Factors
Some transcription factors that have the higher martix similarity are Kruppel-like zinc finger protein 219, Zinc finger protein 263, ZKSCAN12 (zinc finger protein with KRAB and SCAN domains 12), chorion-specific transcription factor GCMa, and Ras-responsive element binding protein 1.
# mRNA
## Isoform
The predicted C11orf16 transcript variant X1 is 2386bp long and has NCBI accession number of XM_017018013.1.
# Homology
## Paralogs
No paralogs were found for the C11orf16 gene through NCBI BLAST.
## Orthologs
## Conservation
The gene C11orf16 is conserved in many animal species including mammals, avians, and reptiles.
# Protein
## Molecular Weight
The predicted molecular weight of the protein encoded by C11orf16 is 51 kiloDaltons.
## Domains and Motifs
Several protein domains and motifs were found including CHD5-like protein, Tyrosine kinase phosphorylation site, Protein kinase C phosphorylation site, N-myristoylation site, Casein kinase II phosphorylation site, and cGMP-dependent protein kinase phosphorylation site. The picture indicates the location of the motifs.
## Secondary Structure
The protein is predicted to be made up with 21.2% of alpha helix, 15.2% of extended strand, and 63% of random coil.
## Post-translational Modifications
No transmembrane helices, potential GPI-modification site, and TM-protein were found. There were 7 predicted sumoylation sites, multiple phosporylation cites with most of them being unsp, and 9 glycosylation cites.
## Subcellular Localization Predictor
The protein is predicted to be localized to the nucleus with the probability of 47.8%; mitochondria with the probability of 26.1%.
## Protein Interaction
Proteins C1orf105(Chromosome 1 open reading frame105 ), PWWP2A, and SMYD1(SET and MYND domain containing 1) were found to be interacting with C11orf16.
# Clinical Significance
## Disease Association
Protein coded by C11orf16 gene is also predicted to have 19.61% sequence identity to tumor suppressor p53-binding protein suggesting that this gene might be involved with tumor suppressing process. | C11orf16
Gene C11orf16, chromosome 11 open reading frame 16, is a protein in humans that is encoded by the C11orf16 gene.[1][2] It has 7 exons, and the size of 467 amino acids.
# Gene
## Location
The gene C11orf16 is located on chromosome 11(p15.4), starting at 8,920,076bp and ending at 8,933,006bp.
## Gene Neighborhood
Gene ASCL3 and AKIP1 are the neighbor genes of C11orf16 on Chromosome 11.
## Expression
### Human
The gene does not have high expression throughout the body tissues. The percentile rank within the sample are higher in pancreas, ovary, and appendix.
### Mouse Brain
Even though the gene does not have a significant high expression in the mouse brain, it is most expressed in midbrain, isocortex, olfactory areas, and medulla.
## Transcription Factors
Some transcription factors that have the higher martix similarity are Kruppel-like zinc finger protein 219, Zinc finger protein 263, ZKSCAN12 (zinc finger protein with KRAB and SCAN domains 12), chorion-specific transcription factor GCMa, and Ras-responsive element binding protein 1.[3]
# mRNA
## Isoform
The predicted C11orf16 transcript variant X1 is 2386bp long and has NCBI accession number of XM_017018013.1.[4]
# Homology
## Paralogs
No paralogs were found for the C11orf16 gene through NCBI BLAST.
## Orthologs
## Conservation
The gene C11orf16 is conserved in many animal species including mammals, avians, and reptiles.
# Protein
## Molecular Weight
The predicted molecular weight of the protein encoded by C11orf16 is 51 kiloDaltons.[5][6]
## Domains and Motifs
Several protein domains and motifs were found including CHD5-like protein, Tyrosine kinase phosphorylation site, Protein kinase C phosphorylation site, N-myristoylation site, Casein kinase II phosphorylation site, and cGMP-dependent protein kinase phosphorylation site.[7] The picture indicates the location of the motifs.
## Secondary Structure
The protein is predicted to be made up with 21.2% of alpha helix, 15.2% of extended strand, and 63% of random coil.
## Post-translational Modifications
No transmembrane helices[8], potential GPI-modification site, and TM-protein were found. There were 7 predicted sumoylation sites[9], multiple phosporylation cites with most of them being unsp[10], and 9 glycosylation cites[11].
## Subcellular Localization Predictor
The protein is predicted to be localized to the nucleus with the probability of 47.8%; mitochondria with the probability of 26.1%.[13]
## Protein Interaction
Proteins C1orf105(Chromosome 1 open reading frame105 ), PWWP2A, and SMYD1(SET and MYND domain containing 1) were found to be interacting with C11orf16[14].
# Clinical Significance
## Disease Association
Protein coded by C11orf16 gene is also predicted to have 19.61% sequence identity to tumor suppressor p53-binding protein suggesting that this gene might be involved with tumor suppressing process[15]. | https://www.wikidoc.org/index.php/C11orf16 | |
f179e207d4be93c9dde420187e02654c041399b6 | wikidoc | C11orf30 | C11orf30
Protein EMSY is a protein that in humans is encoded by the C11orf30 gene.
# Clinical significance
C11orf30 has been shown to associate with atopy and susceptibility to poly-sensitisation.
# Interactions
C11orf30 has been shown to interact with ZMYND11, BRCA2 and CBX1. | C11orf30
Protein EMSY is a protein that in humans is encoded by the C11orf30 gene.[1]
# Clinical significance
C11orf30 has been shown to associate with atopy and susceptibility to poly-sensitisation.[2]
# Interactions
C11orf30 has been shown to interact with ZMYND11,[3] BRCA2[3] and CBX1.[3] | https://www.wikidoc.org/index.php/C11orf30 | |
69ef31c9c7a5c2c56a9a39c82cd3b67695d82b52 | wikidoc | C11orf52 | C11orf52
C11orf52 is an uncharacterized protein that in homo sapiens is encoded by the C11orf52 gene.
# Gene
## Location
C11orf52 is located on chromosome 11 at 11q23.1, starting at 111908620 and ending at 112064278. C11orf52 spans 155658 base pairs and is orientated on the positive strand. Gene C11orf52 has a molecular weight of 14kDa and is a protein coding gene of 7,995 bp containing four exons. The coding region is made up of 1,168 bp.
## Gene neighborhood
Genes HSPB2, CRYAB, OLAT, and PPIHP1 neighbor C11orf52 on chromosome 11.
## Expression
C11orf52 is highly expressed in the thyroid, thalmus, pituitary, placenta, and prostate, kidney, heart, and skeletal muscles. However, in estrogen receptor alpha-silenced MCF-7 breast cancer cells, it is expressed at an extremely low level compared to control tissues.
## Transcript
There is only one variant of C11orf52 RNA. The mRNA sequence is 1,140 base pairs long. There is an upstream stop codon located at nucleotides 65 – 67. The 23rd amino acid varies between threonine and arginine.
# Protein
The 123 amino acid chain is a domain of unknown function. It has a molecular weight of 13,9 kDal and a predicted Isoelectric Point of 9.74 C11orf52 is predicted to be targeted to the nucleus.
There are no isoforms of the protein encoded by C11orf52.
## Structure
The LYS19-22 region is an external domain of the protein structure.
# Homology
## Orthologs
There is only one member of the C11orf52 gene family and no splice isoforms can be found going back to Geospiza fortis - the most distantly related to Homo Sapiens C11orf52 sequence. Gene duplication first occurred approximately 324.5 million years ago in reptiles and birds. There are no paralogs for the C11orf52 gene.
# Clinical significance
Unusual DNA methylation in the C11orf52 gene in some children can be attributed to prenatal smoke exposure.
C11orf52 may also play a role in lung cancer. C11orf52 is expressed in the lungs and has been associated with increased phosphorylation in cell lung cancer tumors. There is evidence that phosphorylation mechanisms exist which enhance proteins and pathways which should have inhibited phosphorylation in order to prevent extreme proliferation. C11orf52 is one gene where the phosphorylation is significantly different between the cancerous cells and normal tissue.
# Further reading
- Varjosalo M, Keskitalo S, Van Drogen A, Nurkkala H, Vichalkovski A, Aebersold R, Gstaiger M (April 2013). "The protein interaction landscape of the human CMGC kinase group". Cell Reports. 3 (4): 1306–20. doi:10.1016/j.celrep.2013.03.027. PMID 23602568..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}
- Oláh J, Vincze O, Virók D, Simon D, Bozsó Z, Tõkési N, Horváth I, Hlavanda E, Kovács J, Magyar A, Szũcs M, Orosz F, Penke B, Ovádi J (September 2011). "Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein". The Journal of Biological Chemistry. 286 (39): 34088–100. doi:10.1074/jbc.M111.243907. PMC 3190826. PMID 21832049. | C11orf52
C11orf52 is an uncharacterized protein that in homo sapiens is encoded by the C11orf52 gene.
# Gene
## Location
C11orf52 is located on chromosome 11 at 11q23.1, starting at 111908620 and ending at 112064278.[1] C11orf52 spans 155658 base pairs and is orientated on the positive strand. Gene C11orf52 has a molecular weight of 14kDa and is a protein coding gene of 7,995 bp containing four exons. The coding region is made up of 1,168 bp.[2]
## Gene neighborhood
Genes HSPB2, CRYAB, OLAT, and PPIHP1 neighbor C11orf52 on chromosome 11.
## Expression
C11orf52 is highly expressed in the thyroid, thalmus, pituitary, placenta, and prostate, kidney, heart, and skeletal muscles.[3] However, in estrogen receptor alpha-silenced MCF-7 breast cancer cells, it is expressed at an extremely low level compared to control tissues.[4]
## Transcript
There is only one variant of C11orf52 RNA. The mRNA sequence is 1,140 base pairs long.[2] There is an upstream stop codon located at nucleotides 65 – 67. The 23rd amino acid varies between threonine and arginine.[2]
# Protein
The 123 amino acid chain is a domain of unknown function.[5] It has a molecular weight of 13,9 kDal and a predicted Isoelectric Point of 9.74 [2] C11orf52 is predicted to be targeted to the nucleus.
There are no isoforms of the protein encoded by C11orf52.
## Structure
The LYS19-22 region is an external domain of the protein structure.[2]
# Homology
## Orthologs
There is only one member of the C11orf52 gene family and no splice isoforms can be found going back to Geospiza fortis - the most distantly related to Homo Sapiens C11orf52 sequence. Gene duplication first occurred approximately 324.5 million years ago in reptiles and birds. There are no paralogs for the C11orf52 gene.
# Clinical significance
Unusual DNA methylation in the C11orf52 gene in some children can be attributed to prenatal smoke exposure.[6]
C11orf52 may also play a role in lung cancer. C11orf52 is expressed in the lungs and has been associated with increased phosphorylation in cell lung cancer tumors. There is evidence that phosphorylation mechanisms exist which enhance proteins and pathways which should have inhibited phosphorylation in order to prevent extreme proliferation. C11orf52 is one gene where the phosphorylation is significantly different between the cancerous cells and normal tissue.[7]
# Further reading
- Varjosalo M, Keskitalo S, Van Drogen A, Nurkkala H, Vichalkovski A, Aebersold R, Gstaiger M (April 2013). "The protein interaction landscape of the human CMGC kinase group". Cell Reports. 3 (4): 1306–20. doi:10.1016/j.celrep.2013.03.027. PMID 23602568..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}
- Oláh J, Vincze O, Virók D, Simon D, Bozsó Z, Tõkési N, Horváth I, Hlavanda E, Kovács J, Magyar A, Szũcs M, Orosz F, Penke B, Ovádi J (September 2011). "Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein". The Journal of Biological Chemistry. 286 (39): 34088–100. doi:10.1074/jbc.M111.243907. PMC 3190826. PMID 21832049. | https://www.wikidoc.org/index.php/C11orf52 | |
1c62cc2490284884d258542d33989cd4f413f1c8 | wikidoc | C11orf73 | C11orf73
C11orf73 is a protein important in lung and multicellular organismal development that, in humans, is encoded by the C11orf73 gene (chromosome 11 open reading frame 73). C11orf73 is found on chromosome 11 in humans and chromosome 7 in mice. Similar sequences (orthologs) are found in most animal and fungal species. The mouse homolog, lethal gene on chromosome 7 Rinchik 6 protein is encoded by the l7Rn6 gene. When the l7Rn6 protein is disrupted in mice, the mice display severe emphysema at birth as a result of disorganization of the Golgi apparatus and formation of aberrant vesicular structures within clara cells.
# Gene
Chromosome 11 Open Reading Frame 73 is a protein-coding gene in Homo sapiens. Alternate names for the gene are FLJ43020, HSPC138, HSPC179, and L7RN6. Located on long arm of chromosome 11 at area q14.2, the entire gene including introns and exons is 42,698 base pairs on the plus strand. The mRNA of C11orf73 Variant 1 includes exons 1, 3, 4, 5, and 7 amounting to 1,183 base pairs, with base pairs 239 to 832 representing the coding regions.
## Alternative Splicing
Variant 1 is the longest and most common protein coding variant. The three other main variants use an alternate exon sequence that throws off the reading frame, causing early termination of the mRNA sequence and undergoes protein decay. The table below shows the different variants and exon usage.
The four variants shown in the table above are the most common isoforms found in human cells. There are a total of 13 alternatively spliced sequences and 3 unspliced forms that utilize two alternative promoters. The mRNA variants differ on the combination of 8 different exons, alternate, overlapping exons, and the retention of introns. Besides alternative spilcing, the mRNAs differ by truncation on the 3’ end. Variant 1 is one of ten mRNAs that has been shown to code for a protein, while the rest seem bound for nonsense mediated mRNA decay.
AceView representation of C11orf73 isoforms
File:Isoforms of C11orf73.jpg
## Promoter
The Promoter region, GXP 47146, was found using the ElDorado tool from Genomatix. The 840 bp sequence is located before the C11orf73 gene at DNA points 86012753 to 86013592. The promoter is conserved in 12 of 12 orthologs and codes for 6 relevant transcripts.
Conserved transcription factor binding sites from Genomatix ElDorado tool:
## Termination
Termination of the mRNA product is encoded for within the cDNA of the gene. The end termination of an mRNA product generally has three main features: the poly A signal, the poly A tail, and an area of sequence that can form a stem loop structure. The poly A signal is a highly conserved site, six nucleotide long sequence. In eukaryotes the sequence is AATAAA and is located about 10-30 nucleotides from the poly A site. The AATAAA sequence is a highly conserved, eukaryotic polyA signal that signals for polyadenylation of the mRNA product 10-30 base pairs after the signal sequence. The polyA site for C11orf73 is GTA.
# Gene expression
C11orf73 was determined to be expressed ubiquitously at a high level of 2.3 times above the average. C11orf73 is expressed in a large number of human tissues. Between the Expression Profiles and the EST Profile on UniGene, only 11 tissues were shown not to express C11orf73, most likely due to small sample sizes in the tissue.
# Protein
The human C11orf73 gene encodes for a protein called uncharacterized protein C11orf73. The homologous mouse L7rn6 gene encodes a protein called lethal gene on chromosome 7 Rinchik 6.
The encoded human protein is 197 amino acids long and weighs 21,628 Daltons. Through analogy to the mouse protein, the hypothetical function of the human C11orf73 protein is the organization and function of the secretory apparatus in lung cells.
The protein domain known as DUF775 (Domain of Unknown Function 775) is located within both the human C11orf73 and mouse L7rn6 proteins. The DUF775 domain is 197 amino acids long, the same length as the protein. Other proteins that make up the DUF 775 super family by definition include all the orthologs of C11orf73.
Hydropathy analysis shows that there are no extensive hydrophobic regions in the protein and, hence, it is concluded that C11orf73 is a cytoplasmic protein. The isoelectric point for C11orf73 is 5.108 suggesting it functions optimally in a more acidic environment.
## SNP
The only SNP, or single-nucleotide polymorphism, for the C11orf73 sequence results in an amino acid change within the protein. The lack of other SNPs are most likely due to the high level of conservation of C11orf73 and the lethal effect a mutation in the protein bestows upon the organism. The phenotype for the SNP is unknown.
## Gene Neighborhood
The surrounding genes of C11orf73 are CCDC81, ME3, and EED. The genetic neighborhood is looked at in order to get a better understanding of the possible function of the gene by looking at the function of the surrounding genes.
The CCDC81 gene codes for an uncharacterized protein product and is oriented on the plus strand. CCDC81stands for coiled-coil domain containing 81 isoform 1.
The ME3 gene stands for mitochondrial malic enzyme 3 precursor. Malic enzyme catalyzes the oxidative decarboxylation of malate to pyruvate using either NAD+ or NADP+ as a cofactor. Mammalian tissues contain 3 distinct isoforms of malic enzyme: a cytosolic NADP(+)-dependent isoform, a mitochondrial NADP(+)-dependent isoform, and a mitochondrial NAD(+)-dependent isoform. This gene encodes a mitochondrial NADP(+)-dependent isoform. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined.
The EED gene stands for embryonic ectoderm development isoform b and is a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein interacts with enhancer of zeste 2, the cytoplasmic tail of integrin beta7, immunodeficiency virus type 1 (HIV-1) MA protein, and histone deacetylase proteins. This protein mediates repression of gene activity through histone deacetylation, and may act as a specific regulator of integrin function. Two transcript variants encoding distinct isoforms have been identified for this gene.
## Interactions
The programs STRING and Sigma-Aldrich’s Favorite Gene suggested possible protein interactions with C11orf73. ARGUL1, CRHBP, and EED were derived from textmining and HNF4A came from Sigma-Aldrich.
ARGUL1 is an unknown protein with an unknown function. CRHBP is a corticotrophin releasing hormone binding protein which could possibly play a role in a signal cascade that involves or activates C11orf73. EED, a neighboring protein of C11orf73, is an embryonic ectoderm development protein and is a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. HNF4A is a transcription regulator and it is unknown if HNF4A regulates C11orf73's expression or simply interacts with it.[12
# Evolutionary History
The evolutionary history of organisms can be determined using the sequences of orthologs as time references to create a phylogenetic tree. The CLUSTALW compares multiple sequences, the program can also be used to create such a phylogenetic tree based on the orthologs of C11orf73. The tree to the right shows the generated phylogenetic tree with a time line based on time of divergence. The tree made from the C11orf73 orthologs is identical to the literature phylogenetic tree, even grouping together similar organisms such as fish, birds, and fungi.
## Orthologs
Homologous sequences are orthologous if they were separated by a speciation event: when a species diverges into two separate species, the divergent copies of a single gene in the resulting species are said to be orthologous. Orthologs, or orthologous genes, are genes in different species that are similar to each other because they originated from a common ancestor. Orthologous sequences provide useful information in taxonomic classification and phylogenetic studies of organisms. The pattern of genetic divergence can be used to trace the relatedness of organisms. Two organisms that are very closely related are likely to display very similar DNA sequences between two orthologs. Conversely, an organism that is further removed evolutionarily from another organism is likely to display a greater divergence in the sequence of the orthologs being studied.
Table of Chromosome 11 open reading frame 73 Orthologs
The table shows the 13 sequences (12 orthologs, 1 original sequence) along with protein name, accession numbers, nucleotide identity, protein identity, and E-values. The accession numbers are the identification numbers from the NCBI Protein database. The nucleotide sequence can be accessed from the protein’s sequence page from DBSOURCE, which gives the accession number and is a link to the nucleotide’s sequence page. The length of both the nucleotide and protein sequence for each ortholog and its respective organism are listed in the table as well. Next to the sequence lengths are the identities of the ortholog to the original C11orf73 gene. The identities and E-values were acquired using the global alignment program, ALIGN, from the SDSC Biology Workbench and BLAST from NCBI.
The graph shows the percent identity of the ortholog against the divergence time of the organism to produce a mostly linear curve. The two main joints within the curve suggest times of gene duplication, around 450 million years and 1150 million years ago respectively. The paralogs from the gene duplications are probably so dissimilar from the highly conserved orthologs of C11orf73 that it was not found using the Blink or BLAST tools.
The value m (total number of amino acid changes that have occurred in a 100 amino acid segment), which is the corrected value of n (number of amino acid differences from the template sequence), is also used to calculate λ (the average amino acid changes per year, usually represented in values of λE9). | C11orf73
C11orf73 is a protein important in lung and multicellular organismal development[1] that, in humans, is encoded by the C11orf73 gene (chromosome 11 open reading frame 73).[2] C11orf73 is found on chromosome 11 in humans and chromosome 7 in mice. Similar sequences (orthologs) are found in most animal and fungal species. The mouse homolog, lethal gene on chromosome 7 Rinchik 6 protein is encoded by the l7Rn6 gene.[3] When the l7Rn6 protein is disrupted in mice, the mice display severe emphysema at birth as a result of disorganization of the Golgi apparatus and formation of aberrant vesicular structures within clara cells.[1]
# Gene
Chromosome 11 Open Reading Frame 73 is a protein-coding gene in Homo sapiens. Alternate names for the gene are FLJ43020, HSPC138, HSPC179, and L7RN6. Located on long arm of chromosome 11 at area q14.2, the entire gene including introns and exons is 42,698 base pairs on the plus strand. The mRNA of C11orf73 Variant 1 includes exons 1, 3, 4, 5, and 7 amounting to 1,183 base pairs, with base pairs 239 to 832 representing the coding regions.
## Alternative Splicing
Variant 1 is the longest and most common protein coding variant. The three other main variants use an alternate exon sequence that throws off the reading frame, causing early termination of the mRNA sequence and undergoes protein decay. The table below shows the different variants and exon usage.
The four variants shown in the table above are the most common isoforms found in human cells. There are a total of 13 alternatively spliced sequences and 3 unspliced forms that utilize two alternative promoters. The mRNA variants differ on the combination of 8 different exons, alternate, overlapping exons, and the retention of introns. Besides alternative spilcing, the mRNAs differ by truncation on the 3’ end. Variant 1 is one of ten mRNAs that has been shown to code for a protein, while the rest seem bound for nonsense mediated mRNA decay.
AceView[4] representation of C11orf73 isoforms
File:Isoforms of C11orf73.jpg
## Promoter
The Promoter region, GXP 47146, was found using the ElDorado[5] tool from Genomatix. The 840 bp sequence is located before the C11orf73 gene at DNA points 86012753 to 86013592. The promoter is conserved in 12 of 12 orthologs and codes for 6 relevant transcripts.
Conserved transcription factor binding sites from Genomatix ElDorado tool:
## Termination
Termination of the mRNA product is encoded for within the cDNA of the gene. The end termination of an mRNA product generally has three main features: the poly A signal, the poly A tail, and an area of sequence that can form a stem loop structure. The poly A signal is a highly conserved site, six nucleotide long sequence. In eukaryotes the sequence is AATAAA and is located about 10-30 nucleotides from the poly A site. The AATAAA sequence is a highly conserved, eukaryotic polyA signal that signals for polyadenylation of the mRNA product 10-30 base pairs after the signal sequence. The polyA site for C11orf73 is GTA.
# Gene expression
C11orf73 was determined to be expressed ubiquitously at a high level of 2.3 times above the average. C11orf73 is expressed in a large number of human tissues.[6][7] Between the Expression Profiles and the EST Profile on UniGene, only 11 tissues were shown not to express C11orf73, most likely due to small sample sizes in the tissue.
# Protein
The human C11orf73 gene encodes for a protein called uncharacterized protein C11orf73.[2] The homologous mouse L7rn6 gene encodes a protein called lethal gene on chromosome 7 Rinchik 6.[3]
The encoded human protein is 197 amino acids long and weighs 21,628 Daltons. Through analogy to the mouse protein, the hypothetical function of the human C11orf73 protein is the organization and function of the secretory apparatus in lung cells.[1]
The protein domain known as DUF775 (Domain of Unknown Function 775) is located within both the human C11orf73 and mouse L7rn6 proteins. The DUF775 domain is 197 amino acids long, the same length as the protein. Other proteins that make up the DUF 775 super family by definition include all the orthologs of C11orf73.
Hydropathy analysis shows that there are no extensive hydrophobic regions in the protein and, hence, it is concluded that C11orf73 is a cytoplasmic protein. The isoelectric point for C11orf73 is 5.108 suggesting it functions optimally in a more acidic environment.
[8]
## SNP
The only SNP,[9] or single-nucleotide polymorphism, for the C11orf73 sequence results in an amino acid change within the protein. The lack of other SNPs are most likely due to the high level of conservation of C11orf73 and the lethal effect a mutation in the protein bestows upon the organism. The phenotype for the SNP is unknown.
## Gene Neighborhood
The surrounding genes of C11orf73 are CCDC81, ME3, and EED. The genetic neighborhood is looked at in order to get a better understanding of the possible function of the gene by looking at the function of the surrounding genes.
[10]
The CCDC81 gene codes for an uncharacterized protein product and is oriented on the plus strand. CCDC81stands for coiled-coil domain containing 81 isoform 1.
The ME3 gene stands for mitochondrial malic enzyme 3 precursor. Malic enzyme catalyzes the oxidative decarboxylation of malate to pyruvate using either NAD+ or NADP+ as a cofactor. Mammalian tissues contain 3 distinct isoforms of malic enzyme: a cytosolic NADP(+)-dependent isoform, a mitochondrial NADP(+)-dependent isoform, and a mitochondrial NAD(+)-dependent isoform. This gene encodes a mitochondrial NADP(+)-dependent isoform. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined.[11]
The EED gene stands for embryonic ectoderm development isoform b and is a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein interacts with enhancer of zeste 2, the cytoplasmic tail of integrin beta7, immunodeficiency virus type 1 (HIV-1) MA protein, and histone deacetylase proteins. This protein mediates repression of gene activity through histone deacetylation, and may act as a specific regulator of integrin function. Two transcript variants encoding distinct isoforms have been identified for this gene.[12]
## Interactions
The programs STRING[13] and Sigma-Aldrich’s Favorite Gene[14] suggested possible protein interactions with C11orf73. ARGUL1, CRHBP, and EED were derived from textmining and HNF4A came from Sigma-Aldrich.
ARGUL1 is an unknown protein with an unknown function. CRHBP is a corticotrophin releasing hormone binding protein which could possibly play a role in a signal cascade that involves or activates C11orf73. EED, a neighboring protein of C11orf73, is an embryonic ectoderm development protein and is a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. HNF4A is a transcription regulator and it is unknown if HNF4A regulates C11orf73's expression or simply interacts with it.[12
# Evolutionary History
The evolutionary history of organisms can be determined using the sequences of orthologs as time references to create a phylogenetic tree. The CLUSTALW[15] compares multiple sequences, the program can also be used to create such a phylogenetic tree based on the orthologs of C11orf73. The tree to the right shows the generated phylogenetic tree with a time line based on time of divergence. The tree made from the C11orf73 orthologs is identical to the literature phylogenetic tree, even grouping together similar organisms such as fish, birds, and fungi.
## Orthologs
Homologous sequences are orthologous if they were separated by a speciation event: when a species diverges into two separate species, the divergent copies of a single gene in the resulting species are said to be orthologous. Orthologs, or orthologous genes, are genes in different species that are similar to each other because they originated from a common ancestor. Orthologous sequences provide useful information in taxonomic classification and phylogenetic studies of organisms. The pattern of genetic divergence can be used to trace the relatedness of organisms. Two organisms that are very closely related are likely to display very similar DNA sequences between two orthologs. Conversely, an organism that is further removed evolutionarily from another organism is likely to display a greater divergence in the sequence of the orthologs being studied.
Table of Chromosome 11 open reading frame 73 Orthologs
The table shows the 13 sequences (12 orthologs, 1 original sequence) along with protein name, accession numbers, nucleotide identity, protein identity, and E-values. The accession numbers are the identification numbers from the NCBI Protein database. The nucleotide sequence can be accessed from the protein’s sequence page from DBSOURCE, which gives the accession number and is a link to the nucleotide’s sequence page. The length of both the nucleotide and protein sequence for each ortholog and its respective organism are listed in the table as well. Next to the sequence lengths are the identities of the ortholog to the original C11orf73 gene. The identities and E-values were acquired using the global alignment program, ALIGN, from the SDSC Biology Workbench and BLAST from NCBI.
The graph shows the percent identity of the ortholog against the divergence time of the organism to produce a mostly linear curve. The two main joints within the curve suggest times of gene duplication, around 450 million years and 1150 million years ago respectively. The paralogs from the gene duplications are probably so dissimilar from the highly conserved orthologs of C11orf73 that it was not found using the Blink or BLAST tools.
The value m (total number of amino acid changes that have occurred in a 100 amino acid segment), which is the corrected value of n (number of amino acid differences from the template sequence), is also used to calculate λ (the average amino acid changes per year, usually represented in values of λE9). | https://www.wikidoc.org/index.php/C11orf73 | |
2cca2517482329b1e95b5f033e01688b2b03bda7 | wikidoc | C11orf86 | C11orf86
Chromosome 11 open reading frame 86, also known as C11orf86, is a protein-coding gene in humans. It encodes for a protein known as uncharacterized protein C11orf86, which is predicted to be a nuclear protein. The function of this protein is currently unknown.
# Gene
## Location
C11orf86 is located on the long arm of chromosome 11 at 11q13.2. It consists of 1732 base pairs, and is found on the plus strand. Gene neighbors of C11orf86 include uncharacterized LOC105369355, microRNA 6860, microRNA 3163, synaptotagmin 12, ras homolog family member D, and pyruvate carboxylase.
## Promoter
The program ElDorado, by Genomatix, identified the promoter region of C11orf86 on the positive strand from 66974707 to 66975464, for a total length of 758 base pairs.
## Expression
C11orf86 appears to be primarily expressed in the gastrointestinal tract. Expression occurs in ascites, the intestine, the stomach, gastrointestinal tumors, and non-neoplasia.
# mRNA
## Alternative Splicing
According to AceView, transcription of the gene produces three different mRNAs, two of which are alternatively spliced variants, while the third is an unspliced form. All three variants could possibly code for functional proteins. The transcript used for this article is made up of two exons, amounting to 1185 base pairs, and has the reference number NM_001136485.1.
# Protein
## General Properties
C11orf86 protein is 115 amino acids in length. The molecular weight of C11orf86 is 13.2 kdal. Its isoelectric point is predicted to be 11.9.
## Composition
The majority of the C11orf86 protein is composed of arginine (15.7%), glutamine (12.2%), serine (10.4%), glycine (10.4%), and leucine (9.6%). No cysteine, histidine, or asparagine residues are found in this protein.
C11orf86 has no positive, negative, or mixed charge clusters. However, there is a higher presence of arginine, which is positively charged.
## Domain
This protein is a part of the DUF4633 superfamily. Proteins that belong to this family are often between 94 and 123 amino acids in length. This domain is found in bacteria, viruses, fungi, plants, insects, reptiles, birds, and mammals.
## Post-Translational Modification
C11orf86 is predicted to have nine possible phosphorylation sites, of which eight are serine, and one is threonine. It is also predicted to have ten O-linked glycosylation sites.
## Secondary Structure
C11orf86 is primarily composed of random coil and alpha helices.
## Sub-cellular Localization
This protein is predicted to be a nuclear protein. There appears to be a bipartite nuclear localization sequence beginning at position 80.
## Homology
The C11orf86 protein is conserved in mammals, and orthologs can easily be traced back to marsupials, monotremes, and reptiles. No orthologs of C11orf86 appear to be present in plants, fungi, fish, amphibians, or birds. There are no paralogs of C11orf86. The table below shows some orthologs that were found using BLAST. Dates of divergence were found from TimeTree, using the median molecular time estimate.
# Clinical Significance
A bipolar disorder association study identified C11orf86 as one of many genes found in a region of linkage disequilibrium on chromosome 11. Despite evidence of some association, C11orf86 was not found to be in an area of particular significance. C11orf86 is down-regulated from non-neoplastic mucosa to adenomas and carcinomas, down-regulated in renal cell carcinoma, and harbors chromosomal gains that are significantly associated with pure mucinous subtypes in mucinous carcinoma. | C11orf86
Chromosome 11 open reading frame 86, also known as C11orf86, is a protein-coding gene in humans.[1] It encodes for a protein known as uncharacterized protein C11orf86,[2] which is predicted to be a nuclear protein. The function of this protein is currently unknown.
# Gene
## Location
C11orf86 is located on the long arm of chromosome 11 at 11q13.2. It consists of 1732 base pairs, and is found on the plus strand. Gene neighbors of C11orf86 include uncharacterized LOC105369355, microRNA 6860, microRNA 3163, synaptotagmin 12, ras homolog family member D, and pyruvate carboxylase.[3]
## Promoter
The program ElDorado, by Genomatix, identified the promoter region of C11orf86 on the positive strand from 66974707 to 66975464, for a total length of 758 base pairs.[4]
## Expression
C11orf86 appears to be primarily expressed in the gastrointestinal tract.[5] Expression occurs in ascites, the intestine, the stomach, gastrointestinal tumors, and non-neoplasia.[6]
# mRNA
## Alternative Splicing
According to AceView, transcription of the gene produces three different mRNAs, two of which are alternatively spliced variants, while the third is an unspliced form.[7] All three variants could possibly code for functional proteins. The transcript used for this article is made up of two exons, amounting to 1185 base pairs, and has the reference number NM_001136485.1.[8]
# Protein
## General Properties
C11orf86 protein is 115 amino acids in length.[2] The molecular weight of C11orf86 is 13.2 kdal.[9] Its isoelectric point is predicted to be 11.9.[10]
## Composition
The majority of the C11orf86 protein is composed of arginine (15.7%), glutamine (12.2%), serine (10.4%), glycine (10.4%), and leucine (9.6%). No cysteine, histidine, or asparagine residues are found in this protein.[9]
C11orf86 has no positive, negative, or mixed charge clusters. However, there is a higher presence of arginine, which is positively charged.
1 00000+0000 +-0+0000+0 0-000+00-0 00++0000+0 00-+0+0000 -+00-00-00
61 00-+000000 -0-000000+ +00+000++0 000+++0-00 0000000000 00000
## Domain
This protein is a part of the DUF4633 superfamily. Proteins that belong to this family are often between 94 and 123 amino acids in length.[11] This domain is found in bacteria, viruses, fungi, plants, insects, reptiles, birds, and mammals.[12]
## Post-Translational Modification
C11orf86 is predicted to have nine possible phosphorylation sites, of which eight are serine, and one is threonine.[13] It is also predicted to have ten O-linked glycosylation sites.[14]
## Secondary Structure
C11orf86 is primarily composed of random coil and alpha helices.[15][16]
## Sub-cellular Localization
This protein is predicted to be a nuclear protein.[17] There appears to be a bipartite nuclear localization sequence beginning at position 80.[18]
## Homology
The C11orf86 protein is conserved in mammals, and orthologs can easily be traced back to marsupials, monotremes, and reptiles. No orthologs of C11orf86 appear to be present in plants, fungi, fish, amphibians, or birds. There are no paralogs of C11orf86. The table below shows some orthologs that were found using BLAST.[19] Dates of divergence were found from TimeTree, using the median molecular time estimate.[20]
# Clinical Significance
A bipolar disorder association study identified C11orf86 as one of many genes found in a region of linkage disequilibrium on chromosome 11. Despite evidence of some association, C11orf86 was not found to be in an area of particular significance.[21] C11orf86 is down-regulated from non-neoplastic mucosa to adenomas and carcinomas,[22] down-regulated in renal cell carcinoma,[23] and harbors chromosomal gains that are significantly associated with pure mucinous subtypes in mucinous carcinoma.[24] | https://www.wikidoc.org/index.php/C11orf86 | |
6f3a1ff84e87a107e92fc86430a59e0db2e179c2 | wikidoc | C12orf60 | C12orf60
Uncharacterized protein C12orf60 is a protein that in humans (Homo sapiens) is encoded by the C12orf60 gene. The gene is also known as LOC144608 or MGC47869. The protein lacks transmembrane domains and helices, but it is rich in alpha-helices. It is predicted to localize in the nucleus.
The C12orf60 mature mRNA transcript is 1139 nucleotides long and encodes a protein containing 245 amino acids. The protein lacks transmembrane domains and helices, but it is rich in alpha-helices. It is predicted to localize in the nucleus, but its function is not yet well understood by the scientific community. The gene was listed as a potential biomarker for detecting the efficacy of allergen immunotherapy.
The gene is highly expressed in the testes and colon, but it is also expressed in the kidney, breast carcinomas, brain, and various endocrine glands.
# Gene
## Locus and size
C12rf60 is located on Chromosome 12 beginning at 14,803,572 bp and ending at 14,823,858 bp, spanning 20,287 base pairs It is located on the forward/positive strand between the 12p12.3 and 12p13.1 cytogenic bands. Other genes that are within 100 kilobases of this gene include:
- Positive/Forward Strand
H2A histone family member J (H2AFJ)
- H2A histone family member J (H2AFJ)
- Negative/Backwards Strand
Single-pass membrane protein with coiled-coil domains 3 (SMCO3)
WW domain binding protein 11 (WBP11)
ADP-ribosyltransferase 4 (ART4)
Histone cluster 4, H4 (HIST4H4)
LOC105369669
Matrix Gla protein (MGP)
- Single-pass membrane protein with coiled-coil domains 3 (SMCO3)
- WW domain binding protein 11 (WBP11)
- ADP-ribosyltransferase 4 (ART4)
- Histone cluster 4, H4 (HIST4H4)
- LOC105369669
- Matrix Gla protein (MGP)
## Common aliases
C12orf60 is also known as LOC144608 and MGC47869.
# mRNA
A total of 22 exons exist within the gene.5 From these exons, there are 13 transcript variants. 12 of these transcript variants are predicted, and only a further 7 of these are predicted to encode a protein. Furthermore, they are predicted to encode the same protein.
The notable features of the mRNA sequence include two polyadenylation signals in the 3' untranslated region (UTR), and it is the target of several RNA-binding proteins (RBP) including RBP-MBNL1 in the 5' UTR. A single intron splice site exists in the primary transcript, as does an upstream in-frame stop codon.
# Protein
## Composition
C12orf60 has a predicted isoelectric point of 8.19 and a molecular weight of 27.6 kiloDaltons. Glycine and tyrosine residues are relatively less prevalent compared to other proteins in the human proteome, while methionine is more prevalent.
## Topology
The protein product is predicted to have multiple α-helices, coiled coil, and one β-sheet. It is suggested that the protein does not contain transmembrane regions or helices, meaning that the protein is not anchored to the cell membrane nor an intracellular membrane like the Golgi apparatus.
## Conserved domains
In the predicted protein product, C12orf60 contains a conserved protein domain of 225 amino acids. This domain (DUF4533) is within in the pfam15047 family of proteins. Only one other gene is listed within this family: C12orf69, which is also known as SMOC3 (single-pass membrane protein with coiled-coil domains 3).
Analysis of human C12orf60 and 9 of its orthologs reveals a highly conserved ERL motif starting at the 10th residue of the human protein sequence. It is not known whether this motif occurs in other proteins.
Other conserved residues are Asp25, Ser28, Phe37, Met41, Glu69, Leu85, Lys88, Leu143, Pro147, Ile148, Leu151, Gln164, Lys189, Leu191, Ala207, and Glu212, Leu225, and Lys227. Furthermore, these residues lie within DUF4533, suggesting that these conserved amino acids are important for the function of the domain. Also, the region between the 100 and 150 residues are not conserved. Thus, this region is not likely vital to the protein's function.
## Post-translational modification
Since it is predicted that the protein product is intracellular, extracellular modifications are not predicted to occur on C12orf60. Other modifications such as acetylation, phosphorylation, picornaviral protease cleavage, sumolyation, and O-beta-GlcNAcylation are predicted to occur on C12orf60 as well as several of its orthologous proteins. There are two amino acids that serve as sites of both phosphorylation and O-beta-GlcNAcylation, which may indicate a site of protein activation or inactivation.
## Subcellular localization
C12orf60 is predicted to be localized in the nucleus, cytoplasm, or outside the cell. However, current literature supports its localization in the nucleus.
# Expression
## Tissue expression
Expression of C12orf60 is regulated. The gene is highly expressed in the testes and colon, but it is also expressed in the kidney, breast carcinomas, various endocrine glands, and some regions of the brain. It is also expressed in the embryo body and fetus during development.
## Transcriptional regulation
The promoter GXP_71811 regulates the expression of C12orf60. The promotor is 1373 base pairs long and is also located on the positive strand. There are over 400 transcription factors that are possible matches for binding to this promotor, including those of the SOX/SRY-sex/testis determining, human and murine ETS, and homeodomain transcription factors.
# Protein interactions
Rolland et al. found that C12orf60 interacts with BMP4 (bone morphogenetic protein 4). BMP4 induces bone and cartilage formation. It also acts in mesoderm induction and fracture repair.
Several other proteins might also interact with C12orf60, and some are predicted to be co-expressed with the protein. Possible protein interactions include L3MBTL4, C3orf67, FAM78A, and PXDC1. Rats that overexpressed L3MBTL4 had higher blood pressure and heart rate.
Proteins that are thought to be co-expressed alongside C12orf60 include ELMOD2, TTC30B, and BCDIN3D. ELMOD2 is thought to be involved in antiviral responses and causing familial idiopathic pulmonary fibrosis. TTC30B is involved in the organelle biogenesis and maintenance pathway as well as intraflagellar transport. BCDIN3D is a methyltransferase and serves as a negative regulator of miRNA processing. As there is no agreement from various sources on any protein-protein interaction, it is difficult to determine if any of these interactions actually occur.
# Homology
## Paralogs
There are no known paralogs to this gene within the human genome, and no paralogs of C12orf60 were found within the selected species that have a C12orf60 protein ortholog.
## Orthologs
Many orthologs are found in mammals and a couple of bird species.
# Clinical significance
## References in literature
The gene is within 1 Mb of SNPs that were associated with obesity, height, and weight.
The gene was listed along with two other genes in a patent as a potential biomarker for detecting the efficacy of allergen immunotherapy. Specifically, detection of 3 copies of C12orf60 meant that immunotherapy was ineffective.
In one study, the gene was among several identified genes that were translocated in a single patient with recurrent acute lymphoblastic leukemia. This translocation was associated with apoptosis and tumorigenesis.
Another study found that the gene is upregulated by at least 1.5 fold in cells that expressed Constitutive Myocyte Enhancer Factor 2 (MEF2CA). MEF2CA is expressed naturally in the brain.
One study stated the gene contains a “perfect potential antioxidant protein 1 (ATOX1) DNA interaction site in the promotor region.” | C12orf60
Uncharacterized protein C12orf60 is a protein that in humans (Homo sapiens) is encoded by the C12orf60 gene. The gene is also known as LOC144608 or MGC47869. The protein lacks transmembrane domains and helices, but it is rich in alpha-helices. It is predicted to localize in the nucleus.[1]
The C12orf60 mature mRNA transcript is 1139 nucleotides long[2] and encodes a protein containing 245 amino acids.[3] The protein lacks transmembrane domains and helices, but it is rich in alpha-helices. It is predicted to localize in the nucleus, but its function is not yet well understood by the scientific community. The gene was listed as a potential biomarker for detecting the efficacy of allergen immunotherapy.[4]
The gene is highly expressed in the testes and colon, but it is also expressed in the kidney, breast carcinomas, brain, and various endocrine glands.[5]
# Gene
## Locus and size
C12rf60 is located on Chromosome 12 beginning at 14,803,572 bp and ending at 14,823,858 bp, spanning 20,287 base pairs[6] It is located on the forward/positive strand between the 12p12.3 and 12p13.1 cytogenic bands.[7] Other genes that are within 100 kilobases of this gene include:[8]
- Positive/Forward Strand
H2A histone family member J (H2AFJ)
- H2A histone family member J (H2AFJ)
- Negative/Backwards Strand
Single-pass membrane protein with coiled-coil domains 3 (SMCO3)
WW domain binding protein 11 (WBP11)
ADP-ribosyltransferase 4 (ART4)
Histone cluster 4, H4 (HIST4H4)
LOC105369669
Matrix Gla protein (MGP)
- Single-pass membrane protein with coiled-coil domains 3 (SMCO3)
- WW domain binding protein 11 (WBP11)
- ADP-ribosyltransferase 4 (ART4)
- Histone cluster 4, H4 (HIST4H4)
- LOC105369669
- Matrix Gla protein (MGP)
## Common aliases
C12orf60 is also known as LOC144608 and MGC47869.
# mRNA
A total of 22 exons exist within the gene.5 From these exons, there are 13 transcript variants. 12 of these transcript variants are predicted, and only a further 7 of these are predicted to encode a protein. Furthermore, they are predicted to encode the same protein.
The notable features of the mRNA sequence include two polyadenylation signals in the 3' untranslated region (UTR), and it is the target of several RNA-binding proteins (RBP) including RBP-MBNL1 in the 5' UTR. A single intron splice site exists in the primary transcript, as does an upstream in-frame stop codon.
# Protein
## Composition
C12orf60 has a predicted isoelectric point of 8.19 and a molecular weight of 27.6 kiloDaltons. Glycine and tyrosine residues are relatively less prevalent compared to other proteins in the human proteome, while methionine is more prevalent.
## Topology
The protein product is predicted to have multiple α-helices, coiled coil, and one β-sheet. It is suggested that the protein does not contain transmembrane regions or helices, meaning that the protein is not anchored to the cell membrane nor an intracellular membrane like the Golgi apparatus.[10]
## Conserved domains
In the predicted protein product, C12orf60 contains a conserved protein domain of 225 amino acids. This domain (DUF4533) is within in the pfam15047 family of proteins. Only one other gene is listed within this family: C12orf69, which is also known as SMOC3 (single-pass membrane protein with coiled-coil domains 3).[11]
Analysis of human C12orf60 and 9 of its orthologs reveals a highly conserved ERL motif starting at the 10th residue of the human protein sequence. It is not known whether this motif occurs in other proteins.
Other conserved residues are Asp25, Ser28, Phe37, Met41, Glu69, Leu85, Lys88, Leu143, Pro147, Ile148, Leu151, Gln164, Lys189, Leu191, Ala207, and Glu212, Leu225, and Lys227. Furthermore, these residues lie within DUF4533, suggesting that these conserved amino acids are important for the function of the domain. Also, the region between the 100 and 150 residues are not conserved. Thus, this region is not likely vital to the protein's function.
## Post-translational modification
Since it is predicted that the protein product is intracellular, extracellular modifications are not predicted to occur on C12orf60. Other modifications such as acetylation, phosphorylation, picornaviral protease cleavage, sumolyation, and O-beta-GlcNAcylation are predicted to occur on C12orf60 as well as several of its orthologous proteins. There are two amino acids that serve as sites of both phosphorylation and O-beta-GlcNAcylation, which may indicate a site of protein activation or inactivation.
## Subcellular localization
C12orf60 is predicted to be localized in the nucleus, cytoplasm, or outside the cell.[12][13][14][15][16][17] However, current literature supports its localization in the nucleus.
# Expression
## Tissue expression
Expression of C12orf60 is regulated. The gene is highly expressed in the testes and colon, but it is also expressed in the kidney, breast carcinomas, various endocrine glands, and some regions of the brain.[19][20][21] It is also expressed in the embryo body and fetus during development.[19]
## Transcriptional regulation
The promoter GXP_71811 regulates the expression of C12orf60. The promotor is 1373 base pairs long and is also located on the positive strand. There are over 400 transcription factors that are possible matches for binding to this promotor, including those of the SOX/SRY-sex/testis determining, human and murine ETS, and homeodomain transcription factors.[6]
# Protein interactions
Rolland et al. found that C12orf60 interacts with BMP4 (bone morphogenetic protein 4).[22] BMP4 induces bone and cartilage formation. It also acts in mesoderm induction and fracture repair.
Several other proteins might also interact with C12orf60,[23] and some are predicted to be co-expressed with the protein.[24] Possible protein interactions include L3MBTL4, C3orf67, FAM78A, and PXDC1. Rats that overexpressed L3MBTL4 had higher blood pressure and heart rate.[25]
Proteins that are thought to be co-expressed alongside C12orf60 include ELMOD2, TTC30B, and BCDIN3D. ELMOD2 is thought to be involved in antiviral responses and causing familial idiopathic pulmonary fibrosis.[26] TTC30B is involved in the organelle biogenesis and maintenance pathway as well as intraflagellar transport. BCDIN3D is a methyltransferase and serves as a negative regulator of miRNA processing.[27] As there is no agreement from various sources on any protein-protein interaction, it is difficult to determine if any of these interactions actually occur.
# Homology
## Paralogs
There are no known paralogs to this gene within the human genome, and no paralogs of C12orf60 were found within the selected species that have a C12orf60 protein ortholog.
## Orthologs
Many orthologs are found in mammals and a couple of bird species.
# Clinical significance
## References in literature
The gene is within 1 Mb of SNPs that were associated with obesity, height, and weight.[28]
The gene was listed along with two other genes in a patent as a potential biomarker for detecting the efficacy of allergen immunotherapy.[4] Specifically, detection of 3 copies of C12orf60 meant that immunotherapy was ineffective.
In one study, the gene was among several identified genes that were translocated in a single patient with recurrent acute lymphoblastic leukemia.[29] This translocation was associated with apoptosis and tumorigenesis.
Another study found that the gene is upregulated by at least 1.5 fold in cells that expressed Constitutive Myocyte Enhancer Factor 2 (MEF2CA).[30] MEF2CA is expressed naturally in the brain.
One study stated the gene contains a “perfect potential antioxidant protein 1 (ATOX1) DNA interaction site in the promotor region.”[31] | https://www.wikidoc.org/index.php/C12orf60 | |
f3464ee6487002e4ca99ad4b2c0d81e59286475a | wikidoc | C16orf42 | C16orf42
C16orf42, or chromosome 16 open reading frame 42, is a hypothetical human protein found on chromosome 16. Its protein is 312 amino acids long. and its cDNA has 1214 base pairs
# Function
The function of C16orf42 is unknown. It is predicted to be a transmembrane protein, however the cellular or subcellular membrane in which is resides is as well unknown.
# Homology
C16orf42 can also be found in many other organisms, including mammals, and certain fungi and plants. It is not found in bacteria. C16orf42 is highly conserved in many of its orthologs, especially its mammalian orthologs, as high as 95% identity in rhesus monkeys. It also has fairly high conservation in its more distant homologs, 53% identity in corn for example. It has one potential human paralog, the protein EGFL6.
Ortholog Analysis:
# Expression
C16orf42 is not expressed ubiquitously in humans. It is most highly expressed in the ovary, but not expressed at all in the blood and very little in the brain. One microarray experiment suggested that malaria causes its expression in the blood, but further experimentation is needed to support this claim. Its expression in tissues tends to remain constant when the tissue is diseased. However, a brief analysis of its orthologs show inconsistencies in tissue expression. This could be due to a lack of research of this protein in other species.
# Structure
The structure of C16orf42 is unknown. It is predicted to have multiple regions of alpha-helices, and a few short stretches of beta-strands. It contains a potential metal binding domain between amino acids 60-90. It has a predicted molecular weight of 33.6 kdal and an isoelectric point of 6.496000, making it slightly acidic. Compared to other human proteins, C16orf42 is high in the amino acids arginine and alanine, and low in the amino acid threonine. A brief analysis of its strict orthologs show that they too are generally high in arginine and low in threonine as well as compared to the typical protein in their respective species. | C16orf42
C16orf42, or chromosome 16 open reading frame 42, is a hypothetical human protein found on chromosome 16.[1] Its protein is 312 amino acids long.[2] and its cDNA has 1214 base pairs[3]
# Function
The function of C16orf42 is unknown. It is predicted to be a transmembrane protein, however the cellular or subcellular membrane in which is resides is as well unknown.[4]
# Homology
C16orf42 can also be found in many other organisms, including mammals, and certain fungi and plants.[5] It is not found in bacteria.[5] C16orf42 is highly conserved in many of its orthologs, especially its mammalian orthologs, as high as 95% identity in rhesus monkeys.[5] It also has fairly high conservation in its more distant homologs, 53% identity in corn for example.[5] It has one potential human paralog, the protein EGFL6.[6]
Ortholog Analysis:
# Expression
C16orf42 is not expressed ubiquitously in humans. It is most highly expressed in the ovary, but not expressed at all in the blood and very little in the brain.[7] One microarray experiment suggested that malaria causes its expression in the blood,[7] but further experimentation is needed to support this claim. Its expression in tissues tends to remain constant when the tissue is diseased.[7] However, a brief analysis of its orthologs show inconsistencies in tissue expression. This could be due to a lack of research of this protein in other species.
# Structure
The structure of C16orf42 is unknown. It is predicted to have multiple regions of alpha-helices, and a few short stretches of beta-strands.[4] It contains a potential metal binding domain between amino acids 60-90.[2] It has a predicted molecular weight of 33.6 kdal and an isoelectric point of 6.496000, making it slightly acidic.[4] Compared to other human proteins, C16orf42 is high in the amino acids arginine and alanine, and low in the amino acid threonine.[4] A brief analysis of its strict orthologs show that they too are generally high in arginine and low in threonine as well as compared to the typical protein in their respective species.[4] | https://www.wikidoc.org/index.php/C16orf42 | |
a4cef25ae669a832ff756535965ece67e4221b2d | wikidoc | C16orf46 | C16orf46
Chromosome 16 open reading frame 46 is a protein of yet to be determined function in Homo sapiens. It is encoded by the C16orf46 gene with NCBI accession number of NM_001100873. It is a protein-coding gene with an overlapping locus.
# Gene
An alternative name for this gene is FLJ32702, however it is most commonly referred to as C16orf46.
## Location
The C16orf26 gene is found on chromosome 16q23.2 negative strand. The promoter region is 1152 base pairs long. It has three exons, one from 1-380 bp, the second from 381-1254 bp, and the third from 1255-1982 bp.
## Expression
C16orf46 is broadly expressed in the testis and thyroid as well as 18 other tissues. These tissue expression patterns are found to be low to moderate (25-50%). When looking at tissue profiles, the highest expression is in the adult mammalian kidney, liver, prefrontal cortex, cerebellum, heart, and brain.
# Protein
## Protein Analysis
The full C16orf46 protein is 417 amino acids long. It has no isoforms, and its most distant ortholog, Rhincodon typus (whale shark), also has no known isoforms. The molecular weight was found to be 45.8 kdal. The isoelectric point is 7.4, average for all proteins, and C16orf46 is electrically neutral.
C16orf46 is predicted to be found in the nucleus by all orthologs.
The secondary structure of C16orf46 has alternating alpha helices and beta sheets.
## Protein Level Regulation
In C16orf46, there is N-linked glycosylation, O-linked glycosylation, and SUMOylation.
There are phosphorylation sites found with the kinases CKII, CKI, PKC, and cdc2.
A coronavirus cleavage site is predicted at the 235 amino acid position. There are also tyrosine motif locations between amino acids 42-45 and 251-252.
# Transcript Level Regulation
mRNA folding on the 5' UTR predicts a stem loop twice in the area between base pairs 47-90.
# Homologs
## Orthologs
C16orf46 has over 50 orthologs ranging from primate to chordate. The table below shows a representation of the diversity of C16orf46 by listing a selection of orthologs found using NCBI. When C16orf46 Homo sapiens was run through a multiple alignment sequence program, Clustal Omega, against 20 true orthologs and 16 distant orthologs, Trp74 and Pro212 were found to be conserved in all.
## Paralogs
C16orf46 has no known paralogs.
# Mutations
C16orf46 has been compared against Fibrinogen, a protein which mutates rapidly, and Cytochrome C, a protein which mutates slowly.
As can be seen below, when multiple species of the three proteins were plotted, C16orf46 more closely resembled that of Fibrinogen than Cytochrome C, suggesting a possible rapid mutation.
# Interacting Proteins
C16orf46 interacts with FAT3 which has been linked to neurite interactions during development. C16orf46 is thought to have coexpression with the PLAC8L1 and CFAP43 gene, both of unknown function.
# Clinical Significance
There are higher levels of C16orf46 expression in pancreatic adenocarcinoma tumor epithelia tissue compared to the control. There is also higher gene expression in patients with small-cell carcinoma compared to the control. | C16orf46
Chromosome 16 open reading frame 46 is a protein of yet to be determined function in Homo sapiens. It is encoded by the C16orf46 gene with NCBI accession number of NM_001100873. It is a protein-coding gene with an overlapping locus[2].
# Gene
An alternative name for this gene is FLJ32702, however it is most commonly referred to as C16orf46[3].
## Location
The C16orf26 gene is found on chromosome 16q23.2 negative strand[4]. The promoter region is 1152 base pairs long[5]. It has three exons, one from 1-380 bp, the second from 381-1254 bp, and the third from 1255-1982 bp[2].
## Expression
C16orf46 is broadly expressed in the testis and thyroid as well as 18 other tissues[4]. These tissue expression patterns are found to be low to moderate (25-50%)[6]. When looking at tissue profiles, the highest expression is in the adult mammalian kidney, liver, prefrontal cortex, cerebellum, heart, and brain[7].
# Protein
## Protein Analysis
The full C16orf46 protein is 417 amino acids long[9]. It has no isoforms, and its most distant ortholog, Rhincodon typus (whale shark), also has no known isoforms[10]. The molecular weight was found to be 45.8 kdal[11]. The isoelectric point is 7.4, average for all proteins, and C16orf46 is electrically neutral[12].
C16orf46 is predicted to be found in the nucleus by all orthologs[13].
The secondary structure of C16orf46 has alternating alpha helices and beta sheets[14].
## Protein Level Regulation
In C16orf46, there is N-linked glycosylation, O-linked glycosylation, and SUMOylation[15][16].
There are phosphorylation sites found with the kinases CKII, CKI, PKC, and cdc2[17].
A coronavirus cleavage site is predicted at the 235 amino acid position[18]. There are also tyrosine motif locations between amino acids 42-45 and 251-252[19].
# Transcript Level Regulation
mRNA folding on the 5' UTR predicts a stem loop twice in the area between base pairs 47-90[20].
# Homologs
## Orthologs
C16orf46 has over 50 orthologs ranging from primate to chordate[21]. The table below shows a representation of the diversity of C16orf46 by listing a selection of orthologs found using NCBI. When C16orf46 Homo sapiens was run through a multiple alignment sequence program, Clustal Omega, against 20 true orthologs and 16 distant orthologs, Trp74 and Pro212 were found to be conserved in all[22].
## Paralogs
C16orf46 has no known paralogs[21].
# Mutations
C16orf46 has been compared against Fibrinogen, a protein which mutates rapidly, and Cytochrome C, a protein which mutates slowly.
As can be seen below, when multiple species of the three proteins were plotted, C16orf46 more closely resembled that of Fibrinogen than Cytochrome C, suggesting a possible rapid mutation[21].
# Interacting Proteins
C16orf46 interacts with FAT3 which has been linked to neurite interactions during development[23]. C16orf46 is thought to have coexpression with the PLAC8L1 and CFAP43 gene, both of unknown function[24].
# Clinical Significance
There are higher levels of C16orf46 expression in pancreatic adenocarcinoma tumor epithelia tissue compared to the control[25]. There is also higher gene expression in patients with small-cell carcinoma compared to the control[26]. | https://www.wikidoc.org/index.php/C16orf46 | |
e499370093218ce0909bfa7af9d716fc4f29a9dd | wikidoc | C16orf58 | C16orf58
Chromosome 16 open reading frame 58, or C16orf58, also known as FLJ13638 is a protein which in humans is encoded by the C16orf58 gene. The gene itself is 18892 bp long, with mRNA of 2760 bp, and a protein sequence of 468 amino acids. There is a conserved domain of unknown, DUF647. No function has been determined for this gene yet, but it is predicted that it resides in the endoplasmic reticulum in the cytoplasm.
# Species distribution
C16orf58 has very interesting conservation in that it has orthologs back through plants and fungi. However, it has not been found in reptiles, birds, or amphibians. The below table shows some, but not all, orthologs which were found using BLAST.
# Protein Interactions
Though the function is still unknown, C16orf58 has been shown to interact with three different proteins:
- MVD MVD stands for disphosphomevalonate decarboxylase which is an enzyme which functions in cholesterol biosynthesis.
- BSCL2 BSCL2 is the Bernardinelli-Seip congenital lipodystrophy 2, or seipin. It located in the endoplasmic reticulum and is thought to be important in the lipid droplet morphology.
- TSC22D4 The third interacting protein is TSC22D4, TSC22 domain family member 4, and functions as a leucine zipper translational regulation.
# Structure
Although there are several sites that will give predictions on protein structure, C16orf58 does not have a known structure yet. That being said there is at least one transmembrane domain, if not more. Within the protein structure there are several extended areas with uncharged amino acids, these could be possible transmembrane domains, or hydrophobic cores. The below shows the charge of each of the amino acids in the protein sequence, + for positive, - for negative and 0 for uncharged. Note the large segments of uncharged amino acids appear bolded. These stretches of uncharged amino acids are conserved back through distant orthologs. | C16orf58
Chromosome 16 open reading frame 58, or C16orf58, also known as FLJ13638 is a protein which in humans is encoded by the C16orf58 gene.[1] The gene itself is 18892 bp long, with mRNA of 2760 bp, and a protein sequence of 468 amino acids. There is a conserved domain of unknown, DUF647. No function has been determined for this gene yet, but it is predicted that it resides in the endoplasmic reticulum in the cytoplasm.[2]
# Species distribution
C16orf58 has very interesting conservation in that it has orthologs back through plants and fungi. However, it has not been found in reptiles, birds, or amphibians. The below table shows some, but not all, orthologs which were found using BLAST.[3]
# Protein Interactions
Though the function is still unknown, C16orf58 has been shown to interact with three different proteins:
- MVD[4] MVD stands for disphosphomevalonate decarboxylase which is an enzyme which functions in cholesterol biosynthesis.[5]
- BSCL2[6] BSCL2 is the Bernardinelli-Seip congenital lipodystrophy 2, or seipin.[7] It located in the endoplasmic reticulum and is thought to be important in the lipid droplet morphology.
- TSC22D4[6] The third interacting protein is TSC22D4, TSC22 domain family member 4, and functions as a leucine zipper translational regulation.[8]
# Structure
Although there are several sites that will give predictions on protein structure, C16orf58 does not have a known structure yet. That being said there is at least one transmembrane domain, if not more. Within the protein structure there are several extended areas with uncharged amino acids, these could be possible transmembrane domains, or hydrophobic cores.[2] The below shows the charge of each of the amino acids in the protein sequence, + for positive, - for negative and 0 for uncharged. Note the large segments of uncharged amino acids appear bolded. These stretches of uncharged amino acids are conserved back through distant orthologs. | https://www.wikidoc.org/index.php/C16orf58 | |
e5314931effa115c39ca1e8b1c0ff29934b57bea | wikidoc | C16orf71 | C16orf71
Uncharacterized protein Chromosome 16 Open Reading Frame 71 is a protein in humans, encoded by the C16orf71 gene. The gene is expressed in epithelial tissue of the respiratory system, adipose tissue, and the testes. Predicted associated biological processes of the gene include regulation of the cell cycle, cell proliferation, apoptosis, and cell differentiation in those tissue types. 1357 bp of the gene are antisense to spliced genes ZNF500 and ANKS3, indicating possibility of regulated alternate expression.
# Gene
## Locus
The gene is located on the short arm of chromosome 16 at 16p13.1. Its genomic sequence begins on the plus strand at 4,734,242 bp and ends at 4,749,396 bp.
# mRNA
## Alternative Splicing
Three different protein encoding transcript variants, or isoforms, have been identified for C16orf7. One non-protein coding transcript variant was identified for the gene.
# Protein
## General properties
The primary encoded protein consists of 520 amino acid residues, 11 total exons, and is 15.14 kb long, with a molecular weight of approximately 55.68 kDa. The predicted isoelectric point was reported to be 4.81, indicating it is relatively unstable. The gene was reported to be well expressed, at 1.1 times the average gene level.
## Composition
Alanine was the most abundant amino acid, contributing to 11.54% of the molecular weight of the protein. Serine was the second most abundant, contributing 10.19% to the overall molecular weight. The average Alanine frequency in vertebrate proteins is approximately 7.4% and the average Serine frequency is approximately 8.1%.
## Domains
C16orf71 has one identified domain of unknown function, DUF4701, that is conserved in all mammals and some species of reptiles and birds. DUF4701 spans from amino acid residue 21 to 520 in the protein.
## Post-translational modifications
C16orf71 is predicted to undergo multiple post-translational modifications such as phosphorylation, N-glycosylation, and amidation.
## Protein Interactions
### Experimentally proven interactions
Experimentation with C16orf71 has revealed interactions with four other proteins, ARHGAP1, ZNFX1, PLVAP, and MBTPS1. ARHGAP1, ZNFX1, and MBTPS1 are associated with regulation in signaling and metabolism while PLVAP is associated with the formation of small lipid rafts in the plasma membrane of vertebrate endothelial and adipose cells.
### Predicted interactions
The majority of the predicted interactions involved with the protein related to regulation of mitotic processes, cellular differentiation, proliferation, metabolism, and signaling. Additional related processes included the formation and differentiation of B cells, T cells, endothelial cells, endoderm, and endocrine glands.
## Subcellular localization
C16orf71 was observed in nuclear speckles of the nucleus through experimental protocols involving fluorescent in situ hybridization with antibodies. Nuclear speckles, also known as interchromatin granule clusters, are enriched in pre-mRNA splicing factors. These highly dynamic structures are located in interchromatin regions of the nucleoplasm in mammalian cells and have been observed to cycle throughout various nuclear regions and active transcription sites.
# Structure
The secondary structure of C16orf71 is predicted to consist primarily of coils, with small regions of alpha helices and two segments of beta sheets throughout the span of the protein.
Protein sequences of the gene's mammalian orthologs were analyzed to reveal similar results, while distant reptilian and avian ortholog sequences predicted more regions of beta sheets.
# Expression
## Tissue expression pattern
Human expression for the gene has been observed primarily in respiratory epithelial tissue, specifically the trachea, larynx, nasopharynx, and bronchus. C16orf71 is also moderately expressed in adipose tissue and testes.
### DNA microarray experimental data
DNA microarray analysis from various experiments provided information on the expression levels of C16orf71 in unique, varying conditions.
The gene appears to have higher levels of expression in the omental adipose tissue of obese subjects compared to non-obese subjects.
C16orf71 was also observed to have decreased expression when there was a depletion of HIF-1 alpha, HIF-2 beta, or both. HIF, or hypoxia-inducible factors, are responsible for the mediation of hypoxia effects within the body. In addition, HIFs promote clotting and restoration of various epithelial tissues and are vital in the development of mammalian embryos, sperm, and ova.
Data from an experiment also indicated noticeably lower expression of the gene in sperm affected with teratozoospermia, a condition where sperm have abnormal morphology affecting the fertility in males, compared to normal sperm.
C16orf71 was observed to be present in all stages of development, with similar levels of expression throughout.
### Toxicogenomics experimental data
Three chemicals, bisphenol A, butyraldehyde, and polychlorinated biphenyls, have been experimentally tested with C16orf71 for evidence of interaction.
Bisphenol A is suspected to cause impairment in male reproduction. An experiment utilizing seminiferous tubule culture was conducted to observe the effects on meiosis and potential germ-line abnormalities. Gene expression analysis revealed decrease expression for C16orf71 when exposed to the chemical.
Butyraldehyde has been observed to affect inflammatory responses in bronchial airway tissue on a genetic level. Microarray analysis was used to determine levels of expression in human alveolar epithelial cells after exposure to the compound. Results indicated decreased expression for C16orf71 when exposed to the chemical.
Polychlorinated biphenyl was used in an experiment to determine its effects on external male genital development. Human fetal corpora cavernosa cells were used as the model tissue. Toxicogenomic analysis indicated the chemical affected all genes involved with genitourinary development and revealed lowered expression levels for C16orf71.
## Regulation of expression
1357 bp of the gene are antisense to spliced genes ZNF500 and ANKS3, indicating possibility of regulated alternate expression. A ZNF500 transcription factor binding domain was found on the minus strand within the promoter region of the gene. ZNF500 is predicted to play a role in gene regulation, transcription, and cellular differentiation.
The beginning of the promoter region was predicted to be 117 bp upstream from the 5' UTR of C16orf71 and is 1371 bp long. The region was analyzed for predicted transcription factors and regulatory elements. Predicted transcription factors in the promoter region related to the regulation of the cell cycle, proliferation, apoptosis, and differentiation of sperm and epithelial tissue components.
### Predicted transcription factors
# Homology
## Paralogs
No human paralogs for the gene were found.
## Orthologs
Orthologs have been identified in most mammals for which complete genome data is available. C16orf71 and its domain of unknown function, DUF4701, was present in mammals. The most distant orthologs identified were reptilian.
## Molecular evolution
The m value, or number of corrected amino acid changes per 100 residues, for the gene C16orf71 was plotted against the divergence of species in millions of years. When compared to the data of hemoglobin, fibrinopeptides, and cytochrome C, it was determined that the gene has the closest progression to fibrinopeptides, suggesting a relatively rapid pace of evolution. M values for C16orf71 were derived from percentage of identity of species mRNA sequences compared to the human sequence using the formula derived from the Molecular Clock Hypothesis. | C16orf71
Uncharacterized protein Chromosome 16 Open Reading Frame 71 is a protein in humans, encoded by the C16orf71 gene.[1] The gene is expressed in epithelial tissue of the respiratory system, adipose tissue, and the testes.[2] Predicted associated biological processes of the gene include regulation of the cell cycle, cell proliferation, apoptosis, and cell differentiation in those tissue types.[3] 1357 bp of the gene are antisense to spliced genes ZNF500 and ANKS3, indicating possibility of regulated alternate expression.[4]
# Gene
## Locus
The gene is located on the short arm of chromosome 16 at 16p13.1.[5] Its genomic sequence begins on the plus strand at 4,734,242 bp and ends at 4,749,396 bp.[1]
# mRNA
## Alternative Splicing
Three different protein encoding transcript variants, or isoforms, have been identified for C16orf7.[7] One non-protein coding transcript variant was identified for the gene.[8]
# Protein
## General properties
The primary encoded protein consists of 520 amino acid residues, 11 total exons, and is 15.14 kb long, with a molecular weight of approximately 55.68 kDa.[1] The predicted isoelectric point was reported to be 4.81, indicating it is relatively unstable.[13] The gene was reported to be well expressed, at 1.1 times the average gene level.[4]
## Composition
Alanine was the most abundant amino acid, contributing to 11.54% of the molecular weight of the protein.[13] Serine was the second most abundant, contributing 10.19% to the overall molecular weight.[13] The average Alanine frequency in vertebrate proteins is approximately 7.4% and the average Serine frequency is approximately 8.1%.[14]
## Domains
C16orf71 has one identified domain of unknown function, DUF4701, that is conserved in all mammals and some species of reptiles and birds.[1] DUF4701 spans from amino acid residue 21 to 520 in the protein.[1]
## Post-translational modifications
C16orf71 is predicted to undergo multiple post-translational modifications such as phosphorylation, N-glycosylation, and amidation.
## Protein Interactions
### Experimentally proven interactions
Experimentation with C16orf71 has revealed interactions with four other proteins, ARHGAP1, ZNFX1, PLVAP, and MBTPS1.[15] ARHGAP1, ZNFX1, and MBTPS1 are associated with regulation in signaling and metabolism while PLVAP is associated with the formation of small lipid rafts in the plasma membrane of vertebrate endothelial and adipose cells.[3]
### Predicted interactions
The majority of the predicted interactions involved with the protein related to regulation of mitotic processes, cellular differentiation, proliferation, metabolism, and signaling.[3] Additional related processes included the formation and differentiation of B cells, T cells, endothelial cells, endoderm, and endocrine glands.[3]
## Subcellular localization
C16orf71 was observed in nuclear speckles of the nucleus through experimental protocols involving fluorescent in situ hybridization with antibodies.[2] Nuclear speckles, also known as interchromatin granule clusters, are enriched in pre-mRNA splicing factors.[16] These highly dynamic structures are located in interchromatin regions of the nucleoplasm in mammalian cells and have been observed to cycle throughout various nuclear regions and active transcription sites.[16]
# Structure
The secondary structure of C16orf71 is predicted to consist primarily of coils, with small regions of alpha helices and two segments of beta sheets throughout the span of the protein.[13][17]
Protein sequences of the gene's mammalian orthologs were analyzed to reveal similar results, while distant reptilian and avian ortholog sequences predicted more regions of beta sheets.[18][19]
# Expression
## Tissue expression pattern
Human expression for the gene has been observed primarily in respiratory epithelial tissue, specifically the trachea, larynx, nasopharynx, and bronchus.[2] C16orf71 is also moderately expressed in adipose tissue and testes.[2]
### DNA microarray experimental data
DNA microarray analysis from various experiments provided information on the expression levels of C16orf71 in unique, varying conditions.
The gene appears to have higher levels of expression in the omental adipose tissue of obese subjects compared to non-obese subjects.[20]
C16orf71 was also observed to have decreased expression when there was a depletion of HIF-1 alpha, HIF-2 beta, or both. HIF, or hypoxia-inducible factors, are responsible for the mediation of hypoxia effects within the body.[23] In addition, HIFs promote clotting and restoration of various epithelial tissues and are vital in the development of mammalian embryos, sperm, and ova.[24]
Data from an experiment also indicated noticeably lower expression of the gene in sperm affected with teratozoospermia, a condition where sperm have abnormal morphology affecting the fertility in males, compared to normal sperm.[22]
C16orf71 was observed to be present in all stages of development, with similar levels of expression throughout.[25]
### Toxicogenomics experimental data
Three chemicals, bisphenol A, butyraldehyde, and polychlorinated biphenyls, have been experimentally tested with C16orf71 for evidence of interaction.[26]
Bisphenol A is suspected to cause impairment in male reproduction.[27] An experiment utilizing seminiferous tubule culture was conducted to observe the effects on meiosis and potential germ-line abnormalities.[27] Gene expression analysis revealed decrease expression for C16orf71 when exposed to the chemical.[27]
Butyraldehyde has been observed to affect inflammatory responses in bronchial airway tissue on a genetic level.[28] Microarray analysis was used to determine levels of expression in human alveolar epithelial cells after exposure to the compound.[28] Results indicated decreased expression for C16orf71 when exposed to the chemical.[28]
Polychlorinated biphenyl was used in an experiment to determine its effects on external male genital development.[29] Human fetal corpora cavernosa cells were used as the model tissue.[29] Toxicogenomic analysis indicated the chemical affected all genes involved with genitourinary development and revealed lowered expression levels for C16orf71.[29]
## Regulation of expression
1357 bp of the gene are antisense to spliced genes ZNF500 and ANKS3, indicating possibility of regulated alternate expression.[4] A ZNF500 transcription factor binding domain was found on the minus strand within the promoter region of the gene.[30] ZNF500 is predicted to play a role in gene regulation, transcription, and cellular differentiation.[31]
The beginning of the promoter region was predicted to be 117 bp upstream from the 5' UTR of C16orf71 and is 1371 bp long.[30] The region was analyzed for predicted transcription factors and regulatory elements. Predicted transcription factors in the promoter region related to the regulation of the cell cycle, proliferation, apoptosis, and differentiation of sperm and epithelial tissue components.[3]
### Predicted transcription factors
# Homology
## Paralogs
No human paralogs for the gene were found.[32]
## Orthologs
Orthologs have been identified in most mammals for which complete genome data is available.[32] C16orf71 and its domain of unknown function, DUF4701, was present in mammals.[32] The most distant orthologs identified were reptilian.[32][33]
## Molecular evolution
The m value, or number of corrected amino acid changes per 100 residues, for the gene C16orf71 was plotted against the divergence of species in millions of years. When compared to the data of hemoglobin, fibrinopeptides, and cytochrome C, it was determined that the gene has the closest progression to fibrinopeptides, suggesting a relatively rapid pace of evolution. M values for C16orf71 were derived from percentage of identity of species mRNA sequences compared to the human sequence using the formula derived from the Molecular Clock Hypothesis. | https://www.wikidoc.org/index.php/C16orf71 | |
4358eac473737cf1af4d130b33a776616ce91a32 | wikidoc | C16orf95 | C16orf95
Chromosome 16 open reading frame 95 (C16orf95) is a gene which in humans encodes the protein C16orf95. It has orthologs in mammals, and is expressed at a low level in many tissues. C16orf95 evolves quickly compared to other proteins.
# Gene
C16orf95 is a Homo sapiens gene oriented on the minus strand of chromosome 16. It is located on the cytogenic band 16q24.2 and spans 14.62 kilobases. The gene contains 6 introns and 7 exons.
# Homology
## Paralogs
There are no known paralogs of C16orf95.
## Orthologs
Orthologs of C16orf95 exist only in mammals (identified with BLAST). The most distant orthologs are found in opossums and Tasmanian devils.
# mRNA
## Alternative splicing
There are three splice variants of C16orf95. The longest transcript contains 1156 base pairs and 7 exons. Compared to variant 1, the second transcript variant lacks exons 4 and 5. This alternative splicing results in a frameshift of the 3' coding region, and a shorter, unique C-terminus. The third transcript variant lacks exons 4 and 5, and uses an alternate 5' exon and start codon. The resulting peptide has unique N- and C-termini compared to variant 1.
## Secondary structure
The 3' untranslated region of the C16orf95 mRNA contains binding sites for KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3) within an internal loop structure. KHDRBS3 regulates mRNA splicing and may act as a negative regulator of cell growth.
# Expression
The expression of C16orf95 is not well characterized. However, it has been detected at low levels in the following tissue types: bone, brain, ear, eye, intestine, kidney, lung, lymph nodes, prostate, testes, tonsils, skin, and uterus.
# Protein
## Structure
### Primary
The longest isoform of the C16orf95 protein has 239 amino acids. It has a conserved domain of unknown function spanning residues 76 to 239. C16orf95 has a calculated molecular weight of 26.5 kDa, and a predicted isoelectric point of 9.8. Compared to other human proteins, C16orf95 has more cysteine, arginine, and glutamine residues. It has fewer aspartate, glutamate, and asparagine. The high ratio of basic to acidic amino acids contributes to the protein's higher isoelectric point.
### Secondary
C16orf95 is predicted to have several alpha-helices in its C-terminus. This is true for the human and mouse proteins. The N-terminus does not have significant cross-program consensus for secondary structure.
## Post-translational modifications
The tools available at ExPASy were used to predict post-translational modification sites on C16orf95. The following modifications are predicted: palmitoylation, phosphorylation, and O-linked glycosylation. Bolded residues in the table indicate sites that are conserved in more than one species.
## Evolution
C16orf95 has a large number of amino acid changes over time, indicating it is a quickly evolving protein.
# Interacting proteins
There are no proteins known to interact with C16orf95.
# Clinical significance
Deletions of C16orf95 have been associated with hydronephrosis, microcephaly, distichiasis, vesicoureteral reflux, and intellectual impairment. However, the deletions included coding regions of the following genes: F-box Protein 31 (FBXO31), Microtubule-Associated Protein 1 Light Chain 3 Beta (MAP1LC3B), and Zinc Finger CCHC Type 14 (ZCCHC14). The contributions of each of these genes to the observed phenotypes has yet to be scientifically determined. | C16orf95
Chromosome 16 open reading frame 95 (C16orf95) is a gene which in humans encodes the protein C16orf95. It has orthologs in mammals, and is expressed at a low level in many tissues. C16orf95 evolves quickly compared to other proteins.
# Gene
C16orf95 is a Homo sapiens gene oriented on the minus strand of chromosome 16. It is located on the cytogenic band 16q24.2 and spans 14.62 kilobases.[1] The gene contains 6 introns and 7 exons.[1]
# Homology
## Paralogs
There are no known paralogs of C16orf95.
## Orthologs
Orthologs of C16orf95 exist only in mammals (identified with BLAST).[3] The most distant orthologs are found in opossums and Tasmanian devils.
# mRNA
## Alternative splicing
There are three splice variants of C16orf95.[6] The longest transcript contains 1156 base pairs and 7 exons.[7] Compared to variant 1, the second transcript variant lacks exons 4 and 5.[8] This alternative splicing results in a frameshift of the 3' coding region, and a shorter, unique C-terminus. The third transcript variant lacks exons 4 and 5, and uses an alternate 5' exon and start codon.[9] The resulting peptide has unique N- and C-termini compared to variant 1.
## Secondary structure
The 3' untranslated region of the C16orf95 mRNA contains binding sites for KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3) within an internal loop structure. KHDRBS3 regulates mRNA splicing and may act as a negative regulator of cell growth.[12]
# Expression
The expression of C16orf95 is not well characterized. However, it has been detected at low levels in the following tissue types: bone, brain, ear, eye, intestine, kidney, lung, lymph nodes, prostate, testes, tonsils, skin, and uterus.[13]
# Protein
## Structure
### Primary
The longest isoform of the C16orf95 protein has 239 amino acids.[14] It has a conserved domain of unknown function spanning residues 76 to 239.[14] C16orf95 has a calculated molecular weight of 26.5 kDa, and a predicted isoelectric point of 9.8.[5] Compared to other human proteins, C16orf95 has more cysteine, arginine, and glutamine residues.[5] It has fewer aspartate, glutamate, and asparagine.[5] The high ratio of basic to acidic amino acids contributes to the protein's higher isoelectric point.
### Secondary
C16orf95 is predicted to have several alpha-helices in its C-terminus.[5] This is true for the human and mouse proteins. The N-terminus does not have significant cross-program consensus for secondary structure.
## Post-translational modifications
The tools available at ExPASy were used to predict post-translational modification sites on C16orf95.[16] The following modifications are predicted: palmitoylation, phosphorylation, and O-linked glycosylation. Bolded residues in the table indicate sites that are conserved in more than one species.
## Evolution
C16orf95 has a large number of amino acid changes over time, indicating it is a quickly evolving protein.
# Interacting proteins
There are no proteins known to interact with C16orf95.
# Clinical significance
Deletions of C16orf95 have been associated with hydronephrosis, microcephaly, distichiasis, vesicoureteral reflux, and intellectual impairment.[21][22] However, the deletions included coding regions of the following genes: F-box Protein 31 (FBXO31), Microtubule-Associated Protein 1 Light Chain 3 Beta (MAP1LC3B), and Zinc Finger CCHC Type 14 (ZCCHC14). The contributions of each of these genes to the observed phenotypes has yet to be scientifically determined. | https://www.wikidoc.org/index.php/C16orf95 | |
fbe03f26d90a67f29f5257cc553c7e849c4b5ab5 | wikidoc | C16orf96 | C16orf96
C16orf96, or chromosome 16 open reading frame 96, is a protein in humans that is encoded by C16orf96 that is found on the 16th chromosome. In Homo sapiens, the protein is 1141 amino acids in length
# Protein
## Characteristics
The molecular weight of the processed C16orf96 protein in humans is 125kdal with an isoelectric point of 6.58 About 9% of the amino acid makeup of C16orf96 is proline, which is significantly higher than an average human gene.
## Post Translational Modification
Human C16orf96 has a large amount of predicted phosphorylation sites on serines throughout the protein. C16orf96 also has been found in primates and mammals to have both a nuclear import and export signal
## Domains
This gene contains some known domains, such as: an RNA recognition motif, a Merozoite surface protein (MSP-1), a pentapeptide repeat MXKDX, and a domain of unknown function (DUF1387). These domains could give a hint of what the function of this gene is.
## Structure
### Secondary Structure
The majority of the secondary structure of C16orf96 is alpa-helices with coils being the second most abundant structure.
### Tertiary Structure
At this time there is no known tertiary structure for C16orf96.
## Cellular Localization
The C16orf96 protein is predicted to be localized in the nucleus 82% of the time and 4.5% of the time in the cytosol and 4.5% of the time in the mitochondria.
# Expression
C16orf96 expression is generally low in cells. in situ hybridization experiments suggest that C16orf96 RNA is only expressed in the testis while the EST profile for C16orf96 shows gene expression is low in testis and skin only.
Expression of the C16orf96 gene is modulated by the depletion of both hypoxia induced factor 1/2α (HIF1/2α). When only one of the factors is depleted expression does not change suggesting that there is redundancy with these two HIF.
# Homology
Strict orthologs of this gene exist only in mammals. However, a portion of DUF1387 is found in more distant species back to reptiles. No orthologs of this gene can be found in plants, fungi, or bacteria. Suggesting that this gene is relatively new and evolves quickly.
# Function
The function of C16orf96 is currently unknown. Studies have cited this gene among many other genes as a possible candidate that has an effect on childhood obesity. | C16orf96
C16orf96, or chromosome 16 open reading frame 96, is a protein in humans that is encoded by C16orf96 that is found on the 16th chromosome.[1] In Homo sapiens, the protein is 1141 amino acids in length[2]
# Protein
## Characteristics
The molecular weight of the processed C16orf96 protein in humans is 125kdal with an isoelectric point of 6.58[3] About 9% of the amino acid makeup of C16orf96 is proline, which is significantly higher than an average human gene.[4]
## Post Translational Modification
Human C16orf96 has a large amount of predicted phosphorylation sites on serines throughout the protein.[5] C16orf96 also has been found in primates and mammals to have both a nuclear import and export signal[6]
## Domains
This gene contains some known domains, such as: an RNA recognition motif, a Merozoite surface protein (MSP-1), a pentapeptide repeat MXKDX, and a domain of unknown function (DUF1387). These domains could give a hint of what the function of this gene is.[2]
## Structure
### Secondary Structure
The majority of the secondary structure of C16orf96 is alpa-helices with coils being the second most abundant structure.[7]
### Tertiary Structure
At this time there is no known tertiary structure for C16orf96.
## Cellular Localization
The C16orf96 protein is predicted to be localized in the nucleus 82% of the time and 4.5% of the time in the cytosol and 4.5% of the time in the mitochondria.[8]
# Expression
C16orf96 expression is generally low in cells. in situ hybridization experiments suggest that C16orf96 RNA is only expressed in the testis while the EST profile for C16orf96 shows gene expression is low in testis and skin only.[9][10]
Expression of the C16orf96 gene is modulated by the depletion of both hypoxia induced factor 1/2α (HIF1/2α). When only one of the factors is depleted expression does not change suggesting that there is redundancy with these two HIF.[11]
# Homology
Strict orthologs of this gene exist only in mammals. However, a portion of DUF1387 is found in more distant species back to reptiles.[12] No orthologs of this gene can be found in plants, fungi, or bacteria. Suggesting that this gene is relatively new and evolves quickly.
# Function
The function of C16orf96 is currently unknown. Studies have cited this gene among many other genes as a possible candidate that has an effect on childhood obesity.[13] | https://www.wikidoc.org/index.php/C16orf96 | |
6f4758c0ab65e0ae4e70b421b7cae03a1ffad50c | wikidoc | C17orf47 | C17orf47
Uncharacterized protein C17orf47 is a protein that in humans is encoded by the gene C17orf47. The gene is 2,698 base pairs long, contains one gt-ag intron, and is oriented on the minus strand of DNA. The pre-messenger has 2 exons and the predicted protein is 570 amino acids long. There are currently no experimental structures for the C17orf47 gene product with a sequence identity >90%.
# Protein properties
Although C17orf47 is predicted to be an intracellular protein, its exact location is unknown. There is some confidence that the subcellular locations of C17orf47 include the cytosol, the nucleus, and mitochondrion. C17orf47 contains a domain of unknown function DUF4655, which has a length characteristic of that DUF family There are three predicted regions of low complexity in C17orf47. These regions of low complexity may contain stress-response related terms which involve flexible binding for specific functions. There are three known polymorphic SNPs in C17orf47. There are 6 sites of post-translational modification supported by multiple records, according to Phosphosite.
The gene is 2,698 base pairs long, contains one gt-ag intron, and is oriented on the minus strand of DNA. The pre-messenger has 2 exons and the predicted protein is 570 amino acids long. There are currently no experimental structures for the C17orf47 gene product with a sequence identity >90%.
# Homology
Sixty-eight other organisms, mostly mammals, have orthologs with C17orf47.
# Expression
There is positive differential mRNA and protein expression of C17orf47 in normal tissue of testis. Specifically, nucleolar expression of the gene product occurs in the seminiferous ducts of the testis. While C17orf47 is not currently associated with any diseases, several cases of carcinoids displayed strong C17orf47 expression via staining with HPA028424 antibody provided by Sigma-Aldrich. Polyphen predicts C17orf47 variants to be benign.
During a study on the endocytic system, a weak but specific association with C17orf47 in the regulation of endocytosis was found. Knockdown of C17orf47 caused decreased epidermal growth factor endocytosis as well as decreased transferrin endocytosis. In another experiment, knockdown of C17orf47 resulted in decreased infection of cells by vaccinia virus.
# Predicted structure | C17orf47
Uncharacterized protein C17orf47 is a protein that in humans is encoded by the gene C17orf47.[1] The gene is 2,698 base pairs long, contains one gt-ag intron, and is oriented on the minus strand of DNA. The pre-messenger has 2 exons and the predicted protein is 570 amino acids long. There are currently no experimental structures for the C17orf47 gene product with a sequence identity >90%.
# Protein properties
Although C17orf47 is predicted to be an intracellular protein, its exact location is unknown. There is some confidence that the subcellular locations of C17orf47 include the cytosol, the nucleus, and mitochondrion.[2] C17orf47 contains a domain of unknown function DUF4655, which has a length characteristic of that DUF family [3] There are three predicted regions of low complexity in C17orf47. These regions of low complexity may contain stress-response related terms which involve flexible binding for specific functions.[4] There are three known polymorphic SNPs in C17orf47. There are 6 sites of post-translational modification supported by multiple records, according to Phosphosite.
The gene is 2,698 base pairs long, contains one gt-ag intron, and is oriented on the minus strand of DNA. The pre-messenger has 2 exons and the predicted protein is 570 amino acids long. There are currently no experimental structures for the C17orf47 gene product with a sequence identity >90%.
# Homology
Sixty-eight other organisms, mostly mammals, have orthologs with C17orf47.
# Expression
There is positive differential mRNA and protein expression of C17orf47 in normal tissue of testis.[5] Specifically, nucleolar expression of the gene product occurs in the seminiferous ducts of the testis.[6] While C17orf47 is not currently associated with any diseases, several cases of carcinoids displayed strong C17orf47 expression via staining with HPA028424 antibody provided by Sigma-Aldrich.[7] Polyphen predicts C17orf47 variants to be benign.[8]
During a study on the endocytic system, a weak but specific association with C17orf47 in the regulation of endocytosis was found. Knockdown of C17orf47 caused decreased epidermal growth factor endocytosis as well as decreased transferrin endocytosis. In another experiment, knockdown of C17orf47 resulted in decreased infection of cells by vaccinia virus.[9]
# Predicted structure | https://www.wikidoc.org/index.php/C17orf47 | |
ee8d912318d942a0defc64f81abdc06909357cc1 | wikidoc | C17orf50 | C17orf50
Uncharacterized protein C17orf50 is a protein which in humans is encoded by the C17orf50 gene.
# Gene
The gene is located on the long arm of chromosome 17 on the forward strand at position 17q12. C17orf50 spans 4,200 base pairs from 35,760,897 to 35,765,079. In Humans, this gene encodes a protein that is 174 amino acids in length and has three exons.
## Regulation of Transcription
The promoter region for C17orf50 is 1417 base pairs longwith an accession number of GXP_123003 from Genomatix. The first half of the promoter is poorly conserved even among primates.
There are many binding sites for transcription factors found in the brain and embryonic tissue. particularly Brn-5 POU domain factor, which has three binding sites within the conserved region of the promoter. This transcription factor is expressed in layer IV of the neocortex of adults and at its highest levels in the developing brain and spinal cord.
# Homology/Evolution
Orthologs of this gene exist in Eukaryotes, predominantly in mammals. However, some homologs are present in birds, reptiles, and amphibians. There are no paralogs of this gene. The table below shows a short list of orthologs to trace the evolutionary history of C17orf50.
The most distant ortholog found diverged from humans approximately 352 million years ago, indicating that the protein arose shortly before that. When compared to other proteins, namely cytochrome c and fibrinogen alpha chain, uncharacterized protein C17orf50 is a rapidly evolving protein.
# Expression
C17orf50 is expressed at low levels in various tissues, such as lung, prostate, thymus, thyroid, trachea, small intestine, and stomach, and it is most highly expressed in the fetal brain.
# Protein
The unmodified molecular weight of C17orf50 protein is 19.3 kilodaltons. The protein has a negative charge cluster from position 21 to 52; this is a glutamate-rich region. There are 3 nuclear localization signals with no other retention signals, strongly indicating that the protein is localized to the nucleus.
Possible structure of Uncharacterized Protein C17orf50
## Domains
Uncharacterized protein C17orf50 contains a domain of unknown function (DUF4673) from position 5 to 172, which makes up the majority of the protein.
## Post-Translational Modifications
Uncharacterized protein C17orf50 contains two potential sumoylation sites at K7 and K12.
There are possible threonine and serine glycosylation sites throughout the protein.
Potential threonine, serine, and tyrosine phosphorylation sites are also present.
## Interacting Proteins
Uncharacterized protein C17orf50 has potential interactions with zinc finger protein 587(ZNF587), which is expressed throughout fetal tissue, including the brain, ZNF587 is expected to regulate transcription. | C17orf50
Uncharacterized protein C17orf50 is a protein which in humans is encoded by the C17orf50 gene.
# Gene
The gene is located on the long arm of chromosome 17 on the forward strand[1] at position 17q12. C17orf50 spans 4,200 base pairs from 35,760,897 to 35,765,079. In Humans, this gene encodes a protein that is 174 amino acids in length[2] and has three exons.[3]
## Regulation of Transcription
The promoter region for C17orf50 is 1417 base pairs longwith an accession number of GXP_123003 from Genomatix.[4] The first half of the promoter is poorly conserved even among primates.[5][6][7]
There are many binding sites for transcription factors found in the brain and embryonic tissue.[4] particularly Brn-5 POU domain factor, which has three binding sites within the conserved region of the promoter. This transcription factor is expressed in layer IV of the neocortex of adults and at its highest levels in the developing brain and spinal cord.[8]
# Homology/Evolution
Orthologs of this gene exist in Eukaryotes, predominantly in mammals.[5] However, some homologs are present in birds, reptiles, and amphibians. There are no paralogs of this gene. The table below shows a short list of orthologs to trace the evolutionary history of C17orf50.
The most distant ortholog found diverged from humans approximately 352 million years ago, indicating that the protein arose shortly before that. When compared to other proteins, namely cytochrome c and fibrinogen alpha chain, uncharacterized protein C17orf50 is a rapidly evolving protein.
# Expression
C17orf50 is expressed at low levels in various tissues, such as lung, prostate, thymus, thyroid, trachea, small intestine, and stomach, and it is most highly expressed in the fetal brain.[10]
# Protein
The unmodified molecular weight of C17orf50 protein is 19.3 kilodaltons. The protein has a negative charge cluster from position 21 to 52; this is a glutamate-rich region.[11] There are 3 nuclear localization signals with no other retention signals, strongly indicating that the protein is localized to the nucleus.[12]
Possible structure of Uncharacterized Protein C17orf50
## Domains
Uncharacterized protein C17orf50 contains a domain of unknown function (DUF4673) from position 5 to 172, which makes up the majority of the protein.[3]
## Post-Translational Modifications
Uncharacterized protein C17orf50 contains two potential sumoylation sites at K7 and K12.[13][14]
There are possible threonine and serine glycosylation sites throughout the protein.[15]
Potential threonine, serine, and tyrosine phosphorylation sites are also present.[16]
## Interacting Proteins
Uncharacterized protein C17orf50 has potential interactions with zinc finger protein 587(ZNF587),[17][18] which is expressed throughout fetal tissue, including the brain,[19] ZNF587 is expected to regulate transcription.[20] | https://www.wikidoc.org/index.php/C17orf50 |
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