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b0342925e84ec679b698cce29a2ad55234c65b38	wikidoc	Carrageenan	Carrageenan # Overview Carrageenans or carrageenins (Template:PronEng) are a family of linear sulphated polysaccharides extracted from red seaweeds. The name is derived from a type of seaweed that is abundant along the Irish coastline. Gelatinous extracts of the Chondrus crispus seaweed have been used as food additives for hundreds of years, though analysis of carrageenan safety as an additive continues. # Properties Carrageenans are large, highly flexible molecules which curl forming helical structures. This gives them the ability to form a variety of different gels at room temperature. They are widely used in the food and other industries as thickening and stabilizing agents. A particular advantage is that they are pseudoplastic — they thin under shear stress and recover their viscosity once the stress is removed. This means that they are easy to pump but stiffen again afterwards. There are three main commercial classes of carrageenan: - Kappa — strong, rigid gels. Produced from Kappaphycus cottonii - Iota — soft gels. Produced from Eucheuma spinosum - Lambda — form gels when mixed with proteins rather than water, used to thicken dairy products. The most common source is Gigartina from Southern Europe. Many red algal species produce different types of carrageenans during their developmental history. For instance, the genera Gigartina produces mainly Kappa carrageenans during its gametophytic stage, and Lambda carrageenans during its sporophytic stage. See Alternation of generations. All are soluble in hot water, but in cold water only the Lambda form (and the sodium salts of the other two) are soluble. When used in food products, carrageenan has the EU additive E-number E407 or E407a when present as "Processed eucheuma seaweed". Although introduced on an industrial scale in the 1930s, the first use was in China around 600 BC (where Gigartina was used) and in Ireland around 400 AD. The largest producer is the Philippines, where cultivated seaweed produces about 80% of the world supply. The most commonly used are Cottonii (Kappaphycus alvarezii, K.striatum) and Spinosum (Eucheuma denticulatum), which together provide about three quarters of the World production. These grow at sea level down to about 2 metres. The seaweed is normally grown on nylon lines strung between bamboo floats and harvested after three months or so when each plant weighs around 1 kg. The Cottonii variety has been reclassified as Kappaphycus cottonii by Maxwell Doty (1988), thereby introducing the genus Kappaphycus, on the basis of the phycocolloids produced (namely kappa carrageenan). After harvest, the seaweed is dried, baled, and sent to the carrageenan manufacturer. There the seaweed is ground, sifted to remove impurities such as sand, and washed thoroughly. After treatment with hot alkali solution (e.g. 5-8% potassium hydroxide), the cellulose is removed from the carrageenan by centrifugation and filtration. The resulting carrageenan solution is then concentrated by evaporation. It is dried and ground to specification. # Uses - Desserts, ice cream, milk shakes, sweetened condensed milks, sauces — gel to increase viscosity - Beer — clarifier to remove haze-causing proteins - Pâtés and processed meat — Substitute fat to increase water retention and increase volume - Toothpaste — stabilizer to prevent constituents separating - Fire fighting foam — thickener to cause foam to become sticky - Shampoo and cosmetic creams — thickener - Air freshener gels - Marbling -- the ancient art of paper and fabric marbling uses a carrageenan mixuture to float paints or inks upon; the paper or fabric is then laid on it, absorbing the colors. - Shoe polish — gel to increase viscosity - Biotechnology — gel to immobilize cells/enzymes - Pharmaceuticals — used as an inactive excipient in pills/tablets - Carrageenan has also been used to thicken skim milk, in an attempt to emulate the consistency of whole milk. This usage did not become popular. It's used in some brands of soy milk - Diet sodas - Lambda carrageenan is used in animal models of inflammation used to test analgesics, because dilute carrageenan solution (1-2%) injected subcutaneously causes swelling and pain. ## Sexual lubricant and microbicide Laboratory studies suggest that carrageenans might function as topical microbicides, blocking sexually transmitted viruses such as HPV and herpes, though not HIV. ### HSV There are indications that a carrageenan-based gel may offer some protection against HSV-2 transmission by binding to the receptors on the herpes virus thus preventing the virus from binding to cells. Researchers have shown that a carrageenan-based gel effectively prevented HSV-2 infection at a rate of 85% in a mouse model. See Herpes simplex: Polysaccharides ### HPV A study published in August 2006 found it potentially a thousand times as effective against HPV (measuring in vitro infectivity of pseudoviruses, which are believed to mimic the activity of actual viruses). If effective, its cost compared to HPV vaccines and its ability to target any strain of the virus would make it an attractive prevention measure against cervical cancer, especially in developing countries. Some personal and condom lubricants are already made with carrageenan, and several of these products (such as Bioglide and Divine) were found to be potent HPV inhibitors in the study (though others that listed carrageenan in their ingredients were not). Although the researchers are optimistic and show that the products "block HPV infectivity in vitro, even when diluted a million-fold", they emphasize that "it would be inappropriate to recommend currently available products for use as topical microbicides" until further human tests are complete. (By comparison, similarly optimistic results were expected for HIV prevention by cellulose sulfate gels, based on early tests, but the clinical trials had to be halted when the gel was found to increase incidence of HIV infection.) The researchers then tested HPV infectivity in mice. This study, released in July 2007, also found promising results, preventing infection in vivo by HPV-16 pseudoviruses even in the presence of nonoxynol-9, which was shown to greatly increase infection when used alone. The results for the carrageenan tests (including those with Divine and Bioglide commercial lubricants) showed no detectable infection, while the viscous control gel and N-9 gels did. While effectiveness trials have not been completed and side effects have not been ruled out, companies are already planning to capitalize on the discovery, such as Dreamspan naming their lubricant Carrageenan after its principal ingredient. ### HIV A phase 3 clinical trial by Population Council examined whether a carrageenan-based product known as Carraguard was effective as a topical microbicide for blocking HIV infection in women. The trial ran from 2004 to 2007, with more than 4,000 South African women completing the study, but found no statistical difference in infection between those who used the lubricant and those who did not. The trial did provide information about usage patterns, however, and showed that that the gel is safe at least; not increasing infection any more than the baseline or causing significant side effects. As such, they expect to use it as a stable delivery vehicle for experimental antiretrovirals in future studies. # Health concerns There is evidence from studies performed on rats, guinea pigs and monkeys which indicates that degraded carrageenan (poligeenan) may cause ulcerations in the gastro-intestinal tract and gastro-intestinal cancer. Poligeenan is produced from carrageenan subjected to high temperatures and acidity. The average carrageenan molecule weighs over 100,000 Da while poligeenans have a molecular weight of less than 50,000 Da. A scientific committee working on behalf of the European Commission has recommended that the amount of degraded carrageenan be limited to a maximum of 5% (which is the limit of detection) of total carrageenan mass. Upon testing samples of foods containing high molecular weight carrageens, researchers found no poligeenan. A recent publication indicates that carrageenan induces inflammation in human intestinal epithelial cells in tissue culture through a BCL10-mediated pathway that leads to activation of NFkappaB and IL-8. Carrageenan may be immunogenic due to its unusual alpha-1,3-galactosidic link that is part of its disaccharide unit structure. Consumption of carrageenan may have a role in intestinal inflammation and possibly inflammatory bowel disease, since BCL10 resembles NOD2, mutations of which are associated with genetic proclivity to Crohn's Disease.	Carrageenan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Carrageenans or carrageenins (Template:PronEng) are a family of linear sulphated polysaccharides extracted from red seaweeds. The name is derived from a type of seaweed that is abundant along the Irish coastline. Gelatinous extracts of the Chondrus crispus seaweed have been used as food additives for hundreds of years,[1] though analysis of carrageenan safety as an additive continues.[2] # Properties Carrageenans are large, highly flexible molecules which curl forming helical structures. This gives them the ability to form a variety of different gels at room temperature. They are widely used in the food and other industries as thickening and stabilizing agents. A particular advantage is that they are pseudoplastic — they thin under shear stress and recover their viscosity once the stress is removed. This means that they are easy to pump but stiffen again afterwards. There are three main commercial classes of carrageenan: - Kappa — strong, rigid gels. Produced from Kappaphycus cottonii - Iota — soft gels. Produced from Eucheuma spinosum - Lambda — form gels when mixed with proteins rather than water, used to thicken dairy products. The most common source is Gigartina from Southern Europe. Many red algal species produce different types of carrageenans during their developmental history. For instance, the genera Gigartina produces mainly Kappa carrageenans during its gametophytic stage, and Lambda carrageenans during its sporophytic stage. See Alternation of generations. All are soluble in hot water, but in cold water only the Lambda form (and the sodium salts of the other two) are soluble. When used in food products, carrageenan has the EU additive E-number E407 or E407a when present as "Processed eucheuma seaweed". Although introduced on an industrial scale in the 1930s, the first use was in China around 600 BC (where Gigartina was used) and in Ireland around 400 AD. The largest producer is the Philippines, where cultivated seaweed produces about 80% of the world supply. The most commonly used are Cottonii (Kappaphycus alvarezii, K.striatum) and Spinosum (Eucheuma denticulatum), which together provide about three quarters of the World production. These grow at sea level down to about 2 metres. The seaweed is normally grown on nylon lines strung between bamboo floats and harvested after three months or so when each plant weighs around 1 kg. The Cottonii variety has been reclassified as Kappaphycus cottonii by Maxwell Doty (1988), thereby introducing the genus Kappaphycus, on the basis of the phycocolloids produced (namely kappa carrageenan). After harvest, the seaweed is dried, baled, and sent to the carrageenan manufacturer. There the seaweed is ground, sifted to remove impurities such as sand, and washed thoroughly. After treatment with hot alkali solution (e.g. 5-8% potassium hydroxide), the cellulose is removed from the carrageenan by centrifugation and filtration. The resulting carrageenan solution is then concentrated by evaporation. It is dried and ground to specification. # Uses - Desserts, ice cream, milk shakes, sweetened condensed milks, sauces — gel to increase viscosity - Beer — clarifier to remove haze-causing proteins - Pâtés and processed meat — Substitute fat to increase water retention and increase volume - Toothpaste — stabilizer to prevent constituents separating - Fire fighting foam — thickener to cause foam to become sticky - Shampoo and cosmetic creams — thickener - Air freshener gels - Marbling -- the ancient art of paper and fabric marbling uses a carrageenan mixuture to float paints or inks upon; the paper or fabric is then laid on it, absorbing the colors. - Shoe polish — gel to increase viscosity - Biotechnology — gel to immobilize cells/enzymes - Pharmaceuticals — used as an inactive excipient in pills/tablets - Carrageenan has also been used to thicken skim milk, in an attempt to emulate the consistency of whole milk. This usage did not become popular. It's used in some brands of soy milk - Diet sodas - Lambda carrageenan is used in animal models of inflammation used to test analgesics, because dilute carrageenan solution (1-2%) injected subcutaneously causes swelling and pain. ## Sexual lubricant and microbicide Laboratory studies suggest that carrageenans might function as topical microbicides, blocking sexually transmitted viruses such as HPV and herpes, though not HIV. ### HSV There are indications that a carrageenan-based gel may offer some protection against HSV-2 transmission by binding to the receptors on the herpes virus thus preventing the virus from binding to cells. Researchers have shown that a carrageenan-based gel effectively prevented HSV-2 infection at a rate of 85% in a mouse model. See Herpes simplex: Polysaccharides ### HPV A study published in August 2006 found it potentially a thousand times as effective against HPV (measuring in vitro infectivity of pseudoviruses, which are believed to mimic the activity of actual viruses). If effective, its cost compared to HPV vaccines and its ability to target any strain of the virus would make it an attractive prevention measure against cervical cancer, especially in developing countries.[3] Some personal and condom lubricants are already made with carrageenan, and several of these products (such as Bioglide and Divine) were found to be potent HPV inhibitors in the study (though others that listed carrageenan in their ingredients were not).[4] Although the researchers are optimistic and show that the products "block HPV infectivity in vitro, even when diluted a million-fold", they emphasize that "it would be inappropriate to recommend currently available products for use as topical microbicides" until further human tests are complete. (By comparison, similarly optimistic results were expected for HIV prevention by cellulose sulfate gels, based on early tests, but the clinical trials had to be halted when the gel was found to increase incidence of HIV infection.)[5] The researchers then tested HPV infectivity in mice. This study, released in July 2007, also found promising results, preventing infection in vivo by HPV-16 pseudoviruses even in the presence of nonoxynol-9, which was shown to greatly increase infection when used alone.[6] The results for the carrageenan tests (including those with Divine and Bioglide commercial lubricants) showed no detectable infection, while the viscous control gel and N-9 gels did.[7][8] While effectiveness trials have not been completed and side effects have not been ruled out, companies are already planning to capitalize on the discovery, such as Dreamspan naming their lubricant Carrageenan after its principal ingredient.[9][10][11] ### HIV A phase 3 clinical trial by Population Council examined whether a carrageenan-based product known as Carraguard was effective as a topical microbicide for blocking HIV infection in women.[3] The trial ran from 2004 to 2007, with more than 4,000 South African women completing the study, but found no statistical difference in infection between those who used the lubricant and those who did not.[12][13] The trial did provide information about usage patterns, however, and showed that that the gel is safe at least; not increasing infection any more than the baseline or causing significant side effects. As such, they expect to use it as a stable delivery vehicle for experimental antiretrovirals in future studies. # Health concerns There is evidence from studies performed on rats, guinea pigs and monkeys which indicates that degraded carrageenan (poligeenan) may cause ulcerations in the gastro-intestinal tract and gastro-intestinal cancer.[14] Poligeenan is produced from carrageenan subjected to high temperatures and acidity. The average carrageenan molecule weighs over 100,000 Da while poligeenans have a molecular weight of less than 50,000 Da. A scientific committee working on behalf of the European Commission has recommended that the amount of degraded carrageenan be limited to a maximum of 5% (which is the limit of detection) of total carrageenan mass. Upon testing samples of foods containing high molecular weight carrageens, researchers found no poligeenan.[15] A recent publication[16] indicates that carrageenan induces inflammation in human intestinal epithelial cells in tissue culture through a BCL10-mediated pathway that leads to activation of NFkappaB and IL-8. Carrageenan may be immunogenic due to its unusual alpha-1,3-galactosidic link that is part of its disaccharide unit structure. Consumption of carrageenan may have a role in intestinal inflammation and possibly inflammatory bowel disease, since BCL10 resembles NOD2, mutations of which are associated with genetic proclivity to Crohn's Disease.	https://www.wikidoc.org/index.php/Carrageenan
766345a4d7949af48f14ebd3e8e1b0344fa8ff17	wikidoc	Carrier oil	Carrier oil Carrier oil, also known as base oil or vegetable oil, is used to dilute essential oils and absolutes before they are applied to the skin. They are so named because they carry the essential oil onto the skin. Carrier oils do not contain a concentrated aroma, unlike essential oils, nor do they evaporate like them. There are a range of different carrier oils each with their own individual properties and suitability towards different treatments in aromatherapy. Infused oils are a combination of a carrier oil and various herbs. True carrier oils are generally cold-pressed vegetable oils taken, amongst others: - Sweet almond - Grape seed - Avocado - Olive oil - Sesame - Evening primrose - Sunflower - Jojoba oil - Emu oil - Nuts: Walnut Peanut Pecan Macadamia nut Fractionated coconut oil - Walnut - Peanut - Pecan - Macadamia nut - Fractionated coconut oil Sweet almond oil and grapeseed oil are the most popular carrier oils.	Carrier oil Carrier oil, also known as base oil or vegetable oil, is used to dilute essential oils and absolutes before they are applied to the skin. They are so named because they carry the essential oil onto the skin. Carrier oils do not contain a concentrated aroma, unlike essential oils, nor do they evaporate like them. There are a range of different carrier oils each with their own individual properties and suitability towards different treatments in aromatherapy. Infused oils are a combination of a carrier oil and various herbs. True carrier oils are generally cold-pressed vegetable oils taken, amongst others: - Sweet almond - Grape seed - Avocado - Olive oil - Sesame - Evening primrose - Sunflower - Jojoba oil - Emu oil - Nuts: Walnut Peanut Pecan Macadamia nut Fractionated coconut oil - Walnut - Peanut - Pecan - Macadamia nut - Fractionated coconut oil Sweet almond oil and grapeseed oil are the most popular carrier oils. # External links - Carrier Oils Properties Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Carrier_oil
ebd1662138c089f12354b9119499b53e67cb9c92	wikidoc	Case report	Case report In medicine, a case report is a detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually they describe an unusual or novel occurrence. # Types of case reports Robert Iles notes that most case reports are on one of five topics: - An unexpected association between diseases or symptoms. - An unexpected event in the course of observing or treating a patient. - Findings that shed new light on the possible pathogenesis of a disease or an adverse effect. - Unique or rare features of a disease. - Unique therapeutic approaches. (Iles 2004) # Usefulness and validity A case report is a type of anecdotal evidence. As such, it is less scientifically rigorous than controlled clinical data involving a larger sample size. Proponents argue they have value within scientific method: # Famous scientific case reports - Sigmund Freud reported on numerous cases, including Anna O., Dora, Little Hans, Rat Man, and Wolf Man - Frederick Treves reported on "The Elephant Man" - Paul Broca reported on language impairment following left hemisphere lesions in the 1860s. - Joseph Jules Dejerine reported on a case of pure alexia. - William MacIntyre reported on a case of multiple myeloma (described in the 1840s). # Use of term outside science The term is also used to describe non-scientific reports usually prepared for their educational value.	Case report In medicine, a case report is a detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually they describe an unusual or novel occurrence. # Types of case reports Robert Iles notes that most case reports are on one of five topics: - An unexpected association between diseases or symptoms. - An unexpected event in the course of observing or treating a patient. - Findings that shed new light on the possible pathogenesis of a disease or an adverse effect. - Unique or rare features of a disease. - Unique therapeutic approaches. (Iles 2004) # Usefulness and validity A case report is a type of anecdotal evidence. As such, it is less scientifically rigorous than controlled clinical data involving a larger sample size. Proponents argue they have value within scientific method: # Famous scientific case reports - Sigmund Freud reported on numerous cases, including Anna O., Dora, Little Hans, Rat Man, and Wolf Man - Frederick Treves reported on "The Elephant Man" - Paul Broca reported on language impairment following left hemisphere lesions in the 1860s. - Joseph Jules Dejerine reported on a case of pure alexia. - William MacIntyre reported on a case of multiple myeloma (described in the 1840s). # Use of term outside science The term is also used to describe non-scientific reports usually prepared for their educational value.	https://www.wikidoc.org/index.php/Case_report
35564d9b40b55ef748d70718cb3ae24c189a9cdb	wikidoc	Case series	Case series A case series (also known as a clinical series) is a medical research study that tracks patients with a known exposure given similar treatment or examines their medical records for exposure and outcome. A case series can be retrospective or prospective and usually involves a smaller number of patients than more powerful case-control studies or randomized controlled trials. A case series is a type of observational study. Case series may be consecutive or non-consecutive, depending on whether all cases presenting to the reporting authors over a period of time were included, or only a selection. Case series may be confounded by selection bias, which limits statements on the causality of correlations observed.	Case series A case series (also known as a clinical series) is a medical research study that tracks patients with a known exposure given similar treatment[1] or examines their medical records for exposure and outcome. A case series can be retrospective or prospective and usually involves a smaller number of patients than more powerful case-control studies or randomized controlled trials. A case series is a type of observational study. Case series may be consecutive[2] or non-consecutive,[3] depending on whether all cases presenting to the reporting authors over a period of time were included, or only a selection. Case series may be confounded by selection bias, which limits statements on the causality of correlations observed.	https://www.wikidoc.org/index.php/Case_series
6d989012a5b4d5f69ef48c6f616874b385e26320	wikidoc	Casomorphin	Casomorphin Casomorphin is a particular type of peptide, i.e protein fragment, that can be derived from the digestion of casein proteins in milk and milk products. The distinguishing characteristics of casomorphins are that they have opioid (i.e narcotic) effects. There is a range of casomorphins whose effects range from weak to strong. There are also other peptides in milk that can have an ameliorating effect on the opioid effects of the casomorphins. The most important casomorphins from bovine milk are those released from the digestion of β-casein (beta-casein). These are known as β-casomorphins, sometimes written as BCM followed by a numeral indicating the number of amino acids in the sequence. The most important casomorphins appear to be BCM5, BCM7, and BCM9. BCM7 in particular has been implicated in a number of medical conditions including diabetes, heart disease, and the symptoms of autism and schizophrenia. However, it appears that only some individuals are susceptible. In cattle the amount of β-casein, and hence the potential release of β-casomorphins, varies between species and breeds. Typically, beta-casein comprises about one third of the casein, or about 12 grams per litre of milk. However, there are at least 13 different variants of the β-casein protein in cattle, with any one cow producing milk that will contain either one or two of these 13 variants. The variants fit into one of two main categories known as A1 and A2. In cattle, A1-type β-caseins have the amino acid histidine at position 67 whereas the A2-type β-caseins have the amino acid proline at position 67. Laboratory experiments show that the casomorphin known as BCM7 is only released from the A1-type β-caseins (Jimsmaa and Yoshikawa 1999) (ref Jinsmaa Y, Yoshikawa M, 1999. 'Enzymatic release of neocasomorphin and beta-casomorphinfrom bovine beta-casein', Peptides 20:957-962). The potential release of BCM7 is about 0.4 grams per litre of milk (assuming as above that there are 12g of β-casein per litre). There is also the potential for release of casomorphins from human milk. However, human BCM7 (Tyr-Pro-Phe-Val-Glu-Pro-Ile)has two out of seven amino acids different to the bovine form (Tyr-Pro-Phe-Pro-Gly-Pro-Ile) and the opioid effects are much weaker. Scientific understanding of the biochemistry and pharmacology of casomorphins is incomplete. A recent scientific review is provided by Kaminski et al (2007),: In the human body casomorphins may be broken down to inactive dipeptides by the enzyme dipeptidyl peptidase-4. This enzyme is found in the digestive tract and in some endocrine cells. ## Health Casein has been documented to break down in the stomach to produce the peptide casomorphin, an opioid that acts as a histamine releaser. Diets that eliminate foods containing casein are promoted at conferences for parents of children with ASD, and many books, web sites, and discussion groups contain testimonials describing benefits in autism-related symptoms, notably social engagement and verbal skills. Studies supporting these claims have had significant flaws, so the data are inadequate to guide treatment recommendations. Even if they do not help, changes in diet are expected to be harmless aside from their bother and cost. # Some known casomorphins ## β-Casomorphin 1-3 - Structure: H-Tyr-Pro-Phe-OH - Chemical formula: C23H27N3O5 - Molecular weight: 425.48 g/mol ## Bovine β-casomorphin 1-4 - Structure: H-Tyr-Pro-Phe-Pro-OH - Chemical formula: - Molecular weight: 522.61 g/mol ## Bovine β-casomorphin 1-4, amide - Structure: H-Tyr-Pro-Phe-Pro-NH2 - Chemical formula: C28H39N5O7 - Molecular weight: 557.64 g/mol ## Bovine β-casomorphin 5 - Structure: H-Tyr-Pro-Phe-Pro-Gly-OH - Chemical formula: C30H37N5O7 - Molecular weight: 594.66 g/mol ## Bovine β-casomorphin 7 - Structure: H-Tyr-Pro-Phe-Pro-Gly-Pro-Ile-OH - Chemical formula: C41H55N7O9 - Molecular weight: 789.9 g/mol ## Bovine β-casomorphin 8 - Structure: H-Tyr-Pro-Phe-Pro-Gly-Pro-Ile-Pro-OH - Chemical formula: C46H62N8O10 - Molecular weight: 887.00 g/mol (Note there is also a form of bovine β-Casomorphin 8 that has Histideine instead of Proline in position 8, with this depending on whether it is derived from A1 or A2 beta-casein)	Casomorphin Casomorphin is a particular type of peptide, i.e protein fragment, that can be derived from the digestion of casein proteins in milk and milk products. The distinguishing characteristics of casomorphins are that they have opioid (i.e narcotic) effects. There is a range of casomorphins whose effects range from weak to strong. There are also other peptides in milk that can have an ameliorating effect on the opioid effects of the casomorphins. The most important casomorphins from bovine milk are those released from the digestion of β-casein (beta-casein). These are known as β-casomorphins, sometimes written as BCM followed by a numeral indicating the number of amino acids in the sequence. The most important casomorphins appear to be BCM5, BCM7, and BCM9. BCM7 in particular has been implicated in a number of medical conditions including diabetes, heart disease, and the symptoms of autism and schizophrenia. However, it appears that only some individuals are susceptible. In cattle the amount of β-casein, and hence the potential release of β-casomorphins, varies between species and breeds. Typically, beta-casein comprises about one third of the casein, or about 12 grams per litre of milk. However, there are at least 13 different variants of the β-casein protein in cattle, with any one cow producing milk that will contain either one or two of these 13 variants. The variants fit into one of two main categories known as A1 and A2. In cattle, A1-type β-caseins have the amino acid histidine at position 67 whereas the A2-type β-caseins have the amino acid proline at position 67. Laboratory experiments show that the casomorphin known as BCM7 is only released from the A1-type β-caseins (Jimsmaa and Yoshikawa 1999) (ref Jinsmaa Y, Yoshikawa M, 1999. 'Enzymatic release of neocasomorphin and beta-casomorphinfrom bovine beta-casein', Peptides 20:957-962). The potential release of BCM7 is about 0.4 grams per litre of milk (assuming as above that there are 12g of β-casein per litre). There is also the potential for release of casomorphins from human milk. However, human BCM7 (Tyr-Pro-Phe-Val-Glu-Pro-Ile)has two out of seven amino acids different to the bovine form (Tyr-Pro-Phe-Pro-Gly-Pro-Ile) and the opioid effects are much weaker. Scientific understanding of the biochemistry and pharmacology of casomorphins is incomplete. A recent scientific review is provided by Kaminski et al (2007),: [1] In the human body casomorphins may be broken down to inactive dipeptides by the enzyme dipeptidyl peptidase-4.[2][3] This enzyme is found in the digestive tract and in some endocrine cells. ## Health Casein has been documented to break down in the stomach to produce the peptide casomorphin, an opioid that acts as a histamine releaser.[4] Diets that eliminate foods containing casein are promoted at conferences for parents of children with ASD, and many books, web sites, and discussion groups contain testimonials describing benefits in autism-related symptoms, notably social engagement and verbal skills. Studies supporting these claims have had significant flaws, so the data are inadequate to guide treatment recommendations. Even if they do not help, changes in diet are expected to be harmless aside from their bother and cost.[5] # Some known casomorphins ## β-Casomorphin 1-3 - Structure: H-Tyr-Pro-Phe-OH - Chemical formula: C23H27N3O5 - Molecular weight: 425.48 g/mol ## Bovine β-casomorphin 1-4 - Structure: H-Tyr-Pro-Phe-Pro-OH - Chemical formula: - Molecular weight: 522.61 g/mol ## Bovine β-casomorphin 1-4, amide - Structure: H-Tyr-Pro-Phe-Pro-NH2 - Chemical formula: C28H39N5O7 - Molecular weight: 557.64 g/mol ## Bovine β-casomorphin 5 - Structure: H-Tyr-Pro-Phe-Pro-Gly-OH - Chemical formula: C30H37N5O7 - Molecular weight: 594.66 g/mol ## Bovine β-casomorphin 7 - Structure: H-Tyr-Pro-Phe-Pro-Gly-Pro-Ile-OH - Chemical formula: C41H55N7O9 - Molecular weight: 789.9 g/mol ## Bovine β-casomorphin 8 - Structure: H-Tyr-Pro-Phe-Pro-Gly-Pro-Ile-Pro-OH - Chemical formula: C46H62N8O10 - Molecular weight: 887.00 g/mol (Note there is also a form of bovine β-Casomorphin 8 that has Histideine instead of Proline in position 8, with this depending on whether it is derived from A1 or A2 beta-casein)	https://www.wikidoc.org/index.php/Casomorphin
c6b7da494a40069786774b5f0cf9a6123019d52b	wikidoc	Caspofungin	Caspofungin # 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 Caspofungin is an antifungal that is FDA approved for the treatment of fungal infections, candidemia, esophageal candidiasis, invasive aspergillosis refractory or intolerant to other therapies. Common adverse reactions include anemia, febrile neutropenia, neutropenia, thrombocytopenia, arrhythmia, atrial fibrillation, abdominal pain, bacteremia, sepsis, urinary tract infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Caspofungin® is indicated in adults and pediatric patients (3 months and older) for: - Empirical therapy for presumed fungal infections in febrile, neutropenic patients - Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. Caspofungin has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida. - Treatment of esophageal candidiasis. - Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole). Caspofungin has not been studied as initial therapy for invasive aspergillosis. # Dosage ## Recommended Dosing in Adult Patients - The usual dose is 50 mg once daily (following a 70-mg loading dose for most indications). The safety and efficacy of a dose of 150 mg daily (range: 1 to 51 days; median: 14 days) have been studied in 100 adult patients with candidemia and other Candida infections. The efficacy of caspofungin at this higher dose was not significantly better than the efficacy of the 50-mg daily dose of caspofungin. The efficacy of doses higher than 50 mg daily in the other adult patients for whom caspofungin is indicated is not known. Empirical Therapy A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient's clinical response. Empirical therapy should be continued until resolution of neutropenia. Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved. If the 50-mg dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg. Candidemia and Other Candida Infections A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be dictated by the patient's clinical and microbiological response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Patients who remain persistently neutropenic may warrant a longer course of therapy pending resolution of the neutropenia. Esophageal Candidiasis The dose is 50 mg once daily for 7 to 14 days after symptom resolution. A 70-mg loading dose has not been studied for this indication. Because of the risk of relapse of oropharyngeal candidiasis in patients with HIV infections, suppressive oral therapy could be considered. Invasive Aspergillosis A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. ### Patients with Hepatic Impairment Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin 35 mg once daily is recommended based upon pharmacokinetic data. However, where recommended, a 70-mg loading dose should still be administered on Day 1. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) and in pediatric patients with any degree of hepatic impairment. ### Patients Receiving Concomitant Inducers of Drug Clearance - Adult patients on rifampin should receive 70 mg of caspofungin once daily. Adult patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin may require an increase in dose to 70 mg of caspofungin once daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Caspofungin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Caspofungin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Recommended Dosing in Pediatric Patients - For all indications, a single 70-mg/m2 loading dose should be administered on Day 1, followed by 50 mg/m2 once daily thereafter. The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. Dosing in pediatric patients (3 months to 17 years of age) should be based on the patient's body surface area (BSA) as calculated by the Mosteller Formula - Following calculation of the patient's BSA, the loading dose in milligrams should be calculated as BSA (m2) X 70 mg/m2. The maintenance dose in milligrams should be calculated as BSA (m2) X 50 mg/m2. - Duration of treatment should be individualized to the indication, as described for each indication in adults. If the 50-mg/m2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m2 daily (not to exceed 70 mg). ### Patients Receiving Concomitant Inducers of Drug Clearance When caspofungin is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 once daily (not to exceed 70 mg) should be considered ### Special Considerations for Pediatric Patients >3 Months of Age - Follow the reconstitution procedures described above using either the 70-mg or 50-mg vial to create the reconstituted solution. From the reconstituted solution in the vial, remove the volume of drug equal to the calculated loading dose or calculated maintenance dose based on a concentration of 7 mg/mL (if reconstituted from the 70-mg vial) or a concentration of 5 mg/mL (if reconstituted from the 50-mg vial). - The choice of vial should be based on total milligram dose of drug to be administered to the pediatric patient. To help ensure accurate dosing, it is recommended for pediatric doses less than 50 mg that 50-mg vials (with a concentration of 5 mg/mL) be used if available. The 70-mg vial should be reserved for pediatric patients requiring doses greater than 50 mg. The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Caspofungin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Caspofungin in pediatric patients. # Contraindications Caspofungin is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to any component of this product. # Warnings ## Hypersensitivity - Anaphylaxis has been reported during administration of caspofungin. If this occurs, caspofungin should be discontinued and appropriate treatment administered. - Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported and may require discontinuation and/or administration of appropriate treatment. ## Concomitant Use with Cyclosporine - Concomitant use of caspofungin with cyclosporine should be limited to patients for whom the potential benefit outweighs the potential risk. In one clinical study, 3 of 4 healthy adult subjects who received caspofungin 70 mg on Days 1 through 10, and also received two 3 mg/kg doses of cyclosporine 12 hours apart on day 10, developed transient elevations of alanine transaminase (ALT) on day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate panel of adult subjects in the same study, 2 of 8 who received caspofungin 35 mg daily for 3 days and cyclosporine (two 3 mg/kg doses administered 12 hours apart) on day 1 had small increases in ALT (slightly above the ULN) on day 2. In both groups, elevations in aspartate transaminase (AST) paralleled ALT elevations, but were of lesser magnitude. In another clinical study, 2 of 8 healthy men developed transient ALT elevations of less than 2X ULN. In this study, cyclosporine (4 mg/kg) was administered on Days 1 and 12, and caspofungin was administered (70 mg) daily on Days 3 through 13. In one subject, the ALT elevation occurred on days 7 and 9 and, in the other subject, the ALT elevation occurred on Day 19. These elevations returned to normal by Day 27. In all groups, elevations in AST paralleled ALT elevations but were of lesser magnitude. In these clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. - In a retrospective postmarketing study, 40 immunocompromised patients, including 37 transplant recipients, were treated with caspofungin and cyclosporine for 1 to 290 days (median 17.5 days). Fourteen patients (35%) developed transaminase elevations >5X upper limit of normal or >3X baseline during concomitant therapy or the 14-day follow-up period; five were considered possibly related to concomitant therapy. One patient had elevated bilirubin considered possibly related to concomitant therapy. No patient developed clinical evidence of hepatotoxicity or serious hepatic events. Discontinuations due to laboratory abnormalities in hepatic enzymes from any cause occurred in four patients. Of these, 2 were considered possibly related to therapy with caspofungin and/or cyclosporine as well as to other possible causes. - In the prospective invasive aspergillosis and compassionate use studies, there were 4 adult patients treated with caspofungin (50 mg/day) and cyclosporine for 2 to 56 days. None of these patients experienced increases in hepatic enzymes. - Given the limitations of these data, caspofungin and cyclosporine should only be used concomitantly in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver function tests during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated. ## Hepatic Effects - Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with caspofungin. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to caspofungin has not been established. - Patients who develop abnormal liver function tests during caspofungin therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing caspofungin therapy # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed in detail in another section of the labeling: - Hepatic effects - Hypersensitivity - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does provide a basis for identifying adverse reactions that appear to be related to drug use and for approximating rates. ## Clinical Trials Experience in Adults The overall safety of caspofungin was assessed in 1865 adult individuals who received single or multiple doses of caspofungin: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 patients with invasive aspergillosis; and 394 individuals in phase I studies. In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus studies often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications. Empirical Therapy - In the randomized, double-blinded empirical therapy study, patients received either caspofungin 50 mg/day (following a 70-mg loading dose) or AmBisome® (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the caspofungin and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia considered possibly related to caspofungin. Adverse reactions occurring in ≥7.5% of the patients in either treatment group are presented in Table 2 - The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with caspofungin (35%) than in the group treated with AmBisome (52%). - To evaluate the effect of caspofungin and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of ≥1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. Among patients whose baseline creatinine clearance was >30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin (3%) than in the group treated with AmBisome (12%). Clinical renal events, regardless of causality, were similar between caspofungin (75/564, 13%) and AmBisome (85/547, 16%). Candidemia and Other Candida Infections - In the randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70-mg loading dose) or amphotericin B 0.6 to 1 mg/kg/day. Adverse reactions occurring in ≥10% of the patients in either treatment group are presented in Table 3. - The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with caspofungin (20%) than in the group treated with amphotericin B (49%). - To evaluate the effect of caspofungin and amphotericin B on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of ≥1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. In a subgroup of patients whose baseline creatinine clearance was >30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin than in the group treated with amphotericin B. - In a second randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70-mg loading dose) or caspofungin 150 mg/day. The proportion of patients who experienced any adverse reaction was similar in the 2 treatment groups; however, this study was not large enough to detect differences in rare or unexpected adverse events. Adverse reactions occurring in ≥5% of the patients in either treatment group are presented in Table 4. Esophageal Candidiasis and Oropharyngeal Candidiasis Adverse reactions occurring in ≥10% of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 5. Invasive Aspergillosis In an open-label, non comparative aspergillosis study, in which 69 patients received caspofungin (70-mg loading dose on Day 1 followed by 50 mg daily), the following treatment-emergent adverse reactions were observed with an incidence of ≥12.5%: blood alkaline phosphatase increased (22%), hypotension (20%), respiratory failure (20%), pyrexia (17%), diarrhea (15%), nausea (15%), headache (15%), rash (13%), aspergillosis (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (13%), blood bilirubin increased (13%), and blood potassium decreased (13%). Also reported infrequently in this patient population were pulmonary edema, ARDS (adult respiratory distress syndrome), and radiographic infiltrates. ## Clinical Trials Experience in Pediatric Patients (3 months to 17 years of age) - The overall safety of caspofungin was assessed in 171 pediatric patients who received single or multiple doses of caspofungin. The distribution among the 153 pediatric patients who were over the age of 3 months was as follows: 104 febrile, neutropenic patients; 38 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis. The overall safety profile of caspofungin in pediatric patients is comparable to that in adult patients. Table 6 shows the incidence of adverse reactions reported in ≥7.5% of pediatric patients in clinical studies. - One patient (0.6%) receiving caspofungin, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from caspofungin and three patients (12%) were discontinued from AmBisome due to a drug-related adverse reaction. The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was 22% in the group treated with caspofungin and 35% in the group treated with AmBisome. ## Overall Safety Experience of Caspofungin in Clinical Trials - The overall safety of caspofungin was assessed in 2036 individuals (including 1642 adult or pediatric patients and 394 volunteers) from 34 clinical studies. These individuals received single or multiple (once daily) doses of caspofungin, ranging from 5 mg to 210 mg. Full safety data is available from 1951 individuals, as the safety data from 85 patients enrolled in 2 compassionate use studies was limited solely to serious adverse reactions. Treatment emergent adverse reactions, regardless of causality, which occurred in ≥5% of all individuals who received caspofungin in these trials, are shown in Table 7. - Overall, 1665 of the 1951 (85%) patients/volunteers who received caspofungin experienced an adverse reaction. Clinically significant adverse reactions, regardless of causality or incidence which occurred in less than 5% of patients are listed below. - Blood and lymphatic system disorders: anemia, coagulopathy, febrile neutropenia, neutropenia, thrombocytopenia - Cardiac disorders: arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, myocardial infarction, tachycardia - Gastrointestinal disorders: abdominal distension, abdominal pain upper, constipation, dyspepsia - General disorders and administration site conditions: asthenia, fatigue, infusion site pain/pruritus/swelling, mucosal inflammation, edema - Hepatobiliary disorders: hepatic failure, hepatomegaly, hepatotoxicity, hyperbilirubinemia, jaundice - Infections and infestations: bacteremia, sepsis, urinary tract infection - Metabolic and nutrition disorders: anorexia, decreased appetite, fluid overload, hypomagnesemia, hypercalcemia, hyperglycemia, hypokalemia - Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, pain in extremity - Nervous system disorders: convulsion, dizziness, somnolence, tremor - Psychiatric disorders: anxiety, confusional state, depression, insomnia - Renal and urinary disorders: hematuria, renal failure - Respiratory, thoracic, and mediastinal disorders: dyspnea, epistaxis, hypoxia, tachypnea - Skin and subcutaneous tissue disorders: erythema, petechiae, skin lesion, urticaria - Vascular disorders: flushing, hypertension, phlebitis ## Postmarketing Experience The following additional adverse reactions have been identified during the post-approval use of caspofungin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Gastrointestinal disorders: pancreatitis - Hepatobiliary disorders: hepatic necrosis - Skin and subcutaneous tissue disorders: erythema multiforme, Stevens-Johnson, skin exfoliation - Renal and urinary disorders: clinically significant renal dysfunction - General disorders and administration site conditions: swelling and peripheral edema - Laboratory abnormalities: gamma-glutamyltransferase increased # Drug Interactions - In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. - Clinical studies in adult healthy volunteers show that the pharmacokinetics of caspofungin are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate. - Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. caspofungin did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin and cyclosporine were co-administered . - Tacrolimus: For patients receiving caspofungin and tacrolimus, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended. - Rifampin: Adult patients on rifampin should receive 70 mg of caspofungin daily. - Other inducers of drug clearance: - Adults: When caspofungin is co-administered to adult patients with inducers of drug clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of 70 mg of caspofungin should be considered. - Pediatric Patients: When caspofungin is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C - There are no adequate and well-controlled studies with the use of caspofungin in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri-implantation loss, and incomplete ossification at multiple fetal sites. Caspofungin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In offspring born to pregnant rats treated with caspofungin at doses comparable to the human dose based on body surface area comparisons, there was incomplete ossification of the skull and torso and increased incidences of cervical rib. There was also an increase in resorptions and peri-implantation losses. In pregnant rabbits treated with caspofungin at doses comparable to 2 times the human dose based on body surface area comparisons, there was an increased incidence of incomplete ossification of the talus/calcaneus in offspring and increases in fetal resorptions. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Caspofungin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Caspofungin during labor and delivery. ### Nursing Mothers It is not known whether caspofungin is present in human milk. Caspofungin was found in the milk of lactating, drug-treated rats. Because many drugs are excreted in human milk, caution should be exercised when caspofungin is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of caspofungin in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies in pediatric patients 3 months to 17 years of age for the following indications: - Empirical therapy for presumed fungal infections in febrile, neutropenic patients. - Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections. - Treatment of esophageal candidiasis. - Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g.,amphotericin B, lipid formulations of amphotericin B, itraconazole). - The efficacy and safety of caspofungin has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of CNS and multi-organ involvement than in older patients; the ability of caspofungin to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown. - Caspofungin has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. caspofungin has also not been studied as initial therapy for invasive aspergillosis in pediatric patients. - In clinical trials, 171 pediatric patients (0 months to 17 years of age), including 18 patients who were less than 3 months of age, were given intravenous caspofungin. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin in safety and efficacy studies. The majority of the pediatric patients received caspofungin at a once-daily maintenance dose of 50 mg/m2 for a mean duration of 12 days (median 9, range 1-87 days). In all studies, safety was assessed by the investigator throughout study therapy and for 14 days following cessation of study therapy. The most common adverse reactions in pediatric patients treated with caspofungin were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased aspartate aminotransferase (12%), rash (12%), increased alanine aminotransferase (11%), hypotension (11%), and chills (11%). - Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions. ### Geriatic Use Clinical studies of caspofungin did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Although the number of elderly patients was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed between these and younger patients. Plasma concentrations of caspofungin in healthy older men and women (≥65 years of age) were increased slightly (approximately 28% in AUC) compared to young healthy men. A similar effect of age on pharmacokinetics was seen in patients with candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections). No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Caspofungin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Caspofungin with respect to specific racial populations. ### Renal Impairment No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable; thus, supplementary dosing is not required following hemodialysis. ### Hepatic Impairment Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin 35 mg once daily is recommended based upon pharmacokinetic data. However, where recommended, a 70-mg loading dose should still be administered on day 1. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Caspofungin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Caspofungin in patients who are immunocompromised. # Administration and Monitoring ### Administration # Instructions for Use in All Patients - Caspofungin should be administered by slow intravenous (IV) infusion over approximately 1 hour. Caspofungin should not be administered by IV bolus administration. - Do not mix or co-infuse caspofungin with other medications, as there are no data available on the compatibility of caspofungin with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as caspofungin is not stable in diluents containing dextrose. ### Monitoring There is limited information regarding Caspofungin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Caspofungin and IV administrations. # Overdosage - In 6 healthy subjects who received a single 210-mg dose, no significant adverse reactions were reported. Multiple doses above 150 mg daily have not been studied. Caspofungin is not dialyzable. The minimum lethal dose of caspofungin in rats was 50 mg/kg, a dose which is equivalent to 10 times the recommended daily dose based on relative body surface area comparison. - In clinical trials, one pediatric patient (16 years of age) unintentionally received a single dose of caspofungin of 113 mg (on day 1), followed by 80 mg daily for an additional 7 days. No clinically significant adverse reactions were reported. # Pharmacology ## Mechanism of Action There is limited information regarding Caspofungin Mechanism of Action in the drug label. ## Structure - Caspofungin is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. Caspofungin is an echinocandin that inhibits the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall. - CANCIDAS (caspofungin acetate) is 1--N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5- pneumocandin B0 diacetate (salt). Caspofungin 50 mg also contains: 39 mg sucrose, 26 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin 70 mg also contains 54 mg sucrose, 36 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6. The empirical formula is C52H88N10O152C2H4O2 and the formula weight is 1213.42. The structural formula is: ## Pharmacodynamics There is limited information regarding Caspofungin Pharmacodynamics in the drug label. ## Pharmacokinetics Adult and pediatric pharmacokinetic parameters are presented in Table 8. Distribution Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour IV infusions. A short α-phase occurs immediately postinfusion, followed by a β-phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours postdose during which the plasma concentration decreases 10-fold. An additional, longer half-life phase, γ-phase, (half-life of 40-50 hours), also occurs. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin (~97%), and distribution into red blood cells is minimal. Mass balance results showed that approximately 92% of the administered radioactivity was distributed to tissues by 36 to 48 hours after a single 70-mg dose of caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration. Metabolism Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (≥5 days postdose), there is a low level (≤7 picomoles/mg protein, or ≤1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys. Excretion Two single-dose radiolabeled pharmacokinetic studies were conducted. In one study, plasma, urine, and feces were collected over 27 days, and in the second study plasma was collected over 6 months. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter drug levels fell more rapidly. In plasma, caspofungin concentrations fell below the limit of quantitation after 6 to 8 days postdose, while radiolabel fell below the limit of quantitation at 22.3 weeks postdose. After single intravenous administration of caspofungin acetate, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine. A small amount of caspofungin is excreted unchanged in urine (~1.4% of dose). Renal clearance of parent drug is low (~0.15 mL/min) and total clearance of caspofungin is 12 mL/min. Special Populations Renal Impairment In a clinical study of single 70-mg doses, caspofungin pharmacokinetics were similar in healthy adult volunteers with mild renal impairment (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to 49 mL/min), severe (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine clearance <10 mL/min and dialysis dependent) renal impairment moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However, in adult patients with invasive aspergillosis, candidemia, or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections) who received multiple daily doses of caspofungin 50 mg, there was no significant effect of mild to end-stage renal impairment on caspofungin concentrations. No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis. Hepatic Impairment Plasma concentrations of caspofungin after a single 70-mg dose in adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) were increased by approximately 55% in AUC compared to healthy control subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in adult patients with mild hepatic impairment were increased modestly (19 to 25% in AUC) on Days 7 and 14 relative to healthy control subjects. No dosage adjustment is recommended for patients with mild hepatic impairment. Adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9) who received a single 70-mg dose of caspofungin had an average plasma caspofungin increase of 76% in AUC compared to control subjects. A dosage reduction is recommended for adult patients with moderate hepatic impairment based upon these pharmacokinetic data. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) or in pediatric patients with any degree of hepatic impairment. Gender Plasma concentrations of caspofungin in healthy adult men and women were similar following a single 70-mg dose. After 13 daily 50-mg doses, caspofungin plasma concentrations in women were elevated slightly (approximately 22% in area under the curve ) relative to men. No dosage adjustment is necessary based on gender. Race Regression analyses of patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, and Hispanics. No dosage adjustment is necessary on the basis of race. Geriatric Patients Plasma concentrations of caspofungin in healthy older men and women (≥65 years of age) were increased slightly (approximately 28% AUC) compared to young healthy men after a single 70-mg dose of caspofungin. In patients who were treated empirically or who had candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections), a similar modest effect of age was seen in older patients relative to younger patients. No dosage adjustment is necessary for the elderly. Pediatric Patients Caspofungin has been studied in five prospective studies involving pediatric patients under 18 years of age, including three pediatric pharmacokinetic studies . Pharmacokinetic parameters following multiple doses of caspofungin in pediatric and adult patients are presented in Table 8 Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. Clinical studies in adult healthy volunteers show that the pharmacokinetics of caspofungin are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate. Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. Caspofungin did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin and cyclosporine were co-administered. Tacrolimus: caspofungin reduced the blood AUC0-12 of tacrolimus (FK-506, Prograf®) by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of caspofungin 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Rifampin: A drug-drug interaction study with rifampin in adult healthy volunteers has shown a 30% decrease in caspofungin trough concentrations. Adult patients on rifampin should receive 70 mg of caspofungin daily. Other inducers of drug clearance Adults: In addition, results from regression analyses of adult patient pharmacokinetic data suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with caspofungin may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible. When caspofungin is co-administered to adult patients with inducers of drug clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of 70 mg of caspofungin should be considered. Pediatric patients: In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with caspofungin may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults. When caspofungin is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin. - Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of 1 mg/kg based on body surface area comparisons), administered intravenously. - Fertility and reproductive performance were not affected by the intravenous administration of caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients treated with the 70-mg dose. ## Animal Toxicology and/or Pharmacology - In one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in adult patients treated with a 70-mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks duration at similar doses. - No treatment-related findings were seen in a 5-week study in infant monkeys at doses which produced exposures approximately 3 times those achieved in pediatric patients receiving a maintenance dose of 50 mg/m2 daily. # Clinical Studies ## Empirical Therapy in Febrile, Neutropenic Patients - A double-blind study enrolled 1111 febrile, neutropenic (<500 cells/mm3) patients who were randomized to treatment with daily doses of caspofungin (50 mg/day following a 70-mg loading dose on Day 1) or AmBisome (3 mg/kg/day). Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia) and on receipt of prior antifungal prophylaxis. Twenty-four percent of patients were high risk and 56% had received prior antifungal prophylaxis. Patients who remained febrile or clinically deteriorated following 5 days of therapy could receive 70 mg/day of caspofungin or 5 mg/kg/day of AmBisome. Treatment was continued to resolution of neutropenia (but not beyond 28 days unless a fungal infection was documented). - An overall favorable response required meeting each of the following criteria: no documented breakthrough fungal infections up to 7 days after completion of treatment, survival for 7 days after completion of study therapy, no discontinuation of the study drug because of drug-related toxicity or lack of efficacy, resolution of fever during the period of neutropenia, and successful treatment of any documented baseline fungal infection. - Based on the composite response rates, caspofungin was as effective as AmBisome in empirical therapy of persistent febrile neutropenia (see Table 11) - The rate of successful treatment of documented baseline infections, a component of the primary endpoint, was not statistically different between treatment groups. - The response rates did not differ between treatment groups based on either of the stratification variables: risk category or prior antifungal prophylaxis. ## Candidemia and the Following other Candida Infections: Intra-Abdominal Abscesses, Peritonitis and Pleural Space Infections - In a randomized, double-blind study, patients with a proven diagnosis of invasive candidiasis received daily doses of caspofungin (50 mg/day following a 70-mg loading dose on Day 1) or amphotericin B deoxycholate (0.6 to 0.7 mg/kg/day for non-neutropenic patients and 0.7 to 1 mg/kg/day for neutropenic patients). Patients were stratified by both neutropenic status and APACHE II score. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded from this study. - Patients who met the entry criteria and received one or more doses of IV study therapy were included in the modified intention-to-treat analysis of response at the end of IV study therapy. A favorable response at this time point required both symptom/sign resolution/improvement and microbiological clearance of the Candida infection. - Two hundred thirty-nine patients were enrolled. Patient disposition is shown in Table 12. - Of the 239 patients enrolled, 224 met the criteria for inclusion in the MITT population (109 treated with caspofungin and 115 treated with amphotericin B). Of these 224 patients, 186 patients had candidemia (92 treated with caspofungin and 94 treated with amphotericin B). The majority of the patients with candidemia were non-neutropenic (87%) and had an APACHE II score less than or equal to 20 (77%) in both arms. Most candidemia infections were caused by C. albicans (39%), followed by C. parapsilosis (20%), C. tropicalis (17%), C. glabrata (8%), and C. krusei (3%). - At the end of IV study therapy, caspofungin was comparable to amphotericin B in the treatment of candidemia in the MITT population. For the other efficacy time points (Day 10 of IV study therapy, end of all antifungal therapy, 2-week post-therapy follow-up, and 6- to 8-week post-therapy follow-up), caspofungin was as effective as amphotericin B. - Outcome, relapse and mortality data are shown in Table 13. - In this study, the efficacy of caspofungin in patients with intra-abdominal abscesses, peritonitis and pleural space Candida infections was evaluated in 19 non-neutropenic patients. Two of these patients had concurrent candidemia. Candida was part of a polymicrobial infection that required adjunctive surgical drainage in 11 of these 19 patients. A favorable response was seen in 9 of 9 patients with peritonitis, 3 of 4 with abscesses (liver, parasplenic, and urinary bladder abscesses), 2 of 2 with pleural space infections, 1 of 2 with mixed peritoneal and pleural infection, 1 of 1 with mixed abdominal abscess and peritonitis, and 0 of 1 with Candida pneumonia. - Overall, across all sites of infection included in the study, the efficacy of caspofungin was comparable to that of amphotericin B for the primary endpoint. - In this study, the efficacy data for caspofungin in neutropenic patients with candidemia were limited. In a separate compassionate use study, 4 patients with hepatosplenic candidiasis received prolonged therapy with caspofungin following other long-term antifungal therapy; three of these patients had a favorable response. - In a second randomized, double-blind study, 197 patients with proven invasive candidiasis received caspofungin 50 mg/day (following a 70-mg loading dose on Day 1) or caspofungin 150 mg/day. The diagnostic criteria, evaluation time points, and efficacy endpoints were similar to those employed in the prior study. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded. Although this study was designed to compare the safety of the two doses, it was not large enough to detect differences in rare or unexpected adverse events. A significant improvement in efficacy with the 150-mg daily dose was not seen when compared to the 50-mg dose. ## Esophageal Candidiasis (and information on oropharyngeal candidiasis) - The safety and efficacy of caspofungin in the treatment of esophageal candidiasis was evaluated in one large, controlled, noninferiority, clinical trial and two smaller dose-response studies. - In all 3 studies, patients were required to have symptoms and microbiological documentation of esophageal candidiasis; most patients had advanced AIDS (with CD4 counts <50/mm3). - Of the 166 patients in the large study who had culture-confirmed esophageal candidiasis at baseline, 120 had Candida albicans and 2 had Candida tropicalis as the sole baseline pathogen whereas 44 had mixed baseline cultures containing C. albicans and one or more additional Candida species. - In the large, randomized, double-blind study comparing caspofungin 50 mg/day versus intravenous fluconazole 200 mg/day for the treatment of esophageal candidiasis, patients were treated for an average of 9 days (range 7-21 days). Favorable overall response at 5 to 7 days following discontinuation of study therapy required both complete resolution of symptoms and significant endoscopic improvement. The definition of endoscopic response was based on severity of disease at baseline using a 4-grade scale and required at least a two-grade reduction from baseline endoscopic score or reduction to grade 0 for patients with a baseline score of 2 or less. - The proportion of patients with a favorable overall response was comparable for caspofungin and fluconazole as shown in Table 14. - The proportion of patients with a favorable symptom response was also comparable (90.1% and 89.4% for caspofungin and fluconazole, respectively). In addition, the proportion of patients with a favorable endoscopic response was comparable (85.2% and 86.2% for caspofungin and fluconazole, respectively). - As shown in Table 15, the esophageal candidiasis relapse rates at the Day 14 post-treatment visit were similar for the two groups. At the Day 28 post-treatment visit, the group treated with caspofungin had a numerically higher incidence of relapse; however, the difference was not statistically significant. - In this trial, which was designed to establish non inferiority of caspofungin to fluconazole for the treatment of esophageal candidiasis, 122 (70%) patients also had oropharyngeal candidiasis. A favorable response was defined as complete resolution of all symptoms of oropharyngeal disease and all visible oropharyngeal lesions. The proportion of patients with a favorable oropharyngeal response at the 5- to 7-day post-treatment visit was numerically lower for caspofungin; however, the difference was not statistically significant. Oropharyngeal candidiasis relapse rates at day 14 and day 28 post-treatment visits were statistically significantly higher for caspofungin than for fluconazole. The results are shown in Table 16. - The results from the two smaller dose-ranging studies corroborate the efficacy of caspofungin for esophageal candidiasis that was demonstrated in the larger study. - Caspofungin was associated with favorable outcomes in 7 of 10 esophageal C. albicans infections refractory to at least 200 mg of fluconazole given for 7 days, although the in vitro susceptibility of the infecting isolates to fluconazole was not known. ## Invasive Aspergillosis - Sixty-nine patients between the ages of 18 and 80 with invasive aspergillosis were enrolled in an open-label, noncomparative study to evaluate the safety, tolerability, and efficacy of caspofungin. Enrolled patients had previously been refractory to or intolerant of other antifungal therapy(ies). Refractory patients were classified as those who had disease progression or failed to improve despite therapy for at least 7 days with amphotericin B, lipid formulations of amphotericin B, itraconazole, or an investigational azole with reported activity against Aspergillus. Intolerance to previous therapy was defined as a doubling of creatinine (or creatinine ≥2.5 mg/dL while on therapy), other acute reactions, or infusion-related toxicity. To be included in the study, patients with pulmonary disease must have had definite (positive tissue histopathology or positive culture from tissue obtained by an invasive procedure) or probable (positive radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction) invasive aspergillosis. Patients with extrapulmonary disease had to have definite invasive aspergillosis. The definitions were modeled after the Mycoses Study Group Criteria. Patients were administered a single 70-mg loading dose of caspofungin and subsequently dosed with 50 mg daily. The mean duration of therapy was 33.7 days, with a range of 1 to 162 days. - An independent expert panel evaluated patient data, including diagnosis of invasive aspergillosis, response and tolerability to previous antifungal therapy, treatment course on caspofungin, and clinical outcome. - A favorable response was defined as either complete resolution (complete response) or clinically meaningful improvement (partial response) of all signs and symptoms and attributable radiographic findings. Stable, non progressive disease was considered to be an unfavorable response. - Among the 69 patients enrolled in the study, 63 met entry diagnostic criteria and had outcome data; and of these, 52 patients received treatment for >7 days. Fifty-three (84%) were refractory to previous antifungal therapy and 10 (16%) were intolerant. Forty-five patients had pulmonary disease and 18 had extrapulmonary disease. Underlying conditions were hematologic malignancy (N=24), allogeneic bone marrow transplant or stem cell transplant (N=18), organ transplant (N=8), solid tumor (N=3), or other conditions (N=10). All patients in the study received concomitant therapies for their other underlying conditions. Eighteen patients received tacrolimus and caspofungin concomitantly, of whom 8 also received mycophenolate mofetil. - Overall, the expert panel determined that 41% (26/63) of patients receiving at least one dose of caspofungin had a favorable response. For those patients who received >7 days of therapy with caspofungin, 50% (26/52) had a favorable response. The favorable response rates for patients who were either refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10), respectively. The response rates among patients with pulmonary disease and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary disease, 2 of 8 patients who also had definite, probable, or possible CNS involvement had a favorable response. Two of these 8 patients had progression of disease and manifested CNS involvement while on therapy. - Caspofungin is effective for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of itraconazole, amphotericin B, and/or lipid formulations of amphotericin B. However, the efficacy of caspofungin for initial treatment of invasive aspergillosis has not been evaluated in comparator-controlled clinical studies ## Pediatric Patients - The safety and efficacy of caspofungin were evaluated in pediatric patients 3 months to 17 years of age in two prospective, multicenter clinical trials. - The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double-blind study comparing caspofungin (50 mg/m2 IV once daily following a 70-mg/m2 loading dose on Day 1 ) to AmBisome (3 mg/kg IV daily) in a 2:1 treatment fashion (56 on caspofungin, 26 on AmBisome) as empirical therapy in pediatric patients with persistent fever and neutropenia. The study design and criteria for efficacy assessment were similar to the study in adult patients. Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia). Twenty-seven percent of patients in both treatment groups were high risk. Favorable overall response rates of pediatric patients with persistent fever and neutropenia are presented in Table 17. - The second study was a prospective, open-label, non-comparative study estimating the safety and efficacy of caspofungin in pediatric patients (ages 3 months to 17 years) with candidemia and other Candida infections, esophageal candidiasis, and invasive aspergillosis (as salvage therapy). The study employed diagnostic criteria which were based on established EORTC/MSG criteria of proven or probable infection; these criteria were similar to those criteria employed in the adult studies for these various indications. Similarly, the efficacy time points and endpoints used in this study were similar to those employed in the corresponding adult studies. All patients received caspofungin at 50 mg/m2 IV once daily following a 70-mg/m2 loading dose on Day 1 (not to exceed 70 mg daily). Among the 49 enrolled patients who received caspofungin, 48 were included in the efficacy analysis (one patient excluded due to not having a baseline Aspergillus or Candida infection). Of these 48 patients, 37 had candidemia or other Candida infections, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. Most candidemia and other Candida infections were caused by C. albicans (35%), followed by C. parapsilosis (22%), C. tropicalis (14%), and C. glabrata (11%). The favorable response rate, by indication, at the end of caspofungin therapy was as follows: 30/37 (81%) in candidemia or other Candida infections, 5/10 (50%) in invasive aspergillosis, and 1/1 in esophageal candidiasis. # How Supplied - Caspofungin 50 mg is a white to off-white powder/cake for infusion in a vial with a red aluminum band and a plastic cap. - NDC 0006-3822-10 supplied as one single-use vial. - Caspofungin 70 mg is a white to off-white powder/cake for infusion in a vial with a yellow/orange aluminum band and a plastic cap. - NDC 0006-3823-10 supplied as one single-use vial. ## Storage Vials The lyophilized vials should be stored refrigerated at 2° to 8°C (36° to 46°F). Reconstituted Concentrate Reconstituted caspofungin in the vial may be stored at ≤25°C (≤77°F) for one hour prior to the preparation of the patient infusion solution. Diluted Product The final patient infusion solution in the IV bag or bottle can be stored at ≤25°C (≤77°F) for 24 hours or at 2 to 8°C (36 to 46°F) for 48 hours. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ## Hypersensitivity Inform patients that anaphylactic reactions have been reported during administration of caspofungin. Caspofungin can cause hypersensitivity reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasm. Inform patients to report these signs or symptoms to their healthcare providers. ## Hepatic Effects - Inform patients that there have been isolated reports of serious hepatic effects from caspofungin therapy. Physicians will assess the risk/benefit of continuing caspofungin therapy if abnormal liver function tests occur during treatment. # Precautions with Alcohol Alcohol-Caspofungin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names CANCIDA # Look-Alike Drug Names There is limited information regarding Caspofungin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Caspofungin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Caspofungin is an antifungal that is FDA approved for the treatment of fungal infections, candidemia, esophageal candidiasis, invasive aspergillosis refractory or intolerant to other therapies. Common adverse reactions include anemia, febrile neutropenia, neutropenia, thrombocytopenia, arrhythmia, atrial fibrillation, abdominal pain, bacteremia, sepsis, urinary tract infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Caspofungin® is indicated in adults and pediatric patients (3 months and older) for: - Empirical therapy for presumed fungal infections in febrile, neutropenic patients - Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. Caspofungin has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida. - Treatment of esophageal candidiasis. - Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole). Caspofungin has not been studied as initial therapy for invasive aspergillosis. # Dosage ## Recommended Dosing in Adult Patients [≥18 years of age] - The usual dose is 50 mg once daily (following a 70-mg loading dose for most indications). The safety and efficacy of a dose of 150 mg daily (range: 1 to 51 days; median: 14 days) have been studied in 100 adult patients with candidemia and other Candida infections. The efficacy of caspofungin at this higher dose was not significantly better than the efficacy of the 50-mg daily dose of caspofungin. The efficacy of doses higher than 50 mg daily in the other adult patients for whom caspofungin is indicated is not known. Empirical Therapy A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient's clinical response. Empirical therapy should be continued until resolution of neutropenia. Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved. If the 50-mg dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg. Candidemia and Other Candida Infections A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be dictated by the patient's clinical and microbiological response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Patients who remain persistently neutropenic may warrant a longer course of therapy pending resolution of the neutropenia. Esophageal Candidiasis The dose is 50 mg once daily for 7 to 14 days after symptom resolution. A 70-mg loading dose has not been studied for this indication. Because of the risk of relapse of oropharyngeal candidiasis in patients with HIV infections, suppressive oral therapy could be considered. Invasive Aspergillosis A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. ### Patients with Hepatic Impairment Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin 35 mg once daily is recommended based upon pharmacokinetic data. However, where recommended, a 70-mg loading dose should still be administered on Day 1. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) and in pediatric patients with any degree of hepatic impairment. ### Patients Receiving Concomitant Inducers of Drug Clearance - Adult patients on rifampin should receive 70 mg of caspofungin once daily. Adult patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin may require an increase in dose to 70 mg of caspofungin once daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Caspofungin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Caspofungin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Recommended Dosing in Pediatric Patients [3 months to 17 years of age] - For all indications, a single 70-mg/m2 loading dose should be administered on Day 1, followed by 50 mg/m2 once daily thereafter. The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. Dosing in pediatric patients (3 months to 17 years of age) should be based on the patient's body surface area (BSA) as calculated by the Mosteller Formula - Following calculation of the patient's BSA, the loading dose in milligrams should be calculated as BSA (m2) X 70 mg/m2. The maintenance dose in milligrams should be calculated as BSA (m2) X 50 mg/m2. - Duration of treatment should be individualized to the indication, as described for each indication in adults. If the 50-mg/m2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m2 daily (not to exceed 70 mg). ### Patients Receiving Concomitant Inducers of Drug Clearance When caspofungin is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 once daily (not to exceed 70 mg) should be considered ### Special Considerations for Pediatric Patients >3 Months of Age - Follow the reconstitution procedures described above using either the 70-mg or 50-mg vial to create the reconstituted solution. From the reconstituted solution in the vial, remove the volume of drug equal to the calculated loading dose or calculated maintenance dose based on a concentration of 7 mg/mL (if reconstituted from the 70-mg vial) or a concentration of 5 mg/mL (if reconstituted from the 50-mg vial). - The choice of vial should be based on total milligram dose of drug to be administered to the pediatric patient. To help ensure accurate dosing, it is recommended for pediatric doses less than 50 mg that 50-mg vials (with a concentration of 5 mg/mL) be used if available. The 70-mg vial should be reserved for pediatric patients requiring doses greater than 50 mg. The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Caspofungin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Caspofungin in pediatric patients. # Contraindications Caspofungin is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to any component of this product. # Warnings ## Hypersensitivity - Anaphylaxis has been reported during administration of caspofungin. If this occurs, caspofungin should be discontinued and appropriate treatment administered. - Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported and may require discontinuation and/or administration of appropriate treatment. ## Concomitant Use with Cyclosporine - Concomitant use of caspofungin with cyclosporine should be limited to patients for whom the potential benefit outweighs the potential risk. In one clinical study, 3 of 4 healthy adult subjects who received caspofungin 70 mg on Days 1 through 10, and also received two 3 mg/kg doses of cyclosporine 12 hours apart on day 10, developed transient elevations of alanine transaminase (ALT) on day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate panel of adult subjects in the same study, 2 of 8 who received caspofungin 35 mg daily for 3 days and cyclosporine (two 3 mg/kg doses administered 12 hours apart) on day 1 had small increases in ALT (slightly above the ULN) on day 2. In both groups, elevations in aspartate transaminase (AST) paralleled ALT elevations, but were of lesser magnitude. In another clinical study, 2 of 8 healthy men developed transient ALT elevations of less than 2X ULN. In this study, cyclosporine (4 mg/kg) was administered on Days 1 and 12, and caspofungin was administered (70 mg) daily on Days 3 through 13. In one subject, the ALT elevation occurred on days 7 and 9 and, in the other subject, the ALT elevation occurred on Day 19. These elevations returned to normal by Day 27. In all groups, elevations in AST paralleled ALT elevations but were of lesser magnitude. In these clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. - In a retrospective postmarketing study, 40 immunocompromised patients, including 37 transplant recipients, were treated with caspofungin and cyclosporine for 1 to 290 days (median 17.5 days). Fourteen patients (35%) developed transaminase elevations >5X upper limit of normal or >3X baseline during concomitant therapy or the 14-day follow-up period; five were considered possibly related to concomitant therapy. One patient had elevated bilirubin considered possibly related to concomitant therapy. No patient developed clinical evidence of hepatotoxicity or serious hepatic events. Discontinuations due to laboratory abnormalities in hepatic enzymes from any cause occurred in four patients. Of these, 2 were considered possibly related to therapy with caspofungin and/or cyclosporine as well as to other possible causes. - In the prospective invasive aspergillosis and compassionate use studies, there were 4 adult patients treated with caspofungin (50 mg/day) and cyclosporine for 2 to 56 days. None of these patients experienced increases in hepatic enzymes. - Given the limitations of these data, caspofungin and cyclosporine should only be used concomitantly in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver function tests during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated. ## Hepatic Effects - Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with caspofungin. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to caspofungin has not been established. - Patients who develop abnormal liver function tests during caspofungin therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing caspofungin therapy # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed in detail in another section of the labeling: - Hepatic effects - Hypersensitivity - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does provide a basis for identifying adverse reactions that appear to be related to drug use and for approximating rates. ## Clinical Trials Experience in Adults The overall safety of caspofungin was assessed in 1865 adult individuals who received single or multiple doses of caspofungin: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 patients with invasive aspergillosis; and 394 individuals in phase I studies. In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus studies often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications. Empirical Therapy - In the randomized, double-blinded empirical therapy study, patients received either caspofungin 50 mg/day (following a 70-mg loading dose) or AmBisome® (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the caspofungin and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia considered possibly related to caspofungin. Adverse reactions occurring in ≥7.5% of the patients in either treatment group are presented in Table 2 - The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with caspofungin (35%) than in the group treated with AmBisome (52%). - To evaluate the effect of caspofungin and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of ≥1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. Among patients whose baseline creatinine clearance was >30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin (3%) than in the group treated with AmBisome (12%). Clinical renal events, regardless of causality, were similar between caspofungin (75/564, 13%) and AmBisome (85/547, 16%). Candidemia and Other Candida Infections - In the randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70-mg loading dose) or amphotericin B 0.6 to 1 mg/kg/day. Adverse reactions occurring in ≥10% of the patients in either treatment group are presented in Table 3. - The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with caspofungin (20%) than in the group treated with amphotericin B (49%). - To evaluate the effect of caspofungin and amphotericin B on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of ≥1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. In a subgroup of patients whose baseline creatinine clearance was >30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin than in the group treated with amphotericin B. - In a second randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70-mg loading dose) or caspofungin 150 mg/day. The proportion of patients who experienced any adverse reaction was similar in the 2 treatment groups; however, this study was not large enough to detect differences in rare or unexpected adverse events. Adverse reactions occurring in ≥5% of the patients in either treatment group are presented in Table 4. Esophageal Candidiasis and Oropharyngeal Candidiasis Adverse reactions occurring in ≥10% of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 5. Invasive Aspergillosis In an open-label, non comparative aspergillosis study, in which 69 patients received caspofungin (70-mg loading dose on Day 1 followed by 50 mg daily), the following treatment-emergent adverse reactions were observed with an incidence of ≥12.5%: blood alkaline phosphatase increased (22%), hypotension (20%), respiratory failure (20%), pyrexia (17%), diarrhea (15%), nausea (15%), headache (15%), rash (13%), aspergillosis (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (13%), blood bilirubin increased (13%), and blood potassium decreased (13%). Also reported infrequently in this patient population were pulmonary edema, ARDS (adult respiratory distress syndrome), and radiographic infiltrates. ## Clinical Trials Experience in Pediatric Patients (3 months to 17 years of age) - The overall safety of caspofungin was assessed in 171 pediatric patients who received single or multiple doses of caspofungin. The distribution among the 153 pediatric patients who were over the age of 3 months was as follows: 104 febrile, neutropenic patients; 38 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis. The overall safety profile of caspofungin in pediatric patients is comparable to that in adult patients. Table 6 shows the incidence of adverse reactions reported in ≥7.5% of pediatric patients in clinical studies. - One patient (0.6%) receiving caspofungin, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from caspofungin and three patients (12%) were discontinued from AmBisome due to a drug-related adverse reaction. The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was 22% in the group treated with caspofungin and 35% in the group treated with AmBisome. ## Overall Safety Experience of Caspofungin in Clinical Trials - The overall safety of caspofungin was assessed in 2036 individuals (including 1642 adult or pediatric patients and 394 volunteers) from 34 clinical studies. These individuals received single or multiple (once daily) doses of caspofungin, ranging from 5 mg to 210 mg. Full safety data is available from 1951 individuals, as the safety data from 85 patients enrolled in 2 compassionate use studies was limited solely to serious adverse reactions. Treatment emergent adverse reactions, regardless of causality, which occurred in ≥5% of all individuals who received caspofungin in these trials, are shown in Table 7. - Overall, 1665 of the 1951 (85%) patients/volunteers who received caspofungin experienced an adverse reaction. Clinically significant adverse reactions, regardless of causality or incidence which occurred in less than 5% of patients are listed below. - Blood and lymphatic system disorders: anemia, coagulopathy, febrile neutropenia, neutropenia, thrombocytopenia - Cardiac disorders: arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, myocardial infarction, tachycardia - Gastrointestinal disorders: abdominal distension, abdominal pain upper, constipation, dyspepsia - General disorders and administration site conditions: asthenia, fatigue, infusion site pain/pruritus/swelling, mucosal inflammation, edema - Hepatobiliary disorders: hepatic failure, hepatomegaly, hepatotoxicity, hyperbilirubinemia, jaundice - Infections and infestations: bacteremia, sepsis, urinary tract infection - Metabolic and nutrition disorders: anorexia, decreased appetite, fluid overload, hypomagnesemia, hypercalcemia, hyperglycemia, hypokalemia - Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, pain in extremity - Nervous system disorders: convulsion, dizziness, somnolence, tremor - Psychiatric disorders: anxiety, confusional state, depression, insomnia - Renal and urinary disorders: hematuria, renal failure - Respiratory, thoracic, and mediastinal disorders: dyspnea, epistaxis, hypoxia, tachypnea - Skin and subcutaneous tissue disorders: erythema, petechiae, skin lesion, urticaria - Vascular disorders: flushing, hypertension, phlebitis ## Postmarketing Experience The following additional adverse reactions have been identified during the post-approval use of caspofungin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Gastrointestinal disorders: pancreatitis - Hepatobiliary disorders: hepatic necrosis - Skin and subcutaneous tissue disorders: erythema multiforme, Stevens-Johnson, skin exfoliation - Renal and urinary disorders: clinically significant renal dysfunction - General disorders and administration site conditions: swelling and peripheral edema - Laboratory abnormalities: gamma-glutamyltransferase increased # Drug Interactions - In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. - Clinical studies in adult healthy volunteers show that the pharmacokinetics of caspofungin are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate. - Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. caspofungin did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin and cyclosporine were co-administered . - Tacrolimus: For patients receiving caspofungin and tacrolimus, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended. - Rifampin: Adult patients on rifampin should receive 70 mg of caspofungin daily. - Other inducers of drug clearance: - Adults: When caspofungin is co-administered to adult patients with inducers of drug clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of 70 mg of caspofungin should be considered. - Pediatric Patients: When caspofungin is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C - There are no adequate and well-controlled studies with the use of caspofungin in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri-implantation loss, and incomplete ossification at multiple fetal sites. Caspofungin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In offspring born to pregnant rats treated with caspofungin at doses comparable to the human dose based on body surface area comparisons, there was incomplete ossification of the skull and torso and increased incidences of cervical rib. There was also an increase in resorptions and peri-implantation losses. In pregnant rabbits treated with caspofungin at doses comparable to 2 times the human dose based on body surface area comparisons, there was an increased incidence of incomplete ossification of the talus/calcaneus in offspring and increases in fetal resorptions. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Caspofungin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Caspofungin during labor and delivery. ### Nursing Mothers It is not known whether caspofungin is present in human milk. Caspofungin was found in the milk of lactating, drug-treated rats. Because many drugs are excreted in human milk, caution should be exercised when caspofungin is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of caspofungin in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies in pediatric patients 3 months to 17 years of age for the following indications: - Empirical therapy for presumed fungal infections in febrile, neutropenic patients. - Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections. - Treatment of esophageal candidiasis. - Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g.,amphotericin B, lipid formulations of amphotericin B, itraconazole). - The efficacy and safety of caspofungin has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of CNS and multi-organ involvement than in older patients; the ability of caspofungin to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown. - Caspofungin has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. caspofungin has also not been studied as initial therapy for invasive aspergillosis in pediatric patients. - In clinical trials, 171 pediatric patients (0 months to 17 years of age), including 18 patients who were less than 3 months of age, were given intravenous caspofungin. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin in safety and efficacy studies. The majority of the pediatric patients received caspofungin at a once-daily maintenance dose of 50 mg/m2 for a mean duration of 12 days (median 9, range 1-87 days). In all studies, safety was assessed by the investigator throughout study therapy and for 14 days following cessation of study therapy. The most common adverse reactions in pediatric patients treated with caspofungin were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased aspartate aminotransferase (12%), rash (12%), increased alanine aminotransferase (11%), hypotension (11%), and chills (11%). - Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions. ### Geriatic Use Clinical studies of caspofungin did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Although the number of elderly patients was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed between these and younger patients. Plasma concentrations of caspofungin in healthy older men and women (≥65 years of age) were increased slightly (approximately 28% in AUC) compared to young healthy men. A similar effect of age on pharmacokinetics was seen in patients with candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections). No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Caspofungin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Caspofungin with respect to specific racial populations. ### Renal Impairment No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable; thus, supplementary dosing is not required following hemodialysis. ### Hepatic Impairment Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin 35 mg once daily is recommended based upon pharmacokinetic data. However, where recommended, a 70-mg loading dose should still be administered on day 1. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Caspofungin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Caspofungin in patients who are immunocompromised. # Administration and Monitoring ### Administration # Instructions for Use in All Patients - Caspofungin should be administered by slow intravenous (IV) infusion over approximately 1 hour. Caspofungin should not be administered by IV bolus administration. - Do not mix or co-infuse caspofungin with other medications, as there are no data available on the compatibility of caspofungin with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as caspofungin is not stable in diluents containing dextrose. ### Monitoring There is limited information regarding Caspofungin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Caspofungin and IV administrations. # Overdosage - In 6 healthy subjects who received a single 210-mg dose, no significant adverse reactions were reported. Multiple doses above 150 mg daily have not been studied. Caspofungin is not dialyzable. The minimum lethal dose of caspofungin in rats was 50 mg/kg, a dose which is equivalent to 10 times the recommended daily dose based on relative body surface area comparison. - In clinical trials, one pediatric patient (16 years of age) unintentionally received a single dose of caspofungin of 113 mg (on day 1), followed by 80 mg daily for an additional 7 days. No clinically significant adverse reactions were reported. # Pharmacology ## Mechanism of Action There is limited information regarding Caspofungin Mechanism of Action in the drug label. ## Structure - Caspofungin is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. Caspofungin is an echinocandin that inhibits the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall. - CANCIDAS (caspofungin acetate) is 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B0 diacetate (salt). Caspofungin 50 mg also contains: 39 mg sucrose, 26 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin 70 mg also contains 54 mg sucrose, 36 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6. The empirical formula is C52H88N10O15•2C2H4O2 and the formula weight is 1213.42. The structural formula is: ## Pharmacodynamics There is limited information regarding Caspofungin Pharmacodynamics in the drug label. ## Pharmacokinetics Adult and pediatric pharmacokinetic parameters are presented in Table 8. Distribution Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour IV infusions. A short α-phase occurs immediately postinfusion, followed by a β-phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours postdose during which the plasma concentration decreases 10-fold. An additional, longer half-life phase, γ-phase, (half-life of 40-50 hours), also occurs. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin (~97%), and distribution into red blood cells is minimal. Mass balance results showed that approximately 92% of the administered radioactivity was distributed to tissues by 36 to 48 hours after a single 70-mg dose of [3H] caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration. Metabolism Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (≥5 days postdose), there is a low level (≤7 picomoles/mg protein, or ≤1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [3H] caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys. Excretion Two single-dose radiolabeled pharmacokinetic studies were conducted. In one study, plasma, urine, and feces were collected over 27 days, and in the second study plasma was collected over 6 months. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter drug levels fell more rapidly. In plasma, caspofungin concentrations fell below the limit of quantitation after 6 to 8 days postdose, while radiolabel fell below the limit of quantitation at 22.3 weeks postdose. After single intravenous administration of [3H] caspofungin acetate, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine. A small amount of caspofungin is excreted unchanged in urine (~1.4% of dose). Renal clearance of parent drug is low (~0.15 mL/min) and total clearance of caspofungin is 12 mL/min. Special Populations Renal Impairment In a clinical study of single 70-mg doses, caspofungin pharmacokinetics were similar in healthy adult volunteers with mild renal impairment (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to 49 mL/min), severe (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine clearance <10 mL/min and dialysis dependent) renal impairment moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However, in adult patients with invasive aspergillosis, candidemia, or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections) who received multiple daily doses of caspofungin 50 mg, there was no significant effect of mild to end-stage renal impairment on caspofungin concentrations. No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis. Hepatic Impairment Plasma concentrations of caspofungin after a single 70-mg dose in adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) were increased by approximately 55% in AUC compared to healthy control subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in adult patients with mild hepatic impairment were increased modestly (19 to 25% in AUC) on Days 7 and 14 relative to healthy control subjects. No dosage adjustment is recommended for patients with mild hepatic impairment. Adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9) who received a single 70-mg dose of caspofungin had an average plasma caspofungin increase of 76% in AUC compared to control subjects. A dosage reduction is recommended for adult patients with moderate hepatic impairment based upon these pharmacokinetic data. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) or in pediatric patients with any degree of hepatic impairment. Gender Plasma concentrations of caspofungin in healthy adult men and women were similar following a single 70-mg dose. After 13 daily 50-mg doses, caspofungin plasma concentrations in women were elevated slightly (approximately 22% in area under the curve [AUC]) relative to men. No dosage adjustment is necessary based on gender. Race Regression analyses of patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, and Hispanics. No dosage adjustment is necessary on the basis of race. Geriatric Patients Plasma concentrations of caspofungin in healthy older men and women (≥65 years of age) were increased slightly (approximately 28% AUC) compared to young healthy men after a single 70-mg dose of caspofungin. In patients who were treated empirically or who had candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections), a similar modest effect of age was seen in older patients relative to younger patients. No dosage adjustment is necessary for the elderly. Pediatric Patients Caspofungin has been studied in five prospective studies involving pediatric patients under 18 years of age, including three pediatric pharmacokinetic studies [initial study in adolescents (12-17 years of age) and children (2-11 years of age) followed by a study in younger patients (3-23 months of age) and then followed by a study in neonates and infants (<3 months)]. Pharmacokinetic parameters following multiple doses of caspofungin in pediatric and adult patients are presented in Table 8 Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. Clinical studies in adult healthy volunteers show that the pharmacokinetics of caspofungin are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate. Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. Caspofungin did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin and cyclosporine were co-administered. Tacrolimus: caspofungin reduced the blood AUC0-12 of tacrolimus (FK-506, Prograf®) by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of caspofungin 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Rifampin: A drug-drug interaction study with rifampin in adult healthy volunteers has shown a 30% decrease in caspofungin trough concentrations. Adult patients on rifampin should receive 70 mg of caspofungin daily. Other inducers of drug clearance Adults: In addition, results from regression analyses of adult patient pharmacokinetic data suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with caspofungin may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible. When caspofungin is co-administered to adult patients with inducers of drug clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of 70 mg of caspofungin should be considered. Pediatric patients: In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with caspofungin may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults. When caspofungin is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin. - Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of 1 mg/kg based on body surface area comparisons), administered intravenously. - Fertility and reproductive performance were not affected by the intravenous administration of caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients treated with the 70-mg dose. ## Animal Toxicology and/or Pharmacology - In one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in adult patients treated with a 70-mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks duration at similar doses. - No treatment-related findings were seen in a 5-week study in infant monkeys at doses which produced exposures approximately 3 times those achieved in pediatric patients receiving a maintenance dose of 50 mg/m2 daily. # Clinical Studies ## Empirical Therapy in Febrile, Neutropenic Patients - A double-blind study enrolled 1111 febrile, neutropenic (<500 cells/mm3) patients who were randomized to treatment with daily doses of caspofungin (50 mg/day following a 70-mg loading dose on Day 1) or AmBisome (3 mg/kg/day). Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia) and on receipt of prior antifungal prophylaxis. Twenty-four percent of patients were high risk and 56% had received prior antifungal prophylaxis. Patients who remained febrile or clinically deteriorated following 5 days of therapy could receive 70 mg/day of caspofungin or 5 mg/kg/day of AmBisome. Treatment was continued to resolution of neutropenia (but not beyond 28 days unless a fungal infection was documented). - An overall favorable response required meeting each of the following criteria: no documented breakthrough fungal infections up to 7 days after completion of treatment, survival for 7 days after completion of study therapy, no discontinuation of the study drug because of drug-related toxicity or lack of efficacy, resolution of fever during the period of neutropenia, and successful treatment of any documented baseline fungal infection. - Based on the composite response rates, caspofungin was as effective as AmBisome in empirical therapy of persistent febrile neutropenia (see Table 11) - The rate of successful treatment of documented baseline infections, a component of the primary endpoint, was not statistically different between treatment groups. - The response rates did not differ between treatment groups based on either of the stratification variables: risk category or prior antifungal prophylaxis. ## Candidemia and the Following other Candida Infections: Intra-Abdominal Abscesses, Peritonitis and Pleural Space Infections - In a randomized, double-blind study, patients with a proven diagnosis of invasive candidiasis received daily doses of caspofungin (50 mg/day following a 70-mg loading dose on Day 1) or amphotericin B deoxycholate (0.6 to 0.7 mg/kg/day for non-neutropenic patients and 0.7 to 1 mg/kg/day for neutropenic patients). Patients were stratified by both neutropenic status and APACHE II score. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded from this study. - Patients who met the entry criteria and received one or more doses of IV study therapy were included in the modified intention-to-treat [MITT] analysis of response at the end of IV study therapy. A favorable response at this time point required both symptom/sign resolution/improvement and microbiological clearance of the Candida infection. - Two hundred thirty-nine patients were enrolled. Patient disposition is shown in Table 12. - Of the 239 patients enrolled, 224 met the criteria for inclusion in the MITT population (109 treated with caspofungin and 115 treated with amphotericin B). Of these 224 patients, 186 patients had candidemia (92 treated with caspofungin and 94 treated with amphotericin B). The majority of the patients with candidemia were non-neutropenic (87%) and had an APACHE II score less than or equal to 20 (77%) in both arms. Most candidemia infections were caused by C. albicans (39%), followed by C. parapsilosis (20%), C. tropicalis (17%), C. glabrata (8%), and C. krusei (3%). - At the end of IV study therapy, caspofungin was comparable to amphotericin B in the treatment of candidemia in the MITT population. For the other efficacy time points (Day 10 of IV study therapy, end of all antifungal therapy, 2-week post-therapy follow-up, and 6- to 8-week post-therapy follow-up), caspofungin was as effective as amphotericin B. - Outcome, relapse and mortality data are shown in Table 13. - In this study, the efficacy of caspofungin in patients with intra-abdominal abscesses, peritonitis and pleural space Candida infections was evaluated in 19 non-neutropenic patients. Two of these patients had concurrent candidemia. Candida was part of a polymicrobial infection that required adjunctive surgical drainage in 11 of these 19 patients. A favorable response was seen in 9 of 9 patients with peritonitis, 3 of 4 with abscesses (liver, parasplenic, and urinary bladder abscesses), 2 of 2 with pleural space infections, 1 of 2 with mixed peritoneal and pleural infection, 1 of 1 with mixed abdominal abscess and peritonitis, and 0 of 1 with Candida pneumonia. - Overall, across all sites of infection included in the study, the efficacy of caspofungin was comparable to that of amphotericin B for the primary endpoint. - In this study, the efficacy data for caspofungin in neutropenic patients with candidemia were limited. In a separate compassionate use study, 4 patients with hepatosplenic candidiasis received prolonged therapy with caspofungin following other long-term antifungal therapy; three of these patients had a favorable response. - In a second randomized, double-blind study, 197 patients with proven invasive candidiasis received caspofungin 50 mg/day (following a 70-mg loading dose on Day 1) or caspofungin 150 mg/day. The diagnostic criteria, evaluation time points, and efficacy endpoints were similar to those employed in the prior study. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded. Although this study was designed to compare the safety of the two doses, it was not large enough to detect differences in rare or unexpected adverse events. A significant improvement in efficacy with the 150-mg daily dose was not seen when compared to the 50-mg dose. ## Esophageal Candidiasis (and information on oropharyngeal candidiasis) - The safety and efficacy of caspofungin in the treatment of esophageal candidiasis was evaluated in one large, controlled, noninferiority, clinical trial and two smaller dose-response studies. - In all 3 studies, patients were required to have symptoms and microbiological documentation of esophageal candidiasis; most patients had advanced AIDS (with CD4 counts <50/mm3). - Of the 166 patients in the large study who had culture-confirmed esophageal candidiasis at baseline, 120 had Candida albicans and 2 had Candida tropicalis as the sole baseline pathogen whereas 44 had mixed baseline cultures containing C. albicans and one or more additional Candida species. - In the large, randomized, double-blind study comparing caspofungin 50 mg/day versus intravenous fluconazole 200 mg/day for the treatment of esophageal candidiasis, patients were treated for an average of 9 days (range 7-21 days). Favorable overall response at 5 to 7 days following discontinuation of study therapy required both complete resolution of symptoms and significant endoscopic improvement. The definition of endoscopic response was based on severity of disease at baseline using a 4-grade scale and required at least a two-grade reduction from baseline endoscopic score or reduction to grade 0 for patients with a baseline score of 2 or less. - The proportion of patients with a favorable overall response was comparable for caspofungin and fluconazole as shown in Table 14. - The proportion of patients with a favorable symptom response was also comparable (90.1% and 89.4% for caspofungin and fluconazole, respectively). In addition, the proportion of patients with a favorable endoscopic response was comparable (85.2% and 86.2% for caspofungin and fluconazole, respectively). - As shown in Table 15, the esophageal candidiasis relapse rates at the Day 14 post-treatment visit were similar for the two groups. At the Day 28 post-treatment visit, the group treated with caspofungin had a numerically higher incidence of relapse; however, the difference was not statistically significant. - In this trial, which was designed to establish non inferiority of caspofungin to fluconazole for the treatment of esophageal candidiasis, 122 (70%) patients also had oropharyngeal candidiasis. A favorable response was defined as complete resolution of all symptoms of oropharyngeal disease and all visible oropharyngeal lesions. The proportion of patients with a favorable oropharyngeal response at the 5- to 7-day post-treatment visit was numerically lower for caspofungin; however, the difference was not statistically significant. Oropharyngeal candidiasis relapse rates at day 14 and day 28 post-treatment visits were statistically significantly higher for caspofungin than for fluconazole. The results are shown in Table 16. - The results from the two smaller dose-ranging studies corroborate the efficacy of caspofungin for esophageal candidiasis that was demonstrated in the larger study. - Caspofungin was associated with favorable outcomes in 7 of 10 esophageal C. albicans infections refractory to at least 200 mg of fluconazole given for 7 days, although the in vitro susceptibility of the infecting isolates to fluconazole was not known. ## Invasive Aspergillosis - Sixty-nine patients between the ages of 18 and 80 with invasive aspergillosis were enrolled in an open-label, noncomparative study to evaluate the safety, tolerability, and efficacy of caspofungin. Enrolled patients had previously been refractory to or intolerant of other antifungal therapy(ies). Refractory patients were classified as those who had disease progression or failed to improve despite therapy for at least 7 days with amphotericin B, lipid formulations of amphotericin B, itraconazole, or an investigational azole with reported activity against Aspergillus. Intolerance to previous therapy was defined as a doubling of creatinine (or creatinine ≥2.5 mg/dL while on therapy), other acute reactions, or infusion-related toxicity. To be included in the study, patients with pulmonary disease must have had definite (positive tissue histopathology or positive culture from tissue obtained by an invasive procedure) or probable (positive radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction) invasive aspergillosis. Patients with extrapulmonary disease had to have definite invasive aspergillosis. The definitions were modeled after the Mycoses Study Group Criteria. Patients were administered a single 70-mg loading dose of caspofungin and subsequently dosed with 50 mg daily. The mean duration of therapy was 33.7 days, with a range of 1 to 162 days. - An independent expert panel evaluated patient data, including diagnosis of invasive aspergillosis, response and tolerability to previous antifungal therapy, treatment course on caspofungin, and clinical outcome. - A favorable response was defined as either complete resolution (complete response) or clinically meaningful improvement (partial response) of all signs and symptoms and attributable radiographic findings. Stable, non progressive disease was considered to be an unfavorable response. - Among the 69 patients enrolled in the study, 63 met entry diagnostic criteria and had outcome data; and of these, 52 patients received treatment for >7 days. Fifty-three (84%) were refractory to previous antifungal therapy and 10 (16%) were intolerant. Forty-five patients had pulmonary disease and 18 had extrapulmonary disease. Underlying conditions were hematologic malignancy (N=24), allogeneic bone marrow transplant or stem cell transplant (N=18), organ transplant (N=8), solid tumor (N=3), or other conditions (N=10). All patients in the study received concomitant therapies for their other underlying conditions. Eighteen patients received tacrolimus and caspofungin concomitantly, of whom 8 also received mycophenolate mofetil. - Overall, the expert panel determined that 41% (26/63) of patients receiving at least one dose of caspofungin had a favorable response. For those patients who received >7 days of therapy with caspofungin, 50% (26/52) had a favorable response. The favorable response rates for patients who were either refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10), respectively. The response rates among patients with pulmonary disease and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary disease, 2 of 8 patients who also had definite, probable, or possible CNS involvement had a favorable response. Two of these 8 patients had progression of disease and manifested CNS involvement while on therapy. - Caspofungin is effective for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of itraconazole, amphotericin B, and/or lipid formulations of amphotericin B. However, the efficacy of caspofungin for initial treatment of invasive aspergillosis has not been evaluated in comparator-controlled clinical studies ## Pediatric Patients - The safety and efficacy of caspofungin were evaluated in pediatric patients 3 months to 17 years of age in two prospective, multicenter clinical trials. - The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double-blind study comparing caspofungin (50 mg/m2 IV once daily following a 70-mg/m2 loading dose on Day 1 [not to exceed 70 mg daily]) to AmBisome (3 mg/kg IV daily) in a 2:1 treatment fashion (56 on caspofungin, 26 on AmBisome) as empirical therapy in pediatric patients with persistent fever and neutropenia. The study design and criteria for efficacy assessment were similar to the study in adult patients. Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia). Twenty-seven percent of patients in both treatment groups were high risk. Favorable overall response rates of pediatric patients with persistent fever and neutropenia are presented in Table 17. - The second study was a prospective, open-label, non-comparative study estimating the safety and efficacy of caspofungin in pediatric patients (ages 3 months to 17 years) with candidemia and other Candida infections, esophageal candidiasis, and invasive aspergillosis (as salvage therapy). The study employed diagnostic criteria which were based on established EORTC/MSG criteria of proven or probable infection; these criteria were similar to those criteria employed in the adult studies for these various indications. Similarly, the efficacy time points and endpoints used in this study were similar to those employed in the corresponding adult studies. All patients received caspofungin at 50 mg/m2 IV once daily following a 70-mg/m2 loading dose on Day 1 (not to exceed 70 mg daily). Among the 49 enrolled patients who received caspofungin, 48 were included in the efficacy analysis (one patient excluded due to not having a baseline Aspergillus or Candida infection). Of these 48 patients, 37 had candidemia or other Candida infections, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. Most candidemia and other Candida infections were caused by C. albicans (35%), followed by C. parapsilosis (22%), C. tropicalis (14%), and C. glabrata (11%). The favorable response rate, by indication, at the end of caspofungin therapy was as follows: 30/37 (81%) in candidemia or other Candida infections, 5/10 (50%) in invasive aspergillosis, and 1/1 in esophageal candidiasis. # How Supplied - Caspofungin 50 mg is a white to off-white powder/cake for infusion in a vial with a red aluminum band and a plastic cap. - NDC 0006-3822-10 supplied as one single-use vial. - Caspofungin 70 mg is a white to off-white powder/cake for infusion in a vial with a yellow/orange aluminum band and a plastic cap. - NDC 0006-3823-10 supplied as one single-use vial. ## Storage Vials The lyophilized vials should be stored refrigerated at 2° to 8°C (36° to 46°F). Reconstituted Concentrate Reconstituted caspofungin in the vial may be stored at ≤25°C (≤77°F) for one hour prior to the preparation of the patient infusion solution. Diluted Product The final patient infusion solution in the IV bag or bottle can be stored at ≤25°C (≤77°F) for 24 hours or at 2 to 8°C (36 to 46°F) for 48 hours. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ## Hypersensitivity Inform patients that anaphylactic reactions have been reported during administration of caspofungin. Caspofungin can cause hypersensitivity reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasm. Inform patients to report these signs or symptoms to their healthcare providers. ## Hepatic Effects - Inform patients that there have been isolated reports of serious hepatic effects from caspofungin therapy. Physicians will assess the risk/benefit of continuing caspofungin therapy if abnormal liver function tests occur during treatment. # Precautions with Alcohol Alcohol-Caspofungin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names CANCIDA # Look-Alike Drug Names There is limited information regarding Caspofungin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Caspofungin
b5558acf35406b82717f7bc829f335ac29c1239b	wikidoc	Catabolysis	Catabolysis Catabolysis is a biological process in which the body will break down fat and muscle tissue in order to stay alive. Catabolysis only occurs when there is no longer any source of protein, carbohydrate, or vitamin nourishment feeding all body systems and is the most severe type of malnutrition. # Disease settings Catabolysis is seen in starved and malnourished people. According to the Food and Agriculture Organization in the United Nations, over 20,000 people die from starvation each day. Also, the FAO estimates that over 800,000,000 people are "chronically undernourished" and that a child dies from starvation every five seconds. # Mechanism Due to the normal metabolic rate of humans (which requires going approximately 12 hours without food), catabolysis only becomes life-threatening after 1–2 months from the cessation of nutrition going into the body. After this time, the damage to muscles and organs can be permanent and can also eventually cause death, if left untreated. Catabolysis is a last resort effort of the body to keep itself—particularly the nervous system—alive. The situation can become dire when one begins to lose muscle mass; this is a sign that the fat has been expended and the body is now metabolizing the muscle tissue. This results in muscle atrophy, a loss of strength and, ultimately, a depletion of muscular tissue completely. Muscle weakness is not necessarily a symptom of catabolysis: the muscles will normally feel fatigued when they are not receiving enough energy or oxygen. The body has a natural store of fat (also called adipose) that stores reserve energy, one can still stay alive while their body breaks down the fatty tissue (hence people wasting away from starvation). The person may, during catabolysis, have large amounts of lipids, proteins and amino acids in their bloodstream, due to the muscle fibers and adipose tissue being broken down and sent to the nervous system and brain. They may also exhibit a fever, since the body is working hard to transfer the nutrients in the muscles and fat to the blood. # Treatment While catabolysis can be deadly over time, if the person is given medical treatment early enough, the effects of catabolysis can be reversed. However, the person may require intravenous nutrition, a blood transfusion, and/or oxygen replenishment. After that, it may be a few weeks to a few months before the person's muscle mass and fat deposits can build themselves up again; there is a possibility that they may never build back up, depending on the severity of the condition.	Catabolysis Template:SignSymptom infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Catabolysis is a biological process in which the body will break down fat and muscle tissue in order to stay alive. Catabolysis only occurs when there is no longer any source of protein, carbohydrate, or vitamin nourishment feeding all body systems and is the most severe type of malnutrition. # Disease settings Catabolysis is seen in starved and malnourished people. According to the Food and Agriculture Organization in the United Nations, over 20,000 people die from starvation each day.[citation needed] Also, the FAO estimates that over 800,000,000 people are "chronically undernourished" and that a child dies from starvation every five seconds.[citation needed] # Mechanism Due to the normal metabolic rate of humans (which requires going approximately 12 hours without food), catabolysis only becomes life-threatening after 1–2 months from the cessation of nutrition going into the body. After this time, the damage to muscles and organs can be permanent and can also eventually cause death, if left untreated. Catabolysis is a last resort effort of the body to keep itself—particularly the nervous system—alive. The situation can become dire when one begins to lose muscle mass; this is a sign that the fat has been expended and the body is now metabolizing the muscle tissue. This results in muscle atrophy, a loss of strength and, ultimately, a depletion of muscular tissue completely. Muscle weakness is not necessarily a symptom of catabolysis: the muscles will normally feel fatigued when they are not receiving enough energy or oxygen. The body has a natural store of fat (also called adipose) that stores reserve energy, one can still stay alive while their body breaks down the fatty tissue (hence people wasting away from starvation). The person may, during catabolysis, have large amounts of lipids, proteins and amino acids in their bloodstream, due to the muscle fibers and adipose tissue being broken down and sent to the nervous system and brain. They may also exhibit a fever, since the body is working hard to transfer the nutrients in the muscles and fat to the blood. # Treatment While catabolysis can be deadly over time, if the person is given medical treatment early enough, the effects of catabolysis can be reversed. However, the person may require intravenous nutrition, a blood transfusion, and/or oxygen replenishment. After that, it may be a few weeks to a few months before the person's muscle mass and fat deposits can build themselves up again; there is a possibility that they may never build back up, depending on the severity of the condition.	https://www.wikidoc.org/index.php/Catabolysis
d33eeafd8dc1d2a4f6ae09db305903bd27796b71	wikidoc	Cathepsin A	Cathepsin A Cathepsin A is an enzyme that is classified both as a cathepsin and a carboxypeptidase. In humans, it is encoded by the CTSA gene. # Function This gene encodes a glycoprotein that associates with lysosomal enzymes beta-galactosidase and neuraminidase to form a complex of high-molecular-weight multimers. The formation of this complex provides a protective role for stability and activity. It is protective for β-galactosidase and neuraminidase. # Clinical significance Deficiencies in this gene are linked to multiple forms of galactosialidosis. # Interactions Cathepsin A has been shown to interact with NEU1.	Cathepsin A Cathepsin A is an enzyme that is classified both as a cathepsin and a carboxypeptidase. In humans, it is encoded by the CTSA gene.[1] # Function This gene encodes a glycoprotein that associates with lysosomal enzymes beta-galactosidase and neuraminidase to form a complex of high-molecular-weight multimers. The formation of this complex provides a protective role for stability and activity. It is protective for β-galactosidase and neuraminidase.[2] # Clinical significance Deficiencies in this gene are linked to multiple forms of galactosialidosis.[1] # Interactions Cathepsin A has been shown to interact with NEU1.[3]	https://www.wikidoc.org/index.php/Cathepsin_A
bf5fb3c033b7fe3015e94c13db7951a22342d8e1	wikidoc	Cathepsin B	Cathepsin B Cathepsin B is in humans encoded by the CTSB gene. Cathepsin B belongs to a family of lysosomal cysteine proteases and plays an important role in intracellular proteolysis. Upregulation of cathepsin B is found in premalignant lesions and various pathological conditions, as well as cancers. # Structure ## Gene CTSB gene is located at chromosome 8p22, consisting of 13 exons.The promoter of CTSB gene contains a GC-rich region including many SP1 sites, which is similar to housekeeping gene. At least five transcript variants encoding the same protein have been found for this gene. ## Protein Cathepsin B is synthesized on the rough endoplasmic reticulum as a preproenzyme of 339 amino acid with a signal peptide of 17 amino acids. Procathepsin B of 43/46 kDa is then transported to the Golgi apparatus and cathepsin B is formed. Mature cathepsin B is composed of a heavy chain of 25-26 kDa and a light chain of 5kDa, which are linked by a dimer of disulfide. # Function Cathepsin B may enhance the activity of other protease, including matrix metalloproteinase, urokinase (serine protease urokinase plasminogen activator), and cathepsin D, and thus it has an essential position for in the proteolysis of extracellular matrix components, intercellular communication disruption, and reduced protease inhibitor expression. It is also involved in autophagy and catabolism, which is advantageous in tumor malignancy and is possibly involved in specific immune resistance. # Clinical significance Cathepsin B has been proposed as a potentially effective biomarker for a variety of cancers. Overexpression of cathepsin B is correlated with invasive and metastatic cancers. Cathepsin B is produced in muscle tissue during metabolism. It is capable of crossing the blood-brain barrier and is associated with neurogenesis, specifically in the mouse dentate gyrus. A wide array of diseases result in elevated levels of cathepsin B, which causes numerous pathological processes including cell death, inflammation, and production of toxic peptides. Focusing on neurological diseases, cathepsin B gene knockout studies in an epileptic rodent model have shown cathepsin B causes a significant amount of the apoptotic cell death that occurs as a result of inducing epilepsy. Cathepsin B inhibitor treatment of rats in which a seizure was induced resulted in improved neurological scores, learning ability and much reduced neuronal cell death and pro-apoptotic cell death peptides. Similarly, cathepsin B gene knockout and cathepsin B inhibitor treatment studies in traumatic brain injury mouse models have shown cathepsin B to be key to causing the resulting neuromuscular dysfunction, memory loss, neuronal cell death and increased production of pro-necrotic and pro-apoptotic cell death peptides. In ischemic non-human primate and rodent models, cathepsin B inhibitor treatment prevented a significant loss of brain neurons, especially in the hippocampus. In a streptococcus pneumoniae meningitis rodent model, cathepsin B inhibitor treatment greatly improved the clinical course of the infection and reduced brain inflammation and inflammatory Interleukin-1β (IL1-β) and tumor necrosis factor-α (TNF-α). In a transgenic Alzheimer's disease (AD) animal model expressing human amyloid precursor protein (APP) containing the wild-type beta-secretase site sequence found in most AD patients or in guinea pigs, which are a natural model of human wild-type APP processing, genetically deleting the cathepsin B gene or chemically inhibiting cathepsin B brain activity resulted in a significant improvement in the memory deficits that develop in such mice and reduces levels of neurotoxic full-length Abeta(1-40/42) and the particularly pernicious pyroglutamate Abeta(3-40/42), which are thought to cause the disease. In a non-transgenic senescence-accelerated mouse strain, which also has APP containing the wild-type beta-secretase site sequence, treatment with bilobalide, which is an extract of Ginko biloba leaves, also lowered brain Abeta by inhibiting cathepsin B. Moreover, siRNA silencing or chemically inhibiting cathepsin B in primary rodent hippocampal cells or bovine chromaffin cells, which have human wild-type beta-secretase activity, reduces secretion of Abeta by the regulated secretory pathway. Mutations in the CTSB gene have been linked to tropical pancreatitis, a form of chronic pancreatitis. # Interactions Cathepsin B has been shown to interact with: - CTSD - CSTA, - CSTB, and - S100A10. Cathepsin B is inhibited by: - Nitroxoline	Cathepsin B Cathepsin B is in humans encoded by the CTSB gene.[1][2] Cathepsin B belongs to a family of lysosomal cysteine proteases and plays an important role in intracellular proteolysis.[3] Upregulation of cathepsin B is found in premalignant lesions and various pathological conditions, as well as cancers.[4][5][6][7] # Structure ## Gene CTSB gene is located at chromosome 8p22, consisting of 13 exons.The promoter of CTSB gene contains a GC-rich region including many SP1 sites, which is similar to housekeeping gene.[8] At least five transcript variants encoding the same protein have been found for this gene.[9] ## Protein Cathepsin B is synthesized on the rough endoplasmic reticulum as a preproenzyme of 339 amino acid with a signal peptide of 17 amino acids.[10][11] Procathepsin B of 43/46 kDa is then transported to the Golgi apparatus and cathepsin B is formed. Mature cathepsin B is composed of a heavy chain of 25-26 kDa and a light chain of 5kDa, which are linked by a dimer of disulfide. # Function Cathepsin B may enhance the activity of other protease, including matrix metalloproteinase, urokinase (serine protease urokinase plasminogen activator), and cathepsin D,[12][13] and thus it has an essential position for in the proteolysis of extracellular matrix components, intercellular communication disruption, and reduced protease inhibitor expression.[7] It is also involved in autophagy and catabolism, which is advantageous in tumor malignancy and is possibly involved in specific immune resistance.[14] # Clinical significance Cathepsin B has been proposed as a potentially effective biomarker for a variety of cancers.[12][15][16][17][18][19] Overexpression of cathepsin B is correlated with invasive and metastatic cancers.[20] Cathepsin B is produced in muscle tissue during metabolism.[21] It is capable of crossing the blood-brain barrier[22] and is associated with neurogenesis, specifically in the mouse dentate gyrus. A wide array of diseases result in elevated levels of cathepsin B, which causes numerous pathological processes including cell death, inflammation, and production of toxic peptides. Focusing on neurological diseases, cathepsin B gene knockout studies in an epileptic rodent model have shown cathepsin B causes a significant amount of the apoptotic cell death that occurs as a result of inducing epilepsy.[23] Cathepsin B inhibitor treatment of rats in which a seizure was induced resulted in improved neurological scores, learning ability and much reduced neuronal cell death and pro-apoptotic cell death peptides.[24] Similarly, cathepsin B gene knockout and cathepsin B inhibitor treatment studies in traumatic brain injury mouse models have shown cathepsin B to be key to causing the resulting neuromuscular dysfunction, memory loss, neuronal cell death and increased production of pro-necrotic and pro-apoptotic cell death peptides.[25][26] In ischemic non-human primate and rodent models, cathepsin B inhibitor treatment prevented a significant loss of brain neurons, especially in the hippocampus.[27][28][29] In a streptococcus pneumoniae meningitis rodent model, cathepsin B inhibitor treatment greatly improved the clinical course of the infection and reduced brain inflammation and inflammatory Interleukin-1β (IL1-β) and tumor necrosis factor-α (TNF-α).[30] In a transgenic Alzheimer's disease (AD) animal model expressing human amyloid precursor protein (APP) containing the wild-type beta-secretase site sequence found in most AD patients or in guinea pigs, which are a natural model of human wild-type APP processing, genetically deleting the cathepsin B gene or chemically inhibiting cathepsin B brain activity resulted in a significant improvement in the memory deficits that develop in such mice and reduces levels of neurotoxic full-length Abeta(1-40/42) and the particularly pernicious pyroglutamate Abeta(3-40/42), which are thought to cause the disease.[31][32][33][34][35][36][37] In a non-transgenic senescence-accelerated mouse strain, which also has APP containing the wild-type beta-secretase site sequence, treatment with bilobalide, which is an extract of Ginko biloba leaves, also lowered brain Abeta by inhibiting cathepsin B.[38] Moreover, siRNA silencing or chemically inhibiting cathepsin B in primary rodent hippocampal cells or bovine chromaffin cells, which have human wild-type beta-secretase activity, reduces secretion of Abeta by the regulated secretory pathway.[39][40] Mutations in the CTSB gene have been linked to tropical pancreatitis, a form of chronic pancreatitis.[41] # Interactions Cathepsin B has been shown to interact with: - CTSD [42] - CSTA,[43][44] - CSTB,[43][45] and - S100A10.[46] Cathepsin B is inhibited by: - Nitroxoline[47]	https://www.wikidoc.org/index.php/Cathepsin_B
1b12acd24dcc30743a2d22acf689356631e9d750	wikidoc	Cathepsin C	Cathepsin C Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 family. In humans, it is encoded by the CTSC gene. # Function Cathepsin C appears to be a central coordinator for activation of many serine proteases in immune/inflammatory cells. Cathepsin C catalyses excision of dipeptides from the N-terminus of protein and peptide substrates, except if (i) the amino group of the N-terminus is blocked, (ii) the site of cleavage is on either side of a proline residue, (iii) the N-terminal residue is lysine or arginine, or (iv) the structure of the peptide or protein prevents further digestion from the N-terminus. # Structure The cDNAs encoding rat, human, murine, bovine, dog and two Schistosome cathepsin Cs have been cloned and sequenced and show that the enzyme is highly conserved. The human and rat cathepsin C cDNAs encode precursors (prepro-cathepsin C) comprising signal peptides of 24 residues, pro-regions of 205 (rat cathepsin C) or 206 (human cathepsin C) residues and catalytic domains of 233 residues which contain the catalytic residues and are 30-40% identical to the mature amino acid sequences of papain and a number of other cathepsins including cathepsins, B, H, K, L, and S. The translated prepro-cathepsin C is processed into the mature form by at least four cleavages of the polypeptide chain. The signal peptide is removed during translocation or secretion of the pro-enzyme (pro-cathepsin C) and a large N-terminal proregion fragment (also known as the exclusion domain), which is retained in the mature enzyme, is separated from the catalytic domain by excision of a minor C-terminal part of the pro-region, called the activation peptide. A heavy chain of about 164 residues and a light chain of about 69 residues are generated by cleavage of the catalytic domain. Unlike the other members of the papain family, mature cathepsin C consists of four subunits, each composed of the N-terminal proregion fragment, the heavy chain and the light chain. Both the pro-region fragment and the heavy chain are glycosylated. # Clinical significance Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre disease, an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis. Cathepsin C functions as a key enzyme in the activation of granule serine peptidases in inflammatory cells, such as elastase and cathepsin G in neutrophils cells and chymase and tryptase in mast cells. In many inflammatory diseases, such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, asthma, sepsis, and cystic fibrosis, a significant portion of the pathogenesis is caused by increased activity of some of these inflammatory proteases. Once activated by cathepsin C, the proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.	Cathepsin C Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 family. In humans, it is encoded by the CTSC gene.[1][2] # Function Cathepsin C appears to be a central coordinator for activation of many serine proteases in immune/inflammatory cells. Cathepsin C catalyses excision of dipeptides from the N-terminus of protein and peptide substrates, except if (i) the amino group of the N-terminus is blocked, (ii) the site of cleavage is on either side of a proline residue, (iii) the N-terminal residue is lysine or arginine, or (iv) the structure of the peptide or protein prevents further digestion from the N-terminus. # Structure The cDNAs encoding rat, human, murine, bovine, dog and two Schistosome cathepsin Cs have been cloned and sequenced and show that the enzyme is highly conserved.[3] The human and rat cathepsin C cDNAs encode precursors (prepro-cathepsin C) comprising signal peptides of 24 residues, pro-regions of 205 (rat cathepsin C) or 206 (human cathepsin C) residues and catalytic domains of 233 residues which contain the catalytic residues and are 30-40% identical to the mature amino acid sequences of papain and a number of other cathepsins including cathepsins, B, H, K, L, and S.[4] The translated prepro-cathepsin C is processed into the mature form by at least four cleavages of the polypeptide chain. The signal peptide is removed during translocation or secretion of the pro-enzyme (pro-cathepsin C) and a large N-terminal proregion fragment (also known as the exclusion domain),[5] which is retained in the mature enzyme, is separated from the catalytic domain by excision of a minor C-terminal part of the pro-region, called the activation peptide. A heavy chain of about 164 residues and a light chain of about 69 residues are generated by cleavage of the catalytic domain. Unlike the other members of the papain family, mature cathepsin C consists of four subunits, each composed of the N-terminal proregion fragment, the heavy chain and the light chain. Both the pro-region fragment and the heavy chain are glycosylated. # Clinical significance Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre disease,[6][7] an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis. Cathepsin C functions as a key enzyme in the activation of granule serine peptidases in inflammatory cells, such as elastase and cathepsin G in neutrophils cells and chymase and tryptase in mast cells. In many inflammatory diseases, such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, asthma, sepsis, and cystic fibrosis, a significant portion of the pathogenesis is caused by increased activity of some of these inflammatory proteases. Once activated by cathepsin C, the proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.	https://www.wikidoc.org/index.php/Cathepsin_C
1b55cc54813ba953264faa45b73b0dd0f8a20b3b	wikidoc	Cathepsin D	Cathepsin D Cathepsin D is a protein that in humans is encoded by the CTSD gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathepsin D is an aspartic endo-protease that is ubiquitously distributed in lysosomes. The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments. This proteinase, which is a member of the peptidase A1 family, has a specificity similar to but narrower than that of pepsin A. Transcription of the CTSD gene is initiated from several sites, including one that is a start site for an estrogen-regulated transcript. Mutations in this gene are involved in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer disease. Homozygous deletion of the CTSD gene leads to early lethality in the post-natal phase. Deficiency of CTSD gene has been reported an underlying cause of neuronal ceroid lipofuscinosis (NCL). # Structure ## Gene The CTSD gene is located at chromosome 4q32.1, consisting of 8 exons. ## Protein The catalytic sites of cathepsin D include two critical aspartic residues (amino acid 33 and 231) located on the 14 kDa and 34kDa chains. The ultimate form of mature cathepsin D is composed of 337 amino acid residues, 196 amino acid residues in the heavy chain and 141 in the light chain. These two chains are linked by the hydrophobic effect. # Function The optimum pH for cathepsin D in vitro is 4.5-5.0. Cathepsin-D is an aspartic protease that depends critically on protonation of its active site Asp residue. Along with Asp-protonation, lower pH also leads to conformational switch in cathepsin-D : the N-terminal segment of the protease moves out of the active site as pH drops. Similar to other aspartic protainases, cathepsin D accommodates up to 8 amino acid residues in the binding cleft of the active site. The main physiological functions of cathepsin D consist of metabolic degradation of intracellular proteins, activation and degradation of polypeptide hormones and growth factors, activation of enzymatic precursors, processing of enzyme activators and inhibitors, brain antigen processing and regulation of programmed cell death. # Clinical significance The NCLs present with progressive loss of visual function and neurodevelopmental decline, seizure, myoclonic jerks and premature death. The CTSD gene is one of the identified eight genes the deficiency of which is responsible for NCLs. It has been reported that a homozygous single nucleotide duplication in exon 6 could alter the reading frame and causes a premature stop codon at position 255. Over-expression of cathepsin D stimulates tumorigenicity and metastasis as well as initiation of tumor apoptosis. This protease has been regarded an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis. Knock-out of CTSD gene would cause intestinal necrosis and hemorrhage and increase apoptosis in thymus, indicating that cathepsin D is required in certain epithelial cells for tissue remodeling and renewal. It is also reported that there might be a strong effect for CTSD genotype on Alzheimer disease risk in male. Cathepsin D enzymatic activity induces hydrolytic modification of apolipoprotein B-100-containing lipoproteins, including LDL, which means it may be involved in atherosclerosis as well. # Interaction - Pepstatin - Transglutaminase 2 - HEBP1 - A2M - Ceramide	Cathepsin D Cathepsin D is a protein that in humans is encoded by the CTSD gene.[1][2] This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathepsin D is an aspartic endo-protease that is ubiquitously distributed in lysosomes.[3] The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments.[4] This proteinase, which is a member of the peptidase A1 family, has a specificity similar to but narrower than that of pepsin A. Transcription of the CTSD gene is initiated from several sites, including one that is a start site for an estrogen-regulated transcript. Mutations in this gene are involved in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer disease.[2] Homozygous deletion of the CTSD gene leads to early lethality in the post-natal phase.[5] Deficiency of CTSD gene has been reported an underlying cause of neuronal ceroid lipofuscinosis (NCL).[6] # Structure ## Gene The CTSD gene is located at chromosome 4q32.1, consisting of 8 exons. ## Protein The catalytic sites of cathepsin D include two critical aspartic residues (amino acid 33 and 231) located on the 14 kDa and 34kDa chains.[7] The ultimate form of mature cathepsin D is composed of 337 amino acid residues, 196 amino acid residues in the heavy chain and 141 in the light chain. These two chains are linked by the hydrophobic effect.[8] # Function The optimum pH for cathepsin D in vitro is 4.5-5.0.[9] Cathepsin-D is an aspartic protease that depends critically on protonation of its active site Asp residue. Along with Asp-protonation, lower pH also leads to conformational switch in cathepsin-D : the N-terminal segment of the protease moves out of the active site as pH drops.[10][11][12] Similar to other aspartic protainases, cathepsin D accommodates up to 8 amino acid residues in the binding cleft of the active site. The main physiological functions of cathepsin D consist of metabolic degradation of intracellular proteins, activation and degradation of polypeptide hormones and growth factors, activation of enzymatic precursors, processing of enzyme activators and inhibitors, brain antigen processing and regulation of programmed cell death.[13][14][15][16] # Clinical significance The NCLs present with progressive loss of visual function and neurodevelopmental decline, seizure, myoclonic jerks and premature death. The CTSD gene is one of the identified eight genes the deficiency of which is responsible for NCLs.[6] It has been reported that a homozygous single nucleotide duplication in exon 6 could alter the reading frame and causes a premature stop codon at position 255. Over-expression of cathepsin D stimulates tumorigenicity and metastasis as well as initiation of tumor apoptosis. This protease has been regarded an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis.[17][18] Knock-out of CTSD gene would cause intestinal necrosis and hemorrhage and increase apoptosis in thymus, indicating that cathepsin D is required in certain epithelial cells for tissue remodeling and renewal.[5] It is also reported that there might be a strong effect for CTSD genotype on Alzheimer disease risk in male.[19] Cathepsin D enzymatic activity induces hydrolytic modification of apolipoprotein B-100-containing lipoproteins, including LDL, which means it may be involved in atherosclerosis as well.[14][20] # Interaction - Pepstatin[21] - Transglutaminase 2[22] - HEBP1[23] - A2M[24] - Ceramide[25]	https://www.wikidoc.org/index.php/Cathepsin_D
22b221bf7d5141c486bc7f239fba9e42a2da8afc	wikidoc	Cathepsin E	Cathepsin E Cathepsin E is an enzyme (EC 3.4.23.34) that in humans is encoded by the CTSE gene. The enzyme is also known as slow-moving proteinase, erythrocyte membrane aspartic proteinase, SMP, EMAP, non-pepsin proteinase, cathepsin D-like acid proteinase, cathepsin E-like acid proteinase, cathepsin D-type proteinase) is an enzyme. Cathepsin E is a protease found in animals, as well as various other organisms, that belongs to the aspartic protease group. In humans it is encoded by the CTSE gene located at 1q32 on chromosome 1. It is an intracellular non-lysosomal glycoprotein that is mainly found in the skin and in immune cells. The protein is an aspartyl protease that functions as a disulfide-linked homodimer, and has an oligosaccharide chain of the high-mannose type. It is a member of the peptidase A1 family, and therefore observes specificity similar to that of Pepsin A and Cathepsin D. Cathepsin E is an intracellular enzyme and does not appear to be involved in dietary protein digestion. It is found at highest abundance on the stomach’s epithelial mucus producing cell surfaces. It is the first aspartic protease present in the fetal stomach and is found in more than half of gastric cancers, leading to it appearing to be an oncofetal antigen. Transcript variants utilizing alternative polyadenylation signals and two transcript variants encoding different isoforms exist for this gene. A deficiency in the levels of Cathepsin E in the body may play a part in inflammatory skin diseases such as atopic dermatitis, for which treatment would rely on fixing functionality and levels of the protein in the body. Along with renin and Cathepsin D, Cathepsin E is one of the only few aspartic proteases known to be made in human tissues other than those of gastrointestinal and reproductive tracts. # Structure The structure of Cathepsin E is very similar to those of Cathepsin D and BACE1, and all 3 have almost identical active site regions. The differences between them lie in the microenvironments that surround their active sites. Residues DTG 96-98 and DTG 281-283 contribute to the formation of the enzyme’s active site. There are also two pairs of disulfide bonds at residues Cys 272-276 and Cys 314-351. Two other Cys residues at positions 109 and 114 on the amino acid chain reside close to teach other in three dimensional space, however the distance between their sulfur atoms is 3.53 Å which is too large for the formation of a proper disulfide bond. The structure also has four hydrogen bonds between the Asp residues of the active site and the surrounding residues. A distinguishing factor of Cathepsin E in comparison with the structure of Cathepsin D and BACE1 can be seen at the formation of an extra hydrogen bond between the Asp 96 and Ser 99 residues, and absence of a hydrogen bond with Leu/Met at Asp 281. # Location The enzyme is distributed in cells of the gastrointestinal tracts, lymphoid tissues, blood cells, urinary organs and microglia. Its intracellular localization in different mammalian cells is different to that of its analog Cathepsin D. Cathepsin E associates with the membrane tissue in the intracellular canaliculi of gastric parietal cells, bile canaliculi of hepatic cells, cells of the rinal proximal tubule in the kidney, epithelial cells in the intestine, trachea and bronchi, osteoclasts and even in erythrocytes. Its localization in the endosome structures can be seen in many different cell types such as antigen-presenting B cell lymphoblasts, gastric cells and microglia. Its presence is also detected in the cisternae of the cell’s endoplasmic reticulum. # Function Cathepsin E plays a vital role in protein degradation, antigen processing via the MHC class II pathway and bioactive protein generation. The enzyme is also thought to be involved in age induced neuronal death pathway execution as well as the excessive stimulation of glutamate receptors with excitotoxins and transient forebrain ischemia. In an experiment carried out on rats, Cathepsin E was barely detected in the brain tissues of young rats, however in older rats its level was greatly increased in the neostriatum and cerebral cortex. The enzyme was also expressed at high levels in the activated microglia of the hippocampal CA1 region and in degenerating neurons for a week after transient forebrain ischemia. Cathepsin E has a possible role in the development of well differentiated adenocarcinoma from intestinal metaplasia. The enzyme also plays a part in association with dendritic cells where it generates the CD4 repertoire in response to self and foreign proteins. # Post-translational modification The enzyme is glycosylated. Different cell types contribute to the differences in the nature of the carbohydrate chain. A high mannose-type oligosaccharide is observed in the proenzyme in fibroblasts, however the mature enzyme can be seen with a complex-type oligosaccharide. In the membranes of erythrocytes, the mature enzyme and the pro-enzyme both have a complex-type oligosaccharide. Auto catalytic cleavage produces two forms of the enzyme, with Form 1 beginning at residue Ile 54 and Form 2 at Thr 57.	Cathepsin E Cathepsin E is an enzyme (EC 3.4.23.34) that in humans is encoded by the CTSE gene.[1][2][3] The enzyme is also known as slow-moving proteinase, erythrocyte membrane aspartic proteinase, SMP, EMAP, non-pepsin proteinase, cathepsin D-like acid proteinase, cathepsin E-like acid proteinase, cathepsin D-type proteinase) is an enzyme.[4][5][6][7] Cathepsin E is a protease found in animals, as well as various other organisms, that belongs to the aspartic protease group. In humans it is encoded by the CTSE gene located at 1q32 on chromosome 1.[8][9][10][11] It is an intracellular non-lysosomal glycoprotein that is mainly found in the skin and in immune cells.[12] The protein is an aspartyl protease that functions as a disulfide-linked homodimer, and has an oligosaccharide chain of the high-mannose type.[13] It is a member of the peptidase A1 family, and therefore observes specificity similar to that of Pepsin A and Cathepsin D. Cathepsin E is an intracellular enzyme and does not appear to be involved in dietary protein digestion. It is found at highest abundance on the stomach’s epithelial mucus producing cell surfaces. It is the first aspartic protease present in the fetal stomach and is found in more than half of gastric cancers, leading to it appearing to be an oncofetal antigen. Transcript variants utilizing alternative polyadenylation signals and two transcript variants encoding different isoforms exist for this gene.[11][12] A deficiency in the levels of Cathepsin E in the body may play a part in inflammatory skin diseases such as atopic dermatitis, for which treatment would rely on fixing functionality and levels of the protein in the body.[14] Along with renin and Cathepsin D, Cathepsin E is one of the only few aspartic proteases known to be made in human tissues other than those of gastrointestinal and reproductive tracts.[15] # Structure The structure of Cathepsin E is very similar to those of Cathepsin D and BACE1, and all 3 have almost identical active site regions. The differences between them lie in the microenvironments that surround their active sites. Residues DTG 96-98 and DTG 281-283 contribute to the formation of the enzyme’s active site. There are also two pairs of disulfide bonds at residues Cys 272-276 and Cys 314-351. Two other Cys residues at positions 109 and 114 on the amino acid chain reside close to teach other in three dimensional space, however the distance between their sulfur atoms is 3.53 Å which is too large for the formation of a proper disulfide bond. The structure also has four hydrogen bonds between the Asp residues of the active site and the surrounding residues. A distinguishing factor of Cathepsin E in comparison with the structure of Cathepsin D and BACE1 can be seen at the formation of an extra hydrogen bond between the Asp 96 and Ser 99 residues, and absence of a hydrogen bond with Leu/Met at Asp 281.[14] # Location The enzyme is distributed in cells of the gastrointestinal tracts, lymphoid tissues, blood cells, urinary organs and microglia. Its intracellular localization in different mammalian cells is different to that of its analog Cathepsin D. Cathepsin E associates with the membrane tissue in the intracellular canaliculi of gastric parietal cells, bile canaliculi of hepatic cells, cells of the rinal proximal tubule in the kidney, epithelial cells in the intestine, trachea and bronchi, osteoclasts and even in erythrocytes. Its localization in the endosome structures can be seen in many different cell types such as antigen-presenting B cell lymphoblasts, gastric cells and microglia. Its presence is also detected in the cisternae of the cell’s endoplasmic reticulum.[13][16] # Function Cathepsin E plays a vital role in protein degradation, antigen processing via the MHC class II pathway[11] and bioactive protein generation. The enzyme is also thought to be involved in age induced neuronal death pathway execution as well as the excessive stimulation of glutamate receptors with excitotoxins and transient forebrain ischemia. In an experiment carried out on rats, Cathepsin E was barely detected in the brain tissues of young rats, however in older rats its level was greatly increased in the neostriatum and cerebral cortex. The enzyme was also expressed at high levels in the activated microglia of the hippocampal CA1 region and in degenerating neurons for a week after transient forebrain ischemia.[16] Cathepsin E has a possible role in the development of well differentiated adenocarcinoma from intestinal metaplasia.[13] The enzyme also plays a part in association with dendritic cells where it generates the CD4 repertoire in response to self and foreign proteins.[17] # Post-translational modification The enzyme is glycosylated. Different cell types contribute to the differences in the nature of the carbohydrate chain. A high mannose-type oligosaccharide is observed in the proenzyme in fibroblasts, however the mature enzyme can be seen with a complex-type oligosaccharide. In the membranes of erythrocytes, the mature enzyme and the pro-enzyme both have a complex-type oligosaccharide. Auto catalytic cleavage produces two forms of the enzyme, with Form 1 beginning at residue Ile 54 and Form 2 at Thr 57.[18]	https://www.wikidoc.org/index.php/Cathepsin_E
19261009ef3a2fea0985db4e6479ba6a995e287f	wikidoc	Cathepsin G	Cathepsin G Cathepsin G is a protein that in humans is encoded by the CTSG gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response. # Structure ## Gene The CTSG gene is located at chromosome 14q11.2, consisting of 5 exons. Each residue of the catalytic triad is located on a separate exon. Five polymorphisms have been identified by scanning the entire coding region. Cathepsin G is one of those homologous protease that evolved from a common ancestor by gene duplication. ## Protein Cathepsin G is a 255-amino-acid-residue protein including an 18-residue signal peptide, a two-residue activation peptide at the N-terminus and a carboxy terminal extension. The activity of cathepsin G depends on a catalytic triad composed of aspartate, histidine and serine residues which are widely separated in the primary sequence but close to each other at the active site of the enzyme in the tertiary structure. # Function Cathepsin G has a specificity similar to that of chymotrypsin C, but it is most closely related to other immune serine proteases, such as neutrophil elastase and the granzymes. As a neutrophil serine protease, was first identified as degradative enzyme that acts intracellularly to degrade ingested host pathogens and extracellularly in the breakdown of ECM components at inflammatory sites. It localizes to Neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases. Transcript variants utilizing alternative polyadenylation signals exist for this gene. Cathepsin G was also found to exert broad-spectrum antibacterial action against Gram-negative and –positive bacteria independent of the function mentioned above. Other functions of cathepsin G have been reported, including cleavage of receptors, conversion of angiotensin Ⅰ to angiotensin Ⅱ, platelet activation, and induction of airway submucosal gland secretion. Potential implications of the enzyme in blood-brain barrier breakdown was also found. # Clinical significance Cathepsin G has been reported to play an important role in a variety of diseases, including rheumatoid arthritis, coronary artery disease, periodontitis, ischemic reperfusion injury, and bone metastasis. It is also implicated in a variety of infectious inflammatory diseases, including chronic obstructive pulmonary disease, acute respiratory distress syndrome, and cystic fibrosis. A recent study shows that patients with CTSG gene polymorphisms have higher risk of chronic postsurgical pain, suggesting cathepsin G may serve as a novel target for pain control and a potential marker to predict chronic postsurgical pain. An upregulation of cathepsin G was reported in studies of keratoconus. # Interactions Cathepsin G has been found to interact with: - SERPINB1 Cathepsin G is inhibited by: - carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (KPA) - Caesalpinia echinata elastase inhibitor - N-Arylacyl O-sulfonated aminoglycosides Cathepsin G lowers levels of: - Low-density lipoprotein	Cathepsin G Cathepsin G is a protein that in humans is encoded by the CTSG gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response.[1][2][3][4] # Structure ## Gene The CTSG gene is located at chromosome 14q11.2, consisting of 5 exons. Each residue of the catalytic triad is located on a separate exon. Five polymorphisms have been identified by scanning the entire coding region.[5] Cathepsin G is one of those homologous protease that evolved from a common ancestor by gene duplication.[6] ## Protein Cathepsin G is a 255-amino-acid-residue protein including an 18-residue signal peptide, a two-residue activation peptide at the N-terminus and a carboxy terminal extension.[7] The activity of cathepsin G depends on a catalytic triad composed of aspartate, histidine and serine residues which are widely separated in the primary sequence but close to each other at the active site of the enzyme in the tertiary structure.[8] # Function Cathepsin G has a specificity similar to that of chymotrypsin C, but it is most closely related to other immune serine proteases, such as neutrophil elastase and the granzymes.[9] As a neutrophil serine protease, was first identified as degradative enzyme that acts intracellularly to degrade ingested host pathogens and extracellularly in the breakdown of ECM components at inflammatory sites.[10] It localizes to Neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases.[9] Transcript variants utilizing alternative polyadenylation signals exist for this gene.[11] Cathepsin G was also found to exert broad-spectrum antibacterial action against Gram-negative and –positive bacteria independent of the function mentioned above.[12] Other functions of cathepsin G have been reported, including cleavage of receptors, conversion of angiotensin Ⅰ to angiotensin Ⅱ, platelet activation, and induction of airway submucosal gland secretion.[13][14][15][16][17] Potential implications of the enzyme in blood-brain barrier breakdown was also found.[18] # Clinical significance Cathepsin G has been reported to play an important role in a variety of diseases, including rheumatoid arthritis, coronary artery disease, periodontitis, ischemic reperfusion injury, and bone metastasis.[19][20][21][22][23] It is also implicated in a variety of infectious inflammatory diseases, including chronic obstructive pulmonary disease, acute respiratory distress syndrome, and cystic fibrosis.[24][25][26] A recent study shows that patients with CTSG gene polymorphisms have higher risk of chronic postsurgical pain, suggesting cathepsin G may serve as a novel target for pain control and a potential marker to predict chronic postsurgical pain.[27] An upregulation of cathepsin G was reported in studies of keratoconus.[28] # Interactions Cathepsin G has been found to interact with: - SERPINB1[29] Cathepsin G is inhibited by: - [2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (KPA) [30] - Caesalpinia echinata elastase inhibitor[31] - N-Arylacyl O-sulfonated aminoglycosides[32] Cathepsin G lowers levels of: - Low-density lipoprotein[33]	https://www.wikidoc.org/index.php/Cathepsin_G
2a8853a35ec88ff06e1a8f37f2ac6f67b9dd4899	wikidoc	Cathepsin K	Cathepsin K Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene. # Function The protein encoded by this gene is a lysosomal cysteine protease involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is expressed predominantly in osteoclasts. Cathepsin K is a protease, which is defined by its high specificity for kinins, that is involved in bone resorption. The enzyme's ability to catabolize elastin, collagen, and gelatin allows it to break down bone and cartilage. This catabolic activity is also partially responsible for the loss of lung elasticity and recoil in emphysema. Cathepsin K inhibitors show great potential in the treatment of osteoporosis. Cathepsin K is degraded by Cathepsin S, called Controlled Cathepsin Cannibalism. Cathepsin K expression is stimulated by inflammatory cytokines that are released after tissue injury. # Clinical significance Cathepsin K is expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness. Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature. Cathepsin K has also been found to be over-expressed in glioblastoma. That the expression of cathepsin K is characteristic for some cancers and not others has been documented. Cathepsin K antibodies are marketed for research into expression of this enyzme by various cells. Merck had a cathepsin K inhibitor, odanacatib, in Phase III clinical trials for osteoporosis. In September, 2016, Merck announced they were discontinuing development of odanacatib after their own assessment of adverse events and an independent assessment showed increased risk of stroke. Other cathepsin K inhibitors are in various stages of development. Medivir has a cathepsin K inhibitor, MIV-711 (L-006235), in Phase IIa clinical trial, as a disease modifying osteoarthritis drug, as of October 2017.	Cathepsin K Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene.[1][2] # Function The protein encoded by this gene is a lysosomal cysteine protease involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is expressed predominantly in osteoclasts. Cathepsin K is a protease, which is defined by its high specificity for kinins, that is involved in bone resorption. The enzyme's ability to catabolize elastin, collagen, and gelatin allows it to break down bone and cartilage. This catabolic activity is also partially responsible for the loss of lung elasticity and recoil in emphysema. Cathepsin K inhibitors show great potential in the treatment of osteoporosis. Cathepsin K is degraded by Cathepsin S, called Controlled Cathepsin Cannibalism. Cathepsin K expression is stimulated by inflammatory cytokines that are released after tissue injury. # Clinical significance Cathepsin K is expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness.[3] Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature.[4] Cathepsin K has also been found to be over-expressed in glioblastoma.[5] That the expression of cathepsin K is characteristic for some cancers and not others has been documented.[6] Cathepsin K antibodies are marketed for research into expression of this enyzme by various cells.[7][8][9] Merck had a cathepsin K inhibitor, odanacatib, in Phase III clinical trials for osteoporosis. In September, 2016, Merck announced they were discontinuing development of odanacatib after their own assessment of adverse events and an independent assessment showed increased risk of stroke.[10][11] Other cathepsin K inhibitors are in various stages of development.[12][13][14] Medivir has a cathepsin K inhibitor, MIV-711 (L-006235[15][16][17]), in Phase IIa clinical trial, as a disease modifying osteoarthritis drug, as of October 2017.	https://www.wikidoc.org/index.php/Cathepsin_K
17b42a4d530546ee98e7679429081eb2e2e0c216	wikidoc	Cathepsin S	Cathepsin S Cathepsin S is a protein that in humans is encoded by the CTSS gene. Transcript variants utilizing alternative polyadenylation signals exist for this gene. Cathepsin S is a member of the peptidase C1 family and is a lysosomal cysteine protease that may participate in the degradation of antigenic proteins to peptides for presentation to the MHC class II. Cathepsin S can function as an elastase over a broad pH range in alveolar macrophages. # Function Cathepsin S is a lysosomal enzyme that belongs to the papain family of cysteine proteases. While a role in antigen presentation has long been recognized, it is now understood that cathepsin S has a role in itch and pain, or nociception . The nociceptive activity results from cathepsin S functioning as a signaling molecule via activation of protease-activated receptors 2 and 4 members of the G-protein coupled receptor family. Cathepsin S is expressed by antigen presenting cells including macrophages, B-lymphocytes, dendritic cells and microglia. Cathepsin S is expressed by some epithelial cells. Its expression is markedly increased in human keratinocytes following stimulation with interferon-gamma and its expression is elevated in psoriatic keratinocytes due to stimulation by proinflammatory factors. In contrast, cortical thymic epithelial cells do not express cathepsin S. While pH optima of many lysosomal proteases are acidic, cathepsin S is an exception. This enzyme remains catalytically active under the neutral pH and has pH optimum between the pH values 6.0 and 7.5. Many lysosomal proteases are trapped inside the lysosome due to a problem with their stability. In contrast, cathepsin S remains stable and has a physiological role outside the lysosome. Immune cells, including macrophages and microglia, secrete cathepsin S in response to inflammatory mediators including lipopolysaccharides, proinflammatory cytokines and neutrophils. In vitro, cathepsin S retains some enzyme activity in the presence of 3M urea. Cathepsin S is produced as a zymogen and is activated by processing. The activity of cathepsin S is tightly regulated by its endogenous inhibitor, cystatin C, which also has a role in antigen presentation. Cystatin A and B have a lower activity compared to cystatin C. The active cleavage sites -(-Val-Val-Arg-)- of cathepsin S are supposed to have at least two amino acids surrounding it from each side. While lysosomal proteases terminally degrade proteins in lysosomes, cathepsin S has own distinctive physiological role. # Role in antigen presentation This enzyme has a critical role in antigen presentation. Major histocompatibility complex class II molecules interact with small peptide fragments for presentation on the surface of antigen-presenting immune cells. Cathepsin S participates in the degradation of the invariant or Ii chain that prevents loading the antigen into the complex. This degradation occurs in the lysosome. Chronologically, action of cathepsin S follows two cleavages performed by aspartyl proteases. Cathepsin S cleaves the remaining fragment of Ii (IiP1) and leaves a small part of Ii known as CLIP which stays directly associated with the complex. Proteolytic degradation of Ii is important since it facilitates dissociation of CLIP from MHC II and then, complex can load the selected antigen. After loading the antigen, MHC II molecule moves to the cell surface. Thus, we can speculate that overexpression of cathepsin S may lead to premature degradation of Ii, occasional loading of MHC II and an autoimmune attack. Contrary, inhibition of cathepsin S will lead to a delay in degradation of Ii and loading the antigen into MHC II as well as inappropriate presence of uncleaved Li-fragments in MHC II on the cell surface. It will impair and weaken the immune response. For instance, this kind of MHC II will not be very efficient to induce proliferation of T-cells. In macrophages, cathepsin S can be replaced by cathepsin F. # Role in degradation of ECM Secreted cathepsin S cleaves some extracellular matrix (ECM) proteins. Cathepsin S may be considered the most potent elastase known. The list of proposed cathepsin S substrates includes laminin, fibronectin elastin, osteocalcin and some collagens. It also cleaves chondroitin sulfate, heparan sulfate and proteoglycans of the basal membrane. Cathepsin S plays an active role in blood vessels permeability and angiogenesis due to its elastolytic and collagenolytic activities. For instance, cleavage of laminin-5 by cathepsin S leads to generation of proangiogenic peptides. The expression of cathepsin S can be triggered by proinflammatory factors secreted by tumor cells. In tumorogenesis, cathepsin S promotes a tumor growth. # Role in cytokine regulation Cathepsin S expression and activity has also been shown to be upregulated in the skin of psoriasis patients. Whether it has a definitive role in causing the pathology of psoriasis is as yet unknown, however in the same study it was shown to specially cleave and activate the psoriasis-associated proinflammatory cytokine IL-36γ # Nociception Cathepsin S has a role in nociception, including itch and gastrointestinal pain. The mechanism by which cathepsin S leads to itch and pain is consistent with the capacity of this cysteine protease to activate protease-activated receptors 2 and 4. # Cathepsin S inhibitors Synthetic inhibitors of cathepsin S participated in numerous preclinical studies for the immune disorders including rheumatoid arthritis. Currently, at least one of them participates in a clinical trial for psoriasis. LHVS (morpholinurea-leucine-homophenylalanine-vinylsulfone-phenyl) is the most extensively studied synthetic inhibitor of cathepsin S. IC50 of LHVS is about 5 nM. Inhibition of cathepsin S by LHVS has shown to be neuroprotective after traumatic brain injury. The list of commercial inhibitors also includes paecilopeptin (acetyl-Leu-Val-CHO) and some others. # Clinical significance Cathepsin S has been shown to be a significant prognostic factor for patients with type IV astrocytomas (glioblastoma multiforme), and its inhibition has shown improvement in survival time by mean average 5 months. This is because the cysteine enzyme can no longer act together with other proteases to break up the brain extracellular matrix. So the spread of the tumor is halted. Scientists have just announced that this enzyme predicts death, as it has been shown to be associated with both heart disease and cancer.	Cathepsin S Cathepsin S is a protein that in humans is encoded by the CTSS gene.[1] Transcript variants utilizing alternative polyadenylation signals exist for this gene.[1] Cathepsin S is a member of the peptidase C1 family and is a lysosomal cysteine protease that may participate in the degradation of antigenic proteins to peptides for presentation to the MHC class II. Cathepsin S can function as an elastase over a broad pH range in alveolar macrophages. # Function Cathepsin S is a lysosomal enzyme that belongs to the papain family of cysteine proteases. While a role in antigen presentation has long been recognized, it is now understood that cathepsin S has a role in itch and pain, or nociception . The nociceptive activity results from cathepsin S functioning as a signaling molecule via activation of protease-activated receptors 2 and 4 members of the G-protein coupled receptor family.[2] Cathepsin S is expressed by antigen presenting cells including macrophages, B-lymphocytes, dendritic cells and microglia. Cathepsin S is expressed by some epithelial cells. Its expression is markedly increased in human keratinocytes following stimulation with interferon-gamma and its expression is elevated in psoriatic keratinocytes due to stimulation by proinflammatory factors. In contrast, cortical thymic epithelial cells do not express cathepsin S. While pH optima of many lysosomal proteases are acidic, cathepsin S is an exception. This enzyme remains catalytically active under the neutral pH and has pH optimum between the pH values 6.0 and 7.5. Many lysosomal proteases are trapped inside the lysosome due to a problem with their stability. In contrast, cathepsin S remains stable and has a physiological role outside the lysosome. Immune cells, including macrophages and microglia, secrete cathepsin S in response to inflammatory mediators including lipopolysaccharides, proinflammatory cytokines and neutrophils. In vitro, cathepsin S retains some enzyme activity in the presence of 3M urea. Cathepsin S is produced as a zymogen and is activated by processing. The activity of cathepsin S is tightly regulated by its endogenous inhibitor, cystatin C, which also has a role in antigen presentation. Cystatin A and B have a lower activity compared to cystatin C. The active cleavage sites -(-Val-Val-Arg-)- of cathepsin S are supposed to have at least two amino acids surrounding it from each side. While lysosomal proteases terminally degrade proteins in lysosomes, cathepsin S has own distinctive physiological role. # Role in antigen presentation This enzyme has a critical role in antigen presentation. Major histocompatibility complex class II molecules interact with small peptide fragments for presentation on the surface of antigen-presenting immune cells. Cathepsin S participates in the degradation of the invariant or Ii chain that prevents loading the antigen into the complex. This degradation occurs in the lysosome. Chronologically, action of cathepsin S follows two cleavages performed by aspartyl proteases. Cathepsin S cleaves the remaining fragment of Ii (IiP1) and leaves a small part of Ii known as CLIP which stays directly associated with the complex. Proteolytic degradation of Ii is important since it facilitates dissociation of CLIP from MHC II and then, complex can load the selected antigen. After loading the antigen, MHC II molecule moves to the cell surface. Thus, we can speculate that overexpression of cathepsin S may lead to premature degradation of Ii, occasional loading of MHC II and an autoimmune attack. Contrary, inhibition of cathepsin S will lead to a delay in degradation of Ii and loading the antigen into MHC II as well as inappropriate presence of uncleaved Li-fragments in MHC II on the cell surface. It will impair and weaken the immune response. For instance, this kind of MHC II will not be very efficient to induce proliferation of T-cells. In macrophages, cathepsin S can be replaced by cathepsin F. # Role in degradation of ECM Secreted cathepsin S cleaves some extracellular matrix (ECM) proteins. Cathepsin S may be considered the most potent elastase known. The list of proposed cathepsin S substrates includes laminin, fibronectin elastin, osteocalcin and some collagens. It also cleaves chondroitin sulfate, heparan sulfate and proteoglycans of the basal membrane. Cathepsin S plays an active role in blood vessels permeability and angiogenesis due to its elastolytic and collagenolytic activities. For instance, cleavage of laminin-5 by cathepsin S leads to generation of proangiogenic peptides. The expression of cathepsin S can be triggered by proinflammatory factors secreted by tumor cells. In tumorogenesis, cathepsin S promotes a tumor growth. # Role in cytokine regulation Cathepsin S expression and activity has also been shown to be upregulated in the skin of psoriasis patients. Whether it has a definitive role in causing the pathology of psoriasis is as yet unknown, however in the same study it was shown to specially cleave and activate the psoriasis-associated proinflammatory cytokine IL-36γ[3] # Nociception Cathepsin S has a role in nociception, including itch and gastrointestinal pain. The mechanism by which cathepsin S leads to itch and pain is consistent with the capacity of this cysteine protease to activate protease-activated receptors 2 and 4.[4][2] # Cathepsin S inhibitors Synthetic inhibitors of cathepsin S participated in numerous preclinical studies for the immune disorders including rheumatoid arthritis. Currently, at least one of them participates in a clinical trial for psoriasis. LHVS (morpholinurea-leucine-homophenylalanine-vinylsulfone-phenyl) is the most extensively studied synthetic inhibitor of cathepsin S. IC50 of LHVS is about 5 nM. Inhibition of cathepsin S by LHVS has shown to be neuroprotective after traumatic brain injury.[5] The list of commercial inhibitors also includes paecilopeptin (acetyl-Leu-Val-CHO) and some others. # Clinical significance Cathepsin S has been shown to be a significant prognostic factor for patients with type IV astrocytomas (glioblastoma multiforme), and its inhibition has shown improvement in survival time by mean average 5 months. This is because the cysteine enzyme can no longer act together with other proteases to break up the brain extracellular matrix. So the spread of the tumor is halted. Scientists have just announced that this enzyme predicts death, as it has been shown to be associated with both heart disease and cancer.	https://www.wikidoc.org/index.php/Cathepsin_S
6ac1950f05d7c2b74acd017f88162fe297a40263	wikidoc	Cathepsin Z	Cathepsin Z Cathepsin Z, also called cathepsin X or cathepsin P, is a protein that in humans is encoded by the CTSZ gene. It is a member of the cysteine cathepsin protease family, which has 11 members. As one of the 11 cathepsins, cathepsin Z contains distinctive features from others. Cathepsin Z has been reported involved in cancer malignancy and inflammation. # Structure ## Gene The CTSZ gene is located at 20q13.32 on chromosome 20, consisting of 6 exons. At least two transcript variants of this gene have been found, but the full-length nature of only one of them has been determined. ## Protein Cathepsin Z is characterized by an unusual and unique 3-amino acid insertion in the highly conserved region between the glutamine of the putative oxynion hole and the active site cysteine. The pro-region of cathepsin Z shares no significant similarity with other cathepsin family sequences. It contains only 41 amino acid residues without the conserved motif of ERFNIN or GNFD found in other cysteine proteinases. Besides, the proregion sequence contains no lysine residue. # Function The protein encoded by this gene is a lysosomal cysteine proteinase and member of the peptidase C1 family. It exhibits both carboxy-monopeptidase and carboxy-dipeptidase activities. Up to date, eleven human cysteine proteinases have been identified, including cathepsin B, cathepsin C, cathepsin G, cathepsin H, cathepsin K, cathepsin L, cathepsin L2, cathepsin O, cathepsin S, cathepsin Z, and cathepsin W. These cysteine proteinases belong to the papain family and represent a major component of the lysosomal proteolytic system.In addition to playing a critical role in protein degradation and turnover, these proteinases appear to play an extracellular role in a number of normal and pathological conditions. The human cathepsin Z contains distinctive features from other human cysteine proteases. It is an exopeptidase with strict carboxypeptidase activity, while most other cathepsins are endopeptidases. Cathepsin Z has an exposed integrin-bindign Arg-Gly-Asp motif within the propeptide of the enzyme, through which cathepsin Z has been shown to interact with several integrins during normal homeostasis, immune processes and cancer. It is also shown to bind cell surface heparin sulphate proteoglycans, indicating possible functions in cellular adhesion and phagocytosis. # Clinical significance This gene is expressed ubiquitously in cancer cell lines and primary tumors and, like other members of this family, may be involved in tumorigenesis.For instance, cathepsin Z promotes invasion and migration via a noncatalytic mechanism, suggesting multiple modes of cell invasion may be involved in cancer malignancy. Cathepsin Z is also reported to have a protective, but not proteolytic, function in inflammatory gastric disease. It is reported in another study that cathepsin Z may be responsible for dopamine neuron death and thus involved in the pathogenic cascade event. Single-nucleotide polymorphism in CTSZ is found associated with tuberculosis susceptibility, indicating that the pathways involving this protein could yield novel therapies for tuberculosis. # Interactions Cathepsin Z has been shown to interact with the following proteins: CEP55, FBXO6, KIFC1, KRT40, KRTAP5-9, KRTAP5-9, LYPLAL1, MID2, MSN, MTUS2, NOTCH2NL, PLK2, PLSCR1, SGOL2, and SPRED2. Cathepsin Z has also been found to interact with: - Integrin, - PRLP0, and - γ-Enolase.	Cathepsin Z Cathepsin Z, also called cathepsin X or cathepsin P, is a protein that in humans is encoded by the CTSZ gene.[1][2] It is a member of the cysteine cathepsin protease family, which has 11 members.[3] As one of the 11 cathepsins, cathepsin Z contains distinctive features from others. Cathepsin Z has been reported involved in cancer malignancy and inflammation. # Structure ## Gene The CTSZ gene is located at 20q13.32 on chromosome 20, consisting of 6 exons. At least two transcript variants of this gene have been found, but the full-length nature of only one of them has been determined.[2] ## Protein Cathepsin Z is characterized by an unusual and unique 3-amino acid insertion in the highly conserved region between the glutamine of the putative oxynion hole and the active site cysteine. The pro-region of cathepsin Z shares no significant similarity with other cathepsin family sequences.[4] It contains only 41 amino acid residues without the conserved motif of ERFNIN or GNFD found in other cysteine proteinases. Besides, the proregion sequence contains no lysine residue. # Function The protein encoded by this gene is a lysosomal cysteine proteinase and member of the peptidase C1 family. It exhibits both carboxy-monopeptidase and carboxy-dipeptidase activities. Up to date, eleven human cysteine proteinases have been identified, including cathepsin B, cathepsin C, cathepsin G, cathepsin H, cathepsin K, cathepsin L, cathepsin L2, cathepsin O, cathepsin S, cathepsin Z, and cathepsin W. These cysteine proteinases belong to the papain family and represent a major component of the lysosomal proteolytic system.In addition to playing a critical role in protein degradation and turnover, these proteinases appear to play an extracellular role in a number of normal and pathological conditions. The human cathepsin Z contains distinctive features from other human cysteine proteases.[5] It is an exopeptidase with strict carboxypeptidase activity, while most other cathepsins are endopeptidases.[3] Cathepsin Z has an exposed integrin-bindign Arg-Gly-Asp motif within the propeptide of the enzyme, through which cathepsin Z has been shown to interact with several integrins during normal homeostasis, immune processes and cancer.[6][7][8][9] It is also shown to bind cell surface heparin sulphate proteoglycans, indicating possible functions in cellular adhesion and phagocytosis.[10] # Clinical significance This gene is expressed ubiquitously in cancer cell lines and primary tumors and, like other members of this family, may be involved in tumorigenesis.For instance, cathepsin Z promotes invasion and migration via a noncatalytic mechanism, suggesting multiple modes of cell invasion may be involved in cancer malignancy.[9] Cathepsin Z is also reported to have a protective, but not proteolytic, function in inflammatory gastric disease.[11] It is reported in another study that cathepsin Z may be responsible for dopamine neuron death and thus involved in the pathogenic cascade event.[12] Single-nucleotide polymorphism in CTSZ is found associated with tuberculosis susceptibility, indicating that the pathways involving this protein could yield novel therapies for tuberculosis.[13] # Interactions Cathepsin Z has been shown to interact with the following proteins: CEP55, FBXO6, KIFC1, KRT40, KRTAP5-9, KRTAP5-9, LYPLAL1, MID2, MSN, MTUS2, NOTCH2NL, PLK2, PLSCR1, SGOL2, and SPRED2.[14] Cathepsin Z has also been found to interact with: - Integrin,[9] - PRLP0,[10] and - γ-Enolase.[15]	https://www.wikidoc.org/index.php/Cathepsin_Z
31485ae06e3b837f679cacf194c4863f4a2976ae	wikidoc	Catumaxomab	Catumaxomab # Overview Catumaxomab (trade name Removab) is a rat-mouse hybrid monoclonal antibody which is used to treat malignant ascites, a condition occurring in patients with metastasizing cancer. It binds to antigens CD3 and EpCAM. It is in clinical trials in the United States currently and is used in Europe. It was developed by Fresenius Biotech and Trion Pharma (Germany). # History Catumaxomab was developed by Trion Pharma, based on preliminary work by the Helmholtz Zentrum München. Fresenius Biotech conducted clinical trials and filed the drug for approval with the European Medicines Agency (EMA). It was approved in Europe on 20 April 2009. # Indications The drug is approved for the treatment of malignant ascites in patients with EpCAM-positive cancer if a standard therapy is not available. Ascites is an accumulation of fluid in the peritoneal cavity. ## Application The usual treatment of malignant ascites is to puncture the peritoneum to let the accumulated fluid drain out. After the puncture, catumaxomab is given as an intraperitoneal infusion. The procedure is repeated four times within about eleven days. It has been shown that puncture free survival can be increased from 11 to 46 days with this treatment. # Adverse effects Common adverse effects include fever, nausea and vomiting. Fever and pain should be controlled by giving NSAIDs, analgetics or antipyretics before application of catumaxomab. # Chemical structure Catumaxomab consists of one "half" (one heavy chain and one light chain) of an anti-EpCAM antibody and one half of an anti-CD3 antibody, so that each molecule of catumaxomab can bind both EpCAM and CD3. In addition, the Fc-region can bind to an Fc receptor on accessory cells like other antibodies, which has led to calling the drug a trifunctional antibody. # Mechanism of action Many types of cancer cells carry EpCAM (epithelial cell adhesion molecule) on their surface. By binding to such a cell via one arm, to a T lymphocyte via the other arm and to an antigen-presenting cell like a macrophage, a natural killer cell or a dendritic cell via the heavy chains, an immunological reaction against the cancer cell is triggered. Removing cancer cells from the abdominal cavity reduces the tumour burden which is seen as the cause for ascites in cancer patients.	Catumaxomab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Catumaxomab[1] (trade name Removab) is a rat-mouse hybrid monoclonal antibody which is used to treat malignant ascites, a condition occurring in patients with metastasizing cancer. It binds to antigens CD3 and EpCAM. It is in clinical trials in the United States currently and is used in Europe. It was developed by Fresenius Biotech and Trion Pharma (Germany). # History Catumaxomab was developed by Trion Pharma, based on preliminary work by the Helmholtz Zentrum München. Fresenius Biotech conducted clinical trials and filed the drug for approval with the European Medicines Agency (EMA). It was approved in Europe on 20 April 2009. # Indications The drug is approved for the treatment of malignant ascites in patients with EpCAM-positive cancer if a standard therapy is not available. Ascites is an accumulation of fluid in the peritoneal cavity. ## Application The usual treatment of malignant ascites is to puncture the peritoneum to let the accumulated fluid drain out. After the puncture, catumaxomab is given as an intraperitoneal infusion. The procedure is repeated four times within about eleven days. It has been shown that puncture free survival can be increased from 11 to 46 days with this treatment. # Adverse effects Common adverse effects include fever, nausea and vomiting. Fever and pain should be controlled by giving NSAIDs, analgetics or antipyretics before application of catumaxomab. # Chemical structure Catumaxomab consists of one "half" (one heavy chain and one light chain) of an anti-EpCAM antibody and one half of an anti-CD3 antibody, so that each molecule of catumaxomab can bind both EpCAM and CD3. In addition, the Fc-region can bind to an Fc receptor on accessory cells like other antibodies, which has led to calling the drug a trifunctional antibody. # Mechanism of action Many types of cancer cells carry EpCAM (epithelial cell adhesion molecule) on their surface. By binding to such a cell via one arm, to a T lymphocyte via the other arm and to an antigen-presenting cell like a macrophage, a natural killer cell or a dendritic cell via the heavy chains, an immunological reaction against the cancer cell is triggered. Removing cancer cells from the abdominal cavity reduces the tumour burden which is seen as the cause for ascites in cancer patients.	https://www.wikidoc.org/index.php/Catumaxomab
f504afb50b8dca020441b8963e649d36738632ae	wikidoc	Cefamandole	Cefamandole Synonyms and keywords: Cephamandole # Overview Cefamandole is a second-generation broad-spectrum cephalosporin antibiotic. The clinically used form of cefamandole is the formate ester cefamandole nafate, a prodrug which is administered parenterally. Cefamandole is no longer available in the United States. # Category Cephalosporin, Second-Generation # US Brand Names MANDOL® (DISCONTINUED) # FDA Package Insert Description # Spectrum of Bacterial Susceptibility Cefamandole has a broad spectrum of activity and can be used to treat bacterial infections of the skin, bones and joints, urinary tract, and lower respiratory tract. The following represents cefamandole MIC susceptibility data for a few medically significant microorganisms. - Escherichia coli: 0.12 μg/mL - 400 μg/mL - Haemophilus influenzae: 0.06 μg/mL - >16 μg/mL - Staphylococcus aureus: 0.1 μg/mL - 12.5 μg/mL # Adverse Reactions The chemical structure of cefamandole, like that of several other cephalosporins, contains an N-methylthiotetrazole (NMTT or 1-MTT) side chain. As the antibiotic is broken down in the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of the enzyme vitamin K epoxide reductase)(vitamin K supplement is recommended during therapy) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase. # Report CO2 is generated during the normal constitution of cefamandole & ceftazidim resulting in explosive like reaction in syringe. # Mechanism of Action Cefamandole, as a second-generation cephalosporin, binds to specific penicillin-binding proteins (PBPs) and inhibits bacterial cell wall synthesis.	Cefamandole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: Cephamandole # Overview Cefamandole is a second-generation broad-spectrum cephalosporin antibiotic. The clinically used form of cefamandole is the formate ester cefamandole nafate, a prodrug which is administered parenterally. Cefamandole is no longer available in the United States. # Category Cephalosporin, Second-Generation # US Brand Names MANDOL® (DISCONTINUED) # FDA Package Insert Description # Spectrum of Bacterial Susceptibility Cefamandole has a broad spectrum of activity and can be used to treat bacterial infections of the skin, bones and joints, urinary tract, and lower respiratory tract. The following represents cefamandole MIC susceptibility data for a few medically significant microorganisms. - Escherichia coli: 0.12 μg/mL - 400 μg/mL - Haemophilus influenzae: 0.06 μg/mL - >16 μg/mL - Staphylococcus aureus: 0.1 μg/mL - 12.5 μg/mL # Adverse Reactions The chemical structure of cefamandole, like that of several other cephalosporins, contains an N-methylthiotetrazole (NMTT or 1-MTT) side chain. As the antibiotic is broken down in the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of the enzyme vitamin K epoxide reductase)(vitamin K supplement is recommended during therapy) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase. # Report CO2 is generated during the normal constitution of cefamandole & ceftazidim resulting in explosive like reaction in syringe.[1] # Mechanism of Action Cefamandole, as a second-generation cephalosporin, binds to specific penicillin-binding proteins (PBPs) and inhibits bacterial cell wall synthesis.	https://www.wikidoc.org/index.php/Cefamandole
64bae50f4a1d63a45f765afaa195cb9350e92c9f	wikidoc	Cefmetazole	Cefmetazole # Overview Cefmetazole is a cephamycin antibiotic, usually grouped with the second-generation cephalosporins. # Adverse effects The chemical structure of cefmetazole, like that of several other cephalosporins, contains an N-methylthiotetrazole (NMTT or 1-MTT) side chain. As the antibiotic is broken down in the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of the enzyme vitamin K epoxide reductase) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase. # Spectrum of bacterial susceptibility Cefmetazole is a broad-spectrum cephalosporin antimicrobial and has been effective in treating bacteria responsible for causing urinary tract and skin infections. The following represents MIC susceptibility data for a few medically significant microorganisms. - Bacteroides fragilis: 0.06 - >256 µg/ml - Clostridium difficile: 8 - >128 µg/ml - Staphylococcus aureus: 0.5 - 256 µg/ml (includes MRSA)	Cefmetazole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cefmetazole is a cephamycin antibiotic, usually grouped with the second-generation cephalosporins. # Adverse effects The chemical structure of cefmetazole, like that of several other cephalosporins, contains an N-methylthiotetrazole (NMTT or 1-MTT) side chain. As the antibiotic is broken down in the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of the enzyme vitamin K epoxide reductase) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase.[1] # Spectrum of bacterial susceptibility Cefmetazole is a broad-spectrum cephalosporin antimicrobial and has been effective in treating bacteria responsible for causing urinary tract and skin infections. The following represents MIC susceptibility data for a few medically significant microorganisms. - Bacteroides fragilis: 0.06 - >256 µg/ml - Clostridium difficile: 8 - >128 µg/ml - Staphylococcus aureus: 0.5 - 256 µg/ml (includes MRSA) [2]	https://www.wikidoc.org/index.php/Cefmetazole
bc15252a28e3858ae26305b5bdfeecfe78cc0498	wikidoc	Cefpodoxime	Cefpodoxime Headache - Acute otitis media caused by Streptococcus pneumoniae (excluding penicillin-resistant strains), Streptococcus pyogenes, Haemophilus influenzae (including beta-lactamase-producing strains), or Moraxella (Branhamella) catarrhalis (including beta-lactamase-producing strains). - Pharyngitis and/or tonsillitis caused by Streptococcus pyogenes. - Community-acquired pneumonia caused by S. pneumoniae or H. Influenzae (including beta-lactamase-producing strains). - Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, H. influenzae (non-beta-lactamase-producing strains only), or M. catarrhalis. - Acute, uncomplicated urethral and cervical gonorrhea caused by Neisseria gonorrhoeae (including penicillinase-producing strains). - Acute, uncomplicated ano-rectal infections in women due to Neisseria gonorrhoeae (including penicillinase-producing strains). - Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (including penicillinase-producing strains) or Streptococcus pyogenes. Abscesses should be surgically drained as clinically indicated. - Acute maxillary sinusitis caused by Haemophilus influenzae (including beta-lactamase-producing strains), Streptococcus pneumoniae, and Moraxella catarrhalis. - Uncomplicated urinary tract infections (cystitis) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Staphylococcus saprophyticus. # Dosage ## Film Coated Tablets ## Granules for oral suspension ## Patients with Renal Dysfunction - For patients with severe renal impairment (<30 mL/min creatinine clearance), the dosing intervals should be increased to Q 24 hours. In patients maintained on hemodialysis, the dose frequency should be 3 times/week after hemodialysis. - When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to estimate creatinine clearance (mL/min). For this estimate to be valid, the serum creatinine level should represent a steady state of renal function. - Males: Weight (kg) x (140 - age) (mL/min) 72 x serum creatinine (mg/100 mL) - Females: 0.85 x above value (mL/min) ## Patients with Cirrhosis - Cefpodoxime pharmacokinetics in cirrhotic patients (with or without ascites) are similar to those in healthy subjects. Dose adjustment is not necessary in this population - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefpodoxime proxetil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - A concerted effort to monitor for C. difficile in cefpodoxime-treated patients with diarrhea was undertaken because of an increased incidence of diarrhea associated with C. difficile in early trials in normal subjects. C. difficile organisms or toxin was reported in 10% of the cefpodoxime-treated adult patients with diarrhea; however, no specific diagnosis of pseudomembranous colitis was made in these patients. - In post-marketing experience outside the United States, reports of pseudomembranous colitis associated with the use of cefpodoxime proxetil have been received. ## Precautions - In patients with transient or persistent reduction in urinary output due to renal insufficiency, the total daily dose of cefpodoxime proxetil should be reduced because high and prolonged serum antibiotic concentrations can occur in such individuals following usual doses. Cefpodoxime, like other cephalosporins, should be administered with caution to patients receiving concurrent treatment with potent diuretics. - As with other antibiotics, prolonged use of cefpodoxime proxetil may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. - Prescribing cefpodoxime proxetil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. - Diarrhea - Nausea - Vaginal Fungal Infections - Vulvovaginal Infections - Abdominal Pain - Headache - congestive heart failure - migraine - palpitations - vasodilation - hematoma - hypertension - hypotension - vomiting - dyspepsia - dry mouth - flatulence - decreased appetite - constipation - oral moniliasis - anorexia - eructation - gastritis - mouth ulcer - gastrointestinal disorders - rectal disorders - tongue disorders - tooth disorders - increased thirst - oral lesions - tenesmus - dry throat - toothache - anemia - Thrombocythemia - positive direct Coombs’ test - eosinophilia - leukocytosis - leukopenia - prolonged partial thromboplastin time - thrombocytopenic purpura - dehydration - gout - peripheral edema - weight increase - Increased SGPT - myalgia - dizziness - insomnia - somnolence - anxiety - shakiness - nervousness - cerebral infarction - change in dreams - impaired concentration - confusion - nightmares - paresthesia - vertigo - Hallucination - hyperkinesia - asthma - cough - epistaxis - rhinitis - wheezing - bronchitis - dyspnea - pleural effusion - pneumonia - sinusitis - urticaria - rash - pruritus - diaphoresis - maculopapular rash - fungal dermatitis - desquamation - dry skin non-application site - hair loss - vesiculobullous rash - sunburn - taste alterations - eye irritation - taste loss - tinnitus - hematuria - urinary tract infections - metrorrhagia - dysuria - urinary frequency - nocturia - penile infection - proteinuria - vaginal pain - fungal infections - abdominal distention - malaise - fatigue - asthenia - fever - chest pain - back pain - chills - generalized pain - abnormal microbiological test - moniliasis - abscess - allergic reaction - facial edema - bacterial infections - parasitic infections - localized edema - localized pain ## Laboratory Changes - Hepatic: Transient increases in AST (SGOT), ALT (SGPT), GGT, alkaline phosphatase, bilirubin, and LDH. - Hematologic: Eosinophilia, leukocytosis, lymphocytosis, granulocytosis, basophilia, monocytosis, thrombocytosis, decreased hemoglobin, decreased hematocrit, leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, thrombocythemia, positive Coombs’ test, and prolonged PT, and PTT. - Serum Chemistry: Hyperglycemia, hypoglycemia, hypoalbuminemia, hypoproteinemia, hyperkalemia, and hyponatremia. - Renal: Increases in BUN and creatinine. ## Cephalosporin Class Labeling - In addition to the adverse reactions listed above which have been observed in patients treated with cefpodoxime proxetil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin class antibiotics. - Adverse Reactions and Abnormal Laboratory Tests: Renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, serum sickness-like reaction, hemorrhage, agranulocytosis, pancytopenia and seizures. - One death was attributed to pseudomembranous colitis and disseminated intravascular coagulation. - Probenecid: As with other beta-lactam antibiotics, renal excretion of cefpodoxime was inhibited by probenecid and resulted in an approximately 31% increase in AUC and 20% increase in peak cefpodoxime plasma levels. - Nephrotoxic drugs: Although nephrotoxicity has not been noted when cefpodoxime proxetil was given alone, close monitoring of renal function is advised when cefpodoxime proxetil is administered concomitantly with compounds of known nephrotoxic potential. - Cefpodoxime proxetil was neither teratogenic nor embryocidal when administered to rats during organogenesis at doses up to 100 mg/kg/day (2 times the human dose based on mg/m2) or to rabbits at doses up to 30 mg/kg/day (1 to 2 times the human dose based on mg/m2). There are, however, no adequate and well-controlled studies of cefpodoxime proxetil use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Dose adjustment in elderly patients with normal renal function is not necessary. - Oral Suspension : give without regard to food - Close monitoring of renal function is advised when cefpodoxime proxetil is administered concomitantly with compounds of known nephrotoxic potential - In the event of serious toxic reaction from overdosage, hemodialysis or peritoneal dialysis may aid in the removal of cefpodoxime from the body, particularly if renal function is compromised. - The toxic symptoms following an overdose of beta-lactam antibiotics may include nausea, vomiting, epigastric distress, and diarrhea. - Its molecular formula is C21 H27 N5 O9 S2 and its structural formula is represented below: - Cefpodoxime proxetil is a prodrug that is absorbed from the gastrointestinal tract and de-esterified to its active metabolite, cefpodoxime. Following oral administration of 100 mg of cefpodoxime proxetil to fasting subjects, approximately 50% of the administered cefpodoxime dose was absorbed systemically. Over the recommended dosing range (100 to 400 mg), approximately 29 to 33% of the administered cefpodoxime dose was excreted unchanged in the urine in 12 hours. There is minimal metabolism of cefpodoxime in vivo. ## Effects of Food - The extent of absorption (mean AUC) and the mean peak plasma concentration increased when film-coated tablets were administered with food. Following a 200 mg tablet dose taken with food, the AUC was 21 to 33% higher than under fasting conditions, and the peak plasma concentration averaged 3.1 mcg/mL in fed subjects versus 2.6 mcg/mL in fasted subjects. Time to peak concentration was not significantly different between fed and fasted subjects. - When a 200 mg dose of the suspension was taken with food, the extent of absorption (mean AUC) and mean peak plasma concentration in fed subjects were not significantly different from fasted subjects, but the rate of absorption was slower with food 48% increase in Tmax ). ## Pharmacokinetics of Cefpodoxime Proxetil Film-coated Tablets - Over the recommended dosing range, (100 to 400 mg), the rate and extent of cefpodoxime absorption exhibited dose-dependency; dose-normalized Cmax and AUC decreased by up to 32% with increasing dose. Over the recommended dosing range, the Tmax was approximately 2 to 3 hours and the T1/2 ranged from 2.09 to 2.84 hours. Mean Cmax was 1.4 mcg/mL for the 100 mg dose, 2.3 mcg/mL for the 200 mg dose, and 3.9 mcg/mL for the 400 mg dose. In patients with normal renal function, neither accumulation nor significant changes in other pharmacokinetic parameters were noted following multiple oral doses of up to 400 mg Q 12 hours. ## Pharmacokinetics of Cefpodoxime Proxetil Suspension - In adult subjects, a 100 mg dose of oral suspension produced an average peak cefpodoxime concentration of approximately 1.5 mcg/mL (range: 1.1 to 2.1 mcg/mL), which is equivalent to that reported following administration of the 100 mg tablet. Time to peak plasma concentration and area under the plasma concentration-time curve (AUC) for the oral suspension were also equivalent to those produced with film-coated tablets in adults following a 100 mg oral dose. - The pharmacokinetics of cefpodoxime were investigated in 29 patients aged 1 to 17 years. Each patient received a single, oral, 5 mg/kg dose of cefpodoxime oral suspension. Plasma and urine samples were collected for 12 hours after dosing. The plasma levels reported from this study are as follows: ## Distribution - Protein binding of cefpodoxime ranges from 22 to 33% in serum and from 21 to 29% in plasma. - Following multiple-dose administration every 12 hours for 5 days of 200 mg or 400 mg cefpodoxime proxetil, the mean maximum cefpodoxime concentration in skin blister fluid averaged 1.6 and 2.8 mcg/mL, respectively. Skin blister fluid cefpodoxime levels at 12 hours after dosing averaged 0.2 and 0.4 mcg/mL for the 200 mg and 400 mg multiple-dose regimens, respectively. - Following a single, oral 100 mg cefpodoxime proxetil film-coated tablet, the mean maximum cefpodoxime concentration in tonsil tissue averaged 0.24 mcg/g at 4 hours post-dosing and 0.09 mcg/g at 7 hours post-dosing. Equilibrium was achieved between plasma and tonsil tissue within 4 hours of dosing. No detection of cefpodoxime in tonsillar tissue was reported 12 hours after dosing. These results demonstrated that concentrations of cefpodoxime exceeded the MIC90 of S. pyogenes for at least 7 hours after dosing of 100 mg of cefpodoxime proxetil. - Following a single, oral 200 mg cefpodoxime proxetil film-coated tablet, the mean maximum cefpodoxime concentration in lung tissue averaged 0.63 mcg/g at 3 hours post-dosing, 0.52 mcg/g at 6 hours post-dosing, and 0.19 mcg/g at 12 hours post-dosing. The results of this study indicated that cefpodoxime penetrated into lung tissue and produced sustained drug concentrations for at least 12 hours after dosing at levels that exceeded the MIC90 for S. pneumoniae and H. influenzae. - Adequate data on CSF levels of cefpodoxime are not available. ## Effects of Decreased Renal Function - Elimination of cefpodoxime is reduced in patients with moderate to severe renal impairment (<50 mL/min creatinine clearance).In subjects with mild impairment of renal function (50 to 80 mL/min creatinine clearance), the average plasma half-life of cefpodoxime was 3.5 hours. In subjects with moderate (30 to 49 mL/min creatinine clearance) or severe renal impairment (5 to 29 mL/min creatinine clearance), the half-life increased to 5.9 and 9.8 hours, respectively. Approximately 23% of the administered dose was cleared from the body during a standard 3-hour hemodialysis procedure. ## Effect of Hepatic Impairment (cirrhosis) - Absorption was somewhat diminished and elimination unchanged in patients with cirrhosis. The mean cefpodoxime T1/2 and renal clearance in cirrhotic patients were similar to those derived in studies of healthy subjects. Ascites did not appear to affect values in cirrhotic subjects. No dosage adjustment is recommended in this patient population. ## Pharmacokinetics in Elderly Subjects - Elderly subjects do not require dosage adjustments unless they have diminished renal function.In healthy geriatric subjects, cefpodoxime half-life in plasma averaged 4.2 hours (vs 3.3 in younger subjects) and urinary recovery averaged 21% after a 400 mg dose was administered every 12 hours. Other pharmacokinetic parameters (Cmax , AUC, and Tmax ) were unchanged relative to those observed in healthy young subjects. ## Microbiology - Resistance to cefpodoxime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability. - Cefpodoxime has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections: - Staphylococcus aureus (methicillin-susceptible strains, including those producing penicillinases) - Staphylococcus saprophyticus - Streptococcus pneumoniae (excluding penicillin-resistant isolates) - Streptococcus pyogenes - Escherichia coli - Klebsiella pneumonia - Proteus mirabilis - Haemophilus influenzae (including beta-lactamase producing isolates) - Moraxella catarrhalis - Neisseria gonorrhoeae (including penicillinase-producing isolates) - The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefpodoxime. However, the efficacy of cefpodoxime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials. - Streptococcus agalactiae - Streptococcus spp. (Groups C, F, G) - Citrobacter diversus - Klebsiella oxytoca - Proteus vulgaris - Providencia rettgeri - Haemophilus parainfluenzae - Peptostreptococcus magnus - When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. - Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method. The MIC values should be interpreted according to criteria provided in Table 1. - Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. This procedure uses paper disks impregnated with 10 mcg cefpodoxime to test the susceptibility of microorganisms to cefpodoxime. The disk diffusion interpretive criteria are provided in Table 1. - A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. - Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. Standard Cefpodoxime powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 10 mcg disk, the criteria in Table 2 should be achieved. - In two double-blind, 2:1 randomized, comparative trials performed in adults in the United States, cefpodoxime proxetil was compared to other beta-lactam antibiotics. In these studies, the following bacterial eradication rates were obtained at 5 to 9 days after therapy: - In these studies, clinical cure rates and bacterial eradication rates for cefpodoxime proxetil were comparable to the comparator agents; however, the clinical cure rates and bacteriologic eradication rates were lower than those observed with some other classes of approved agents for cystitis. In controlled studies of acute otitis media performed in the United States, where significant rates of beta-lactamase-producing organisms were found, cefpodoxime proxetil was compared to cefixime. In these studies, using very strict evaluability criteria and microbiologic and clinical response criteria at the 4 to 21 day post-therapy follow-up, the following presumptive bacterial eradication/clinical success outcomes (cured and improved) were obtained. - Bottles of 20 (NDC 65862-095-20) - Bottles of 100 (NDC 65862-095-01) - Bottles of 1000 (NDC 65862-095-99) - Cefpodoxime Proxetil Tablets, USP 200 mg are coral red, elliptical, film-coated tablets debossed with ‘C’ on one side and ‘62’ on the other side. - Bottles of 20 (NDC 65862-096-20) - Bottles of 100 (NDC 65862-096-01) - Bottles of 1000 (NDC 65862-096-99) - Dispense in tight, light-resistant container. - Replace cap securely after each opening. ## Package Label-principal display panel - 200 MG (20 tablet bottle) ## Ingredients and Appearance - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. - ↑ "CEFPODOXIME PROXETIL - cefpodoxime proxetil tablet, film coated"..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}	Cefpodoxime Headache - Acute otitis media caused by Streptococcus pneumoniae (excluding penicillin-resistant strains), Streptococcus pyogenes, Haemophilus influenzae (including beta-lactamase-producing strains), or Moraxella (Branhamella) catarrhalis (including beta-lactamase-producing strains). - Pharyngitis and/or tonsillitis caused by Streptococcus pyogenes. - Community-acquired pneumonia caused by S. pneumoniae or H. Influenzae (including beta-lactamase-producing strains). - Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, H. influenzae (non-beta-lactamase-producing strains only), or M. catarrhalis. - Acute, uncomplicated urethral and cervical gonorrhea caused by Neisseria gonorrhoeae (including penicillinase-producing strains). - Acute, uncomplicated ano-rectal infections in women due to Neisseria gonorrhoeae (including penicillinase-producing strains). - Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (including penicillinase-producing strains) or Streptococcus pyogenes. Abscesses should be surgically drained as clinically indicated. - Acute maxillary sinusitis caused by Haemophilus influenzae (including beta-lactamase-producing strains), Streptococcus pneumoniae, and Moraxella catarrhalis. - Uncomplicated urinary tract infections (cystitis) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Staphylococcus saprophyticus. ## Dosage ### Film Coated Tablets ### Granules for oral suspension ### Patients with Renal Dysfunction - For patients with severe renal impairment (<30 mL/min creatinine clearance), the dosing intervals should be increased to Q 24 hours. In patients maintained on hemodialysis, the dose frequency should be 3 times/week after hemodialysis. - When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to estimate creatinine clearance (mL/min). For this estimate to be valid, the serum creatinine level should represent a steady state of renal function. - Males: Weight (kg) x (140 - age) (mL/min) 72 x serum creatinine (mg/100 mL) - Females: 0.85 x above value (mL/min) ### Patients with Cirrhosis - Cefpodoxime pharmacokinetics in cirrhotic patients (with or without ascites) are similar to those in healthy subjects. Dose adjustment is not necessary in this population - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefpodoxime proxetil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - A concerted effort to monitor for C. difficile in cefpodoxime-treated patients with diarrhea was undertaken because of an increased incidence of diarrhea associated with C. difficile in early trials in normal subjects. C. difficile organisms or toxin was reported in 10% of the cefpodoxime-treated adult patients with diarrhea; however, no specific diagnosis of pseudomembranous colitis was made in these patients. - In post-marketing experience outside the United States, reports of pseudomembranous colitis associated with the use of cefpodoxime proxetil have been received. ### Precautions - In patients with transient or persistent reduction in urinary output due to renal insufficiency, the total daily dose of cefpodoxime proxetil should be reduced because high and prolonged serum antibiotic concentrations can occur in such individuals following usual doses. Cefpodoxime, like other cephalosporins, should be administered with caution to patients receiving concurrent treatment with potent diuretics. - As with other antibiotics, prolonged use of cefpodoxime proxetil may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. - Prescribing cefpodoxime proxetil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. - Diarrhea - Nausea - Vaginal Fungal Infections - Vulvovaginal Infections - Abdominal Pain - Headache - congestive heart failure - migraine - palpitations - vasodilation - hematoma - hypertension - hypotension - vomiting - dyspepsia - dry mouth - flatulence - decreased appetite - constipation - oral moniliasis - anorexia - eructation - gastritis - mouth ulcer - gastrointestinal disorders - rectal disorders - tongue disorders - tooth disorders - increased thirst - oral lesions - tenesmus - dry throat - toothache - anemia - Thrombocythemia - positive direct Coombs’ test - eosinophilia - leukocytosis - leukopenia - prolonged partial thromboplastin time - thrombocytopenic purpura - dehydration - gout - peripheral edema - weight increase - Increased SGPT - myalgia - dizziness - insomnia - somnolence - anxiety - shakiness - nervousness - cerebral infarction - change in dreams - impaired concentration - confusion - nightmares - paresthesia - vertigo - Hallucination - hyperkinesia - asthma - cough - epistaxis - rhinitis - wheezing - bronchitis - dyspnea - pleural effusion - pneumonia - sinusitis - urticaria - rash - pruritus - diaphoresis - maculopapular rash - fungal dermatitis - desquamation - dry skin non-application site - hair loss - vesiculobullous rash - sunburn - taste alterations - eye irritation - taste loss - tinnitus - hematuria - urinary tract infections - metrorrhagia - dysuria - urinary frequency - nocturia - penile infection - proteinuria - vaginal pain - fungal infections - abdominal distention - malaise - fatigue - asthenia - fever - chest pain - back pain - chills - generalized pain - abnormal microbiological test - moniliasis - abscess - allergic reaction - facial edema - bacterial infections - parasitic infections - localized edema - localized pain ### Laboratory Changes - Hepatic: Transient increases in AST (SGOT), ALT (SGPT), GGT, alkaline phosphatase, bilirubin, and LDH. - Hematologic: Eosinophilia, leukocytosis, lymphocytosis, granulocytosis, basophilia, monocytosis, thrombocytosis, decreased hemoglobin, decreased hematocrit, leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, thrombocythemia, positive Coombs’ test, and prolonged PT, and PTT. - Serum Chemistry: Hyperglycemia, hypoglycemia, hypoalbuminemia, hypoproteinemia, hyperkalemia, and hyponatremia. - Renal: Increases in BUN and creatinine. ### Cephalosporin Class Labeling - In addition to the adverse reactions listed above which have been observed in patients treated with cefpodoxime proxetil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin class antibiotics. - Adverse Reactions and Abnormal Laboratory Tests: Renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, serum sickness-like reaction, hemorrhage, agranulocytosis, pancytopenia and seizures. - One death was attributed to pseudomembranous colitis and disseminated intravascular coagulation. - Probenecid: As with other beta-lactam antibiotics, renal excretion of cefpodoxime was inhibited by probenecid and resulted in an approximately 31% increase in AUC and 20% increase in peak cefpodoxime plasma levels. - Nephrotoxic drugs: Although nephrotoxicity has not been noted when cefpodoxime proxetil was given alone, close monitoring of renal function is advised when cefpodoxime proxetil is administered concomitantly with compounds of known nephrotoxic potential. - Cefpodoxime proxetil was neither teratogenic nor embryocidal when administered to rats during organogenesis at doses up to 100 mg/kg/day (2 times the human dose based on mg/m2) or to rabbits at doses up to 30 mg/kg/day (1 to 2 times the human dose based on mg/m2). There are, however, no adequate and well-controlled studies of cefpodoxime proxetil use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Dose adjustment in elderly patients with normal renal function is not necessary. - Oral Suspension : give without regard to food - Close monitoring of renal function is advised when cefpodoxime proxetil is administered concomitantly with compounds of known nephrotoxic potential - In the event of serious toxic reaction from overdosage, hemodialysis or peritoneal dialysis may aid in the removal of cefpodoxime from the body, particularly if renal function is compromised. - The toxic symptoms following an overdose of beta-lactam antibiotics may include nausea, vomiting, epigastric distress, and diarrhea. - Its molecular formula is C21 H27 N5 O9 S2 and its structural formula is represented below: - Cefpodoxime proxetil is a prodrug that is absorbed from the gastrointestinal tract and de-esterified to its active metabolite, cefpodoxime. Following oral administration of 100 mg of cefpodoxime proxetil to fasting subjects, approximately 50% of the administered cefpodoxime dose was absorbed systemically. Over the recommended dosing range (100 to 400 mg), approximately 29 to 33% of the administered cefpodoxime dose was excreted unchanged in the urine in 12 hours. There is minimal metabolism of cefpodoxime in vivo. ### Effects of Food - The extent of absorption (mean AUC) and the mean peak plasma concentration increased when film-coated tablets were administered with food. Following a 200 mg tablet dose taken with food, the AUC was 21 to 33% higher than under fasting conditions, and the peak plasma concentration averaged 3.1 mcg/mL in fed subjects versus 2.6 mcg/mL in fasted subjects. Time to peak concentration was not significantly different between fed and fasted subjects. - When a 200 mg dose of the suspension was taken with food, the extent of absorption (mean AUC) and mean peak plasma concentration in fed subjects were not significantly different from fasted subjects, but the rate of absorption was slower with food 48% increase in Tmax ). ### Pharmacokinetics of Cefpodoxime Proxetil Film-coated Tablets - Over the recommended dosing range, (100 to 400 mg), the rate and extent of cefpodoxime absorption exhibited dose-dependency; dose-normalized Cmax and AUC decreased by up to 32% with increasing dose. Over the recommended dosing range, the Tmax was approximately 2 to 3 hours and the T1/2 ranged from 2.09 to 2.84 hours. Mean Cmax was 1.4 mcg/mL for the 100 mg dose, 2.3 mcg/mL for the 200 mg dose, and 3.9 mcg/mL for the 400 mg dose. In patients with normal renal function, neither accumulation nor significant changes in other pharmacokinetic parameters were noted following multiple oral doses of up to 400 mg Q 12 hours. ### Pharmacokinetics of Cefpodoxime Proxetil Suspension - In adult subjects, a 100 mg dose of oral suspension produced an average peak cefpodoxime concentration of approximately 1.5 mcg/mL (range: 1.1 to 2.1 mcg/mL), which is equivalent to that reported following administration of the 100 mg tablet. Time to peak plasma concentration and area under the plasma concentration-time curve (AUC) for the oral suspension were also equivalent to those produced with film-coated tablets in adults following a 100 mg oral dose. - The pharmacokinetics of cefpodoxime were investigated in 29 patients aged 1 to 17 years. Each patient received a single, oral, 5 mg/kg dose of cefpodoxime oral suspension. Plasma and urine samples were collected for 12 hours after dosing. The plasma levels reported from this study are as follows: ### Distribution - Protein binding of cefpodoxime ranges from 22 to 33% in serum and from 21 to 29% in plasma. - Following multiple-dose administration every 12 hours for 5 days of 200 mg or 400 mg cefpodoxime proxetil, the mean maximum cefpodoxime concentration in skin blister fluid averaged 1.6 and 2.8 mcg/mL, respectively. Skin blister fluid cefpodoxime levels at 12 hours after dosing averaged 0.2 and 0.4 mcg/mL for the 200 mg and 400 mg multiple-dose regimens, respectively. - Following a single, oral 100 mg cefpodoxime proxetil film-coated tablet, the mean maximum cefpodoxime concentration in tonsil tissue averaged 0.24 mcg/g at 4 hours post-dosing and 0.09 mcg/g at 7 hours post-dosing. Equilibrium was achieved between plasma and tonsil tissue within 4 hours of dosing. No detection of cefpodoxime in tonsillar tissue was reported 12 hours after dosing. These results demonstrated that concentrations of cefpodoxime exceeded the MIC90 of S. pyogenes for at least 7 hours after dosing of 100 mg of cefpodoxime proxetil. - Following a single, oral 200 mg cefpodoxime proxetil film-coated tablet, the mean maximum cefpodoxime concentration in lung tissue averaged 0.63 mcg/g at 3 hours post-dosing, 0.52 mcg/g at 6 hours post-dosing, and 0.19 mcg/g at 12 hours post-dosing. The results of this study indicated that cefpodoxime penetrated into lung tissue and produced sustained drug concentrations for at least 12 hours after dosing at levels that exceeded the MIC90 for S. pneumoniae and H. influenzae. - Adequate data on CSF levels of cefpodoxime are not available. ### Effects of Decreased Renal Function - Elimination of cefpodoxime is reduced in patients with moderate to severe renal impairment (<50 mL/min creatinine clearance).In subjects with mild impairment of renal function (50 to 80 mL/min creatinine clearance), the average plasma half-life of cefpodoxime was 3.5 hours. In subjects with moderate (30 to 49 mL/min creatinine clearance) or severe renal impairment (5 to 29 mL/min creatinine clearance), the half-life increased to 5.9 and 9.8 hours, respectively. Approximately 23% of the administered dose was cleared from the body during a standard 3-hour hemodialysis procedure. ### Effect of Hepatic Impairment (cirrhosis) - Absorption was somewhat diminished and elimination unchanged in patients with cirrhosis. The mean cefpodoxime T1/2 and renal clearance in cirrhotic patients were similar to those derived in studies of healthy subjects. Ascites did not appear to affect values in cirrhotic subjects. No dosage adjustment is recommended in this patient population. ### Pharmacokinetics in Elderly Subjects - Elderly subjects do not require dosage adjustments unless they have diminished renal function.In healthy geriatric subjects, cefpodoxime half-life in plasma averaged 4.2 hours (vs 3.3 in younger subjects) and urinary recovery averaged 21% after a 400 mg dose was administered every 12 hours. Other pharmacokinetic parameters (Cmax , AUC, and Tmax ) were unchanged relative to those observed in healthy young subjects. ### Microbiology - Resistance to cefpodoxime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability. - Cefpodoxime has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections: - Staphylococcus aureus (methicillin-susceptible strains, including those producing penicillinases) - Staphylococcus saprophyticus - Streptococcus pneumoniae (excluding penicillin-resistant isolates) - Streptococcus pyogenes - Escherichia coli - Klebsiella pneumonia - Proteus mirabilis - Haemophilus influenzae (including beta-lactamase producing isolates) - Moraxella catarrhalis - Neisseria gonorrhoeae (including penicillinase-producing isolates) - The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefpodoxime. However, the efficacy of cefpodoxime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials. - Streptococcus agalactiae - Streptococcus spp. (Groups C, F, G) - Citrobacter diversus - Klebsiella oxytoca - Proteus vulgaris - Providencia rettgeri - Haemophilus parainfluenzae - Peptostreptococcus magnus - When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. - Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method. The MIC values should be interpreted according to criteria provided in Table 1. - Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. This procedure uses paper disks impregnated with 10 mcg cefpodoxime to test the susceptibility of microorganisms to cefpodoxime. The disk diffusion interpretive criteria are provided in Table 1. - A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. - Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. Standard Cefpodoxime powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 10 mcg disk, the criteria in Table 2 should be achieved. - In two double-blind, 2:1 randomized, comparative trials performed in adults in the United States, cefpodoxime proxetil was compared to other beta-lactam antibiotics. In these studies, the following bacterial eradication rates were obtained at 5 to 9 days after therapy: - In these studies, clinical cure rates and bacterial eradication rates for cefpodoxime proxetil were comparable to the comparator agents; however, the clinical cure rates and bacteriologic eradication rates were lower than those observed with some other classes of approved agents for cystitis. In controlled studies of acute otitis media performed in the United States, where significant rates of beta-lactamase-producing organisms were found, cefpodoxime proxetil was compared to cefixime. In these studies, using very strict evaluability criteria and microbiologic and clinical response criteria at the 4 to 21 day post-therapy follow-up, the following presumptive bacterial eradication/clinical success outcomes (cured and improved) were obtained. - Bottles of 20 (NDC 65862-095-20) - Bottles of 100 (NDC 65862-095-01) - Bottles of 1000 (NDC 65862-095-99) - Cefpodoxime Proxetil Tablets, USP 200 mg are coral red, elliptical, film-coated tablets debossed with ‘C’ on one side and ‘62’ on the other side. - Bottles of 20 (NDC 65862-096-20) - Bottles of 100 (NDC 65862-096-01) - Bottles of 1000 (NDC 65862-096-99) - Dispense in tight, light-resistant container. - Replace cap securely after each opening. ### Package Label-principal display panel - 200 MG (20 tablet bottle) ### Ingredients and Appearance - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. - ↑ "CEFPODOXIME PROXETIL - cefpodoxime proxetil tablet, film coated"..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}	https://www.wikidoc.org/index.php/Cefpodoxime
20317270c35c47ae58c52ae891e814f3b79202c6	wikidoc	Ceftazidime	Ceftazidime # 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 Ceftazidime is a cephalosporin that is FDA approved for the treatment of bacterial infections of gram negative, gram positive aerobic bacterias and for anaerobic bacterias. Common adverse reactions include diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Pneumonia: caused by Pseudomonas aeruginosa and other Pseudomonas spp.; Haemophilus influenzae, including ampicillin-resistant strains; Klebsiella spp.; Enterobacter spp; Proteus mirabilis; Escherichia coli; Serratia spp; Citrobacter spp; Streptococcus pneumoniae; and Staphylococcus aureus (methicillin-susceptible strains). - Caused by Pseudomonas aeruginosa; Klebsiella spp.; Escherichia coli; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Enterobacter spp.; Serratia spp.; Staphylococcus aureus (methicillin-susceptible strains); and Streptococcus pyogenes (group A beta-hemolytic streptococci). - Both complicated and uncomplicated, caused by Pseudomonas aeruginosa; Enterobacter spp; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Klebsiella spp.; and Escherichia coli. - Caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin-susceptible strains). - Caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible strains). - Including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli. - Including peritonitis caused by Escherichia coli, Klebsiella spp., and Staphylococcus aureus (methicillin-susceptible strains) and polymicrobial infections caused by aerobic and anaerobic organisms and Bacteroides spp (many strains of Bacteroides fragilis are resistant). - Including meningitis, caused] by Haemophilus influenzae and Neisseria meningitidis. Ceftazidime has also been used successfully in a limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae. - The usual adult dosage is 1 gram administered intravenously every 8 to 12 hours. The dosage should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient. - The guidelines for dosage of ceftazidime for injection are listed in the following table. The following dosage schedule is recommended: - In patients with severe infections who would normally receive 6 grams of ceftazidime for injection daily were it not for renal insufficiency, the unit dose given in the table above may be increased by 50% or the dosing frequency may be increased appropriately. Further dosing should be determined by therapeutic monitoring, severity of the infection, and susceptibility of the causative organism. - In pediatric patients as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass, and the dosing frequency should be reduced in cases of renal insufficiency. - In patients undergoing hemodialysis, a loading dose of 1 gram is recommended, followed by 1 gram after each hemodialysis period. Ceftazidime for injection can also be used in patients undergoing intraperitoneal dialysis and continuous ambulatory peritoneal dialysis. In such patients, a loading dose of 1 gram of ceftazidime for injection may be given, followed by 500 mg every 24 hours. In addition to IV use, ceftazidime for injection can be incorporated in the dialysis fluid at a concentration of 250 mg for 2 L of dialysis fluid. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Single Therapy - Double Therapy Ceftazidime + Amikacin Ceftazidine + Tobramycin - Ceftazidime + Amikacin - Ceftazidine + Tobramycin ### Non–Guideline-Supported Use - Dosage Scheme 1: 4 milligrams/kilogram/hour after a 12 milligrams/kilogram (mg/kg) loading dose Scheme 2: 40 mg/kg every 8 hours - Scheme 1: 4 milligrams/kilogram/hour after a 12 milligrams/kilogram (mg/kg) loading dose - Scheme 2: 40 mg/kg every 8 hours # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - An antipseudomonal drug, such as ceftazidime or imipenem, should be added for neutropenic patients, with the addition of an aminoglycoside if infection with pseudomonas is likely - For patients with neutropenia, chronic lung disease other than asthma (lymphoid interstitial pneumonia, bronchiectasis), or indwelling venous catheter, consider regimens that include activity against P. aeruginosa, such as cefepime or ceftazidime instead of ceftriaxone - Single Therapy - Double Therapy Ceftazidime + Amikacin Ceftazidine + Tobramycin - Ceftazidime + Amikacin - Ceftazidine + Tobramycin ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftazidime in pediatric patients. # Contraindications - Ceftazidime for injection is contraindicated in patients who have shown hypersensitivity to ceftazidime or the cephalosporin group of antibiotics. # Warnings ### Hypersensitivity - Before therapy with Ceftazidime for injection is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. if this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. if an allergic reaction to ceftazidime for injection occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, IV fluids, iv antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. ### Clostridium Difficile Associated Diarrhea - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftazidime for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Elevated levels of ceftazidime in patients with renal insufficiency can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia. # Adverse Reactions ## Clinical Trials Experience Ceftazidime is generally well tolerated. The incidence of adverse reactions associated with the administration of ceftazidime was low in clinical trials. The most common were local reactions following IV injection and allergic and gastrointestinal reactions. Other adverse reactions were encountered infrequently. No disulfiram-like reactions were reported. The following adverse effects from clinical trials were considered to be either related to ceftazidime therapy or were of uncertain etiology: - Phlebitis - Inflammation at the site of injection (1 in 69 patients). - Pruritus - Rash - Fever - Toxic epidermal necrolysis - Stevens-Johnson syndrome - Erythema multiform - Angioedema - Anaphylaxis (bronchospasm and/or hypotension) have been reported very rarely. - Diarrhea - Nausea - Vomiting - Abdominal pain - The onset of pseudomembranous colitis symptoms may occur during or after treatment - Headache - Dizziness and - Paresthesia - Seizures - Encephalopathy - Coma - Asterixis - Neuromuscular excitability - Myoclonia have been reported in renally impaired patients treated with unadjusted dosing regimens of ceftazidime. - Candidiasis - Vaginitis - Rare cases of hemolytic anemia - Transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and lymphocytosis were seen very rarely. - Eosinophilia - Positive Coombs test without hemolysis - Thrombocytosis - Liver enzyme elevation: Aspartate aminotransferase (AST, SGOT) Alanine aminotransferase (ALT, SGPT) LDH GGT Alkaline phosphatase - Aspartate aminotransferase (AST, SGOT) - Alanine aminotransferase (ALT, SGPT) - LDH - GGT - Alkaline phosphatase - As with some other cephalosporins, transient elevations of blood urea, blood urea nitrogen, and/or serum creatinine were observed occasionally. ## Postmarketing Experience In addition to the adverse events reported during clinical trials, the following events have been observed during clinical practice in patients treated with ceftazidime and were reported spontaneously. For some of these events, data are insufficient to allow an estimate of incidence or to establish causation. - Anaphylaxis - Allergic reactions - Urticaria - Pain at injection site - Hyperbilirubinemia - Jaundice - Renal impairment In addition to the adverse reactions listed above that have been observed in patients treated with ceftazidime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: - Adverse Reactions: Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage. - Altered Laboratory Tests: Prolonged prothrombin time, false-positive test for urinary glucose, pancytopenia. # Drug Interactions - Nephrotoxicity has been reported following concomitant administration of cephalosporins with aminoglycoside antibiotics or potent diuretics such as furosemide. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycosidic antibiotics. Nephrotoxicity and ototoxicity were not noted when ceftazidime was given alone in clinical trials. - Chloramphenicol has been shown to be antagonistic to beta-lactam antibiotics, including ceftazidime, based on in vitro studies and time kill curves with enteric gram-negative bacilli. Due to the possibility of antagonism in vivo, particularly when bactericidal activity is desired, this drug combination should be avoided. - In common with other antibiotics, ceftazidime may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. - The administration of ceftazidime may result in a false-positive reaction for glucose in the urine when using CLINITEST® tablets, Benedict's solution, or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX®) be used. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ceftazidime for injection. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftazidime in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ceftazidime during labor and delivery. ### Nursing Mothers - Ceftazidime is excreted in human milk in low concentrations. Caution should be exercised when ceftazidime is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Ceftazidime in pediatric settings. ### Geriatic Use - Of the 2,221 subjects who received ceftazidime in 11 clinical studies, 824 (37%) were 65 and over while 391 (18%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater susceptibility of some older individuals to drug effects cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Ceftazidime with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ceftazidime with respect to specific racial populations. ### Renal Impairment - Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (glomerular filtration rate <50 mL/min), it is recommended that the dosage of ceftazidime be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1 gram of ceftazidime may be given. An estimate of GFR should be made to determine the appropriate maintenance dosage. ### Hepatic Impairment - No adjustment in dosage is required for patients with hepatic dysfunction. ### Females of Reproductive Potential and Males - Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse Micronucleus test and an Ames test were both negative for mutagenic effects. ### Immunocompromised Patients There is no FDA guidance one the use of Ceftazidime in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ceftazidime for injection may be given intravenously. Intra-arterial administration should be avoided. The IV route is preferable for patients with bacterial septicemia, bacterial meningitis, peritonitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or pending. - Not for direct infusion. This Pharmacy Bulk Package is for use in a hospital pharmacy admixture service, only in a suitable work area, such as a laminar flow hood. Using aseptic technique, the container closure may be penetrated only one time using a suitable sterile dispensing set or transfer device that allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 4 HOURS from initial closure entry is permitted to complete fluid transfer operations. This time limit should begin with the introduction of the solvent or diluent into the Pharmacy Bulk Package. Discard any unused portion after 4 hours. Not for direct infusion. This pharmacy bulk package is not intended to be dispensed as a unit. - For IV infusion, constitute the 6 g Pharmacy Bulk Package bottle with Sterile Water for Injection and add an appropriate quantity of the resulting solution to an IV container with one of the compatible IV fluids. - Intermittent IV infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution. ### Monitoring There is limited information regarding Ceftazidime Monitoring in the drug label. # IV Compatibility - Ceftazidime for injection, when constituted as directed with Sterile Water for Injection should have the contents withdrawn within 4 hours. Solutions in Sterile Water for Injection in the infusion vial or in 0.9% Sodium Chloride Injection in VIAFLEX® small-volume containers that are frozen immediately after constitution are stable for 6 months when stored at -20°C. Do not force thaw by immersion in water baths or by microwave irradiation. Once thawed, solutions should not be refrozen. Thawed solutions may be stored for up to 24 hours at room temperature or for 7 days in a refrigerator. - Ceftazidime is compatible with the more commonly used IV infusion fluids. Solutions at concentrations between 1 and 40 mg/mL in 0.9% Sodium Chloride Injection; 1/6 M Sodium Lactate Injection; 5% Dextrose Injection; 5% Dextrose and 0.225% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 10% Dextrose Injection; Ringer's Injection, USP; Lactated Ringer's Injection, USP; 10% Invert Sugar in Water for Injection; and NORMOSOL®-M in 5% Dextrose Injection may be stored for up to 24 hours at room temperature or for 7 days if refrigerated. - Ceftazidime for injection is less stable in Sodium Bicarbonate Injection than in other IV fluids. It is not recommended as a diluent. Solutions of ceftazidime for injection in 5% Dextrose Injection and 0.9% Sodium Chloride Injection are stable for at least 6 hours at room temperature in plastic tubing, drip chambers, and volume control devices of common IV infusion sets. - Ceftazidime at a concentration of 4 mg/mL has been found compatible for 24 hours at room temperature or for 7 days under refrigeration in 0.9% Sodium Chloride Injection or 5% Dextrose Injection when admixed with: cefuroxime sodium 3 mg/mL, heparin 10 or 50 U/mL, or potassium chloride 10 or 40 mEq/L. - Vancomycin solution exhibits a physical incompatibility when mixed with a number of drugs, including ceftazidime. The likelihood of precipitation with ceftazidime is dependent on the concentrations of vancomycin and ceftazidime present. It is therefore recommended, when both drugs are to be administered by intermittent IV infusion, that they be given separately, flushing the IV lines (with 1 of the compatible IV fluids) between the administration of these 2 agents. Note: Parenteral drug products should be inspected visually for particulate matter before administration whenever solution and container permit. As with other cephalosporins, ceftazidime for injection powder, as well as solutions, tend to darken depending on storage conditions; within the stated recommendations, however, product potency is not adversely affected. # Overdosage - Ceftazidime overdosage has occurred in patients with renal failure. Reactions have included seizure activity, encephalopathy, asterixis, neuromuscular excitability, and coma. Patients who receive an acute overdosage should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis or peritoneal dialysis may aid in the removal of ceftazidime from the body. # Pharmacology ## Mechanism of Action - Ceftazidime is bactericidal in action, exerting its effect by inhibition of enzymes responsible for cell-wall synthesis. A wide range of gram-negative organisms is susceptible to ceftazidime in vitro, including strains resistant to gentamicin and other aminoglycosides. In addition, ceftazidime has been shown to be active against gram-positive organisms. It is highly stable to most clinically important beta-lactamases, plasmid or chromosomal, which are produced by both gram-negative and gram-positive organisms and, consequently, is active against many strains resistant to ampicillin and other cephalosporins. ## Structure - Ceftazidime is a semisynthetic, broad-spectrum, beta-lactam antibiotic for parenteral administration. It is the pentahydrate of pyridinium, 1-acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclooct-2-en-3-yl]methyl]-, hydroxide, inner salt, ]]]. It has the following structural formula: The molecular formula is C22H32N6O12S2, representing a molecular weight of 636.6. ## Pharmacodynamics There is limited information regarding Ceftazidime Pharmacodynamics in the drug label. ## Pharmacokinetics - After IV administration of 500 mg and 1 g doses of ceftazidime over 5 minutes to normal adult male volunteers, mean peak serum concentrations of 45 and 90 mcg/mL, respectively, were achieved. After IV infusion of 500 mg, 1 g, and 2 g doses of ceftazidime over 20 to 30 minutes to normal adult male volunteers, mean peak serum concentrations of 42, 69, and 170 mcg/mL, respectively, were achieved. The average serum concentrations following IV infusion of 500 mg, 1 g, and 2 g doses to these volunteers over an 8-hour interval are given in the following table: - The absorption and elimination of ceftazidime were directly proportional to the size of the dose. The half-life following IV administration was approximately 1.9 hours. Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. There was no evidence of accumulation of ceftazidime in the serum in individuals with normal renal function following multiple IV doses of 1 and 2 g every 8 hours for 10 days. - The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 g intravenously every 8 hours for 5 days. Therefore, a dosage adjustment from the normal recommended dosage is not required for patients with hepatic dysfunction, provided renal function is not impaired. - Approximately 80% to 90% of an IV dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. After the IV administration of single 500 mg or 1 g doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The elimination of ceftazidime by the kidneys resulted in high therapeutic concentrations in the urine. - The mean renal clearance of ceftazidime was approximately 100 mL/min. The calculated plasma clearance of approximately 115 mL/min indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid before dosing had no effect on the elimination kinetics of ceftazidime. This suggested that ceftazidime is eliminated by glomerular filtration and is not actively secreted by renal tubular mechanisms. Since ceftazidime is eliminated almost solely by the kidneys, its serum half-life is significantly prolonged in patients with impaired renal function. Consequently, dosage adjustments in such patients as described in the "Dosage and Administration" section are suggested. Therapeutic concentrations of ceftazidime are achieved in the following body tissues and fluids. ## Nonclinical Toxicology There is limited information regarding Ceftazidime Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Ceftazidime Clinical Studies in the drug label. # How Supplied - Ceftazidime for Injection, USP is a white to cream-colored crystalline powder supplied in Pharmacy Bulk Package Bottles as follows: ## Storage - Ceftazidime for injection in the dry state should be stored at 20° to 25°C (68° to 77°F) and protected from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Ceftazidime Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Ceftazidime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Fortaz - Tazicef # Look-Alike Drug Names There is limited information regarding Ceftazidime Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ceftazidime Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Ceftazidime is a cephalosporin that is FDA approved for the treatment of bacterial infections of gram negative, gram positive aerobic bacterias and for anaerobic bacterias. Common adverse reactions include diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Pneumonia: caused by Pseudomonas aeruginosa and other Pseudomonas spp.; Haemophilus influenzae, including ampicillin-resistant strains; Klebsiella spp.; Enterobacter spp; Proteus mirabilis; Escherichia coli; Serratia spp; Citrobacter spp; Streptococcus pneumoniae; and Staphylococcus aureus (methicillin-susceptible strains). - Caused by Pseudomonas aeruginosa; Klebsiella spp.; Escherichia coli; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Enterobacter spp.; Serratia spp.; Staphylococcus aureus (methicillin-susceptible strains); and Streptococcus pyogenes (group A beta-hemolytic streptococci). - Both complicated and uncomplicated, caused by Pseudomonas aeruginosa; Enterobacter spp; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Klebsiella spp.; and Escherichia coli. - Caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin-susceptible strains). - Caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible strains). - Including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli. - Including peritonitis caused by Escherichia coli, Klebsiella spp., and Staphylococcus aureus (methicillin-susceptible strains) and polymicrobial infections caused by aerobic and anaerobic organisms and Bacteroides spp (many strains of Bacteroides fragilis are resistant). - Including meningitis, caused] by Haemophilus influenzae and Neisseria meningitidis. Ceftazidime has also been used successfully in a limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae. - The usual adult dosage is 1 gram administered intravenously every 8 to 12 hours. The dosage should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient. - The guidelines for dosage of ceftazidime for injection are listed in the following table. The following dosage schedule is recommended: - In patients with severe infections who would normally receive 6 grams of ceftazidime for injection daily were it not for renal insufficiency, the unit dose given in the table above may be increased by 50% or the dosing frequency may be increased appropriately. Further dosing should be determined by therapeutic monitoring, severity of the infection, and susceptibility of the causative organism. - In pediatric patients as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass, and the dosing frequency should be reduced in cases of renal insufficiency. - In patients undergoing hemodialysis, a loading dose of 1 gram is recommended, followed by 1 gram after each hemodialysis period. Ceftazidime for injection can also be used in patients undergoing intraperitoneal dialysis and continuous ambulatory peritoneal dialysis. In such patients, a loading dose of 1 gram of ceftazidime for injection may be given, followed by 500 mg every 24 hours. In addition to IV use, ceftazidime for injection can be incorporated in the dialysis fluid at a concentration of 250 mg for 2 L of dialysis fluid. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Single Therapy - Double Therapy Ceftazidime + Amikacin Ceftazidine + Tobramycin - Ceftazidime + Amikacin - Ceftazidine + Tobramycin ### Non–Guideline-Supported Use - Dosage Scheme 1: 4 milligrams/kilogram/hour after a 12 milligrams/kilogram (mg/kg) loading dose Scheme 2: 40 mg/kg every 8 hours - Scheme 1: 4 milligrams/kilogram/hour after a 12 milligrams/kilogram (mg/kg) loading dose - Scheme 2: 40 mg/kg every 8 hours # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - An antipseudomonal drug, such as ceftazidime or imipenem, should be added for neutropenic patients, with the addition of an aminoglycoside if infection with pseudomonas is likely - For patients with neutropenia, chronic lung disease other than asthma (lymphoid interstitial pneumonia, bronchiectasis), or indwelling venous catheter, consider regimens that include activity against P. aeruginosa, such as cefepime or ceftazidime instead of ceftriaxone [3] - Single Therapy - Double Therapy Ceftazidime + Amikacin Ceftazidine + Tobramycin - Ceftazidime + Amikacin - Ceftazidine + Tobramycin ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftazidime in pediatric patients. # Contraindications - Ceftazidime for injection is contraindicated in patients who have shown hypersensitivity to ceftazidime or the cephalosporin group of antibiotics. # Warnings ### Hypersensitivity - Before therapy with Ceftazidime for injection is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. if this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. if an allergic reaction to ceftazidime for injection occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, IV fluids, iv antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. ### Clostridium Difficile Associated Diarrhea - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftazidime for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Elevated levels of ceftazidime in patients with renal insufficiency can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia. # Adverse Reactions ## Clinical Trials Experience Ceftazidime is generally well tolerated. The incidence of adverse reactions associated with the administration of ceftazidime was low in clinical trials. The most common were local reactions following IV injection and allergic and gastrointestinal reactions. Other adverse reactions were encountered infrequently. No disulfiram-like reactions were reported. The following adverse effects from clinical trials were considered to be either related to ceftazidime therapy or were of uncertain etiology: - Phlebitis - Inflammation at the site of injection (1 in 69 patients). - Pruritus - Rash - Fever - Toxic epidermal necrolysis - Stevens-Johnson syndrome - Erythema multiform - Angioedema - Anaphylaxis (bronchospasm and/or hypotension) have been reported very rarely. - Diarrhea - Nausea - Vomiting - Abdominal pain - The onset of pseudomembranous colitis symptoms may occur during or after treatment - Headache - Dizziness and - Paresthesia - Seizures - Encephalopathy - Coma - Asterixis - Neuromuscular excitability - Myoclonia have been reported in renally impaired patients treated with unadjusted dosing regimens of ceftazidime. - Candidiasis - Vaginitis - Rare cases of hemolytic anemia - Transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and lymphocytosis were seen very rarely. - Eosinophilia - Positive Coombs test without hemolysis - Thrombocytosis - Liver enzyme elevation: Aspartate aminotransferase (AST, SGOT) Alanine aminotransferase (ALT, SGPT) LDH GGT Alkaline phosphatase - Aspartate aminotransferase (AST, SGOT) - Alanine aminotransferase (ALT, SGPT) - LDH - GGT - Alkaline phosphatase - As with some other cephalosporins, transient elevations of blood urea, blood urea nitrogen, and/or serum creatinine were observed occasionally. ## Postmarketing Experience In addition to the adverse events reported during clinical trials, the following events have been observed during clinical practice in patients treated with ceftazidime and were reported spontaneously. For some of these events, data are insufficient to allow an estimate of incidence or to establish causation. - Anaphylaxis - Allergic reactions - Urticaria - Pain at injection site - Hyperbilirubinemia - Jaundice - Renal impairment In addition to the adverse reactions listed above that have been observed in patients treated with ceftazidime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: - Adverse Reactions: Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage. - Altered Laboratory Tests: Prolonged prothrombin time, false-positive test for urinary glucose, pancytopenia. # Drug Interactions - Nephrotoxicity has been reported following concomitant administration of cephalosporins with aminoglycoside antibiotics or potent diuretics such as furosemide. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycosidic antibiotics. Nephrotoxicity and ototoxicity were not noted when ceftazidime was given alone in clinical trials. - Chloramphenicol has been shown to be antagonistic to beta-lactam antibiotics, including ceftazidime, based on in vitro studies and time kill curves with enteric gram-negative bacilli. Due to the possibility of antagonism in vivo, particularly when bactericidal activity is desired, this drug combination should be avoided. - In common with other antibiotics, ceftazidime may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. - The administration of ceftazidime may result in a false-positive reaction for glucose in the urine when using CLINITEST® tablets, Benedict's solution, or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX®) be used. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ceftazidime for injection. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftazidime in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ceftazidime during labor and delivery. ### Nursing Mothers - Ceftazidime is excreted in human milk in low concentrations. Caution should be exercised when ceftazidime is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Ceftazidime in pediatric settings. ### Geriatic Use - Of the 2,221 subjects who received ceftazidime in 11 clinical studies, 824 (37%) were 65 and over while 391 (18%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater susceptibility of some older individuals to drug effects cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Ceftazidime with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ceftazidime with respect to specific racial populations. ### Renal Impairment - Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (glomerular filtration rate [GFR] <50 mL/min), it is recommended that the dosage of ceftazidime be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1 gram of ceftazidime may be given. An estimate of GFR should be made to determine the appropriate maintenance dosage. ### Hepatic Impairment - No adjustment in dosage is required for patients with hepatic dysfunction. ### Females of Reproductive Potential and Males - Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse Micronucleus test and an Ames test were both negative for mutagenic effects. ### Immunocompromised Patients There is no FDA guidance one the use of Ceftazidime in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ceftazidime for injection may be given intravenously. Intra-arterial administration should be avoided. The IV route is preferable for patients with bacterial septicemia, bacterial meningitis, peritonitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or pending. - Not for direct infusion. This Pharmacy Bulk Package is for use in a hospital pharmacy admixture service, only in a suitable work area, such as a laminar flow hood. Using aseptic technique, the container closure may be penetrated only one time using a suitable sterile dispensing set or transfer device that allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 4 HOURS from initial closure entry is permitted to complete fluid transfer operations. This time limit should begin with the introduction of the solvent or diluent into the Pharmacy Bulk Package. Discard any unused portion after 4 hours. Not for direct infusion. This pharmacy bulk package is not intended to be dispensed as a unit. - For IV infusion, constitute the 6 g Pharmacy Bulk Package bottle with Sterile Water for Injection and add an appropriate quantity of the resulting solution to an IV container with one of the compatible IV fluids. - Intermittent IV infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution. ### Monitoring There is limited information regarding Ceftazidime Monitoring in the drug label. # IV Compatibility - Ceftazidime for injection, when constituted as directed with Sterile Water for Injection should have the contents withdrawn within 4 hours. Solutions in Sterile Water for Injection in the infusion vial or in 0.9% Sodium Chloride Injection in VIAFLEX® small-volume containers that are frozen immediately after constitution are stable for 6 months when stored at -20°C. Do not force thaw by immersion in water baths or by microwave irradiation. Once thawed, solutions should not be refrozen. Thawed solutions may be stored for up to 24 hours at room temperature or for 7 days in a refrigerator. - Ceftazidime is compatible with the more commonly used IV infusion fluids. Solutions at concentrations between 1 and 40 mg/mL in 0.9% Sodium Chloride Injection; 1/6 M Sodium Lactate Injection; 5% Dextrose Injection; 5% Dextrose and 0.225% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 10% Dextrose Injection; Ringer's Injection, USP; Lactated Ringer's Injection, USP; 10% Invert Sugar in Water for Injection; and NORMOSOL®-M in 5% Dextrose Injection may be stored for up to 24 hours at room temperature or for 7 days if refrigerated. - Ceftazidime for injection is less stable in Sodium Bicarbonate Injection than in other IV fluids. It is not recommended as a diluent. Solutions of ceftazidime for injection in 5% Dextrose Injection and 0.9% Sodium Chloride Injection are stable for at least 6 hours at room temperature in plastic tubing, drip chambers, and volume control devices of common IV infusion sets. - Ceftazidime at a concentration of 4 mg/mL has been found compatible for 24 hours at room temperature or for 7 days under refrigeration in 0.9% Sodium Chloride Injection or 5% Dextrose Injection when admixed with: cefuroxime sodium 3 mg/mL, heparin 10 or 50 U/mL, or potassium chloride 10 or 40 mEq/L. - Vancomycin solution exhibits a physical incompatibility when mixed with a number of drugs, including ceftazidime. The likelihood of precipitation with ceftazidime is dependent on the concentrations of vancomycin and ceftazidime present. It is therefore recommended, when both drugs are to be administered by intermittent IV infusion, that they be given separately, flushing the IV lines (with 1 of the compatible IV fluids) between the administration of these 2 agents. Note: Parenteral drug products should be inspected visually for particulate matter before administration whenever solution and container permit. As with other cephalosporins, ceftazidime for injection powder, as well as solutions, tend to darken depending on storage conditions; within the stated recommendations, however, product potency is not adversely affected. # Overdosage - Ceftazidime overdosage has occurred in patients with renal failure. Reactions have included seizure activity, encephalopathy, asterixis, neuromuscular excitability, and coma. Patients who receive an acute overdosage should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis or peritoneal dialysis may aid in the removal of ceftazidime from the body. # Pharmacology ## Mechanism of Action - Ceftazidime is bactericidal in action, exerting its effect by inhibition of enzymes responsible for cell-wall synthesis. A wide range of gram-negative organisms is susceptible to ceftazidime in vitro, including strains resistant to gentamicin and other aminoglycosides. In addition, ceftazidime has been shown to be active against gram-positive organisms. It is highly stable to most clinically important beta-lactamases, plasmid or chromosomal, which are produced by both gram-negative and gram-positive organisms and, consequently, is active against many strains resistant to ampicillin and other cephalosporins. ## Structure - Ceftazidime is a semisynthetic, broad-spectrum, beta-lactam antibiotic for parenteral administration. It is the pentahydrate of pyridinium, 1-[[7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-, hydroxide, inner salt, [6R-[6α,7β(Z)]]]]. It has the following structural formula: The molecular formula is C22H32N6O12S2, representing a molecular weight of 636.6. ## Pharmacodynamics There is limited information regarding Ceftazidime Pharmacodynamics in the drug label. ## Pharmacokinetics - After IV administration of 500 mg and 1 g doses of ceftazidime over 5 minutes to normal adult male volunteers, mean peak serum concentrations of 45 and 90 mcg/mL, respectively, were achieved. After IV infusion of 500 mg, 1 g, and 2 g doses of ceftazidime over 20 to 30 minutes to normal adult male volunteers, mean peak serum concentrations of 42, 69, and 170 mcg/mL, respectively, were achieved. The average serum concentrations following IV infusion of 500 mg, 1 g, and 2 g doses to these volunteers over an 8-hour interval are given in the following table: - The absorption and elimination of ceftazidime were directly proportional to the size of the dose. The half-life following IV administration was approximately 1.9 hours. Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. There was no evidence of accumulation of ceftazidime in the serum in individuals with normal renal function following multiple IV doses of 1 and 2 g every 8 hours for 10 days. - The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 g intravenously every 8 hours for 5 days. Therefore, a dosage adjustment from the normal recommended dosage is not required for patients with hepatic dysfunction, provided renal function is not impaired. - Approximately 80% to 90% of an IV dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. After the IV administration of single 500 mg or 1 g doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The elimination of ceftazidime by the kidneys resulted in high therapeutic concentrations in the urine. - The mean renal clearance of ceftazidime was approximately 100 mL/min. The calculated plasma clearance of approximately 115 mL/min indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid before dosing had no effect on the elimination kinetics of ceftazidime. This suggested that ceftazidime is eliminated by glomerular filtration and is not actively secreted by renal tubular mechanisms. Since ceftazidime is eliminated almost solely by the kidneys, its serum half-life is significantly prolonged in patients with impaired renal function. Consequently, dosage adjustments in such patients as described in the "Dosage and Administration" section are suggested. Therapeutic concentrations of ceftazidime are achieved in the following body tissues and fluids. ## Nonclinical Toxicology There is limited information regarding Ceftazidime Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Ceftazidime Clinical Studies in the drug label. # How Supplied - Ceftazidime for Injection, USP is a white to cream-colored crystalline powder supplied in Pharmacy Bulk Package Bottles as follows: ## Storage - Ceftazidime for injection in the dry state should be stored at 20° to 25°C (68° to 77°F) and protected from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Ceftazidime Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Ceftazidime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Fortaz - Tazicef # Look-Alike Drug Names There is limited information regarding Ceftazidime Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ceftazidime
073fc464bdf752a5b01b4107caea0d9e91237c8b	wikidoc	Ceftizoxime	Ceftizoxime # 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 Ceftizoxime is a 3rd Generation Cephalosporin that is FDA approved for the treatment of Lower Respiratory Tract Infections, Urinary Tract Infections, Gonorrhea, Pelvic Inflammatory Disease, IntraAbdominal Infections, Septicemia, Skin and Skin Structure Infections, Bone and Joint Infections, Meningitis,. Common adverse reactions include Injection site pain, Pruritus, Rash, Increased liver enzymes, Fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Cefizox (ceftizoxime for injection, USP) is indicated in the treatment of infections due to susceptible strains of the microorganisms listed below. - Lower Respiratory Tract Infections caused by Klebsiella spp.; Proteus mirabilis; Escherichia coli; Haemophilus influenzae including ampicillinresistant strains; Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Serratia spp.; Enterobacter spp.; Bacteroides spp.; and Streptococcus spp. including S. pneumoniae, but excluding enterococci. - Urinary Tract Infections caused by Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Escherichia coli; Pseudomonas spp. including P.aeruginosa; Proteus mirabilis; P. vulgaris; Providencia rettgeri (formerly Proteus rettgeri) and Morganella morganii (formerly Proteus morganii); Klebsiella spp.; Serratia spp. including S. marcescens; and Enterobacter spp. - Gonorrhea including uncomplicated cervical and urethral gonorrhea caused by Neisseria gonorrhoeae. - Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae, Escherichia coli or Streptococcus agalactiae. NOTE: Ceftizoxime, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added. - IntraAbdominal Infections caused by Escherichia coli; Staphylococcusepidermidis; Streptococcus spp. (excluding enterococci); Enterobacter spp.; Klebsiella spp.; Bacteroides spp. including B. fragilis; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp. - Septicemia caused by Streptococcus spp. including S. pneumoniae (but excluding enterococci); Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Escherichia coli; Bacteroides spp. including B. fragilis; Klebsiella spp.; and Serratia spp. - Skin and Skin Structure Infections caused by Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Staphylococcus epidermidis; Escherichia coli; Klebsiella spp.; Streptococcus spp. including Streptococcus pyogenes (but excluding enterococci); Proteus mirabilis; Serratia spp.; Enterobacter spp.; Bacteroides spp. including B. fragilis; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp. - Bone and Joint Infections caused by Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Streptococcus spp. (excluding enterococci); Proteusmirabilis; Bacteroides spp.; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp. - Meningitis caused by Haemophilus influenzae. Cefizox has also been used successfully in the treatment of a limited number of pediatric and adult cases of meningitis caused by Streptococcus pneumoniae. - Cefizox has been effective in the treatment of seriously ill, compromised patients, including those who were debilitated, immunosuppressed, or neutropenic. - Infections caused by aerobic gramnegative and by mixtures of organisms resistant to other cephalosporins, aminoglycosides, or penicillins have responded to treatment with Cefizox. - Because of the serious nature of some urinary tract infections due to P. aeruginosa and because many strains of Pseudomonas species are only moderately susceptible to Cefizox, higher dosage is recommended. Other therapy should be instituted if the response is not prompt. - Susceptibility studies on specimens obtained prior to therapy should be used to determine the response of causative organisms to Cefizox. Therapy with Cefizox may be initiated pending results of the studies; however, treatment should be adjusted according to study findings. In serious infections, Cefizox has been used - concomitantly with aminoglycosides. Before using Cefizox - concomitantly with other antibiotics, the prescribing information for those agents - should be reviewed for contraindications, warnings, precautions, and adverse reactions. Renal function should be carefully monitored. - To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefizox and other antibacterial drugs, Cefizox should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. ### Dosage - The usual adult dosage is 1 or 2 grams of Cefizox (ceftizoxime for injection, USP) every 8 to 12 hours. Proper dosage and route of administration should be determined by the condition of the patient, severity of the infection, and susceptibility of the causative organisms. - Because of the serious nature of urinary tract infections due to P. aeruginosa and because many strains of Pseudomonas species are only moderately susceptible to Cefizox, higher dosage is recommended. Other therapy should be instituted if the response is not prompt. - A single, 1 gram IM dose is the usual dose for treatment of uncomplicated gonorrhea. - The IV route may be preferable for patients with bacterial septicemia, localized parenchymal abscesses (such as intraabdominal abscess), peritonitis, or other severe or lifethreatening infections. - In those with normal renal function, the IV dosage for such infections is 2 to 12 grams of Cefizox (ceftizoxime for injection, USP) daily. In conditions such as bacterial septicemia, 6 to 12 grams/day may be given initially by the IV route for several days, and the dosage may then be gradually reduced according to clinical response and laboratory findings. - Dosage may be increased to a total daily dose of 200 mg/kg (not to exceed the maximum adult dose for serious infection). - Modification of Cefizox dosage is necessary in patients with impaired renal function. Following an initial loading dose of 500 mg-1 gram IM or IV, the maintenance dosing schedule shown below should be followed. Further dosing should be determined by therapeutic monitoring, severity of the infection, and susceptibility of the causative organisms. - When only the serum creatinine level is available, creatinine clearance may be calculated from the following formula. The serum creatinine level should represent current renal function at the steady state. - Females are 0.85 of the calculated clearance values for males. - In patients undergoing hemodialysis, no additional supplemental dosing is required following hemodialysis; however, dosing should be timed so that the patient receives the dose (according to the table below) at the end of the dialysis. - RECONSTITUTION - IM Administration: Reconstitute with Sterile Water for Injection. SHAKE WELL. - These solutions of Cefizox are stable 24 hours at room temperature or 96 hours if refrigerated (5ºC). - Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, then the drug solution should be discarded. Reconstituted solutions may range from yellow to amber without changes in potency. - Piggyback Vials: Reconstitute with 50 to 100 mL of Sodium Chloride Injection or any other IV solution listed below. - SHAKE WELL. - Administer with primary IV fluids, as a single dose. These Piggyback vial solutions of Cefizox are stable 24 hours at room temperature or 96 hours if refrigerated (5ºC). - A solution of 1 gram Cefizox in 13 mL Sterile Water for Injection is isotonic. - IM Injection - Inject well within the body of a relatively large muscle. Aspiration is necessary to avoid inadvertent injection into a blood vessel. When administering 2 gram IM doses, the dose should be divided and given in different large muscle masses. - IV Administration - Direct (bolus) injection, slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below). Intermittent or continuous infusion, dilute reconstituted Cefizox in 50 to 100 mL of one of the following solutions: - Sodium Chloride Injection - 5% or 10% Dextrose Injection - 5% Dextrose and 0.9%, 0.45%, or 0.2% Sodium Chloride Injection - Ringer’s Injection - Lactated Ringer’s Injection - Invert Sugar 10% in Sterile Water for Injection - 5% Sodium Bicarbonate in Sterile Water for Injection - 5% Dextrose in Lactated Ringer’s Injection (only when reconstituted with 4% Sodium Bicarbonate Injection) - In these fluids, Cefizox is stable 24 hours at room temperature or 96 hours if refrigerated (5ºC). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ceftizoxime in adult patients. ### Non–Guideline-Supported Use - Bacterial infectious disease - Cancer - Gonorrhea, Disseminated - Postoperative infection; Prophylaxis # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Dosage ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ceftizoxime in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftizoxime in pediatric patients. # Contraindications - Cefizox (ceftizoxime for injection, USP) is contraindicated in patients who have known allergy to the drug. # Warnings - BEFORE THERAPY WITH CEFIZOX IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFIZOX, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLINSENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS HYPERSENSITIVITY AMONG BETALACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFIZOX OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED. - Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftizoxime, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. - Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibioticassociated” colitis. - After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. ### Precautions - As with all broadspectrum antibiotics, Cefizox (ceftizoxime for injection, USP) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. - Although Cefizox has not been shown to produce an alteration in renal function, renal status should be evaluated, especially in seriously ill patients receiving maximum dose therapy. As with any antibiotic, prolonged use may result in overgrowth of nonsusceptible organisms. Careful observation is essential; appropriate measures should be taken if superinfection occurs. - Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. - Prescribing Cefizox in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. # Adverse Reactions ## Clinical Trials Experience - Cefizox® (ceftizoxime for injection, USP) is generally well tolerated. The most frequent adverse reactions (greater than 1% but less than 5%) are: - Rash, pruritus, fever - Transient elevation in AST (SGOT), ALT (SGPT), and alkaline phosphatase. - Transient eosinophilia, thrombocytosis. Some individuals have developed a positive Coombs test. - Injection site--Burning, cellulitis, phlebitis with IV administration, pain, induration, tenderness, paresthesia. - The less frequent adverse reactions (less than 1%) are: - Numbness and anaphylaxis have been reported rarely. - Elevation of bilirubin has been reported rarely. - Transient elevations of BUN and creatinine have been occasionally observed with Cefizox. - Anemia, including hemolytic anemia with occasional fatal outcome, leukopenia, neutropenia, and thrombocytopenia have been reported rarely. - Vaginitis has occurred rarely. - Diarrhea; nausea and vomiting have been reported occasionally. - Symptoms of pseudomembranous colitis can appear during or after antibiotic treatment. - In addition to the adverse reactions listed above which have been observed in patients treated with ceftizoxime, the following adverse reactions and altered laboratory tests have been reported for cephalosporinclass antibiotics: - StevensJohnson syndrome, erythema multiforme, toxic epidermal necrolysis, serumsickness like reaction, toxic nephropathy, aplastic anemia, hemorrhage, prolonged prothrombin time, elevated LDH, pancytopenia, and agranulocytosis. - Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment, when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Ceftizoxime in the drug label. # Drug Interactions - Although the occurrence has not been reported with Cefizox, nephrotoxicity has been reported following concomitant administration of other cephalosporins and aminoglycosides. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies performed in rats and rabbits have revealed no evidence of impaired fertility or harm to the fetus due to Cefizox. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human effects, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftizoxime in women who are pregnant. ### Labor and Delivery - Safety of Cefizox use during labor and delivery has not been established. ### Nursing Mothers - Cefizox is excreted in human milk in low concentrations. Caution should be exercised when Cefizox is administered to a nursing woman. ### Pediatric Use - Safety and efficacy in pediatric patients from birth to six months of age have not been established. In pediatric patients six months of age and older, treatment with Cefizox has been associated with transient elevated levels of eosinophils, AST (SGOT), ALT (SGPT), and CPK (creatine phosphokinase). The CPK elevation may be related to IM administration. The potential for the toxic effect in pediatric patients from chemicals that may leach from the singledose IV preparation in plastic has not been determined. ### Geriatic Use - Clinical studies of ceftizoxime did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Ceftizoxime with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ceftizoxime with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ceftizoxime in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ceftizoxime in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ceftizoxime in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ceftizoxime in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. # IV Compatibility There is limited information regarding IV Compatibility of Ceftizoxime in the drug label. # Overdosage There is limited information regarding Overdose of Ceftizoxime in the drug label. # Pharmacology ## Mechanism of Action - The bactericidal action of ceftizoxime results from inhibition of cellwall synthesis. Ceftizoxime is highly resistant to a broad spectrum of betalactamases (penicillinase and cephalosporinase), including Richmond types I, II, III, TEM, and IV, produced by both aerobic and anaerobic grampositive and gramnegative organisms. ## Structure - Cefizox® (ceftizoxime for injection, USP) is a sterile, semisynthetic, broadspectrum, betalactamase resistant cephalosporin antibiotic for parenteral (IV, IM) administration. It is the sodium salt of 7(2,3dihydro2imino4 thiazolyl) (methoxyimino) acetyl amino8oxo5thia1azabicyclo oct2ene2carboxylic acid. Its sodium content is approximately 60 mg (2.6 mEq) per gram of ceftizoxime activity. - It has the following structural formula: - Ceftizoxime for injection, USP is a white to pale yellow crystalline powder. - Cefizox is supplied in vials equivalent to 500 mg, 1 gram or 2 grams of ceftizoxime, and in Piggyback Vials for IV admixture equivalent to 1 gram or 2 grams of ceftizoxime. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ceftizoxime in the drug label. ## Pharmacokinetics - The table below demonstrates the serum levels and duration of Cefizox (ceftizoxime for injection, USP) following IM administration of 500 mg and 1 gram doses, respectively, to normal volunteers. - A serum halflife of approximately 1.7 hours was observed after IV or IM administration. - Cefizox is 30% protein bound. - Cefizox is not metabolized, and is excreted virtually unchanged by the kidneys in 24 hours. This provides a high urinary concentration. Concentrations greater than 6000 μg/mL have been achieved in the urine by 2 hours after a 1 gram dose of Cefizox intravenously. Probenecid slows tubular secretion and produces even higher serum levels, increasing the duration of measurable serum concentrations. - Cefizox achieves therapeutic levels in various body fluids, e.g., cerebrospinal fluid (in patients with inflamed meninges), bile, surgical wound fluid, pleural fluid, aqueous humor, ascitic fluid, peritoneal fluid, prostatic fluid and saliva, and in the following body tissues: heart, gallbladder, bone, biliary, peritoneal, prostatic, and uterine. - In clinical experience to date, no disulfiramlike reactions have been reported with Cefizox. - The bactericidal action of ceftizoxime results from inhibition of cellwall synthesis. Ceftizoxime is highly resistant to a broad spectrum of betalactamases (penicillinase and cephalosporinase), including Richmond types I, II, III, TEM, and IV, produced by both aerobic and anaerobic grampositive and gramnegative organisms. Ceftizoxime has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections described in the INDICATIONS AND USAGE section: - Staphylococcus aureus (including penicillinase producing strains) - NOTE: Methicillinresistant staphylococci are resistant to cephalosporins, including ceftizoxime. - Staphylococcus epidermidis (including penicillinase producing strains) - Streptococcus agalactiae - Streptococcus pneumoniae - Streptococcus pyogenes - NOTE: A streptococcal isolate that is susceptible to penicillin can be considered susceptible to ceftizoxime. - NOTE: Ceftizoxime is usually inactive against most strains of Enterococcus faecalis. - Enterobacter spp. - Escherichia coli - Haemophilus influenzae (including ampicillinresistant strains) - Klebsiella pneumoniae - Morganella morganii - Neisseria gonorrhoeae - Proteus mirabilis - Proteus vulgaris - Providencia rettgeri - Pseudomonas aeruginosa - Serratia marcescens - Bacteroides spp. - Peptococcus spp. - Peptostreptococcus spp. - The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftizoxime. However, the safety and effectiveness of ceftizoxime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. - Aeromonas hydrophila - Citrobacter spp. - Moraxellacatarrhalis - Neisseria meningitidis - Providencia stuartii - Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ceftizoxime powder. The MIC values should be interpreted according to the following criteria: - A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable, other therapy should be selected. - Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ceftizoxime powder should provide the following MIC values: - Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-μg ceftizoxime to test the susceptibility of microorganisms to ceftizoxime. - Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-μg ceftizoxime disk should be interpreted according to the following criteria: - Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ceftizoxime. - As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-μg ceftizoxime disk should provide the following zone diameters in these laboratory test quality control strains: - For anaerobic bacteria, the susceptibility to ceftizoxime as MICs can be determined by standardized test methods. Agar dilution results can vary widely when using ceftizoxime. It is recommended that broth microdilution method be used when possible.3 The MIC values obtained should be interpreted according to following criteria: - Interpretation is identical to that described in Susceptibility Testing: Dilution Techniques. - As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ceftizoxime powder should provide the following MIC values: - Most strains of Pseudomonas aeruginosa are moderately susceptible to ceftizoxime. - Ceftizoxime achieves high levels in the urine (greater than 6000 μg/mL at 2 hours with 1 gram IV) and, therefore, the following zone sizes should be used when testing ceftizoxime for treatment of urinary tract infections caused by Pseudomonas aeruginosa. - Susceptible organisms produce zones of 20 mm or greater, indicating that the test organism is likely to respond to therapy. - Organisms that produce zones of 11 to 19 mm are expected to be susceptible when the infection is confined to the urinary tract (in which high antibiotic levels are attained). - Resistant organisms produce zones of 10 mm or less, indicating that other therapy should be selected. ## Nonclinical Toxicology - Longterm studies in animals to evaluate the carcinogenic potential of ceftizoxime have not been conducted. - In an in vitro bacterial cell assay (i.e., Ames test), there was no evidence of mutagenicity at ceftizoxime concentrations of 0.0010.5 mcg/plate. Ceftizoxime did not produce increases in micronuclei in the in vivo mouse micronucleus test when given to animals at doses up to 7500 mg/kg, approximately six times greater than the maximum human daily dose on a mg/M2 basis. - Ceftizoxime had no effect on fertility when administered subcutaneously to rats at daily doses of up to 1000 mg/kg/day, approximately two times the maximum human daily dose on a mg/M2 basis. Ceftizoxime produced no histological changes in the sexual organs of male and female dogs when given intravenously for thirteen weeks at a dose of 1000 mg/kg/day, approximately five times greater than the maximum human daily dose on a mg/M2 basis. # Clinical Studies There is limited information regarding Clinical Studies of Ceftizoxime in the drug label. # How Supplied - Cefizox® (ceftizoxime for injection, USP) - Equivalent to 500 mg ceftizoxime in 10 mL, singledose, fliptop vials, individually packaged - Equivalent to 1 gram ceftizoxime in 20 mL, singledose, fliptop vials, individually packaged - Equivalent to 1 gram ceftizoxime in 100 mL, singledose, Piggyback, fliptop vials, packaged in tens - Equivalent to 2 grams ceftizoxime in 20 mL, singledose, fliptop vials, individually packaged - Equivalent to 2 grams ceftizoxime in 100 mL, singledose, Piggyback, fliptop vials, packaged in tens ## Storage - Unreconstituted Cefizox should be protected from excessive light, and stored at controlled room temperature (59º86ºF) in the original package until used. # Images ## Drug Images ## Package and Label Display Panel ### Ingredients and Appearance # Patient Counseling Information - Patients should be counseled that antibacterial drugs including Cefizox should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefizox is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefizox or other antibacterial drugs in the future. # Precautions with Alcohol - Alcohol-Ceftizoxime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cefizox® # Look-Alike Drug Names There is limited information regarding Ceftizoxime Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ceftizoxime Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Ceftizoxime is a 3rd Generation Cephalosporin that is FDA approved for the treatment of Lower Respiratory Tract Infections, Urinary Tract Infections, Gonorrhea, Pelvic Inflammatory Disease, IntraAbdominal Infections, Septicemia, Skin and Skin Structure Infections, Bone and Joint Infections, Meningitis,. Common adverse reactions include Injection site pain, Pruritus, Rash, Increased liver enzymes, Fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Cefizox (ceftizoxime for injection, USP) is indicated in the treatment of infections due to susceptible strains of the microorganisms listed below. - Lower Respiratory Tract Infections caused by Klebsiella spp.; Proteus mirabilis; Escherichia coli; Haemophilus influenzae including ampicillinresistant strains; Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Serratia spp.; Enterobacter spp.; Bacteroides spp.; and Streptococcus spp. including S. pneumoniae, but excluding enterococci. - Urinary Tract Infections caused by Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Escherichia coli; Pseudomonas spp. including P.aeruginosa; Proteus mirabilis; P. vulgaris; Providencia rettgeri (formerly Proteus rettgeri) and Morganella morganii (formerly Proteus morganii); Klebsiella spp.; Serratia spp. including S. marcescens; and Enterobacter spp. - Gonorrhea including uncomplicated cervical and urethral gonorrhea caused by Neisseria gonorrhoeae. - Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae, Escherichia coli or Streptococcus agalactiae. NOTE: Ceftizoxime, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added. - IntraAbdominal Infections caused by Escherichia coli; Staphylococcusepidermidis; Streptococcus spp. (excluding enterococci); Enterobacter spp.; Klebsiella spp.; Bacteroides spp. including B. fragilis; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp. - Septicemia caused by Streptococcus spp. including S. pneumoniae (but excluding enterococci); Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Escherichia coli; Bacteroides spp. including B. fragilis; Klebsiella spp.; and Serratia spp. - Skin and Skin Structure Infections caused by Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Staphylococcus epidermidis; Escherichia coli; Klebsiella spp.; Streptococcus spp. including Streptococcus pyogenes (but excluding enterococci); Proteus mirabilis; Serratia spp.; Enterobacter spp.; Bacteroides spp. including B. fragilis; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp. - Bone and Joint Infections caused by Staphylococcus aureus (penicillinase and nonpenicillinaseproducing); Streptococcus spp. (excluding enterococci); Proteusmirabilis; Bacteroides spp.; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp. - Meningitis caused by Haemophilus influenzae. Cefizox has also been used successfully in the treatment of a limited number of pediatric and adult cases of meningitis caused by Streptococcus pneumoniae. - Cefizox has been effective in the treatment of seriously ill, compromised patients, including those who were debilitated, immunosuppressed, or neutropenic. - Infections caused by aerobic gramnegative and by mixtures of organisms resistant to other cephalosporins, aminoglycosides, or penicillins have responded to treatment with Cefizox. - Because of the serious nature of some urinary tract infections due to P. aeruginosa and because many strains of Pseudomonas species are only moderately susceptible to Cefizox, higher dosage is recommended. Other therapy should be instituted if the response is not prompt. - Susceptibility studies on specimens obtained prior to therapy should be used to determine the response of causative organisms to Cefizox. Therapy with Cefizox may be initiated pending results of the studies; however, treatment should be adjusted according to study findings. In serious infections, Cefizox has been used - concomitantly with aminoglycosides. Before using Cefizox - concomitantly with other antibiotics, the prescribing information for those agents - should be reviewed for contraindications, warnings, precautions, and adverse reactions. Renal function should be carefully monitored. - To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefizox and other antibacterial drugs, Cefizox should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. ### Dosage - The usual adult dosage is 1 or 2 grams of Cefizox (ceftizoxime for injection, USP) every 8 to 12 hours. Proper dosage and route of administration should be determined by the condition of the patient, severity of the infection, and susceptibility of the causative organisms. - Because of the serious nature of urinary tract infections due to P. aeruginosa and because many strains of Pseudomonas species are only moderately susceptible to Cefizox, higher dosage is recommended. Other therapy should be instituted if the response is not prompt. - A single, 1 gram IM dose is the usual dose for treatment of uncomplicated gonorrhea. - The IV route may be preferable for patients with bacterial septicemia, localized parenchymal abscesses (such as intraabdominal abscess), peritonitis, or other severe or lifethreatening infections. - In those with normal renal function, the IV dosage for such infections is 2 to 12 grams of Cefizox (ceftizoxime for injection, USP) daily. In conditions such as bacterial septicemia, 6 to 12 grams/day may be given initially by the IV route for several days, and the dosage may then be gradually reduced according to clinical response and laboratory findings. - Dosage may be increased to a total daily dose of 200 mg/kg (not to exceed the maximum adult dose for serious infection). - Modification of Cefizox dosage is necessary in patients with impaired renal function. Following an initial loading dose of 500 mg-1 gram IM or IV, the maintenance dosing schedule shown below should be followed. Further dosing should be determined by therapeutic monitoring, severity of the infection, and susceptibility of the causative organisms. - When only the serum creatinine level is available, creatinine clearance may be calculated from the following formula. The serum creatinine level should represent current renal function at the steady state. - Females are 0.85 of the calculated clearance values for males. - In patients undergoing hemodialysis, no additional supplemental dosing is required following hemodialysis; however, dosing should be timed so that the patient receives the dose (according to the table below) at the end of the dialysis. - RECONSTITUTION - IM Administration: Reconstitute with Sterile Water for Injection. SHAKE WELL. - These solutions of Cefizox are stable 24 hours at room temperature or 96 hours if refrigerated (5ºC). - Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, then the drug solution should be discarded. Reconstituted solutions may range from yellow to amber without changes in potency. - Piggyback Vials: Reconstitute with 50 to 100 mL of Sodium Chloride Injection or any other IV solution listed below. - SHAKE WELL. - Administer with primary IV fluids, as a single dose. These Piggyback vial solutions of Cefizox are stable 24 hours at room temperature or 96 hours if refrigerated (5ºC). - A solution of 1 gram Cefizox in 13 mL Sterile Water for Injection is isotonic. - IM Injection - Inject well within the body of a relatively large muscle. Aspiration is necessary to avoid inadvertent injection into a blood vessel. When administering 2 gram IM doses, the dose should be divided and given in different large muscle masses. - IV Administration - Direct (bolus) injection, slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below). Intermittent or continuous infusion, dilute reconstituted Cefizox in 50 to 100 mL of one of the following solutions: - Sodium Chloride Injection - 5% or 10% Dextrose Injection - 5% Dextrose and 0.9%, 0.45%, or 0.2% Sodium Chloride Injection - Ringer’s Injection - Lactated Ringer’s Injection - Invert Sugar 10% in Sterile Water for Injection - 5% Sodium Bicarbonate in Sterile Water for Injection - 5% Dextrose in Lactated Ringer’s Injection (only when reconstituted with 4% Sodium Bicarbonate Injection) - In these fluids, Cefizox is stable 24 hours at room temperature or 96 hours if refrigerated (5ºC). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ceftizoxime in adult patients. ### Non–Guideline-Supported Use - Bacterial infectious disease - Cancer[1][2] - Gonorrhea, Disseminated - Postoperative infection; Prophylaxis[3] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Dosage ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ceftizoxime in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftizoxime in pediatric patients. # Contraindications - Cefizox (ceftizoxime for injection, USP) is contraindicated in patients who have known allergy to the drug. # Warnings - BEFORE THERAPY WITH CEFIZOX IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFIZOX, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLINSENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS HYPERSENSITIVITY AMONG BETALACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFIZOX OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED. - Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftizoxime, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. - Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibioticassociated” colitis. - After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. ### Precautions - As with all broadspectrum antibiotics, Cefizox (ceftizoxime for injection, USP) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. - Although Cefizox has not been shown to produce an alteration in renal function, renal status should be evaluated, especially in seriously ill patients receiving maximum dose therapy. As with any antibiotic, prolonged use may result in overgrowth of nonsusceptible organisms. Careful observation is essential; appropriate measures should be taken if superinfection occurs. - Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. - Prescribing Cefizox in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. # Adverse Reactions ## Clinical Trials Experience - Cefizox® (ceftizoxime for injection, USP) is generally well tolerated. The most frequent adverse reactions (greater than 1% but less than 5%) are: - Rash, pruritus, fever - Transient elevation in AST (SGOT), ALT (SGPT), and alkaline phosphatase. - Transient eosinophilia, thrombocytosis. Some individuals have developed a positive Coombs test. - Injection site--Burning, cellulitis, phlebitis with IV administration, pain, induration, tenderness, paresthesia. - The less frequent adverse reactions (less than 1%) are: - Numbness and anaphylaxis have been reported rarely. - Elevation of bilirubin has been reported rarely. - Transient elevations of BUN and creatinine have been occasionally observed with Cefizox. - Anemia, including hemolytic anemia with occasional fatal outcome, leukopenia, neutropenia, and thrombocytopenia have been reported rarely. - Vaginitis has occurred rarely. - Diarrhea; nausea and vomiting have been reported occasionally. - Symptoms of pseudomembranous colitis can appear during or after antibiotic treatment. - In addition to the adverse reactions listed above which have been observed in patients treated with ceftizoxime, the following adverse reactions and altered laboratory tests have been reported for cephalosporinclass antibiotics: - StevensJohnson syndrome, erythema multiforme, toxic epidermal necrolysis, serumsickness like reaction, toxic nephropathy, aplastic anemia, hemorrhage, prolonged prothrombin time, elevated LDH, pancytopenia, and agranulocytosis. - Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment, when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Ceftizoxime in the drug label. # Drug Interactions - Although the occurrence has not been reported with Cefizox, nephrotoxicity has been reported following concomitant administration of other cephalosporins and aminoglycosides. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies performed in rats and rabbits have revealed no evidence of impaired fertility or harm to the fetus due to Cefizox. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human effects, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftizoxime in women who are pregnant. ### Labor and Delivery - Safety of Cefizox use during labor and delivery has not been established. ### Nursing Mothers - Cefizox is excreted in human milk in low concentrations. Caution should be exercised when Cefizox is administered to a nursing woman. ### Pediatric Use - Safety and efficacy in pediatric patients from birth to six months of age have not been established. In pediatric patients six months of age and older, treatment with Cefizox has been associated with transient elevated levels of eosinophils, AST (SGOT), ALT (SGPT), and CPK (creatine phosphokinase). The CPK elevation may be related to IM administration. The potential for the toxic effect in pediatric patients from chemicals that may leach from the singledose IV preparation in plastic has not been determined. ### Geriatic Use - Clinical studies of ceftizoxime did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Ceftizoxime with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ceftizoxime with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ceftizoxime in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ceftizoxime in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ceftizoxime in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ceftizoxime in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. # IV Compatibility There is limited information regarding IV Compatibility of Ceftizoxime in the drug label. # Overdosage There is limited information regarding Overdose of Ceftizoxime in the drug label. # Pharmacology ## Mechanism of Action - The bactericidal action of ceftizoxime results from inhibition of cellwall synthesis. Ceftizoxime is highly resistant to a broad spectrum of betalactamases (penicillinase and cephalosporinase), including Richmond types I, II, III, TEM, and IV, produced by both aerobic and anaerobic grampositive and gramnegative organisms. ## Structure - Cefizox® (ceftizoxime for injection, USP) is a sterile, semisynthetic, broadspectrum, betalactamase resistant cephalosporin antibiotic for parenteral (IV, IM) administration. It is the sodium salt of [6R6a,7β(Z)]7(2,3dihydro2imino4 thiazolyl) (methoxyimino) acetyl amino8oxo5thia1azabicyclo [4.2.0] oct2ene2carboxylic acid. Its sodium content is approximately 60 mg (2.6 mEq) per gram of ceftizoxime activity. - It has the following structural formula: - Ceftizoxime for injection, USP is a white to pale yellow crystalline powder. - Cefizox is supplied in vials equivalent to 500 mg, 1 gram or 2 grams of ceftizoxime, and in Piggyback Vials for IV admixture equivalent to 1 gram or 2 grams of ceftizoxime. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ceftizoxime in the drug label. ## Pharmacokinetics - The table below demonstrates the serum levels and duration of Cefizox (ceftizoxime for injection, USP) following IM administration of 500 mg and 1 gram doses, respectively, to normal volunteers. - A serum halflife of approximately 1.7 hours was observed after IV or IM administration. - Cefizox is 30% protein bound. - Cefizox is not metabolized, and is excreted virtually unchanged by the kidneys in 24 hours. This provides a high urinary concentration. Concentrations greater than 6000 μg/mL have been achieved in the urine by 2 hours after a 1 gram dose of Cefizox intravenously. Probenecid slows tubular secretion and produces even higher serum levels, increasing the duration of measurable serum concentrations. - Cefizox achieves therapeutic levels in various body fluids, e.g., cerebrospinal fluid (in patients with inflamed meninges), bile, surgical wound fluid, pleural fluid, aqueous humor, ascitic fluid, peritoneal fluid, prostatic fluid and saliva, and in the following body tissues: heart, gallbladder, bone, biliary, peritoneal, prostatic, and uterine. - In clinical experience to date, no disulfiramlike reactions have been reported with Cefizox. - The bactericidal action of ceftizoxime results from inhibition of cellwall synthesis. Ceftizoxime is highly resistant to a broad spectrum of betalactamases (penicillinase and cephalosporinase), including Richmond types I, II, III, TEM, and IV, produced by both aerobic and anaerobic grampositive and gramnegative organisms. Ceftizoxime has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections described in the INDICATIONS AND USAGE section: - Staphylococcus aureus (including penicillinase producing strains) - NOTE: Methicillinresistant staphylococci are resistant to cephalosporins, including ceftizoxime. - Staphylococcus epidermidis (including penicillinase producing strains) - Streptococcus agalactiae - Streptococcus pneumoniae - Streptococcus pyogenes - NOTE: A streptococcal isolate that is susceptible to penicillin can be considered susceptible to ceftizoxime. - NOTE: Ceftizoxime is usually inactive against most strains of Enterococcus faecalis. - Enterobacter spp. - Escherichia coli - Haemophilus influenzae (including ampicillinresistant strains) - Klebsiella pneumoniae - Morganella morganii - Neisseria gonorrhoeae - Proteus mirabilis - Proteus vulgaris - Providencia rettgeri - Pseudomonas aeruginosa - Serratia marcescens - Bacteroides spp. - Peptococcus spp. - Peptostreptococcus spp. - The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftizoxime. However, the safety and effectiveness of ceftizoxime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. - Aeromonas hydrophila - Citrobacter spp. - Moraxellacatarrhalis - Neisseria meningitidis - Providencia stuartii - Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ceftizoxime powder. The MIC values should be interpreted according to the following criteria: - A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable, other therapy should be selected. - Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ceftizoxime powder should provide the following MIC values: - Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-μg ceftizoxime to test the susceptibility of microorganisms to ceftizoxime. - Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-μg ceftizoxime disk should be interpreted according to the following criteria: - Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ceftizoxime. - As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-μg ceftizoxime disk should provide the following zone diameters in these laboratory test quality control strains: - For anaerobic bacteria, the susceptibility to ceftizoxime as MICs can be determined by standardized test methods. Agar dilution results can vary widely when using ceftizoxime. It is recommended that broth microdilution method be used when possible.3 The MIC values obtained should be interpreted according to following criteria: - Interpretation is identical to that described in Susceptibility Testing: Dilution Techniques. - As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ceftizoxime powder should provide the following MIC values: - Most strains of Pseudomonas aeruginosa are moderately susceptible to ceftizoxime. - Ceftizoxime achieves high levels in the urine (greater than 6000 μg/mL at 2 hours with 1 gram IV) and, therefore, the following zone sizes should be used when testing ceftizoxime for treatment of urinary tract infections caused by Pseudomonas aeruginosa. - Susceptible organisms produce zones of 20 mm or greater, indicating that the test organism is likely to respond to therapy. - Organisms that produce zones of 11 to 19 mm are expected to be susceptible when the infection is confined to the urinary tract (in which high antibiotic levels are attained). - Resistant organisms produce zones of 10 mm or less, indicating that other therapy should be selected. ## Nonclinical Toxicology - Longterm studies in animals to evaluate the carcinogenic potential of ceftizoxime have not been conducted. - In an in vitro bacterial cell assay (i.e., Ames test), there was no evidence of mutagenicity at ceftizoxime concentrations of 0.0010.5 mcg/plate. Ceftizoxime did not produce increases in micronuclei in the in vivo mouse micronucleus test when given to animals at doses up to 7500 mg/kg, approximately six times greater than the maximum human daily dose on a mg/M2 basis. - Ceftizoxime had no effect on fertility when administered subcutaneously to rats at daily doses of up to 1000 mg/kg/day, approximately two times the maximum human daily dose on a mg/M2 basis. Ceftizoxime produced no histological changes in the sexual organs of male and female dogs when given intravenously for thirteen weeks at a dose of 1000 mg/kg/day, approximately five times greater than the maximum human daily dose on a mg/M2 basis. # Clinical Studies There is limited information regarding Clinical Studies of Ceftizoxime in the drug label. # How Supplied - Cefizox® (ceftizoxime for injection, USP) - Equivalent to 500 mg ceftizoxime in 10 mL, singledose, fliptop vials, individually packaged - Equivalent to 1 gram ceftizoxime in 20 mL, singledose, fliptop vials, individually packaged - Equivalent to 1 gram ceftizoxime in 100 mL, singledose, Piggyback, fliptop vials, packaged in tens - Equivalent to 2 grams ceftizoxime in 20 mL, singledose, fliptop vials, individually packaged - Equivalent to 2 grams ceftizoxime in 100 mL, singledose, Piggyback, fliptop vials, packaged in tens ## Storage - Unreconstituted Cefizox should be protected from excessive light, and stored at controlled room temperature (59º86ºF) in the original package until used. # Images ## Drug Images ## Package and Label Display Panel ### Ingredients and Appearance # Patient Counseling Information - Patients should be counseled that antibacterial drugs including Cefizox should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefizox is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefizox or other antibacterial drugs in the future. # Precautions with Alcohol - Alcohol-Ceftizoxime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cefizox®[4] # Look-Alike Drug Names There is limited information regarding Ceftizoxime Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ceftizoxime
3fc67d72bfa7756ccdcd4a626fcbe58e2b03dd38	wikidoc	Ceftriaxone	Ceftriaxone # 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 Ceftriaxone is an antibiotic that is FDA approved for the treatment of lower respiratory tract infections, acute bacterial otitis media, skin infections, urinary tract infections, pelvic inflammatory disease, bacterial septicemia, bone and joint infections, intraabdominal infection, meningitis, and surgical prophylaxis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, pseudomembranous enterocolitis, hemolytic anemia, hypersensitivity reaction, kernicterus, renal failure, and lung injury. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Before instituting treatment with ceftriaxone appropriate specimens should be obtained for isolation of the causative organism and for determination of its susceptibility to the drug. Therapy may be instituted prior to obtaining results of susceptibility testing. - Ceftriaxone for injection may be administered intravenously or intramuscularly. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for intravenous infusion only. - Ceftriaxone for injection should be administered intravenously by infusion over a period of 30 minutes. - Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. - Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. - There have been no reports of an interaction between ceftriaxone and oral calcium- containing products or interactions between intramuscular ceftriaxone and calcium- containing products (IV or oral). - To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftriaxone and other antibacterial drugs, ceftriaxone for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. - Ceftriaxone for injection, USP is indicated for the treatment of the following infections when caused by susceptible organisms: - LOWER RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens. - ACUTE BACTERIAL OTITIS MEDIA caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains). - NOTE: In one study lower clinical cure rates were observed with a single dose of ceftriaxone compared to 10 days of oral therapy. In a second study comparable cure rates were observed between single dose ceftriaxone for injection, USP and the comparator. The potentially lower clinical cure rate of ceftriaxone should be balanced against the potential advantages of parenteral therapy. - SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci,Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii],- Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis- or Peptostreptococcus species. - URINARY TRACT INFECTIONS (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae. - UNCOMPLICATED GONORRHEA (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae. - PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae. Ceftriaxone sodium, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and Chlamydia trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added. - BACTERIAL SEPTICEMIA caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae. - BONE AND JOINT INFECTIONS caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species. - INTRA-ABDOMINAL INFECTIONS caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most strains of Clostridium difficile are resistant) or Peptostreptococcus species. - MENINGITIS caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae. Ceftriaxone has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis- and Escherichia coli. - Efficacy for this organism in this organ system was studied in fewer than ten infections. - The preoperative administration of a single 1 g dose of ceftriaxone may reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated (e.g., vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous cholecystitis in high-risk patients, such as those over 70 years of age, with acute cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common duct bile stones) and in surgical patients for whom infection at the operative site would present serious risk (e.g., during coronary artery bypass surgery). - Although ceftriaxone has been shown to have been as effective as cefazolin in the prevention of infection following coronary artery bypass surgery, no placebo-controlled trials have been conducted to evaluate any cephalosporin antibiotic in the prevention of infection following coronary artery bypass surgery. - When administered prior to surgical procedures for which it is indicated, a single 1 g dose of ceftriaxone provides protection from most infections due to susceptible organisms throughout the course of the procedure. - The usual adult daily dose is 1 to 2 g given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. - For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 g, in order to achieve >90% target attainment. The total daily dose should not exceed 4 g. - If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism. - For preoperative use (surgical prophylaxis), a single dose of 1 g administered intravenously 1/2 to 2 hours before surgery is recommended. - Generally, ceftriaxone therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required. - When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days. - No dosage adjustment is necessary for patients with impairment of renal or hepatic function. - RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION - The 10 g bottle should be reconstituted with 95 mL of an appropriate IV diluent in a suitable work area such as a laminar flow hood. - The resulting solution will contain approximately 100 mg/mL of ceftriaxone. - The container closure may be penetrated only one time, utilizing a suitable sterile transfer device or dispensing set which allows measured distribution of the contents. (A sterile substance which must be reconstituted prior to use may require a separate closure entry). - Use of this product is restricted to a suitable work area, such as a laminar flow hood. - The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum of 4 hours from initial closure entry is permitted to complete fluid transfer operations. If reconstitution is necessary, this time limit should begin with the introduction of solvent or diluent into the Pharmacy Bulk Package. - Unused portions of solutions held longer than the recommended time periods should be discarded. - Transfer individual dose to appropriate intravenous solutions as soon as possible following reconstitution of the bulk package. The stability of the solution that has been transferred into a container varies according to diluent, concentration and temperature (see COMPATIBILITY AND STABILITY). - Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. - Ceftriaxone has been shown to be compatible with Flagyl®- IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. - The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl®- IV RTU® (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur. - Registered trademark of G.D Searle & Co. - Vancomycin, amsacrine, aminoglycosides, and fluconazole are physically incompatible with ceftriaxone in admixtures. When any of these drugs are to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations. - Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone for injection or to further dilute a reconstituted pharmacy bulk package bottle for IV administration. Particulate formation can result. - Ceftriaxone for injection solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Acute otitis media - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day. - Bacteremia associated with intravascular line - (Due to Escherichia coli and Klebsiella species, extended-spectrum beta-lactamase negative) 1 to 2 g IV daily. - Bacterial endocarditis; Prophylaxis: (high-risk patients; dental, respiratory, or infected skin/skin structure or musculoskeletal tissue procedures) 1 g IV or IM 30 to 60 minutes prior to procedure - Bacterial meningitis - 4 g/day IV divided every 12 to 24 hours; maximum 4 g/day - Bacterial musculoskeletal infection - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day - Chancroid - 250 mg IM as a single dose. - Epididymitis - 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 10 days. - Gonorrhea - Uncomplicated, 250 mg IM as a single dose plus either a single dose of azithromycin 1 g ORALLY or doxycycline 100 mg ORALLY twice daily for 7 days - Gonorrhea - Conjunctivitis, 1 g IM as a single dose - Gonorrhea - Disseminated, 1 g IV or IM every 24 hours for 24 to 48 hours after improvement begins then switch to appropriate oral therapy to complete at least 1 week of therapy - Gonorrhea - Meningitis and endocarditis, 1 to 2 g IV every 12 hours, for 10 to 14 days (meningitis) or at least 4 weeks (endocarditis) - Infection of skin AND/OR subcutaneous tissue: 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day - Infectious disease of abdomen: 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day - Infective endocarditis - (Native valve, highly penicillin-susceptible streptococci) 2 g IV/IM every 24 hours for 4 weeks - Infective endocarditis: (native valve, highly penicillin-susceptible streptococci) alternative therapy, 2 g IV/IM every 24 hours AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks - Infective endocarditis: (native valve, relatively penicillin-resistant streptococci) 2 g IV/IM every 24 hours for 4 weeks AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks. - Infective endocarditis - (Prosthetic valve, penicillin-susceptible streptococci) 2 g IV/IM every 24 hours for 6 weeks WITH or WITHOUT gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks. - Infective endocarditis - (Prosthetic valve, penicillin-resistant streptococci) 2 g IV/IM every 24 hours AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 6 weeks. - Infective endocarditis: (enterococcal, strains resistant to penicillin, aminoglycoside, and vancomycin (E faecalis)) 2 g IV/IM every 12 hours AND ampicillin sodium 2 g IV every 4 hours for a minimum of 8 weeks. - Infective endocarditis - (HACEK microorganisms) 2 g IV/IM every 24 hours for 4 to 6 weeks. - Infective endocarditis - (Suspected Bartonella, culture-negative) 2 g IV/IM every 24 hours for 6 weeks AND gentamicin sulfate 1 mg/kg IV/IM every 8 hours for 2 weeks WITH or WITHOUT doxycycline 100 mg IV or ORALLY every 12 hours for 6 weeks. - Infective proctitis - 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 7 days - Lower respiratory tract infection - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day - Lyme disease - 2 g IV once daily for 14 days (range, 10 to 28 days) for early Lyme disease with acute neurological disease manifested by meningitis or radiculopathy, or patients with seventh-cranial-nerve palsy with CNS involvement; for 14 to 21 days for the initial treatment of hospitalized patients with Lyme carditis; for 14 to 28 days for Lyme arthritis with neurological involvement, including those refractory to oral therapy, or late neurologic Lyme disease. - Pelvic inflammatory disease - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day. - Pelvic inflammatory disease - 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 14 days, with or without metronidazole 500 mg ORALLY twice daily for 14 days. - Postoperative infection; Prophylaxis - 1 g IV 0.5 to 2 hours prior to surgery. - Septicemia - 1 to 2 g IV every 24 hours or in divided doses twice a day; maximum 4 g/day. - Sexually transmitted infectious disease; Prophylaxis - Victim of sexual aggression - 250 mg IM as a single dose plus metronidazole 2 g ORALLY as a single dose plus either azithromycin 1 g ORALLY as a single dose or doxycycline 100 mg ORALLY twice daily for 7 days. - Urinary tract infectious disease - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day. ### Non–Guideline-Supported Use - Bacteremia associated with intravascular line. - Bacterial endocarditis; Prophylaxis - Bacterial endocarditis - Streptococcal infectious disease - Chancroid - Epididymitis - Febrile neutropenia - Infective endocarditis - Infective proctitis - Lyme disease - Peritonitis. - Salmonella infection - Sexually transmitted infectious disease; Prophylaxis - Victim of sexual aggression - Typhoid fever # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 g. - For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 g. - In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 g). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 g daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ceftriaxone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftriaxone in pediatric patients. # Contraindications - Ceftriaxone for injection is contraindicated in patients with known allergy to the cephalosporin class of antibiotics. - Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone for injection. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a possible risk of bilirubin encephalopathy in these patients. - Ceftriaxone is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium. - A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. - At least one fatality has been reported in a neonate in whom ceftriaxone and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates. # Warnings - BEFORE THERAPY WITH CEFTRIAXONE FOR INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY MEASURES. - As with other cephalosporins, anaphylactic reactions with fatal outcome have been reported, even if a patient is not known to be allergic or previously exposed. - Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. - Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium. - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined. # Adverse Reactions ## Clinical Trials Experience - BEFORE THERAPY WITH CEFTRIAXONE FOR INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY MEASURES. - As with other cephalosporins, anaphylactic reactions with fatal outcome have been reported, even if a patient is not known to be allergic or previously exposed. - Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium. - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined. ## Postmarketing Experience - In addition to the adverse reactions reported during clinical trials, the following adverse experiences have been reported during clinical practice in patients treated with ceftriaxone. Data are generally insufficient to allow an estimate of incidence or to establish causation. - A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom ceftriaxone and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates. - GASTROINTESTINAL - Stomatitis and glossitis. - GENITOURINARY - Oliguria. - DERMATOLOGIC - Exanthema, allergic dermatitis, urticaria, edema. As with many medications, isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis) have been reported. - In addition to the adverse reactions listed above which have been observed in patients treated with ceftriaxone, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics: - Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and superinfection. - Altered Laboratory Tests: Positive direct Coombs' test, false-positive test for urinary glucose, and elevated LDH. - Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced . If seizures associated with drug therapy occur, the drug should be discontinued. - Anticonvulsant therapy can be given if clinically indicated. # Drug Interactions There is limited information regarding Ceftriaxone Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose. - There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. - In rats, in the Segment I (fertility and general reproduction) and Segment III (perinatal and postnatal) studies with intravenously administered ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftriaxone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ceftriaxone during labor and delivery. ### Nursing Mothers - Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone for injection is administered to a nursing woman ### Pediatric Use - In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone for injection should not be administered to hyperbilirubinemic neonates, especially prematures. ### Geriatic Use - Of the total number of subjects in clinical studies of ceftriaxone, 32% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - The pharmacokinetics of ceftriaxone were only minimally altered in geriatric patients compared to healthy adult subjects and dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to 2 g per day. ### Gender There is no FDA guidance on the use of Ceftriaxone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ceftriaxone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ceftriaxone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ceftriaxone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ceftriaxone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ceftriaxone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during ceftriaxone treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy. # IV Compatibility There is limited information regarding IV Compatibility of Ceftriaxone in the drug label. # Overdosage - In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic. # Pharmacology ## Mechanism of Action Ceftriaxone inhibits bacterial cell wall synthesis by means of binding to the penicillin-binding proteins (PBPs). Inhibition of PBPs would in turn inhibit the transpeptidation step in peptidoglycan synthesis which is required for bacterial cell walls. Like other cephalosporins, ceftriaxone is bacteriocidal and exhibits time-dependent killing ## Structure - Ceftriaxone for injection, USP is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone sodium is (6R,7R)-7--8-oxo-3-methyl]]-5-thia-1-azabicyclooct-2-ene-2-carboxylic acid, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate. - The chemical formula of ceftriaxone sodium is C18H16N8Na2O7S33.5H2O. It has a calculated molecular weight of 661.60 and the following structural formula: - Ceftriaxone sodium is white or yellowish, crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. - The pH of a 1% aqueous solution is approximately 6.7. The color of ceftriaxone solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used. - Each Pharmacy Bulk Package is supplied as a dry powder in Pharmacy Bulk Package bottles containing sterile ceftriaxone sodium, USP equivalent to 10 g of ceftriaxone and is intended for intravenous infusion only. - Ceftriaxone sodium, USP contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity. - A Pharmacy Bulk Package is a container of sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ceftriaxone in the drug label. ## Pharmacokinetics Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0.5, 1 or 2 g dose and intramuscular (IM) administration of a single 0.5 (250 mg/mL or 350 mg/mL concentrations) or 1 g dose in healthy subjects are presented in Table 1. Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. Multiple IV or IM doses ranging from 0.5 to 2 g at 12- to 24-hour intervals resulted in 15% to 36% accumulation of ceftriaxone above single dose values. Ceftriaxone concentrations in urine are shown in Table 2. Thirty-three percent to 67% of a ceftriaxone dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After a 1 g IV dose, average concentrations of ceftriaxone, determined from 1 to 3 hours after dosing, were 581 mcg/mL in the gallbladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/g in the gallbladder wall and 62.1 mcg/mL in the concurrent plasma. Over a 0.15 to 3 g dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours; apparent volume of distribution from 5.78 to 13.5 L; plasma clearance from 0.58 to 1.45 L/hour; and renal clearance from 0.32 to 0.73 L/hour. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of <25 mcg/mL to a value of 85% bound at 300 mcg/mL Ceftriaxone crosses the blood placenta barrier. The average values of maximum plasma concentration, elimination half-life, plasma clearance and volume of distribution after a 50 mg/kg IV dose and after a 75 mg/kg IV dose in pediatric patients suffering from bacterial meningitis are shown in Table 3. Ceftriaxone penetrated the inflamed meninges of infants and pediatric patients; CSF concentrations after a 50 mg/kg IV dose and after a 75 mg/kg IV dose are also shown in Table 3. Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction (Table 4); therefore, dosage adjustments are not necessary for these patients with ceftriaxone dosages up to 2 g per day. Ceftriaxone was not removed to any significant extent from the plasma by hemodialysis. In 6 of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced. The elimination of ceftriaxone is not altered when ceftriaxone is co-administered with probenecid. Pharmacokinetics in the Middle Ear Fluid In one study, total ceftriaxone concentrations (bound and unbound) were measured in middle ear fluid obtained during the insertion of tympanostomy tubes in 42 pediatric patients with otitis media. Sampling times were from 1 to 50 hours after a single intramuscular injection of 50 mg/kg of ceftriaxone. Mean (±SD) ceftriaxone levels in the middle ear reached a peak of 35 (±12) mcg/mL at 24 hours, and remained at 19 (±7) mcg/mL at 48 hours. Based on middle ear fluid ceftriaxone concentrations in the 23 to 25 hour and the 46 to 50 hour sampling time intervals, a half-life of 25 hours was calculated. Ceftriaxone is highly bound to plasma proteins. The extent of binding to proteins in the middle ear fluid is unknown. Interaction with Calcium Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 g ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxone-calcium precipitation. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Ceftriaxone in the drug label. # Clinical Studies - Clinical Trials in Pediatric Patients With Acute Bacterial Otitis Media: In two adequate and well-controlled U.S. clinical trials a single IM dose of ceftriaxone was compared with a 10 day course of oral antibiotic in pediatric patients between the ages of 3 months and 6 years. The clinical cure rates and statistical outcome appear in the table below: - An open-label bacteriologic study of ceftriaxone without a comparator enrolled 108 pediatric patients, 79 of whom had positive baseline cultures for one or more of the common pathogens. The results of this study are tabulated as follows: - Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by pathogen: # How Supplied - Ceftriaxone for Injection, USP in Pharmacy Bulk Package is supplied as a sterile crystalline powder in glass bottles containing ceftriaxone sodium equivalent to 10g ceftriaxone. NOT FOR DIRECT ADMINISTRATION. ## Storage - Ceftriaxone for injection sterile powder should be stored at 20° to 25°C (68° to 77°F) and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used. Ceftriaxone intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers: - The following intravenous ceftriaxone solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container). - After the indicated stability time periods, unused portions of solutions should be discarded. - NOTE: Parenteral drug products should be inspected visually for particulate matter before administration. - Ceftriaxone for injection reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks. - Frozen solutions of ceftriaxone for injection should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Ceftriaxone in the drug label. # Precautions with Alcohol - Alcohol-Ceftriaxone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - CEFTRIAXONE® # Look-Alike Drug Names There is limited information regarding Ceftriaxone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ceftriaxone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Ceftriaxone is an antibiotic that is FDA approved for the treatment of lower respiratory tract infections, acute bacterial otitis media, skin infections, urinary tract infections, pelvic inflammatory disease, bacterial septicemia, bone and joint infections, intraabdominal infection, meningitis, and surgical prophylaxis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, pseudomembranous enterocolitis, hemolytic anemia, hypersensitivity reaction, kernicterus, renal failure, and lung injury. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Before instituting treatment with ceftriaxone appropriate specimens should be obtained for isolation of the causative organism and for determination of its susceptibility to the drug. Therapy may be instituted prior to obtaining results of susceptibility testing. - Ceftriaxone for injection may be administered intravenously or intramuscularly. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for intravenous infusion only. * Ceftriaxone for injection should be administered intravenously by infusion over a period of 30 minutes. - Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. - Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. - There have been no reports of an interaction between ceftriaxone and oral calcium- containing products or interactions between intramuscular ceftriaxone and calcium- containing products (IV or oral). - To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftriaxone and other antibacterial drugs, ceftriaxone for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. - Ceftriaxone for injection, USP is indicated for the treatment of the following infections when caused by susceptible organisms: - LOWER RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens. - ACUTE BACTERIAL OTITIS MEDIA caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains). - NOTE: In one study lower clinical cure rates were observed with a single dose of ceftriaxone compared to 10 days of oral therapy. In a second study comparable cure rates were observed between single dose ceftriaxone for injection, USP and the comparator. The potentially lower clinical cure rate of ceftriaxone should be balanced against the potential advantages of parenteral therapy. - SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci,Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii],* Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis* or Peptostreptococcus species. - URINARY TRACT INFECTIONS (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae. - UNCOMPLICATED GONORRHEA (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae. - PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae. Ceftriaxone sodium, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and Chlamydia trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added. - BACTERIAL SEPTICEMIA caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae. - BONE AND JOINT INFECTIONS caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species. - INTRA-ABDOMINAL INFECTIONS caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most strains of Clostridium difficile are resistant) or Peptostreptococcus species. - MENINGITIS caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae. Ceftriaxone has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis* and Escherichia coli. - Efficacy for this organism in this organ system was studied in fewer than ten infections. - The preoperative administration of a single 1 g dose of ceftriaxone may reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated (e.g., vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous cholecystitis in high-risk patients, such as those over 70 years of age, with acute cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common duct bile stones) and in surgical patients for whom infection at the operative site would present serious risk (e.g., during coronary artery bypass surgery). - Although ceftriaxone has been shown to have been as effective as cefazolin in the prevention of infection following coronary artery bypass surgery, no placebo-controlled trials have been conducted to evaluate any cephalosporin antibiotic in the prevention of infection following coronary artery bypass surgery. - When administered prior to surgical procedures for which it is indicated, a single 1 g dose of ceftriaxone provides protection from most infections due to susceptible organisms throughout the course of the procedure. - The usual adult daily dose is 1 to 2 g given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. - For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 g, in order to achieve >90% target attainment. The total daily dose should not exceed 4 g. - If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism. - For preoperative use (surgical prophylaxis), a single dose of 1 g administered intravenously 1/2 to 2 hours before surgery is recommended. - Generally, ceftriaxone therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required. - When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days. - No dosage adjustment is necessary for patients with impairment of renal or hepatic function. - RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION - The 10 g bottle should be reconstituted with 95 mL of an appropriate IV diluent in a suitable work area such as a laminar flow hood. - The resulting solution will contain approximately 100 mg/mL of ceftriaxone. - The container closure may be penetrated only one time, utilizing a suitable sterile transfer device or dispensing set which allows measured distribution of the contents. (A sterile substance which must be reconstituted prior to use may require a separate closure entry). - Use of this product is restricted to a suitable work area, such as a laminar flow hood. - The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum of 4 hours from initial closure entry is permitted to complete fluid transfer operations. If reconstitution is necessary, this time limit should begin with the introduction of solvent or diluent into the Pharmacy Bulk Package. - Unused portions of solutions held longer than the recommended time periods should be discarded. - Transfer individual dose to appropriate intravenous solutions as soon as possible following reconstitution of the bulk package. The stability of the solution that has been transferred into a container varies according to diluent, concentration and temperature (see COMPATIBILITY AND STABILITY). - Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. - Ceftriaxone has been shown to be compatible with Flagyl®* IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. - The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl®* IV RTU® (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur. - Registered trademark of G.D Searle & Co. - Vancomycin, amsacrine, aminoglycosides, and fluconazole are physically incompatible with ceftriaxone in admixtures. When any of these drugs are to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations. - Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone for injection or to further dilute a reconstituted pharmacy bulk package bottle for IV administration. Particulate formation can result. - Ceftriaxone for injection solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Acute otitis media - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day. - Bacteremia associated with intravascular line - (Due to Escherichia coli and Klebsiella species, extended-spectrum beta-lactamase negative) 1 to 2 g IV daily.[1] - Bacterial endocarditis; Prophylaxis: (high-risk patients; dental, respiratory, or infected skin/skin structure or musculoskeletal tissue procedures) 1 g IV or IM 30 to 60 minutes prior to procedure [2] - Bacterial meningitis - 4 g/day IV divided every 12 to 24 hours; maximum 4 g/day[3] - Bacterial musculoskeletal infection - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day - Chancroid - 250 mg IM as a single dose.[4] - Epididymitis - 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 10 days. - Gonorrhea - Uncomplicated, 250 mg IM as a single dose plus either a single dose of azithromycin 1 g ORALLY or doxycycline 100 mg ORALLY twice daily for 7 days - Gonorrhea - Conjunctivitis, 1 g IM as a single dose - Gonorrhea - Disseminated, 1 g IV or IM every 24 hours for 24 to 48 hours after improvement begins then switch to appropriate oral therapy to complete at least 1 week of therapy - Gonorrhea - Meningitis and endocarditis, 1 to 2 g IV every 12 hours, for 10 to 14 days (meningitis) or at least 4 weeks (endocarditis) - Infection of skin AND/OR subcutaneous tissue: 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day - Infectious disease of abdomen: 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day - Infective endocarditis - (Native valve, highly penicillin-susceptible streptococci) 2 g IV/IM every 24 hours for 4 weeks[5] - Infective endocarditis: (native valve, highly penicillin-susceptible streptococci) alternative therapy, 2 g IV/IM every 24 hours AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks[6] - Infective endocarditis: (native valve, relatively penicillin-resistant streptococci) 2 g IV/IM every 24 hours for 4 weeks AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks. - Infective endocarditis - (Prosthetic valve, penicillin-susceptible streptococci) 2 g IV/IM every 24 hours for 6 weeks WITH or WITHOUT gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks. - Infective endocarditis - (Prosthetic valve, penicillin-resistant streptococci) 2 g IV/IM every 24 hours AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 6 weeks. - Infective endocarditis: (enterococcal, strains resistant to penicillin, aminoglycoside, and vancomycin (E faecalis)) 2 g IV/IM every 12 hours AND ampicillin sodium 2 g IV every 4 hours for a minimum of 8 weeks. - Infective endocarditis - (HACEK microorganisms) 2 g IV/IM every 24 hours for 4 to 6 weeks. - Infective endocarditis - (Suspected Bartonella, culture-negative) 2 g IV/IM every 24 hours for 6 weeks AND gentamicin sulfate 1 mg/kg IV/IM every 8 hours for 2 weeks WITH or WITHOUT doxycycline 100 mg IV or ORALLY every 12 hours for 6 weeks. - Infective proctitis - 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 7 days - Lower respiratory tract infection - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day - Lyme disease - 2 g IV once daily for 14 days (range, 10 to 28 days) for early Lyme disease with acute neurological disease manifested by meningitis or radiculopathy, or patients with seventh-cranial-nerve palsy with CNS involvement; for 14 to 21 days for the initial treatment of hospitalized patients with Lyme carditis; for 14 to 28 days for Lyme arthritis with neurological involvement, including those refractory to oral therapy, or late neurologic Lyme disease. - Pelvic inflammatory disease - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day. - Pelvic inflammatory disease - 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 14 days, with or without metronidazole 500 mg ORALLY twice daily for 14 days. - Postoperative infection; Prophylaxis - 1 g IV 0.5 to 2 hours prior to surgery. - Septicemia - 1 to 2 g IV every 24 hours or in divided doses twice a day; maximum 4 g/day. - Sexually transmitted infectious disease; Prophylaxis - Victim of sexual aggression - 250 mg IM as a single dose plus metronidazole 2 g ORALLY as a single dose plus either azithromycin 1 g ORALLY as a single dose or doxycycline 100 mg ORALLY twice daily for 7 days. - Urinary tract infectious disease - 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day. ### Non–Guideline-Supported Use - Bacteremia associated with intravascular line. - Bacterial endocarditis; Prophylaxis - Bacterial endocarditis - Streptococcal infectious disease - Chancroid - Epididymitis - Febrile neutropenia - Infective endocarditis - Infective proctitis - Lyme disease - Peritonitis. - Salmonella infection - Sexually transmitted infectious disease; Prophylaxis - Victim of sexual aggression - Typhoid fever # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 g. - For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 g. - In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 g). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 g daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ceftriaxone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftriaxone in pediatric patients. # Contraindications - Ceftriaxone for injection is contraindicated in patients with known allergy to the cephalosporin class of antibiotics. - Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone for injection. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a possible risk of bilirubin encephalopathy in these patients. - Ceftriaxone is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium. - A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. - At least one fatality has been reported in a neonate in whom ceftriaxone and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates. # Warnings - BEFORE THERAPY WITH CEFTRIAXONE FOR INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY MEASURES. - As with other cephalosporins, anaphylactic reactions with fatal outcome have been reported, even if a patient is not known to be allergic or previously exposed. - Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. - Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium. - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined. # Adverse Reactions ## Clinical Trials Experience - BEFORE THERAPY WITH CEFTRIAXONE FOR INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY MEASURES. - As with other cephalosporins, anaphylactic reactions with fatal outcome have been reported, even if a patient is not known to be allergic or previously exposed. - Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium. - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined. ## Postmarketing Experience - In addition to the adverse reactions reported during clinical trials, the following adverse experiences have been reported during clinical practice in patients treated with ceftriaxone. Data are generally insufficient to allow an estimate of incidence or to establish causation. - A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom ceftriaxone and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates. - GASTROINTESTINAL - Stomatitis and glossitis. - GENITOURINARY - Oliguria. - DERMATOLOGIC - Exanthema, allergic dermatitis, urticaria, edema. As with many medications, isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis) have been reported. - In addition to the adverse reactions listed above which have been observed in patients treated with ceftriaxone, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics: - Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and superinfection. - Altered Laboratory Tests: Positive direct Coombs' test, false-positive test for urinary glucose, and elevated LDH. - Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced . If seizures associated with drug therapy occur, the drug should be discontinued. - Anticonvulsant therapy can be given if clinically indicated. # Drug Interactions There is limited information regarding Ceftriaxone Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose. - There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. - In rats, in the Segment I (fertility and general reproduction) and Segment III (perinatal and postnatal) studies with intravenously administered ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftriaxone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ceftriaxone during labor and delivery. ### Nursing Mothers - Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone for injection is administered to a nursing woman ### Pediatric Use - In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone for injection should not be administered to hyperbilirubinemic neonates, especially prematures. ### Geriatic Use - Of the total number of subjects in clinical studies of ceftriaxone, 32% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - The pharmacokinetics of ceftriaxone were only minimally altered in geriatric patients compared to healthy adult subjects and dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to 2 g per day. ### Gender There is no FDA guidance on the use of Ceftriaxone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ceftriaxone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ceftriaxone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ceftriaxone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ceftriaxone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ceftriaxone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during ceftriaxone treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy. # IV Compatibility There is limited information regarding IV Compatibility of Ceftriaxone in the drug label. # Overdosage - In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic. # Pharmacology ## Mechanism of Action Ceftriaxone inhibits bacterial cell wall synthesis by means of binding to the penicillin-binding proteins (PBPs). Inhibition of PBPs would in turn inhibit the transpeptidation step in peptidoglycan synthesis which is required for bacterial cell walls. Like other cephalosporins, ceftriaxone is bacteriocidal and exhibits time-dependent killing ## Structure - Ceftriaxone for injection, USP is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone sodium is (6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl]]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate. - The chemical formula of ceftriaxone sodium is C18H16N8Na2O7S3•3.5H2O. It has a calculated molecular weight of 661.60 and the following structural formula: - Ceftriaxone sodium is white or yellowish, crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. - The pH of a 1% aqueous solution is approximately 6.7. The color of ceftriaxone solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used. - Each Pharmacy Bulk Package is supplied as a dry powder in Pharmacy Bulk Package bottles containing sterile ceftriaxone sodium, USP equivalent to 10 g of ceftriaxone and is intended for intravenous infusion only. - Ceftriaxone sodium, USP contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity. - A Pharmacy Bulk Package is a container of sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ceftriaxone in the drug label. ## Pharmacokinetics Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0.5, 1 or 2 g dose and intramuscular (IM) administration of a single 0.5 (250 mg/mL or 350 mg/mL concentrations) or 1 g dose in healthy subjects are presented in Table 1. Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. Multiple IV or IM doses ranging from 0.5 to 2 g at 12- to 24-hour intervals resulted in 15% to 36% accumulation of ceftriaxone above single dose values. Ceftriaxone concentrations in urine are shown in Table 2. Thirty-three percent to 67% of a ceftriaxone dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After a 1 g IV dose, average concentrations of ceftriaxone, determined from 1 to 3 hours after dosing, were 581 mcg/mL in the gallbladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/g in the gallbladder wall and 62.1 mcg/mL in the concurrent plasma. Over a 0.15 to 3 g dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours; apparent volume of distribution from 5.78 to 13.5 L; plasma clearance from 0.58 to 1.45 L/hour; and renal clearance from 0.32 to 0.73 L/hour. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of <25 mcg/mL to a value of 85% bound at 300 mcg/mL Ceftriaxone crosses the blood placenta barrier. The average values of maximum plasma concentration, elimination half-life, plasma clearance and volume of distribution after a 50 mg/kg IV dose and after a 75 mg/kg IV dose in pediatric patients suffering from bacterial meningitis are shown in Table 3. Ceftriaxone penetrated the inflamed meninges of infants and pediatric patients; CSF concentrations after a 50 mg/kg IV dose and after a 75 mg/kg IV dose are also shown in Table 3. Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction (Table 4); therefore, dosage adjustments are not necessary for these patients with ceftriaxone dosages up to 2 g per day. Ceftriaxone was not removed to any significant extent from the plasma by hemodialysis. In 6 of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced. The elimination of ceftriaxone is not altered when ceftriaxone is co-administered with probenecid. Pharmacokinetics in the Middle Ear Fluid In one study, total ceftriaxone concentrations (bound and unbound) were measured in middle ear fluid obtained during the insertion of tympanostomy tubes in 42 pediatric patients with otitis media. Sampling times were from 1 to 50 hours after a single intramuscular injection of 50 mg/kg of ceftriaxone. Mean (±SD) ceftriaxone levels in the middle ear reached a peak of 35 (±12) mcg/mL at 24 hours, and remained at 19 (±7) mcg/mL at 48 hours. Based on middle ear fluid ceftriaxone concentrations in the 23 to 25 hour and the 46 to 50 hour sampling time intervals, a half-life of 25 hours was calculated. Ceftriaxone is highly bound to plasma proteins. The extent of binding to proteins in the middle ear fluid is unknown. Interaction with Calcium Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 g ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxone-calcium precipitation. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Ceftriaxone in the drug label. # Clinical Studies - Clinical Trials in Pediatric Patients With Acute Bacterial Otitis Media: In two adequate and well-controlled U.S. clinical trials a single IM dose of ceftriaxone was compared with a 10 day course of oral antibiotic in pediatric patients between the ages of 3 months and 6 years. The clinical cure rates and statistical outcome appear in the table below: - An open-label bacteriologic study of ceftriaxone without a comparator enrolled 108 pediatric patients, 79 of whom had positive baseline cultures for one or more of the common pathogens. The results of this study are tabulated as follows: - Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by pathogen: # How Supplied - Ceftriaxone for Injection, USP in Pharmacy Bulk Package is supplied as a sterile crystalline powder in glass bottles containing ceftriaxone sodium equivalent to 10g ceftriaxone. NOT FOR DIRECT ADMINISTRATION. ## Storage - Ceftriaxone for injection sterile powder should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used. Ceftriaxone intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers: - The following intravenous ceftriaxone solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container). - After the indicated stability time periods, unused portions of solutions should be discarded. - NOTE: Parenteral drug products should be inspected visually for particulate matter before administration. - Ceftriaxone for injection reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks. - Frozen solutions of ceftriaxone for injection should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Ceftriaxone in the drug label. # Precautions with Alcohol - Alcohol-Ceftriaxone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - CEFTRIAXONE®[7] # Look-Alike Drug Names There is limited information regarding Ceftriaxone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ceftriaxone
0e7966fe5ecc9a91fb40677ee99ec7630750f769	wikidoc	Cell growth	Cell growth The term cell growth is used in two different ways in biology. When used in the context of reproduction of living cells the phrase "cell growth" is shorthand for the idea of "growth in cell populations by means of cell reproduction." During cell reproduction one cell (the "mother" cell) divides to produce two daughter cells. # Cell populations Cell populations go through a type of exponential growth called doubling. Thus, each generation of cells should be twice as numerous as the previous generation. However, as noted by Richard Dawkins (1997), this view is naive as the number of generations only gives a maximum figure. This is due to the fact that not all cells survive in each generation. # Cell size ## Yeast cell size regulation The relationship between cell size and cell division has been extensively studied in yeast. For some cells, there is a mechanism by which cell division is not initiated until a cell has reached a certain size. If the nutrient supply is restricted (after time t = 2 in the diagram, below) and the rate of increase in cell size is slowed, the time period between cell divisions is increased. Yeast cell size mutants were isolated that begin cell division before reaching the normal size (wee mutants). The Wee1 protein is a tyrosine kinase. It normally phosphorylates the Cdc2 cell cycle regulatory protein (cyclin-dependent kinase-1, CDK1) on a tyrosine residue. This covalent modification of the molecular structure of Cdc2 inhibits the enzymatic activity of Cdc2 and prevents cell division. In Wee1 mutants, there is less Wee1 activity and Cdc2 becomes active in smaller cells, causing cell division before the yeast cells reach their normal size. Cell division may be regulated in part by dilution of Wee1 protein in cells as they grow larger. ## Cell size regulation in mammals The protein mTOR is a serine/threonine kinase that regulates translation and cell division. Nutrient availability influences mTOR so that when cells are not able to grow to normal size they will not undergo cell division. The details of the molecular mechanisms of mammalian cell size control are currently being investigated. The size of post-mitotic neurons depends on the size of the cell body, axon and dendrites. In vertebrates, neuron size is often a reflection of the number of synaptic contacts onto the neuron or from a neuron onto other cells. For example, the size of motoneurons usually reflects the size of the motor unit that is controlled by the motoneuron. Invertebrates often have giant neurons and axons that provide special functions such as rapid action potential propagation. Mammals also use this trick for increasing the speed of signals in the nervous system, but they can also use myelin to accomplish this, so most human neurons are releatively small. ## Other experimental systems for the study of cell size regulation One common means to produce very large cells is by cell fusion to form syncytia. For example, very long (several inches) skeletal muscle cells are formed by fusion of thousands of myocytes. Genetic studies of the fruit fly Drosophila have revealed several genes that are required for the formation of multinucleated muscle cells by fusion of myoblasts. Some of the key proteins are important for cell adhesion between myocytes and some are involved in adhesion-dependent cell-to-cell signal transduction that allows for a cascade of cell fusion events. Oocytes can be unusually large cells in species for which embryonic development takes place away from the mother's body. Their large size can be achieved either by pumping in cytosolic components from adjacent cells through cytoplasmic bridges (Drosophila) or by internalization of nutrient storage granules (yolk granules) by endocytosis (frogs). Increases in the size of plant cells is complicated by the fact that almost all plant cells are inside of a solid cell wall. Under the influence of certain plant hormones the cell wall can be remodeled, allowing for increases in cell size that are important for the growth of some plant tissues. Most unicellular organisms are microscopic in size, but there are some giant bacteria and protozoa that are visible to the naked eye. See: Table of cell sizes - Dense populations of a giant sulfur bacterium in Namibian shelf sediments - Large protists of the genus Chaos, closely related to the genus Amoeba # Cell reproduction Cell reproduction is asexual. The process of cell reproduction has three major parts. The first part of cell reproduction involves the replication of the parental cell's DNA. The second major issue is the separation of the duplicated DNA into two equally sized groups of chromosomes. The third major aspect of cell reproduction is the physical division of entire cells, usually called cytokinesis. Cell reproduction is more complex in eukaryotes than in other organisms. Prokaryotic cells such as bacterial cells reproduce by binary fission, a process that includes DNA replication, chromosome segregation, and cytokinesis. Eukaryotic cell reproduction either involves mitosis or a more complex process called meiosis. Mitosis and meiosis are sometimes called the two "nuclear division" processes. Binary fission is similar to eukaryotic cell reproduction that involves mitosis. Both lead to the production of two daughter cells with the same number of chromosomes as the parental cell. Meiosis is used for a special cell reproduction process of diploid organisms. It produces four special daughter cells (gametes) which have half the normal cellular amount of DNA. A male and a female gamete can then combine to produce a zygote, a cell which again has the normal amount of chromosomes. The rest of this article is a comparison of the main features of the three types of cell reproduction that either involve binary fission, mitosis, or meiosis. The diagram below depicts the similarities and differences of these three types of cell reproduction. ## Comparison of the three types of cell reproduction The DNA content of a cell is duplicated at the start of the cell reproduction process. Prior to DNA replication, the DNA content of a cell can be represented as the amount Z (the cell has Z chromosomes). After the DNA replication process, the amount of DNA in the cell is 2Z (multiplication: 2 x Z = 2Z). During Binary fission and mitosis the duplicated DNA content of the reproducing parental cell is separated into two equal halves that are destined to end up in the two daughter cells. The final part of the cell reproduction process is cell division, when daughter cells physically split apart from a parental cell. During meiosis, there are two cell division steps that together produce the four daughter cells. After the completion of binary fission or cell reproduction involving mitosis, each daughter cell has the same amount of DNA (Z) as what the parental cell had before it replicated its DNA. These two types of cell reproduction produced two daughter cells that have the same number of chromosomes as the parental cell. After meiotic cell reproduction the four daughter cells have half the number of chromosomes that the parental cell originally had. This is the haploid amount of DNA, often symbolized as N. Meiosis is used by diploid organisms to produce haploid gametes. In a diploid organism such as the human organism, most cells of the body have the diploid amount of DNA, 2N. Using this notation for counting chromosomes we say that human somatic cells have 46 chromosomes (2N = 46) while human sperm and eggs have 23 chromosomes (N = 23). Humans have 23 distinct types of chromosomes, the 22 autosomes and the special category of sex chromosomes. There are two distinct sex chromosomes, the X chromosome and the Y chromosome. A diploid human cell has 23 chromosomes from that person's father and 23 from the mother. That is, your body has two copies of human chromosome number 2, one from each of your parents. Immediately after DNA replication a human cell will have 46 "double chromosomes". In each double chromosome there are two copies of that chromosome's DNA molecule. During mitosis the double chromosomes are split to produce 92 "single chromosomes", half of which go into each daughter cell. During meiosis, there are two chromosome separation steps which assure that each of the four daughter cells gets one copy of each of the 23 types of chromosome. ## Sexual reproduction Main article: Evolution of sex Though cell reproduction that uses mitosis can reproduce eukaryotic cells, eukaryotes bother with the more complicated process of meiosis because sexual reproduction such as meiosis confers a selective advantage. Notice that when meiosis starts, the two copies of chromosome number 2 are adjacent to each other. During this time, there can be genetic recombination events. Parts of the chromosome 2 DNA gained from one parent (red) will swap over to the chromosome 2 DNA molecule that received from the other parent (green). Notice that in mitosis the two copies of chromosome number 2 do not interact. It is these new combinations of parts of chromosomes that provide the major advantage for sexually reproducing organisms by allowing for new combinations of genes and more efficient evolution. However, in organisms with more than one set of chromosomes at the main life cycle stage, sex may also provide an advantage because, under random mating, it produces homozygotes and heterozygotes according to the Hardy-Weinberg ratio.	Cell growth Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The term cell growth is used in two different ways in biology. When used in the context of reproduction of living cells the phrase "cell growth" is shorthand for the idea of "growth in cell populations by means of cell reproduction." During cell reproduction one cell (the "mother" cell) divides to produce two daughter cells. # Cell populations Cell populations go through a type of exponential growth called doubling. Thus, each generation of cells should be twice as numerous as the previous generation. However, as noted by Richard Dawkins (1997), this view is naive as the number of generations only gives a maximum figure. This is due to the fact that not all cells survive in each generation. # Cell size ## Yeast cell size regulation The relationship between cell size and cell division has been extensively studied in yeast. For some cells, there is a mechanism by which cell division is not initiated until a cell has reached a certain size. If the nutrient supply is restricted (after time t = 2 in the diagram, below) and the rate of increase in cell size is slowed, the time period between cell divisions is increased. Yeast cell size mutants were isolated that begin cell division before reaching the normal size (wee mutants)[1]. The Wee1 protein is a tyrosine kinase. It normally phosphorylates the Cdc2 cell cycle regulatory protein (cyclin-dependent kinase-1, CDK1) on a tyrosine residue. This covalent modification of the molecular structure of Cdc2 inhibits the enzymatic activity of Cdc2 and prevents cell division. In Wee1 mutants, there is less Wee1 activity and Cdc2 becomes active in smaller cells, causing cell division before the yeast cells reach their normal size. Cell division may be regulated in part by dilution of Wee1 protein in cells as they grow larger. ## Cell size regulation in mammals The protein mTOR is a serine/threonine kinase that regulates translation and cell division[2]. Nutrient availability influences mTOR so that when cells are not able to grow to normal size they will not undergo cell division. The details of the molecular mechanisms of mammalian cell size control are currently being investigated. The size of post-mitotic neurons depends on the size of the cell body, axon and dendrites. In vertebrates, neuron size is often a reflection of the number of synaptic contacts onto the neuron or from a neuron onto other cells. For example, the size of motoneurons usually reflects the size of the motor unit that is controlled by the motoneuron. Invertebrates often have giant neurons and axons that provide special functions such as rapid action potential propagation. Mammals also use this trick for increasing the speed of signals in the nervous system, but they can also use myelin to accomplish this, so most human neurons are releatively small. ## Other experimental systems for the study of cell size regulation One common means to produce very large cells is by cell fusion to form syncytia. For example, very long (several inches) skeletal muscle cells are formed by fusion of thousands of myocytes. Genetic studies of the fruit fly Drosophila have revealed several genes that are required for the formation of multinucleated muscle cells by fusion of myoblasts[3]. Some of the key proteins are important for cell adhesion between myocytes and some are involved in adhesion-dependent cell-to-cell signal transduction that allows for a cascade of cell fusion events. Oocytes can be unusually large cells in species for which embryonic development takes place away from the mother's body. Their large size can be achieved either by pumping in cytosolic components from adjacent cells through cytoplasmic bridges (Drosophila) or by internalization of nutrient storage granules (yolk granules) by endocytosis (frogs). Increases in the size of plant cells is complicated by the fact that almost all plant cells are inside of a solid cell wall. Under the influence of certain plant hormones the cell wall can be remodeled, allowing for increases in cell size that are important for the growth of some plant tissues. Most unicellular organisms are microscopic in size, but there are some giant bacteria and protozoa that are visible to the naked eye. See: Table of cell sizes - Dense populations of a giant sulfur bacterium in Namibian shelf sediments - Large protists of the genus Chaos, closely related to the genus Amoeba # Cell reproduction Cell reproduction is asexual. The process of cell reproduction has three major parts. The first part of cell reproduction involves the replication of the parental cell's DNA. The second major issue is the separation of the duplicated DNA into two equally sized groups of chromosomes. The third major aspect of cell reproduction is the physical division of entire cells, usually called cytokinesis. Cell reproduction is more complex in eukaryotes than in other organisms. Prokaryotic cells such as bacterial cells reproduce by binary fission, a process that includes DNA replication, chromosome segregation, and cytokinesis. Eukaryotic cell reproduction either involves mitosis or a more complex process called meiosis. Mitosis and meiosis are sometimes called the two "nuclear division" processes. Binary fission is similar to eukaryotic cell reproduction that involves mitosis. Both lead to the production of two daughter cells with the same number of chromosomes as the parental cell. Meiosis is used for a special cell reproduction process of diploid organisms. It produces four special daughter cells (gametes) which have half the normal cellular amount of DNA. A male and a female gamete can then combine to produce a zygote, a cell which again has the normal amount of chromosomes. The rest of this article is a comparison of the main features of the three types of cell reproduction that either involve binary fission, mitosis, or meiosis. The diagram below depicts the similarities and differences of these three types of cell reproduction. ## Comparison of the three types of cell reproduction The DNA content of a cell is duplicated at the start of the cell reproduction process. Prior to DNA replication, the DNA content of a cell can be represented as the amount Z (the cell has Z chromosomes). After the DNA replication process, the amount of DNA in the cell is 2Z (multiplication: 2 x Z = 2Z). During Binary fission and mitosis the duplicated DNA content of the reproducing parental cell is separated into two equal halves that are destined to end up in the two daughter cells. The final part of the cell reproduction process is cell division, when daughter cells physically split apart from a parental cell. During meiosis, there are two cell division steps that together produce the four daughter cells. After the completion of binary fission or cell reproduction involving mitosis, each daughter cell has the same amount of DNA (Z) as what the parental cell had before it replicated its DNA. These two types of cell reproduction produced two daughter cells that have the same number of chromosomes as the parental cell. After meiotic cell reproduction the four daughter cells have half the number of chromosomes that the parental cell originally had. This is the haploid amount of DNA, often symbolized as N. Meiosis is used by diploid organisms to produce haploid gametes. In a diploid organism such as the human organism, most cells of the body have the diploid amount of DNA, 2N. Using this notation for counting chromosomes we say that human somatic cells have 46 chromosomes (2N = 46) while human sperm and eggs have 23 chromosomes (N = 23). Humans have 23 distinct types of chromosomes, the 22 autosomes and the special category of sex chromosomes. There are two distinct sex chromosomes, the X chromosome and the Y chromosome. A diploid human cell has 23 chromosomes from that person's father and 23 from the mother. That is, your body has two copies of human chromosome number 2, one from each of your parents. Immediately after DNA replication a human cell will have 46 "double chromosomes". In each double chromosome there are two copies of that chromosome's DNA molecule. During mitosis the double chromosomes are split to produce 92 "single chromosomes", half of which go into each daughter cell. During meiosis, there are two chromosome separation steps which assure that each of the four daughter cells gets one copy of each of the 23 types of chromosome. ## Sexual reproduction Main article: Evolution of sex Though cell reproduction that uses mitosis can reproduce eukaryotic cells, eukaryotes bother with the more complicated process of meiosis because sexual reproduction such as meiosis confers a selective advantage. Notice that when meiosis starts, the two copies of chromosome number 2 are adjacent to each other. During this time, there can be genetic recombination events. Parts of the chromosome 2 DNA gained from one parent (red) will swap over to the chromosome 2 DNA molecule that received from the other parent (green). Notice that in mitosis the two copies of chromosome number 2 do not interact. It is these new combinations of parts of chromosomes that provide the major advantage for sexually reproducing organisms by allowing for new combinations of genes and more efficient evolution. However, in organisms with more than one set of chromosomes at the main life cycle stage, sex may also provide an advantage because, under random mating, it produces homozygotes and heterozygotes according to the Hardy-Weinberg ratio.	https://www.wikidoc.org/index.php/Cell_growth
2200e05c50ca4591640051df49f4fd14efdfdd23	wikidoc	Cell theory	Cell theory Cell theory refers to the idea that cells are the basic unit of structure in all living things. Development of this theory during the Mid 1600s was made possible by advances in microscopy. This theory is one of the foundations of biology. The theory says that new cells are formed from other existing cells and the cell is a fundamental unit of structure, physiology, and organization in all living organisms. # History of Cell Theory The cell was first named by Robert Hooke in 1665. He remarked that it looked strangely similar to cellulae or small rooms which monks inhabited, thus deriving the name. However what Hooke actually saw was the non-living cell walls from a cork (cork) . Hooke's description of these cells was published in Micrographia.. The cell walls observed by Hooke gave no indication of the nucleus and other organelles found in most living cells. The first man to witness a live cell under a microscope was Antonie van Leeuwenhoek, who in 1674 described the algae Spirogyra and named the moving organisms animalcules, meaning "little animals".(see). Leeuwenhoek probably also saw bacteria . Cell theory was in contrast to the vitalism theories that had been proposed before the discovery of cells. The idea that cells were separable into individual units was proposed by Ludolph Christian Treviranus and Johann Jacob Paul Moldenhawer. All of this finally led to Henri Dutrochet formulating one of the fundamental tenets of modern cell theory by declaring that "The cell is the fundamental element of organization" The observations of Hooke, Leeuwenhoek, Schleiden, Schwann, Virchow, and others led to the development of the cell theory. The cell theory is a widely accepted explanation of the relationship between cells and living things. The cell theory states: - All living things are composed of cells. - Cells are the basic unit of structure and function in living things. - All cells are produced from other cells. The cell theory holds true for all living things, no matter how big or small, or how simple or complex. Since according to research, cells are common to all living things, they can provide information about all life. And because all cells come from other cells, scientists can study cells to learn about growth, reproduction, and all other functions that living things perform. By learning about cells and how they function, you can learn about all types of living things. Credit for developing Cell Theory is usually given to three scientists, Theodor Schwann, Matthias Jakob Schleiden, and Rudolf Virchow. In 1839 Schwann and Schleiden suggested that cells were the basic unit of life. Their theory accepted the first two tenets of modern cell theory (see next section, below). However the cell theory of Schleiden differed from modern cell theory in that it proposed a method of spontaneous crystallization that he called "Free Cell Formation". In 1858, Rudolf Virchow concluded that all cells come from pre-existing cells thus completing the classical cell theory. ## Classical Cell Theory - All organisms are made up of one or more cells .. - Cells are the fundamental and structural unit of life. - All cells come from pre-existing cells. ## Modern Cell Theory The generally accepted parts of modern cell theory include: - The cell is the fundamental unit of structure and function in living things. - All cells come from pre-existing cells by division. - Energy flow (metabolism and biochemistry) occurs within cells. - Cells contain hereditary information (DNA) which is passed from cell to cell during cell division - All cells are basically the same in chemical composition. - All known living things are made up of cells. - Some organisms are unicellular, made up of only one cell. - Others are multicellular, composed of countless number of cells. - The activity of an organism depends on the total activity of independent cells ## Exceptions to the Theory - Viruses are considered by some to be alive, yet they are not made up of cells. - The first cell did not originate from a pre-existing cell. See: Origin of life. ## Types of cells Cells can be subdivided into the following subcategories: prokaryotes and eukaryotes. Prokaryotes lack a nucleus (though they do have circular DNA) and other membrane-bound organelles (though they do contain ribosomes). Eubacteria and Archeabacteria are two divisions of prokaryotes. Eukaryotes, on the other hand, have distinct nuclei and membrane-bound organelles (mitochondria, chloroplasts, lysosomes, rough and smooth endoplasmic reticulum, vacuoles). In addition, they possess organized chromosomes which store genetic material.	Cell theory Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Cell theory refers to the idea that cells are the basic unit of structure in all living things. Development of this theory during the Mid 1600s was made possible by advances in microscopy. This theory is one of the foundations of biology. The theory says that new cells are formed from other existing cells and the cell is a fundamental unit of structure, physiology, and organization in all living organisms. # History of Cell Theory The cell was first named by Robert Hooke in 1665. He remarked that it looked strangely similar to cellulae or small rooms which monks inhabited, thus deriving the name. However what Hooke actually saw was the non-living cell walls from a cork (cork) . Hooke's description of these cells was published in Micrographia.[1]. The cell walls observed by Hooke gave no indication of the nucleus and other organelles found in most living cells. The first man to witness a live cell under a microscope was Antonie van Leeuwenhoek, who in 1674 described the algae Spirogyra and named the moving organisms animalcules, meaning "little animals".(see). Leeuwenhoek probably also saw bacteria [2]. Cell theory was in contrast to the vitalism theories that had been proposed before the discovery of cells. The idea that cells were separable into individual units was proposed by Ludolph Christian Treviranus[3] and Johann Jacob Paul Moldenhawer[4]. All of this finally led to Henri Dutrochet formulating one of the fundamental tenets of modern cell theory by declaring that "The cell is the fundamental element of organization"[5] The observations of Hooke, Leeuwenhoek, Schleiden, Schwann, Virchow, and others led to the development of the cell theory. The cell theory is a widely accepted explanation of the relationship between cells and living things. The cell theory states: - All living things are composed of cells. - Cells are the basic unit of structure and function in living things. - All cells are produced from other cells. The cell theory holds true for all living things, no matter how big or small, or how simple or complex. Since according to research, cells are common to all living things, they can provide information about all life. And because all cells come from other cells, scientists can study cells to learn about growth, reproduction, and all other functions that living things perform. By learning about cells and how they function, you can learn about all types of living things. Credit for developing Cell Theory is usually given to three scientists, Theodor Schwann, Matthias Jakob Schleiden, and Rudolf Virchow. In 1839 Schwann and Schleiden suggested that cells were the basic unit of life. Their theory accepted the first two tenets of modern cell theory (see next section, below). However the cell theory of Schleiden differed from modern cell theory in that it proposed a method of spontaneous crystallization that he called "Free Cell Formation"[6]. In 1858, Rudolf Virchow concluded that all cells come from pre-existing cells thus completing the classical cell theory. ## Classical Cell Theory - All organisms are made up of one or more cells .. - Cells are the fundamental and structural unit of life. - All cells come from pre-existing cells. ## Modern Cell Theory The generally accepted parts of modern cell theory include: - The cell is the fundamental unit of structure and function in living things. - All cells come from pre-existing cells by division. - Energy flow (metabolism and biochemistry) occurs within cells. - Cells contain hereditary information (DNA) which is passed from cell to cell during cell division - All cells are basically the same in chemical composition. - All known living things are made up of cells. - Some organisms are unicellular, made up of only one cell. - Others are multicellular, composed of countless number of cells. - The activity of an organism depends on the total activity of independent cells ## Exceptions to the Theory - Viruses are considered by some to be alive, yet they are not made up of cells. - The first cell did not originate from a pre-existing cell. See: Origin of life. ## Types of cells Cells can be subdivided into the following subcategories: prokaryotes and eukaryotes. Prokaryotes lack a nucleus (though they do have circular DNA) and other membrane-bound organelles (though they do contain ribosomes). Eubacteria and Archeabacteria are two divisions of prokaryotes. Eukaryotes, on the other hand, have distinct nuclei and membrane-bound organelles (mitochondria, chloroplasts, lysosomes, rough and smooth endoplasmic reticulum, vacuoles). In addition, they possess organized chromosomes which store genetic material.	https://www.wikidoc.org/index.php/Cell_theory
72e3e49a9cac79e2a9973a016dd0f5d0c6b3baa4	wikidoc	Spinal cord	Spinal cord # Overview The spinal cord is a thin, tubular bundle of nerves that is an extension of the central nervous system from the brain and is enclosed in and protected by the bony vertebral column. The main function of the spinal cord is transmission of neural inputs between the periphery and the brain. # Structure The human spinal cord extends from the medulla oblongata in the brain and continues to the conus medullaris near the lumbar level at L1-2, terminating in a fibrous extension known as the filum terminale. It is about 45 cm long in men and 42 cm long in women, ovoid-shaped, and is enlarged in the cervical and lumbar regions. The peripheral regions of the cord contains neuronal white matter tracts containing sensory and motor neurons. The central region is a four-leaf clover shape that surrounds the central canal (an anatomic extension of the fourth ventricle) and contains nerve cell bodies. The three meninges that cover the spinal cord -- the outer dura mater, the arachnoid membrane, and the innermost pia mater -- are continuous with that in the brainstem and cerebral hemispheres, with cerebrospinal fluid found in the subarachnoid space. The cord within the pia mater is stabilized within the dura mater by the connecting denticulate ligaments which extends from the pia mater laterally between the dorsal and ventral roots. The dural sac ends at the vertebral level of S2. # Sensory Organization Somatosensory organization is divided into a touch/proprioception/vibration sensory pathway and a pain/temperature sensory pathway, which are more formally known as the dorsal column-medial lemniscus tract and the spinothalamic tract, respectively. Each of these sensory pathways utilizes three different neurons to get from the sensory receptors to the cerebral cortex. These neurons are designated primary, secondary and tertiary sensory neurons. The primary neuron has its cell body in the dorsal root ganglia and its axon projects into the spinal cord. In the case of the touch/proprioception/vibration sensory pathway, the primary neuron enters the spinal cord and travels in the dorsal column. Below level T6, the neuron travels in the fasciculus gracilis - the most medial part of the column. Above level T6, the neuron enters the fasciculus cuneatus - lateral to the fasiculus gracilis. As the primary axons reach the caudal medulla, they leave their respective fasiculi and enter and synapse on secondary neurons within the nucleus gracilis and the nucleus cuneatus, respectively. At this point, the seconday neuronal axons decussate and continue to ascend as the medial leminiscus. They run up to the VPL nucleus of the thalamus,and synapse there on the tertiary neurons. From there, the tertiary neurons ascend via the posterior limb of the internal capsule to the post central gyrus, or Brodmann's Area 3,1,2. The pain/temperature sensory pathway differs from that of the touch/proprioception/vibration pathway. The pain neurons enter as primary neurons and ascend 1-2 levels before synapsing in the substantia gelatinosa. The tract that ascends those 1-2 levels before synapsing is known as Lissauer's tract. After synapsing, the secondary neurons cross decussate and ascend as the spinothalamic tract in the anterior lateral portion of the spinal cord. Hence, the spinothalamic tract is also known as the anterior lateral system (ALS). The tract ascends all the way to the VPL of the thalamus where it synapses on the tertiary neurons. The tertiary neuronal axons then project via the posterior limb of the internal capsule to the post-central gyrus or Broadmann's Area 3,1,2. It should be noted that the pain fibers in the ALS can also deviate in their pathway towards the VPL. In one pathway, the axons project towards the reticular formation in the midbrain. The reticular formation then project to a number of places including the hippocampus (to create memories about the pain), to the centromedian nucleus (to cause diffuse, non-specific pain) and the various places on the cortex. The third place that the neurons project to is the periaqueductal gray in the pons. The neurons form the periaqueductal gray then project to the nucleus raphe magnus which projects back down to where the pain signal is coming in from and inhibits it. This reduces the pain sensation to some degree. # Motor Organization Upper motor neuronal input comes from two places- first from the cerebral cortex and second from more primitive brain stem nuclei. Cortical upper motor neurons originate in Brodmann Areas 4, 6, 3, 1 and 2. They then descend through the genu and the posterior limb of the internal capsule. This pathway is known as the corticospinal tract. After passing through the internal capsule, the tract descends through the cerebral peduncles, down through the pons and to the medullary pyramids. At this point, ~85% of these upper motor neuronal axons decussate. These fibers then descend as the lateral corticospinal tract. The remaining ~15% descend as the anterior corticospinal tract. The midbrain nuclei include four motor tracts that send upper motor neuronal axons down the spinal cord to lower motor neurons. These are the rubrospinal tract, the vestibulospinal tract, the tectospinal tract and the reticulospinal tract. The rubrospinal tract descends with the lateral corticospinal tract and the remaining three descend with the anterior corticospinal tract. The function of lower motor neurons can be divided into two different groups--first,the lateral corticospinal tract and second, the anterior cortical spinal tract. The lateral tract contains upper motor neuronal axons which synapse on dorsal lateral (DL) lower motor neurons. The DL neurons are involved in distal limb control. Therefore, these DL neurons are found specifically only in the cervical and lumbosaccral enlargements within the spinal cord. There is no decussation in the lateral corticospinal tract after the decussation at the medullary pyramids. The anterior corticospinal tract descends ipsilaterally in the anterior column where the axons emerge and either synapse on lower motor neurons, known as ventromedial (VM) lower motor neurons, in the ventral horn ipsilaterally, or descussate at the anterior white commissure where they synapse on VM lower motor neurons contralaterally . The tectospinal, vestibulospinal and reticulospinal descend ipsilaterally in the anterior column, but do not synapse across the anterior white commissure. Rather, they only synapse on VM lower motor neurons ipsilaterally. The VM lower motor neurons control axial motor function-- the large, postural muscles. These lower motor neurons, unlike those of the DL, are located in the ventral horn all the way throughout the spinal cord. # Spinocerebellar Tracts Proprioceptiveinformation in the body travels up the spinal cord via three tracts. Below L2 the proprioceptive information travels up the spinal cord in the ventral spinocerebellar tract. Also known as the anterior spinocerebellar tract, sensory receptors take in the information and travel into the spinal cord. The cell bodies of these primary neurons are located in the dorsal root ganglia. In the spinal cord, the axons synapse and the secondary neuronal axons decussate and then travel up to the superior cerebellar peduncle where they decussate again. From here, the information is brought to deep nuclei of the cerebellum including the fastigial and interposed nuclei. From the levels of L2 to T1, the proprioceptive information enters the spinal cord and ascends ipsilaterally where it synapses in the Dorsal Nucleus of Clark. The secondary neuronal axons continue to ascend ispilaterally and enter the pass into the cerebellum via the inferior cerebellar peduncle. This tract is known as the dorsal spinocerebellar tract and also as the posterior spinocerebellar tract. From above T1, proprioceptive primary axons enter the spinal cord and ascend ipsilaterally until reaching the accessory cuneate nucleus, where they synapse. The secondary axons pass into the cerebellum via the inferior cerebellar peduncle where again, these axons synapse on cerebellar deep nuclei. This tract is known as the cuneocerebellar tract. ## Spinal cord segments The human spinal cord is divided into 31 different segments, with motor nerve roots exiting in the ventral aspects and sensory nerve roots entering in the dorsal aspects. The ventral and dorsal roots later join to form paired spinal nerves, one on each side of the spinal cord. There are 31 spinal cord nerve segments in a human spinal cord: - 8 cervical segments (cervical nerves exit spinal column above C1 and below C1-C7) - 12 thoracic segments (nerves exit spinal column below T1-T12) - 5 lumbar segments (nerves exit spinal column below L1-L5) - 5 sacral segments (nerves exit spinal column below S1-S5) - 1 coccygeal segment (nerves exit spinal column at coccyx) Because the vertebral column grows longer than the spinal cord, spinal cord segments become higher than the corresponding vertebra, especially in the lower spinal cord segments in adults. In a fetus, the vertebral levels originally correspond with the spinal cord segments. In the adult, the cord ends around the L1/L2 vertebral level at the conus medullaris, with all of the spinal cord segments located superiorly to this. For example, the segments for the lumbar and sacral regions are found between the vertebral levels of T9 and L2. The S4 spinal nerve roots arise from the cord around the upper lumbar/lower thoracic vertebral region, and descend downward in the vertebral canal. After they pass the end of the spinal cord, they are considered to be part of the cauda equina. The roots for S4 finally leave the vertebral canal in the sacrum. There are two regions where the spinal cord enlarges: - Cervical enlargement - corresponds roughly to the brachial plexus nerves, which innervate the upper limb. It includes spinal cord segments from about C4 to T1. The vertebral levels of the enlargement are roughly the same (C4 to T1). - Lumbosacral enlargement - corresponds to the lumbosacral plexus nerves, which innervate the lower limb. It comprises the spinal cord segments from L2 to S3, and is found about the vertebral levels of T9 to T12. ## Embryology The spinal cord is made from part of the neural tube during development. As the neural tube begins to develop, the notochord begins to secrete a factor known as Sonic hedgehog or SHH. As a result, the floor plate then also begins to secrete SHH and this will induce the basal plate to develop motor neurons. Meanwhile, the overlying ectoderm secretes bone morphogenetic protein (BMP). This will induce the roof plate to begin to also secrete BMP which will induce the alar plate to develop sensory neurons. The alar plate and the basal plate are separated by the sulcus limitans. Additionally, the floor plate will also secrete netrins. The netrins act as chemoattractants to decussation of pain and temperature sensory neurons in the alar plate across the anterior white commissure where they will then ascend towards the thalamus. Lastly it is important to note that the past studies of Viktor Hamburger and Rita Levi-Montalcini in the chick embryo have been further proven by more recent studies which demonstrated that the elimination of neuronal cells by programmed cell death (PCD) is necessary for the correct assembly of the nervous system. Overall, spontaneous embryonic activity has been shown to play a role in neuron and muscle development, but is probably not involved in the initial formation of connections between spinal neurons. # Injury Spinal cord injuries can be caused by falling on the neck or back, or having the spinal cord moved or disrupted in another way. The vertebral bones or intervertebral disks can shatter, causing the spinal cord to be punctured by a sharp fragment of bone. Usually victims of spinal cord injuries will suffer loss of feeling in certain parts of their body. In milder cases a victim might only suffer loss of hand or foot function. More severe injury may result in paraplegia, tetraplegia, or full body paralysis below the site of injury to the spinal cord. Damage to upper motor neurons axons in the spinal cord results in a characteristic pattern of ipsilateral deficits. These include hyperreflexia, hypertonia and muscle weakness. Lower motor neuronal damage results in its own characteristic pattern of deficits. Rather than an entire side of deficits, there is a pattern relating to the myotome affected by the damage. Additionally, lower motor neurons are characterized by muscle weakness, hypotonia, hyporeflexia and muscle atrophy. The two areas of the spinal cord most commonly injured are the cervical spine (C1-C7) and the lumbar spine (L1-L5). (The notation C1, C7, L1, L5 refer to the location of a specific vertebra in either the cervical, thoracic, or lumbar region of the spine.) # Additional images - Diagrams of the spinal cord. - Cross-section through the spinal cord at the mid-thoracic level. - Cross-sections of the spinal cord at varying levels.	Spinal cord Editor-in-Chief: Muqtadeer Aziz Ansari, M.B.B.S. # Overview The spinal cord is a thin, tubular bundle of nerves that is an extension of the central nervous system from the brain and is enclosed in and protected by the bony vertebral column. The main function of the spinal cord is transmission of neural inputs between the periphery and the brain. # Structure The human spinal cord extends from the medulla oblongata in the brain and continues to the conus medullaris near the lumbar level at L1-2, terminating in a fibrous extension known as the filum terminale. It is about 45 cm long in men and 42 cm long in women, ovoid-shaped, and is enlarged in the cervical and lumbar regions. The peripheral regions of the cord contains neuronal white matter tracts containing sensory and motor neurons. The central region is a four-leaf clover shape that surrounds the central canal (an anatomic extension of the fourth ventricle) and contains nerve cell bodies. The three meninges that cover the spinal cord -- the outer dura mater, the arachnoid membrane, and the innermost pia mater -- are continuous with that in the brainstem and cerebral hemispheres, with cerebrospinal fluid found in the subarachnoid space. The cord within the pia mater is stabilized within the dura mater by the connecting denticulate ligaments which extends from the pia mater laterally between the dorsal and ventral roots. The dural sac ends at the vertebral level of S2. # Sensory Organization Somatosensory organization is divided into a touch/proprioception/vibration sensory pathway and a pain/temperature sensory pathway, which are more formally known as the dorsal column-medial lemniscus tract and the spinothalamic tract, respectively. Each of these sensory pathways utilizes three different neurons to get from the sensory receptors to the cerebral cortex. These neurons are designated primary, secondary and tertiary sensory neurons. The primary neuron has its cell body in the dorsal root ganglia and its axon projects into the spinal cord. In the case of the touch/proprioception/vibration sensory pathway, the primary neuron enters the spinal cord and travels in the dorsal column. Below level T6, the neuron travels in the fasciculus gracilis - the most medial part of the column. Above level T6, the neuron enters the fasciculus cuneatus - lateral to the fasiculus gracilis. As the primary axons reach the caudal medulla, they leave their respective fasiculi and enter and synapse on secondary neurons within the nucleus gracilis and the nucleus cuneatus, respectively. At this point, the seconday neuronal axons decussate and continue to ascend as the medial leminiscus. They run up to the VPL nucleus of the thalamus,and synapse there on the tertiary neurons. From there, the tertiary neurons ascend via the posterior limb of the internal capsule to the post central gyrus, or Brodmann's Area 3,1,2. The pain/temperature sensory pathway differs from that of the touch/proprioception/vibration pathway. The pain neurons enter as primary neurons and ascend 1-2 levels before synapsing in the substantia gelatinosa. The tract that ascends those 1-2 levels before synapsing is known as Lissauer's tract. After synapsing, the secondary neurons cross decussate and ascend as the spinothalamic tract in the anterior lateral portion of the spinal cord. Hence, the spinothalamic tract is also known as the anterior lateral system (ALS). The tract ascends all the way to the VPL of the thalamus where it synapses on the tertiary neurons. The tertiary neuronal axons then project via the posterior limb of the internal capsule to the post-central gyrus or Broadmann's Area 3,1,2. It should be noted that the pain fibers in the ALS can also deviate in their pathway towards the VPL. In one pathway, the axons project towards the reticular formation in the midbrain. The reticular formation then project to a number of places including the hippocampus (to create memories about the pain), to the centromedian nucleus (to cause diffuse, non-specific pain) and the various places on the cortex. The third place that the neurons project to is the periaqueductal gray in the pons. The neurons form the periaqueductal gray then project to the nucleus raphe magnus which projects back down to where the pain signal is coming in from and inhibits it. This reduces the pain sensation to some degree. # Motor Organization Upper motor neuronal input comes from two places- first from the cerebral cortex and second from more primitive brain stem nuclei. Cortical upper motor neurons originate in Brodmann Areas 4, 6, 3, 1 and 2. They then descend through the genu and the posterior limb of the internal capsule. This pathway is known as the corticospinal tract. After passing through the internal capsule, the tract descends through the cerebral peduncles, down through the pons and to the medullary pyramids. At this point, ~85% of these upper motor neuronal axons decussate. These fibers then descend as the lateral corticospinal tract. The remaining ~15% descend as the anterior corticospinal tract. The midbrain nuclei include four motor tracts that send upper motor neuronal axons down the spinal cord to lower motor neurons. These are the rubrospinal tract, the vestibulospinal tract, the tectospinal tract and the reticulospinal tract. The rubrospinal tract descends with the lateral corticospinal tract and the remaining three descend with the anterior corticospinal tract. The function of lower motor neurons can be divided into two different groups--first,the lateral corticospinal tract and second, the anterior cortical spinal tract. The lateral tract contains upper motor neuronal axons which synapse on dorsal lateral (DL) lower motor neurons. The DL neurons are involved in distal limb control. Therefore, these DL neurons are found specifically only in the cervical and lumbosaccral enlargements within the spinal cord. There is no decussation in the lateral corticospinal tract after the decussation at the medullary pyramids. The anterior corticospinal tract descends ipsilaterally in the anterior column where the axons emerge and either synapse on lower motor neurons, known as ventromedial (VM) lower motor neurons, in the ventral horn ipsilaterally, or descussate at the anterior white commissure where they synapse on VM lower motor neurons contralaterally . The tectospinal, vestibulospinal and reticulospinal descend ipsilaterally in the anterior column, but do not synapse across the anterior white commissure. Rather, they only synapse on VM lower motor neurons ipsilaterally. The VM lower motor neurons control axial motor function-- the large, postural muscles. These lower motor neurons, unlike those of the DL, are located in the ventral horn all the way throughout the spinal cord. # Spinocerebellar Tracts Proprioceptiveinformation in the body travels up the spinal cord via three tracts. Below L2 the proprioceptive information travels up the spinal cord in the ventral spinocerebellar tract. Also known as the anterior spinocerebellar tract, sensory receptors take in the information and travel into the spinal cord. The cell bodies of these primary neurons are located in the dorsal root ganglia. In the spinal cord, the axons synapse and the secondary neuronal axons decussate and then travel up to the superior cerebellar peduncle where they decussate again. From here, the information is brought to deep nuclei of the cerebellum including the fastigial and interposed nuclei. From the levels of L2 to T1, the proprioceptive information enters the spinal cord and ascends ipsilaterally where it synapses in the Dorsal Nucleus of Clark. The secondary neuronal axons continue to ascend ispilaterally and enter the pass into the cerebellum via the inferior cerebellar peduncle. This tract is known as the dorsal spinocerebellar tract and also as the posterior spinocerebellar tract. From above T1, proprioceptive primary axons enter the spinal cord and ascend ipsilaterally until reaching the accessory cuneate nucleus, where they synapse. The secondary axons pass into the cerebellum via the inferior cerebellar peduncle where again, these axons synapse on cerebellar deep nuclei. This tract is known as the cuneocerebellar tract. ## Spinal cord segments The human spinal cord is divided into 31 different segments, with motor nerve roots exiting in the ventral aspects and sensory nerve roots entering in the dorsal aspects. The ventral and dorsal roots later join to form paired spinal nerves, one on each side of the spinal cord. There are 31 spinal cord nerve segments in a human spinal cord: - 8 cervical segments (cervical nerves exit spinal column above C1 and below C1-C7) - 12 thoracic segments (nerves exit spinal column below T1-T12) - 5 lumbar segments (nerves exit spinal column below L1-L5) - 5 sacral segments (nerves exit spinal column below S1-S5) - 1 coccygeal segment (nerves exit spinal column at coccyx) Because the vertebral column grows longer than the spinal cord, spinal cord segments become higher than the corresponding vertebra, especially in the lower spinal cord segments in adults. In a fetus, the vertebral levels originally correspond with the spinal cord segments. In the adult, the cord ends around the L1/L2 vertebral level at the conus medullaris, with all of the spinal cord segments located superiorly to this. For example, the segments for the lumbar and sacral regions are found between the vertebral levels of T9 and L2. The S4 spinal nerve roots arise from the cord around the upper lumbar/lower thoracic vertebral region, and descend downward in the vertebral canal. After they pass the end of the spinal cord, they are considered to be part of the cauda equina. The roots for S4 finally leave the vertebral canal in the sacrum. There are two regions where the spinal cord enlarges: - Cervical enlargement - corresponds roughly to the brachial plexus nerves, which innervate the upper limb. It includes spinal cord segments from about C4 to T1. The vertebral levels of the enlargement are roughly the same (C4 to T1). - Lumbosacral enlargement - corresponds to the lumbosacral plexus nerves, which innervate the lower limb. It comprises the spinal cord segments from L2 to S3, and is found about the vertebral levels of T9 to T12. ## Embryology The spinal cord is made from part of the neural tube during development. As the neural tube begins to develop, the notochord begins to secrete a factor known as Sonic hedgehog or SHH. As a result, the floor plate then also begins to secrete SHH and this will induce the basal plate to develop motor neurons. Meanwhile, the overlying ectoderm secretes bone morphogenetic protein (BMP). This will induce the roof plate to begin to also secrete BMP which will induce the alar plate to develop sensory neurons. The alar plate and the basal plate are separated by the sulcus limitans. Additionally, the floor plate will also secrete netrins. The netrins act as chemoattractants to decussation of pain and temperature sensory neurons in the alar plate across the anterior white commissure where they will then ascend towards the thalamus. Lastly it is important to note that the past studies of Viktor Hamburger and Rita Levi-Montalcini in the chick embryo have been further proven by more recent studies which demonstrated that the elimination of neuronal cells by programmed cell death (PCD) is necessary for the correct assembly of the nervous system. Overall, spontaneous embryonic activity has been shown to play a role in neuron and muscle development, but is probably not involved in the initial formation of connections between spinal neurons. # Injury Spinal cord injuries can be caused by falling on the neck or back, or having the spinal cord moved or disrupted in another way. The vertebral bones or intervertebral disks can shatter, causing the spinal cord to be punctured by a sharp fragment of bone. Usually victims of spinal cord injuries will suffer loss of feeling in certain parts of their body. In milder cases a victim might only suffer loss of hand or foot function. More severe injury may result in paraplegia, tetraplegia, or full body paralysis below the site of injury to the spinal cord. Damage to upper motor neurons axons in the spinal cord results in a characteristic pattern of ipsilateral deficits. These include hyperreflexia, hypertonia and muscle weakness. Lower motor neuronal damage results in its own characteristic pattern of deficits. Rather than an entire side of deficits, there is a pattern relating to the myotome affected by the damage. Additionally, lower motor neurons are characterized by muscle weakness, hypotonia, hyporeflexia and muscle atrophy. The two areas of the spinal cord most commonly injured are the cervical spine (C1-C7) and the lumbar spine (L1-L5). (The notation C1, C7, L1, L5 refer to the location of a specific vertebra in either the cervical, thoracic, or lumbar region of the spine.) # Additional images - Diagrams of the spinal cord. - Cross-section through the spinal cord at the mid-thoracic level. - Cross-sections of the spinal cord at varying levels.	https://www.wikidoc.org/index.php/Cervical_segments
5eedc675b8abeb4d071f755a6cd5b38416d0b815	wikidoc	Spondylosis	Spondylosis # Overview Spondylosis is spinal degeneration and deformity of the joint(s) of two or more vertebrae that commonly occurs with aging. Often there is herniation of the nucleus pulposus of one or more intervertebral discs and/or formation of osteophytes. When the space between two adjacent vertebrae narrows, compression of a nerve root emerging from the spinal cord may result in sensory system and motor system disturbances, such as severe pain in the neck, shoulder, arm, back, and/or leg, accompanied by muscular weakness. Less commonly, direct pressure on the spinal cord may result in global weakness, gait dysfunction, loss of balance, and loss of bowel and/or bladder control. The patient may experience a phenomenon of shocks in hands and legs because of nerves contraction and lack of blood flow. If vertebrae of the neck are involved it is labeled Cervical Spondylosis. Lower back spondylosis is labeled Lumbar Spondylosis. # Treatment Neck pain can be relieved by wearing a hard collar around the neck which keeps the affected vertebrae slightly apart, and hence the pressure on the nerves is released. However, the use of a collar is not usually recommended as it can weaken the muscles supporting the vertebrae and hence exacerbate the problem in the long term. Chiropractic treatment of this condition is often successful. Symptoms are often reduced or eliminated without the need for drugs or surgery. Among skilled practitioners, there is frequently an improvement in the alignment of the spine which reduces the inflammation and irritation of the spinal nerves. Most people who are aware of the benefits of chiropractic care prefer this conservative approach to the more radical approach of surgery. Physiotherapy and Massage Therapy treatments focus on neck exercises and soft tissue balancing, and is now generally used as the preferred treatment. Symptomatic relief can be managed, but is limited in the presence of bony deformities. Acupuncture, while often effective when neuropathy results from muscle dysfunction or inflammation, symptoms resulting from bony deformities are unlikely to get better. Injections of the spinal joints can be useful for relief of acute pain for otherwise intractable discomfort. Naturally, any spine injection should be performed by a physician with training in spine injection techniques. These injections should be done with x-ray assistance (flouroscopy) to ensure accuracy. Evidential support for mobility (physiotherapy) or manipulative (chiropractic) therapies has shown an observed improvement in perceived pain and immobility in mechanical neck disorders. However such therapies are not supported as being of greater use in relieving pain and inflammation than conventional medicine and neither was identified as being superior to the other. # Surgery There are many different surgical procedures to correct spinal deformity. The vertebra can be approached by the surgeon from the front, side, or rear. Portions of a disc may be removed. To prevent further dislocation, fusion of two vertebrae may be done by taking pieces of bone from the patient's hip and inserting them between the two vertebrae which are fused together and secured by screws. # Related Chapters - Spinal disc herniation - Laminectomy de:Spondylose	Spondylosis Template:DiseaseDisorder infobox Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] # Overview Spondylosis is spinal degeneration and deformity of the joint(s) of two or more vertebrae that commonly occurs with aging. Often there is herniation of the nucleus pulposus of one or more intervertebral discs and/or formation of osteophytes. When the space between two adjacent vertebrae narrows, compression of a nerve root emerging from the spinal cord may result in sensory system and motor system disturbances, such as severe pain in the neck, shoulder, arm, back, and/or leg, accompanied by muscular weakness. Less commonly, direct pressure on the spinal cord may result in global weakness, gait dysfunction, loss of balance, and loss of bowel and/or bladder control. The patient may experience a phenomenon of shocks in hands and legs because of nerves contraction and lack of blood flow. If vertebrae of the neck are involved it is labeled Cervical Spondylosis. Lower back spondylosis is labeled Lumbar Spondylosis. # Treatment Neck pain can be relieved by wearing a hard collar around the neck which keeps the affected vertebrae slightly apart, and hence the pressure on the nerves is released. However, the use of a collar is not usually recommended as it can weaken the muscles supporting the vertebrae and hence exacerbate the problem in the long term. Chiropractic treatment of this condition is often successful. Symptoms are often reduced or eliminated without the need for drugs or surgery. Among skilled practitioners, there is frequently an improvement in the alignment of the spine which reduces the inflammation and irritation of the spinal nerves. Most people who are aware of the benefits of chiropractic care prefer this conservative approach to the more radical approach of surgery. Physiotherapy and Massage Therapy treatments focus on neck exercises and soft tissue balancing, and is now generally used as the preferred treatment. Symptomatic relief can be managed, but is limited in the presence of bony deformities. Acupuncture, while often effective when neuropathy results from muscle dysfunction or inflammation, symptoms resulting from bony deformities are unlikely to get better. Injections of the spinal joints can be useful for relief of acute pain for otherwise intractable discomfort. Naturally, any spine injection should be performed by a physician with training in spine injection techniques. These injections should be done with x-ray assistance (flouroscopy) to ensure accuracy. Evidential support for mobility (physiotherapy) or manipulative (chiropractic) therapies has shown an observed improvement in perceived pain and immobility in mechanical neck disorders. However such therapies are not supported as being of greater use in relieving pain and inflammation than conventional medicine and neither was identified as being superior to the other. # Surgery There are many different surgical procedures to correct spinal deformity. The vertebra can be approached by the surgeon from the front, side, or rear. Portions of a disc may be removed. To prevent further dislocation, fusion of two vertebrae may be done by taking pieces of bone from the patient's hip and inserting them between the two vertebrae which are fused together and secured by screws. # Related Chapters - Spinal disc herniation - Laminectomy Template:Diseases of the musculoskeletal system and connective tissue de:Spondylose Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Cervical_spondylosis
fc3cb1396c2d32c7f934db5b84308d52af3a3f60	wikidoc	Ion channel	Ion channel # Overview Ion channels are pore-forming proteins that help to establish and control the small voltage gradient across the plasma membrane of all living cells (see cell potential) by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells. # Basic features Ion channels regulate the flow of ions across the membrane in all cells. It is an integral membrane protein; or, more typically, an assembly of several proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or homologous proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer. The pore-forming subunit(s) are called the α subunit, while the auxiliary subunits are denoted β, γ, and so on. While some channels permit the passage of ions based solely on charge, the archetypal channel pore is just one or two atoms wide at its narrowest point. It conducts a specific species of ion, such as sodium or potassium, and conveys them through the membrane single file--nearly as quickly as the ions move through free fluid. In some ion channels, passage through the pore is governed by a "gate," which may be opened or closed by chemical or electrical signals, temperature, or mechanical force, depending on the variety of channel. # Biological role Because "voltage-gated" channels underlie the nerve impulse and because "transmitter-gated" channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, most of the offensive and defensive toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g., the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails and others) work by plugging ion channel pores. In addition, ion channels figure in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation and pancreatic beta-cell insulin release. In the search for new drugs, ion channels are a favorite target. # Diversity Ion channels may be classified by the nature of their gating, the species of ions passing through those gates, and the number of gates (pores). ## By gating Ion channels may be classified by gating, i.e. what opens and closes the channels. Voltage-gated ion channels activate/inactivate depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels activate/inactivate depending on binding of ligands to the channel. ### Voltage-gated voltage-gated channels open and close in response to membrane potential. - Voltage-gated sodium channels: This family contains at least 9 members and is largely responsible for action potential creation and propagation. The pore-forming α subunits are very large (up to 4,000 amino acids) and consist of four homologous repeat domains (I-IV) each comprising six transmembrane segments (S1-S6) for a total of 24 transmembrane segments. The members of this family also coassemble with auxiliary β subunits, each spanning the membrane once. Both α and β subunits are extensively glycosylated. - Voltage-gated calcium channels: This family contains 10 members, though these members are known to coassemble with α2δ, β, and γ subunits. These channels play an important role in both linking muscle excitation with contraction as well as neuronal excitation with transmitter release. The α subunits have an overall structural resemblance to those of the sodium channels and are equally large. Cation channels of sperm: This small family of channels, normally referred to as Catsper channels, is related to the two-pore channels and distantly related to TRP channels. - Cation channels of sperm: This small family of channels, normally referred to as Catsper channels, is related to the two-pore channels and distantly related to TRP channels. - Voltage-gated potassium channels (KV): This family contains almost 40 members, which are further divided into 12 subfamilies. These channels are known mainly for their role in repolarizing the cell membrane following action potentials. The α subunits have six transmembrane segments, homologous to a single domain of the sodium channels. Correspondingly, they assemble as tetramers to produce a functioning channel. - some Transient receptor potential channels: This group of channels, normally referred to simply as TRP channels, is named after their role in Drosophila phototransduction. This family, containing at least 28 members, is incredibly diverse in its method of activation. Some TRP channels seem to be constitutively open, while others are gated by voltage, intracellular Ca2+, pH, redox state, osmolarity, and mechanical stretch. These channels also vary according to the ion(s) they pass, some being selective for Ca2+ while others are less selective, acting as cation channels. This family is subdivided into 6 subfamilies based on homology: classical (TRPC), vanilloid receptors (TRPV), melastatin (TRPM), polycystins (TRPP), mucolipins (TRPML), and ankyrin transmembrane protein 1 (TRPA). - Hyperpolarization-activated cyclic nucleotide-gated channels: The opening of these channels is due to hyperpolarization rather than the depolarization required for other cyclic nucleotide-gated channels. These channels are also sensitive to the cyclic nucleotides cAMP and cGMP, which alter the voltage sensitivity of the channel’s opening. These channels are permeable to the monovalent cations K+ and Na+. There are 4 members of this family, all of which form tetramers of six-transmembrane α subunits. As these channels open under hyperpolarizing conditions, they function as pacemaking channels in the heart, particularly the SA node. - Voltage-gated proton channels: Voltage-gated proton channels openin with depolarization, but in a strongly pH-sensitive manner. The result is that these channels open only when the electrochemical gradient is outward, such that their opening will only allow protons to leave cells. Their function thus appears to be acid extrusion from cells. Another important function occurs in phagocytes (e.g. eosinophils, neutrophils, macrophages) during the "respiratory burst." When bacteria or other microbes are engulfed by phagocytes, the enzyme NADPH oxidase assembles in the membrane and begins to produce reactive oxygen species (ROS) that help kill bacteria. NADPH oxidase is electrogenic, moving electrons across the membrane, and proton channels open to allow proton flux to balance the electron movement electrically. ### Ligand-gated Ligand-gated ion channels (LGICs) activate/inactivate depending on binding of ligands to the channel. They are also known as ionotropic receptors. This group of channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein. Ligand binding causes a conformational change in the structure of the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane. Examples of LGICs include the cation-permeable "nicotinic" Acetylcholine receptor, ionotropic glutamate-gated receptors and ATP-gated P2X receptors, and the anion-permeable γ-aminobutyric acid-gated GABAA receptor. Ion channels activated by may also count to this group, although ligands and second messengers otherwise are distinguished from each other. ### Other gating Other gating include activation/inactivation by e.g. second messengers from the inside of the cell membrane, rather as from outside, as in the case for ligands. Ions may count to such second messengers, and then causes direct activation, rather than indirect, as in the case were the electric potential of ions cause activation/inactivation of voltage-gated ion channels. - Some potassium channels Inward-rectifier potassium channels: These channels allow potassium to flow into the cell in an inwardly rectifying manner, i.e, potassium flows effectively into, but not out of, the cell. This family is composed of 15 official and 1 unofficial members and is further subdivided into 7 subfamilies based on homology. These channels are affected by intracellular ATP, PIP2, and G-protein βγ subunits. They are involved in important physiological processes such as the pacemaker activity in the heart, insulin release, and potassium uptake in glial cells. They contain only two transmembrane segments, corresponding to the core pore-forming segments of the KV and KCa channels. Their α subunits form tetramers. Calcium-activated potassium channels: This family of channels is, for the most part, activated by intracellular Ca2+ and contains 8 members. Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels, and they follow Goldman-Hodgkin-Katz (open) rectification. - Inward-rectifier potassium channels: These channels allow potassium to flow into the cell in an inwardly rectifying manner, i.e, potassium flows effectively into, but not out of, the cell. This family is composed of 15 official and 1 unofficial members and is further subdivided into 7 subfamilies based on homology. These channels are affected by intracellular ATP, PIP2, and G-protein βγ subunits. They are involved in important physiological processes such as the pacemaker activity in the heart, insulin release, and potassium uptake in glial cells. They contain only two transmembrane segments, corresponding to the core pore-forming segments of the KV and KCa channels. Their α subunits form tetramers. - Calcium-activated potassium channels: This family of channels is, for the most part, activated by intracellular Ca2+ and contains 8 members. - Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels, and they follow Goldman-Hodgkin-Katz (open) rectification. - Light-gated channels like channelrhodopsin are directly opened by the action of light. - Cyclic nucleotide-gated channels: This superfamily of channels contains two families: the cyclic nucleotide-gated (CNG) channels and the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. It should be noted that this grouping is functional rather than evolutionary. Cyclic nucleotide-gated channels: This family of channels is characterized by activation due to the binding of intracellular cAMP or cGMP, with specificity varying by member. These channels are primarily permeable to monovalent cations such as K+ and Na+. They are also permeable to Ca2+, though it acts to close them. There are 6 members of this family, which is divided into 2 subfamilies. Hyperpolarization-activated cyclic nucleotide-gated channels - Cyclic nucleotide-gated channels: This family of channels is characterized by activation due to the binding of intracellular cAMP or cGMP, with specificity varying by member. These channels are primarily permeable to monovalent cations such as K+ and Na+. They are also permeable to Ca2+, though it acts to close them. There are 6 members of this family, which is divided into 2 subfamilies. - Hyperpolarization-activated cyclic nucleotide-gated channels ## By ions - Chloride channels: This superfamily of poorly understood channels consists of approximately 13 members. - Potassium channels Voltage-gated potassium channels Calcium-activated potassium channels Inward-rectifier potassium channels Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels, and they follow Goldman-Hodgkin-Katz (open) rectification. - Voltage-gated potassium channels - Calcium-activated potassium channels - Inward-rectifier potassium channels - Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels, and they follow Goldman-Hodgkin-Katz (open) rectification. - Sodium channels - Calcium channels - Proton channels Voltage-gated proton channels - Voltage-gated proton channels - General ion channels: These are relatively non-specific for ions and thus let many types of ions through the channel. Most Transient receptor potential channels - Most Transient receptor potential channels ## Other classifications There are other types of ion channel classifications that are based on less normal characteristics, e.g. multiple pores and transient potentials. Almost all ion channels have one single pore. However, there are also those with two: - Two-pore channels: This small family of 2 members putatively forms cation-selective ion channels. They are predicted to contain two KV-style six-transmembrane domains, suggesting they form a dimer in the membrane. These channels are related to catsper channels channels and, more distantly, TRP channels. Most ion channels make a relatively long-lasting potential change. However, there are also channels that only make a transient one: - Transient receptor potential channels: This group of channels, normally referred to simply as TRP channels, is named after their role in Drosophila phototransduction. This family, containing at least 28 members, is incredibly diverse in its method of activation. Some TRP channels seem to be constitutively open, while others are gated by voltage, intracellular Ca2+, pH, redox state, osmolarity, and mechanical stretch. These channels also vary according to the ion(s) they pass, some being selective for Ca2+ while others are less selective, acting as cation channels. This family is subdivided into 6 subfamilies based on homology: cannonical (TRPC), vanilloid receptors (TRPV), melastatin (TRPM), polycystins (TRPP), mucolipins (TRPML), and ankyrin transmembrane protein 1 (TRPA). # Detailed structure Channels differ with respect to the ion they let pass (for example, Na+, K+, Cl−), the ways in which they may be regulated, the number of subunits of which they are composed and other aspects of structure. Channels belonging to the largest class, which includes the voltage-gated channels that underlie the nerve impulse, consists of four subunits with six transmembrane helices each. On activation, these helices move about and open the pore. Two of these six helices are separated by a loop that lines the pore and is the primary determinant of ion selectivity and conductance in this channel class and some others. The existence and mechanism for ion selectivity was first postulated in the 1960s by Clay Armstrong. The channel subunits of one such other class, for example, consist of just this "P" loop and two transmembrane helices. The determination of their molecular structure by Roderick MacKinnon using X-ray crystallography won a share of the 2003 Nobel Prize in Chemistry. Because of their small size and the difficulty of crystallizing integral membrane proteins for X-ray analysis, it is only very recently that scientists have been able to directly examine what channels "look like." Particularly in cases where the crystallography required removing channels from their membranes with detergent, many researchers regard images that have been obtained as tentative. An example is the long-awaited crystal structure of a voltage-gated potassium channel, which was reported in May 2003. The detailed 3D structure of the magnesium channel from bacteria can be seen here. One inevitable ambiguity about these structures relates to the strong evidence that channels change conformation as they operate (they open and close, for example), such that the structure in the crystal could represent any one of these operational states. Most of what researchers have deduced about channel operation so far they have established through electrophysiology, biochemistry, gene sequence comparison and mutagenesis. # Diseases of Ion Channels There are a number of chemicals and genetic disorders which disrupt normal functioning of ion channels and have disastrous consequences for the organism. Genetic disorders of ion channels and their modifiers are known as Channelopathies. See Category:Channelopathy for a full list. Chemicals - Tetrodotoxin (TTX), used by puffer fish and some types of newts for defense. It is a sodium channel blocker. - Saxitoxin, produced by a dinoflagellate also known as "red tide". It blocks voltage dependent sodium channels. - Conotoxin, which is used by cone snails to hunt prey. - Lidocaine and Novocaine belong to a class of local anesthetics which block sodium ion channels. - Dendrotoxin is produced by mamba snakes which blocks potassium channels. - Iberiotoxin is produced by the Buthus tamulus which blocks potassium channels. - heteropodatoxin is produced by Heteropoda venatoria which blocks potassium channels. Genetic - Shaker gene mutations cause a defect in the voltage gated ion channels, slowing down the repolarization of the cell. - Equine hyperkalaemic periodic paralysis as well as Human hyperkalaemic periodic paralysis (HyperPP) are caused by a defect in voltage dependent sodium channels. - Paramyotonia congenita (PC) and potassium aggravated myotonias (PAM) - Generalized epilepsy with febrile seizures plus (GEFS+) - Episodic Ataxia (EA), characterized by sporadic bouts of severe discoordination with or without myokymia, and can be provoked by stress, startle, or heavy exertion such as exercise. - Familial hemiplegic migraine (FHM) - spinocerebellar ataxia type 13 - Long QT syndrome is a ventricular arrhythmia syndrome caused by mutations in one or more of presently ten different genes, most of which are potassium channels and all of which affect cardiac repolarization. - Brugada syndrome is another ventricular arrhythmia caused by voltage-gated sodium channel gene mutations. - Cystic fibrosis is caused by mutations in the CFTR gene, which is a chloride channel. # History The existence of ion channels was hypothesized by the British biophysicists Alan Hodgkin and Andrew Huxley as part of their Nobel Prize-winning theory of the nerve impulse, published in 1952. The existence of ion channels was confirmed in the 1970s with an electrical recording technique known as the "patch clamp," which led to a Nobel Prize to Erwin Neher and Bert Sakmann, the technique's inventors. Hundreds if not thousands of researchers continue to pursue a more detailed understanding of how these proteins work. In recent years the development of automated patch clamp devices helped to increase the throughput in ion channel screening significantly. The Nobel Prize in Chemistry for 2003 was awarded to two American scientists: Roderick MacKinnon for his studies on the physico-chemical properties of ion channel function, including x-ray crystallographic structure studies and Peter Agre for his similar work on aquaporins. Reference: - Nobel Prize Press Release # The Ion Channel in Fine Art Roderick MacKinnon commissioned "Birth of an Idea", a 5' (1.50 m) tall sculpture based on the KcsA potassium channel. The artwork contains a wire object representing the pore liner with a blown glass object representing the main cavity of the channel structure.	Ion channel Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Ion channels are pore-forming proteins that help to establish and control the small voltage gradient across the plasma membrane of all living cells (see cell potential) by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells. # Basic features Ion channels regulate the flow of ions across the membrane in all cells. It is an integral membrane protein; or, more typically, an assembly of several proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or homologous proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer.[1] The pore-forming subunit(s) are called the α subunit, while the auxiliary subunits are denoted β, γ, and so on. While some channels permit the passage of ions based solely on charge, the archetypal channel pore is just one or two atoms wide at its narrowest point. It conducts a specific species of ion, such as sodium or potassium, and conveys them through the membrane single file--nearly as quickly as the ions move through free fluid. In some ion channels, passage through the pore is governed by a "gate," which may be opened or closed by chemical or electrical signals, temperature, or mechanical force, depending on the variety of channel. # Biological role Because "voltage-gated" channels underlie the nerve impulse and because "transmitter-gated" channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, most of the offensive and defensive toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g., the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails and others) work by plugging ion channel pores. In addition, ion channels figure in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation and pancreatic beta-cell insulin release. In the search for new drugs, ion channels are a favorite target. # Diversity Ion channels may be classified by the nature of their gating, the species of ions passing through those gates, and the number of gates (pores). ## By gating Ion channels may be classified by gating, i.e. what opens and closes the channels. Voltage-gated ion channels activate/inactivate depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels activate/inactivate depending on binding of ligands to the channel. ### Voltage-gated voltage-gated channels open and close in response to membrane potential. - Voltage-gated sodium channels: This family contains at least 9 members and is largely responsible for action potential creation and propagation. The pore-forming α subunits are very large (up to 4,000 amino acids) and consist of four homologous repeat domains (I-IV) each comprising six transmembrane segments (S1-S6) for a total of 24 transmembrane segments. The members of this family also coassemble with auxiliary β subunits, each spanning the membrane once. Both α and β subunits are extensively glycosylated. - Voltage-gated calcium channels: This family contains 10 members, though these members are known to coassemble with α2δ, β, and γ subunits. These channels play an important role in both linking muscle excitation with contraction as well as neuronal excitation with transmitter release. The α subunits have an overall structural resemblance to those of the sodium channels and are equally large. Cation channels of sperm: This small family of channels, normally referred to as Catsper channels, is related to the two-pore channels and distantly related to TRP channels. - Cation channels of sperm: This small family of channels, normally referred to as Catsper channels, is related to the two-pore channels and distantly related to TRP channels. - Voltage-gated potassium channels (KV): This family contains almost 40 members, which are further divided into 12 subfamilies. These channels are known mainly for their role in repolarizing the cell membrane following action potentials. The α subunits have six transmembrane segments, homologous to a single domain of the sodium channels. Correspondingly, they assemble as tetramers to produce a functioning channel. - some Transient receptor potential channels: This group of channels, normally referred to simply as TRP channels, is named after their role in Drosophila phototransduction. This family, containing at least 28 members, is incredibly diverse in its method of activation. Some TRP channels seem to be constitutively open, while others are gated by voltage, intracellular Ca2+, pH, redox state, osmolarity, and mechanical stretch. These channels also vary according to the ion(s) they pass, some being selective for Ca2+ while others are less selective, acting as cation channels. This family is subdivided into 6 subfamilies based on homology: classical (TRPC), vanilloid receptors (TRPV), melastatin (TRPM), polycystins (TRPP), mucolipins (TRPML), and ankyrin transmembrane protein 1 (TRPA). - Hyperpolarization-activated cyclic nucleotide-gated channels: The opening of these channels is due to hyperpolarization rather than the depolarization required for other cyclic nucleotide-gated channels. These channels are also sensitive to the cyclic nucleotides cAMP and cGMP, which alter the voltage sensitivity of the channel’s opening. These channels are permeable to the monovalent cations K+ and Na+. There are 4 members of this family, all of which form tetramers of six-transmembrane α subunits. As these channels open under hyperpolarizing conditions, they function as pacemaking channels in the heart, particularly the SA node. - Voltage-gated proton channels: Voltage-gated proton channels openin with depolarization, but in a strongly pH-sensitive manner. The result is that these channels open only when the electrochemical gradient is outward, such that their opening will only allow protons to leave cells. Their function thus appears to be acid extrusion from cells. Another important function occurs in phagocytes (e.g. eosinophils, neutrophils, macrophages) during the "respiratory burst." When bacteria or other microbes are engulfed by phagocytes, the enzyme NADPH oxidase assembles in the membrane and begins to produce reactive oxygen species (ROS) that help kill bacteria. NADPH oxidase is electrogenic, moving electrons across the membrane, and proton channels open to allow proton flux to balance the electron movement electrically. ### Ligand-gated Ligand-gated ion channels (LGICs) activate/inactivate depending on binding of ligands to the channel. They are also known as ionotropic receptors. This group of channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein. Ligand binding causes a conformational change in the structure of the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane. Examples of LGICs include the cation-permeable "nicotinic" Acetylcholine receptor, ionotropic glutamate-gated receptors and ATP-gated P2X receptors, and the anion-permeable γ-aminobutyric acid-gated GABAA receptor. Ion channels activated by may also count to this group, although ligands and second messengers otherwise are distinguished from each other. ### Other gating Other gating include activation/inactivation by e.g. second messengers from the inside of the cell membrane, rather as from outside, as in the case for ligands. Ions may count to such second messengers, and then causes direct activation, rather than indirect, as in the case were the electric potential of ions cause activation/inactivation of voltage-gated ion channels. - Some potassium channels Inward-rectifier potassium channels: These channels allow potassium to flow into the cell in an inwardly rectifying manner, i.e, potassium flows effectively into, but not out of, the cell. This family is composed of 15 official and 1 unofficial members and is further subdivided into 7 subfamilies based on homology. These channels are affected by intracellular ATP, PIP2, and G-protein βγ subunits. They are involved in important physiological processes such as the pacemaker activity in the heart, insulin release, and potassium uptake in glial cells. They contain only two transmembrane segments, corresponding to the core pore-forming segments of the KV and KCa channels. Their α subunits form tetramers. Calcium-activated potassium channels: This family of channels is, for the most part, activated by intracellular Ca2+ and contains 8 members. Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels, and they follow Goldman-Hodgkin-Katz (open) rectification. - Inward-rectifier potassium channels: These channels allow potassium to flow into the cell in an inwardly rectifying manner, i.e, potassium flows effectively into, but not out of, the cell. This family is composed of 15 official and 1 unofficial members and is further subdivided into 7 subfamilies based on homology. These channels are affected by intracellular ATP, PIP2, and G-protein βγ subunits. They are involved in important physiological processes such as the pacemaker activity in the heart, insulin release, and potassium uptake in glial cells. They contain only two transmembrane segments, corresponding to the core pore-forming segments of the KV and KCa channels. Their α subunits form tetramers. - Calcium-activated potassium channels: This family of channels is, for the most part, activated by intracellular Ca2+ and contains 8 members. - Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels, and they follow Goldman-Hodgkin-Katz (open) rectification. - Light-gated channels like channelrhodopsin are directly opened by the action of light. - Cyclic nucleotide-gated channels: This superfamily of channels contains two families: the cyclic nucleotide-gated (CNG) channels and the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. It should be noted that this grouping is functional rather than evolutionary. Cyclic nucleotide-gated channels: This family of channels is characterized by activation due to the binding of intracellular cAMP or cGMP, with specificity varying by member. These channels are primarily permeable to monovalent cations such as K+ and Na+. They are also permeable to Ca2+, though it acts to close them. There are 6 members of this family, which is divided into 2 subfamilies. Hyperpolarization-activated cyclic nucleotide-gated channels - Cyclic nucleotide-gated channels: This family of channels is characterized by activation due to the binding of intracellular cAMP or cGMP, with specificity varying by member. These channels are primarily permeable to monovalent cations such as K+ and Na+. They are also permeable to Ca2+, though it acts to close them. There are 6 members of this family, which is divided into 2 subfamilies. - Hyperpolarization-activated cyclic nucleotide-gated channels ## By ions - Chloride channels: This superfamily of poorly understood channels consists of approximately 13 members. - Potassium channels Voltage-gated potassium channels Calcium-activated potassium channels Inward-rectifier potassium channels Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels, and they follow Goldman-Hodgkin-Katz (open) rectification. - Voltage-gated potassium channels - Calcium-activated potassium channels - Inward-rectifier potassium channels - Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels, and they follow Goldman-Hodgkin-Katz (open) rectification. - Sodium channels - Calcium channels - Proton channels Voltage-gated proton channels - Voltage-gated proton channels - General ion channels: These are relatively non-specific for ions and thus let many types of ions through the channel. Most Transient receptor potential channels - Most Transient receptor potential channels ## Other classifications There are other types of ion channel classifications that are based on less normal characteristics, e.g. multiple pores and transient potentials. Almost all ion channels have one single pore. However, there are also those with two: - Two-pore channels: This small family of 2 members putatively forms cation-selective ion channels. They are predicted to contain two KV-style six-transmembrane domains, suggesting they form a dimer in the membrane. These channels are related to catsper channels channels and, more distantly, TRP channels. Most ion channels make a relatively long-lasting potential change. However, there are also channels that only make a transient one: - Transient receptor potential channels: This group of channels, normally referred to simply as TRP channels, is named after their role in Drosophila phototransduction. This family, containing at least 28 members, is incredibly diverse in its method of activation. Some TRP channels seem to be constitutively open, while others are gated by voltage, intracellular Ca2+, pH, redox state, osmolarity, and mechanical stretch. These channels also vary according to the ion(s) they pass, some being selective for Ca2+ while others are less selective, acting as cation channels. This family is subdivided into 6 subfamilies based on homology: cannonical (TRPC), vanilloid receptors (TRPV), melastatin (TRPM), polycystins (TRPP), mucolipins (TRPML), and ankyrin transmembrane protein 1 (TRPA). # Detailed structure Channels differ with respect to the ion they let pass (for example, Na+, K+, Cl−), the ways in which they may be regulated, the number of subunits of which they are composed and other aspects of structure. Channels belonging to the largest class, which includes the voltage-gated channels that underlie the nerve impulse, consists of four subunits with six transmembrane helices each. On activation, these helices move about and open the pore. Two of these six helices are separated by a loop that lines the pore and is the primary determinant of ion selectivity and conductance in this channel class and some others. The existence and mechanism for ion selectivity was first postulated in the 1960s by Clay Armstrong. The channel subunits of one such other class, for example, consist of just this "P" loop and two transmembrane helices. The determination of their molecular structure by Roderick MacKinnon using X-ray crystallography won a share of the 2003 Nobel Prize in Chemistry. Because of their small size and the difficulty of crystallizing integral membrane proteins for X-ray analysis, it is only very recently that scientists have been able to directly examine what channels "look like." Particularly in cases where the crystallography required removing channels from their membranes with detergent, many researchers regard images that have been obtained as tentative. An example is the long-awaited crystal structure of a voltage-gated potassium channel, which was reported in May 2003. The detailed 3D structure of the magnesium channel from bacteria can be seen here. One inevitable ambiguity about these structures relates to the strong evidence that channels change conformation as they operate (they open and close, for example), such that the structure in the crystal could represent any one of these operational states. Most of what researchers have deduced about channel operation so far they have established through electrophysiology, biochemistry, gene sequence comparison and mutagenesis. # Diseases of Ion Channels There are a number of chemicals and genetic disorders which disrupt normal functioning of ion channels and have disastrous consequences for the organism. Genetic disorders of ion channels and their modifiers are known as Channelopathies. See Category:Channelopathy for a full list. Chemicals - Tetrodotoxin (TTX), used by puffer fish and some types of newts for defense. It is a sodium channel blocker. - Saxitoxin, produced by a dinoflagellate also known as "red tide". It blocks voltage dependent sodium channels. - Conotoxin, which is used by cone snails to hunt prey. - Lidocaine and Novocaine belong to a class of local anesthetics which block sodium ion channels. - Dendrotoxin is produced by mamba snakes which blocks potassium channels. - Iberiotoxin is produced by the Buthus tamulus which blocks potassium channels. - heteropodatoxin is produced by Heteropoda venatoria which blocks potassium channels. Genetic - Shaker gene mutations cause a defect in the voltage gated ion channels, slowing down the repolarization of the cell. - Equine hyperkalaemic periodic paralysis as well as Human hyperkalaemic periodic paralysis (HyperPP) are caused by a defect in voltage dependent sodium channels. - Paramyotonia congenita (PC) and potassium aggravated myotonias (PAM) - Generalized epilepsy with febrile seizures plus (GEFS+) - Episodic Ataxia (EA), characterized by sporadic bouts of severe discoordination with or without myokymia, and can be provoked by stress, startle, or heavy exertion such as exercise. - Familial hemiplegic migraine (FHM) - spinocerebellar ataxia type 13 - Long QT syndrome is a ventricular arrhythmia syndrome caused by mutations in one or more of presently ten different genes, most of which are potassium channels and all of which affect cardiac repolarization. - Brugada syndrome is another ventricular arrhythmia caused by voltage-gated sodium channel gene mutations. - Cystic fibrosis is caused by mutations in the CFTR gene, which is a chloride channel. # History The existence of ion channels was hypothesized by the British biophysicists Alan Hodgkin and Andrew Huxley as part of their Nobel Prize-winning theory of the nerve impulse, published in 1952. The existence of ion channels was confirmed in the 1970s with an electrical recording technique known as the "patch clamp," which led to a Nobel Prize to Erwin Neher and Bert Sakmann, the technique's inventors. Hundreds if not thousands of researchers continue to pursue a more detailed understanding of how these proteins work. In recent years the development of automated patch clamp devices helped to increase the throughput in ion channel screening significantly. The Nobel Prize in Chemistry for 2003 was awarded to two American scientists: Roderick MacKinnon for his studies on the physico-chemical properties of ion channel function, including x-ray crystallographic structure studies and Peter Agre for his similar work on aquaporins. Reference: - Nobel Prize Press Release # The Ion Channel in Fine Art Roderick MacKinnon commissioned "Birth of an Idea", a 5' (1.50 m) tall sculpture based on the KcsA potassium channel. The artwork contains a wire object representing the pore liner with a blown glass object representing the main cavity of the channel structure.	https://www.wikidoc.org/index.php/Channel_blocker
49e6a3cafd388b0ad79992de451a74d993efe7e8	wikidoc	Chemophobia	Chemophobia # Overview Chemophobia literally means "fear of chemicals" and may be used in various ways. It is most often used to describe the assumption that 'chemicals' are bad and that 'natural' things are good. # Definition The most usual use of the term 'chemophobia' is analogous to 'homophobia' - a prejudice against something rather than an irrational fear. See Non-clinical uses of 'phobia' and Prejudices described as phobias. In this sense, chemophobia is akin to technophobia. ## Other uses of the term Some define 'chemophobia' as a full-blown psychological phobia - a 'specific phobia' - but most mainstream sources such as the Oxford Dictionary of Psychology do not recognise chemophobia as a psychological condition. Websites which use the specific phobia definition (such as this) typically sell cures for a very wide range of specific phobias, and seem to include 'chemophobia' simply to enlarge the range of conditions they claim to treat. The National Institute of Health does not list chemophobia as a rare condition. Another definition of 'chemophobia' is that it is a concern about learning chemistry as an academic subject. # Characteristics Research shows that people are primarily afraid that 'chemicals' will cause cancer and that they are reassured when they learn how rigorously pesticides are tested and the unfeasibly high levels of pesticides a human would need to accumulate before coming to harm. # Causes " reputation with the general public, once extremely high, has fallen to an all-time low as a result of accidents such as Bhopal and Seveso, and health scares fed by campaigns by environmental groups, and encouraged by a sometimes gullible media. "But where does this lack of trust originate? According to Bernadette Bensaude-Vincent, ...the present situation originated in the 'fabulous fiction' of Rachel Carson’s book, Silent Spring, which portrayed chemistry as a blind and brutal enemy of birds and other living creatures." A contributory factor to chemophobia is due to increasing sensitivity of analytical techniques which can now detect extremely low levels of chemicals. The levels are so low as to be harmless, but the media report the fact that the chemical can be detected in such-and-such a place, and that it is harmful. What is unreported is the levels which cause harm and the levels at which it was detected. "Away from the high doses of occupational exposure a whole host of unwanted chemicals finds their way into our bodies all the time, chemical baggage we carry is very small. It is only because of the great advances in analytical chemistry that we are able to detect it’s there at all." "you cannot lead a chemical-free life, because everything is made of chemicals." "we can detect some chemicals in the body in parts per billion. A part per billion is equivalent to one grain of sugar in an Olympic swimming pool; or one blade of grass on a football pitch." "To understand whether the presence of a chemical is a problem, we need to know how much of it is present and to look at what kind of effect, if any, it is having."	Chemophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview Chemophobia literally means "fear of chemicals" and may be used in various ways. It is most often used to describe the assumption that 'chemicals' are bad and that 'natural' things are good. Template:Quote box # Definition The most usual use of the term 'chemophobia' is analogous to 'homophobia' - a prejudice against something rather than an irrational fear. See Non-clinical uses of 'phobia' and Prejudices described as phobias. In this sense, chemophobia is akin to technophobia. ## Other uses of the term Some[1] define 'chemophobia' as a full-blown psychological phobia - a 'specific phobia' - but most mainstream sources such as the Oxford Dictionary of Psychology do not recognise chemophobia as a psychological condition. Websites which use the specific phobia definition (such as this) typically sell cures for a very wide range of specific phobias, and seem to include 'chemophobia' simply to enlarge the range of conditions they claim to treat. The National Institute of Health does not list chemophobia as a rare condition.[2] Another definition of 'chemophobia' is that it is a concern about learning chemistry as an academic subject.[3] # Characteristics Research[4] shows that people are primarily afraid that 'chemicals' will cause cancer and that they are reassured when they learn how rigorously pesticides are tested and the unfeasibly high levels of pesticides a human would need to accumulate before coming to harm. # Causes "[The chemical industry's] reputation with the general public, once extremely high, has fallen to an all-time low as a result of accidents such as Bhopal and Seveso, and health scares fed by campaigns by environmental groups, and encouraged by a sometimes gullible media. "But where does this lack of trust [between society and business] originate? According to Bernadette Bensaude-Vincent, ...the present situation originated in the 'fabulous fiction' of Rachel Carson’s book, Silent Spring, which portrayed chemistry as a blind and brutal enemy of birds and other living creatures."[5] A contributory factor to chemophobia is due to increasing sensitivity of analytical techniques which can now detect extremely low levels of chemicals. The levels are so low as to be harmless, but the media report the fact that the chemical can be detected in such-and-such a place, and that it is harmful. What is unreported is the levels which cause harm and the levels at which it was detected. "Away from the high doses of occupational exposure a whole host of unwanted chemicals finds their way into our bodies all the time, [but the] chemical baggage we carry is very small. It is only because of the great advances in analytical chemistry that we are able to detect it’s there at all." [6] "you cannot lead a chemical-free life, because everything is made of chemicals." "we can detect some chemicals in the body in parts per billion. A part per billion is equivalent to one grain of sugar in an Olympic swimming pool; or one blade of grass on a football pitch." "To understand whether the presence of a chemical is a problem, we need to know how much of it is present and to look at what kind of effect, if any, it is having."[7]	https://www.wikidoc.org/index.php/Chemophobia
83fbe0f7a9473f2fbbc9b725a9098d35d72b380b	wikidoc	Chemosensor	Chemosensor A chemosensor, also known as chemoreceptor, is a cell or group of cells that transduce a chemical signal into an action potential. Or, more generally, a chemosensor detects certain chemical stimuli in the environment. # Classes There are two main classes of the chemosensor: direct and distance. - Examples of distance chemoreceptors are: -lfactory receptor neurons in the olfactory system neurons in the vomeronasal organ that detect pheromones - olfactory receptor neurons in the olfactory system - neurons in the vomeronasal organ that detect pheromones - Examples of direct chemoreceptors include taste buds in the gustatory system carotid bodies and aortic bodies that detect changes in pH inside the body. - taste buds in the gustatory system - carotid bodies and aortic bodies that detect changes in pH inside the body. # Systems affected ## Breathing rate Chemoreceptors detect the levels of carbon dioxide in the blood. To do this, they monitor the concentration of hydrogen ions in the blood, which decreases the pH of the blood, as a direct consequence of the raised carbon dioxide concentration. The response is that the inspiratory centre (in the medulla), sends nervous impulses to the external intercostal muscles and the diaphragm, via the phrenic nerve to increase breathing rate and the volume of the lungs during inhalation. Chemoreceptors which affect breathing rate are broken down into two categories. - central chemoreceptors (in the medulla) do not respond to a drop in oxygen, and eventually desensitize. - peripheral chemoreceptors (carotid arteries and aorta) do respond to extreme drops in oxygen, and do not desensitize. Their effect on breathing rate is less than that of the central chemoreceptors. ## Heart rate Chemoreceptors in the medulla oblongata, carotid arteries and aortic arch, detect the levels of carbon dioxide in the blood, in the same way as applicable in the Breathing Rate section. In response to this high concentration, a nervous impulse is sent to the cardiovascular centre in the medulla, which will then feedback to the sympathetic ganglia, increasing nervous impulses here, and prompting the sinoatrial node to stimulate more contractions of the myogenic cardiac muscle increase heart rate. ## Sense organs In taste sensation, the tongue is composed of 5 different taste buds: salty, sour, sweet, bitter, and savory. The salty and sour tastes work directly through the ion channels, the sweet and bitter taste work through G protein-coupled receptors, and the savoury sensation is activated by glutamate. Noses in vertebrates and antennae in many invertebrates act as distance chemoreceptors. Molecules diffused through the air and bind to specific receptors on olfactory sensory neurons, activating an opening ion channel via G-proteins. When inputs from the environment are significant to the survival of the organism the input must be detected. As all life processes are ultimately based on chemistry it is natural that detection and passing on of the external input will involve chemical events. The chemistry of the environment is, of course, relevant to survival, and detection of chemical input from the outside may well articulate directly with cell chemicals. For example: The emissions of a predator's food source, such as odors or pheromones, may be in the air or on a surface where the food source has been. Cells in the head, usually the air passages or mouth, have chemical receptors on their surface that change when in contact with the emissions. The change does not stop there. It passes in either chemical or electrochemical form to the central processor, the brain or spinal cord. The resulting output from the CNS (central nervous system) makes body actions that will engage the food and enhance survival.	Chemosensor Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] A chemosensor, also known as chemoreceptor, is a cell or group of cells that transduce a chemical signal into an action potential. Or, more generally, a chemosensor detects certain chemical stimuli in the environment. # Classes There are two main classes of the chemosensor: direct and distance. - Examples of distance chemoreceptors are: olfactory receptor neurons in the olfactory system neurons in the vomeronasal organ that detect pheromones - olfactory receptor neurons in the olfactory system - neurons in the vomeronasal organ that detect pheromones - Examples of direct chemoreceptors include taste buds in the gustatory system carotid bodies and aortic bodies that detect changes in pH inside the body. - taste buds in the gustatory system - carotid bodies and aortic bodies that detect changes in pH inside the body. # Systems affected ## Breathing rate Chemoreceptors detect the levels of carbon dioxide in the blood. To do this, they monitor the concentration of hydrogen ions in the blood, which decreases the pH of the blood, as a direct consequence of the raised carbon dioxide concentration. The response is that the inspiratory centre (in the medulla), sends nervous impulses to the external intercostal muscles and the diaphragm, via the phrenic nerve to increase breathing rate and the volume of the lungs during inhalation. Chemoreceptors which affect breathing rate are broken down into two categories. - central chemoreceptors (in the medulla) do not respond to a drop in oxygen, and eventually desensitize. - peripheral chemoreceptors (carotid arteries and aorta) do respond to extreme drops in oxygen, and do not desensitize. Their effect on breathing rate is less than that of the central chemoreceptors. ## Heart rate Chemoreceptors in the medulla oblongata, carotid arteries and aortic arch, detect the levels of carbon dioxide in the blood, in the same way as applicable in the Breathing Rate section. In response to this high concentration, a nervous impulse is sent to the cardiovascular centre in the medulla, which will then feedback to the sympathetic ganglia, increasing nervous impulses here, and prompting the sinoatrial node to stimulate more contractions of the myogenic cardiac muscle increase heart rate. ## Sense organs In taste sensation, the tongue is composed of 5 different taste buds: salty, sour, sweet, bitter, and savory. The salty and sour tastes work directly through the ion channels, the sweet and bitter taste work through G protein-coupled receptors, and the savoury sensation is activated by glutamate. Noses in vertebrates and antennae in many invertebrates act as distance chemoreceptors. Molecules diffused through the air and bind to specific receptors on olfactory sensory neurons, activating an opening ion channel via G-proteins. When inputs from the environment are significant to the survival of the organism the input must be detected. As all life processes are ultimately based on chemistry it is natural that detection and passing on of the external input will involve chemical events. The chemistry of the environment is, of course, relevant to survival, and detection of chemical input from the outside may well articulate directly with cell chemicals. For example: The emissions of a predator's food source, such as odors or pheromones, may be in the air or on a surface where the food source has been. Cells in the head, usually the air passages or mouth, have chemical receptors on their surface that change when in contact with the emissions. The change does not stop there. It passes in either chemical or electrochemical form to the central processor, the brain or spinal cord. The resulting output from the CNS (central nervous system) makes body actions that will engage the food and enhance survival.	https://www.wikidoc.org/index.php/Chemoreception
506763a6e6f741c6eb17ce05f83f3a06403c9533	wikidoc	Chenopodium	Chenopodium # Overview Chenopodium is a genus of about 150 species of perennial or annual herbaceous flowering plants known as the goosefoots, which occur almost anywhere in the world. It is placed in the family Amaranthaceae in the APG II system; older classifications separate it and its relatives as Chenopodiaceae, but this leaves the rest of the Amaranthaceae polyphyletic. However, among the Amaranthaceae, the genus Chenopodium is the namesake member of the subfamily Chenopodioideae. The genus Dysphania is closely related, and contains several species formerly placed in Chenopodium, such as epazote (D. ambrosioides). In Australia, the larger Chenopodium species are among the plants called "bluebushes". Chualar in California is named after a Native American term for a goosefoot abundant in the region, probably the California goosefoot (C. californicum). # Uses and ecology The genus Chenopodium contains several plants of minor to moderate importance as food crops as leaf vegetables – used like the closely related spinach (Spinacia oleracea) and similar plants called quelite in Mexico – and pseudocereals. These include white goosefoot (C. album), Good King Henry (C. bonus-henricus), strawberry blite (C. capitatum), leafy goosefoot (C. foliosum), kañiwa (C. pallidicaule) and quinoa (C. quinoa). On the Greek island of Crete, tender shoots and leaves of a species called krouvida (κρουβίδα) or psarovlito (ψαρόβλητο) are eaten by the locals, boiled or steamed. As studied by Kristen Gremillion and others, goosefoots have a history of culinary use dating back to 4000 BC or earlier, when pitseed goosefoot (C. berlandieri) was a staple crop in the Native American eastern agricultural complex, and white goosefoot was apparently used by the Ertebølle culture of Europe. There is increased interest in particular in goosefoot seeds today, which are suitable as part of a gluten-free diet. Quinoa oil, extracted from the seeds of C. quinoa, has similar properties, but is superior in quality, to corn oil. Oil of chenopodium is extracted from the seeds of epazote, which is not in this genus anymore. Shagreen leather was produced in the past using the small, hard goosefoot seeds. C. album was one of the main model organisms for the molecular biological study of chlorophyllase. Goosefoot pollen, in particular of the widespread and usually abundant C. album, is an allergen to many people and a common cause of hay fever. The same species, as well as some others, have seeds which are able to persist for years in the soil seed bank. Many goosefoot species are thus significant weeds, and some have become invasive species. Certain species grow in large thickets, providing cover for small animals. Goosefoot foliage is used as food by the caterpillars of certain Lepidoptera. The seeds are eaten by many birds, such as the yellowhammer (Emberiza citrinella) of Europe or the white-winged fairy-wren (Malurus leucopterus) of Australia. Goosefoot pathogens include the positive-sense ssRNA viruses - apple stem grooving virus, sowbane mosaic virus and tobacco necrosis virus. # Selected species - Chenopodium acuminatum Willd. - Chenopodium album – white goosefoot, nickel greens, dungweed, bathua, chandali, chandaliya, fat hen, lamb's quarters, pigweed Chenopodium album ssp. amaranticolor - Chenopodium album ssp. amaranticolor - Chenopodium atrovirens – dark goosefoot, pinyon goosefoot - Chenopodium auricomiforme - Chenopodium auricomum – Queensland bluebush - Chenopodium berlandieri – pitseed goosefoot, southern huauzontle, lambsquarters Chenopodium berlandieri ssp. nuttalliae (Saff.) H.D.Wilson & Heiser Chenopodium berlandieri var. bushianum Chenopodium berlandieri var. zschackii - Chenopodium berlandieri ssp. nuttalliae (Saff.) H.D.Wilson & Heiser - Chenopodium berlandieri var. bushianum - Chenopodium berlandieri var. zschackii - Chenopodium bonus-henricus – Good King Henry, perennial goosefoot, poor-man's asparagus, Lincolnshire spinach, markery - Chenopodium bushianum – village goosefoot - Chenopodium californicum – California goosefoot, Indian lettuce - Chenopodium capitatum – strawberry blite, blite goosefoot, strawberry goosefoot, strawberry spinach, Indian paint, Indian ink - Chenopodium chenopodioides – small red Goosefoot, saltmarsh goosefoot - Chenopodium curvispicatum - Chenopodium cycloides - Chenopodium desertorum – desert goosefoot Chenopodium desertorum ssp. anidiophyllum Chenopodium desertorum ssp. desertorum Chenopodium desertorum ssp. microphyllum Chenopodium desertorum ssp. rectum Chenopodium desertorum ssp. virosum - Chenopodium desertorum ssp. anidiophyllum - Chenopodium desertorum ssp. desertorum - Chenopodium desertorum ssp. microphyllum - Chenopodium desertorum ssp. rectum - Chenopodium desertorum ssp. virosum - Chenopodium desiccatum – narrowleaf goosefoot - Chenopodium erosum R.Br. - Chenopodium ficifolium – fig-leaved goosefoot, small goosefoot - Chenopodium foggii – Fogg's goosefoot - Chenopodium foliosum – leafy goosefoot - Chenopodium fremontii – Fremont's goosefoot - Chenopodium giganteum D.Don – tree spinach - Chenopodium glaucum – oak-leaved goosefoot, glaucous goosefoot - Chenopodium helenense Aellen - Chenopodium hians – Hians goosefoot - Chenopodium hircinum Schrad. - Chenopodium humile – marshland goosefoot - Chenopodium hybridum – maple-leaved goosefoot, sowbane - Chenopodium incanum – mealy goosefoot - Chenopodium leptophyllum – narrowleaf goosefoot - Chenopodium littoreum - Chenopodium missouriense – Missouri goosefoot (sometimes considered a variety of C. album) - Chenopodium murale – nettle-leaved goosefoot - Chenopodium nitrariaceum (F.Muell.) F.Muell. ex Benth. – nitre goosefoot - Chenopodium nuttalliae – huauzontle - Chenopodium oahuense – Template:OkinaĀheahea (]) - Chenopodium opulifolium Schrad. ex W.D.J.Koch – grey goosefoot - Chenopodium pallidicaule – kañiwa - Chenopodium polyspermum – many-seeded goosefoot Chenopodium polyspermum var. acutifolium - Chenopodium polyspermum var. acutifolium - Chenopodium pratericola Rydb. – pale goosefoot, desert goosefoot, narrowleaf goosefoot - Chenopodium probstii Aellen - Chenopodium purpurascens – purple goosefoot - Chenopodium quinoa – quinoa - Chenopodium retusum - Chenopodium rubrum – red goosefoot, coastblite goosefoot - Chenopodium salinum – Rocky Mountain goosefoot - Chenopodium simplex – giantseed goosefoot - Chenopodium standleyanum – Standley's goosefoot - Chenopodium strictum Roth - Chenopodium subglabrum – smooth arid goosefoot, smooth goosefoot - Chenopodium suecicum – green goosefoot - Chenopodium truncatum - Chenopodium urbicum – upright goosefoot - Chenopodium × variabile (C. album × C. berlandieri) - Chenopodium vulvaria – stinking goosefoot, notchweed - Chenopodium watsonii – Watson's goosefoot Formerly placed here: - Dysphania, all glandular species (as C. botrys, C. carinatum, C. cristatum, C. melanocarpum, C. multifidium, C. pumilio and more) - Rhagodia baccata – berry saltbush (as C. baccatum) - Suaeda australis – austral seablite (as C. australe, C. insulare) ar:زربيح az:Tərə ca:Quenopodi da:Gåsefod de:Gänsefüße et:Hanemalts el:Αγαθόφυτα hsb:Pólšica it:Chenopodium he:כף-אווז ka:ნაცარქათამა kk:Алабұта lt:Balanda hu:Libatop nl:Ganzenvoet qu:Ayara fi:Savikat sv:Mållor	Chenopodium Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Chenopodium is a genus of about 150[verification needed] species of perennial or annual herbaceous flowering plants known as the goosefoots, which occur almost anywhere in the world. It is placed in the family Amaranthaceae in the APG II system; older classifications separate it and its relatives as Chenopodiaceae, but this leaves the rest of the Amaranthaceae polyphyletic. However, among the Amaranthaceae, the genus Chenopodium is the namesake member of the subfamily Chenopodioideae. The genus Dysphania is closely related, and contains several species formerly placed in Chenopodium, such as epazote (D. ambrosioides). In Australia, the larger Chenopodium species are among the plants called "bluebushes". Chualar in California is named after a Native American term for a goosefoot abundant in the region, probably the California goosefoot (C. californicum). # Uses and ecology The genus Chenopodium contains several plants of minor to moderate importance as food crops as leaf vegetables – used like the closely related spinach (Spinacia oleracea) and similar plants called quelite in Mexico – and pseudocereals. These include white goosefoot (C. album), Good King Henry (C. bonus-henricus), strawberry blite (C. capitatum), leafy goosefoot (C. foliosum), kañiwa (C. pallidicaule) and quinoa (C. quinoa). On the Greek island of Crete, tender shoots and leaves of a species called krouvida (κρουβίδα) or psarovlito (ψαρόβλητο) are eaten by the locals, boiled or steamed. As studied by Kristen Gremillion and others, goosefoots have a history of culinary use dating back to 4000 BC or earlier, when pitseed goosefoot (C. berlandieri) was a staple crop in the Native American eastern agricultural complex, and white goosefoot was apparently used by the Ertebølle culture of Europe. There is increased interest in particular in goosefoot seeds today, which are suitable as part of a gluten-free diet. Quinoa oil, extracted from the seeds of C. quinoa, has similar properties, but is superior in quality, to corn oil. Oil of chenopodium is extracted from the seeds of epazote, which is not in this genus anymore. Shagreen leather was produced in the past using the small, hard goosefoot seeds. C. album was one of the main model organisms for the molecular biological study of chlorophyllase. Goosefoot pollen, in particular of the widespread and usually abundant C. album, is an allergen to many people and a common cause of hay fever. The same species, as well as some others, have seeds which are able to persist for years in the soil seed bank. Many goosefoot species are thus significant weeds, and some have become invasive species. Certain species grow in large thickets, providing cover for small animals. Goosefoot foliage is used as food by the caterpillars of certain Lepidoptera. The seeds are eaten by many birds, such as the yellowhammer (Emberiza citrinella) of Europe or the white-winged fairy-wren (Malurus leucopterus) of Australia. Goosefoot pathogens include the positive-sense ssRNA viruses - apple stem grooving virus, sowbane mosaic virus and tobacco necrosis virus. # Selected species - Chenopodium acuminatum Willd. - Chenopodium album – white goosefoot, nickel greens, dungweed, bathua, chandali, chandaliya, fat hen, lamb's quarters, pigweed Chenopodium album ssp. amaranticolor - Chenopodium album ssp. amaranticolor - Chenopodium atrovirens – dark goosefoot, pinyon goosefoot - Chenopodium auricomiforme - Chenopodium auricomum – Queensland bluebush - Chenopodium berlandieri – pitseed goosefoot, southern huauzontle, lambsquarters Chenopodium berlandieri ssp. nuttalliae (Saff.) H.D.Wilson & Heiser Chenopodium berlandieri var. bushianum Chenopodium berlandieri var. zschackii - Chenopodium berlandieri ssp. nuttalliae (Saff.) H.D.Wilson & Heiser - Chenopodium berlandieri var. bushianum - Chenopodium berlandieri var. zschackii - Chenopodium bonus-henricus – Good King Henry, perennial goosefoot, poor-man's asparagus, Lincolnshire spinach, markery - Chenopodium bushianum – village goosefoot - Chenopodium californicum – California goosefoot, Indian lettuce - Chenopodium capitatum – strawberry blite, blite goosefoot, strawberry goosefoot, strawberry spinach, Indian paint, Indian ink - Chenopodium chenopodioides – small red Goosefoot, saltmarsh goosefoot - Chenopodium curvispicatum - Chenopodium cycloides - Chenopodium desertorum – desert goosefoot Chenopodium desertorum ssp. anidiophyllum Chenopodium desertorum ssp. desertorum Chenopodium desertorum ssp. microphyllum Chenopodium desertorum ssp. rectum Chenopodium desertorum ssp. virosum - Chenopodium desertorum ssp. anidiophyllum - Chenopodium desertorum ssp. desertorum - Chenopodium desertorum ssp. microphyllum - Chenopodium desertorum ssp. rectum - Chenopodium desertorum ssp. virosum - Chenopodium desiccatum – narrowleaf goosefoot - Chenopodium erosum R.Br. - Chenopodium ficifolium – fig-leaved goosefoot, small goosefoot - Chenopodium foggii – Fogg's goosefoot - Chenopodium foliosum – leafy goosefoot - Chenopodium fremontii – Fremont's goosefoot - Chenopodium giganteum D.Don – tree spinach - Chenopodium glaucum – oak-leaved goosefoot, glaucous goosefoot - Chenopodium helenense Aellen - Chenopodium hians – Hians goosefoot - Chenopodium hircinum Schrad. - Chenopodium humile – marshland goosefoot - Chenopodium hybridum – maple-leaved goosefoot, sowbane - Chenopodium incanum – mealy goosefoot - Chenopodium leptophyllum – narrowleaf goosefoot - Chenopodium littoreum - Chenopodium missouriense – Missouri goosefoot (sometimes considered a variety of C. album) - Chenopodium murale – nettle-leaved goosefoot - Chenopodium nitrariaceum (F.Muell.) F.Muell. ex Benth. – nitre goosefoot - Chenopodium nuttalliae – huauzontle - Chenopodium oahuense – Template:OkinaĀheahea ([[Hawaii\|HawaiTemplate:Okinai]]) - Chenopodium opulifolium Schrad. ex W.D.J.Koch – grey goosefoot - Chenopodium pallidicaule – kañiwa - Chenopodium polyspermum – many-seeded goosefoot Chenopodium polyspermum var. acutifolium - Chenopodium polyspermum var. acutifolium - Chenopodium pratericola Rydb. – pale goosefoot, desert goosefoot, narrowleaf goosefoot - Chenopodium probstii Aellen - Chenopodium purpurascens – purple goosefoot - Chenopodium quinoa – quinoa - Chenopodium retusum - Chenopodium rubrum – red goosefoot, coastblite goosefoot - Chenopodium salinum – Rocky Mountain goosefoot - Chenopodium simplex – giantseed goosefoot - Chenopodium standleyanum – Standley's goosefoot - Chenopodium strictum Roth - Chenopodium subglabrum – smooth arid goosefoot, smooth goosefoot - Chenopodium suecicum – green goosefoot - Chenopodium truncatum - Chenopodium urbicum – upright goosefoot - Chenopodium × variabile (C. album × C. berlandieri) - Chenopodium vulvaria – stinking goosefoot, notchweed - Chenopodium watsonii – Watson's goosefoot Formerly placed here: - Dysphania, all glandular species (as C. botrys, C. carinatum, C. cristatum, C. melanocarpum, C. multifidium, C. pumilio and more) - Rhagodia baccata – berry saltbush (as C. baccatum) - Suaeda australis – austral seablite (as C. australe, C. insulare) ar:زربيح az:Tərə ca:Quenopodi da:Gåsefod de:Gänsefüße et:Hanemalts el:Αγαθόφυτα hsb:Pólšica it:Chenopodium he:כף-אווז ka:ნაცარქათამა kk:Алабұта lt:Balanda hu:Libatop nl:Ganzenvoet qu:Ayara fi:Savikat sv:Mållor	https://www.wikidoc.org/index.php/Chenopodium
d08e0926dd48e4effd515d90dd3098e67fe32d94	wikidoc	Pulmonology	Pulmonology Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview In medicine, pulmonology (aka pneumology) is the specialty that deals with diseases of the lungs and the respiratory tract. It is called chest medicine and respiratory medicine in some countries and areas. Pulmonology is generally considered a branch of internal medicine, although it is closely related to intensive care medicine when dealing with patients requiring mechanical ventilation. Surgery of the respiratory tract is generally performed by specialists in cardiothoracic surgery (or thoracic surgery). Chest medicine is not a specialty in itself but is an inclusive term which pertains to the treatment of diseases of the chest and contains the fields of pulmonology, thoracic surgery, and intensive care medicine. Pulmonology is concerned with the diagnosis and treatment of lung diseases, as well as secondary prevention (tuberculosis). Physicians specializing in this area are called pulmonologists. # Diagnosis In medicine, 50% of all diagnoses can be made by a thorough medical history, and lung diseases are no different. The pulmonologist will conduct a general review and focus on: - hereditary diseases affecting the lungs (cystic fibrosis, alpha 1-antitrypsin deficiency) - exposure to toxins (tobacco smoke, asbestos, exhaust fumes, coal mining fumes) - exposure to infectious agents (certain types of birds, malt processing) - an autoimmune diathesis that might predispose to certain conditions (pulmonary fibrosis, pulmonary hypertension) Physical diagnostics are as important as in the other fields of medicine. - Inspection of the hands for signs of cyanosis or clubbing, chest wall, and respiratory rate. - Palpation of the cervical lymph nodes, trachea and chest wall movement. - Percussion of the lung fields for dullness or hyperresonance. - Auscultation (with a stethoscope) of the lung fields for diminished or unusual breath sounds. As many heart diseases can give pulmonary signs, a thorough cardiac investigation is usually included. Other tools include: - Laboratory investigation of blood (blood tests). Sometimes arterial blood gas measurements are also required. - Spirometry (the determination of lung volumes in time by breathing into a dedicated machine; response to bronchodilatators and diffusion of carbon monoxide) - Bronchoscopy with bronchoalveolar lavage (BAL), endobronchial and transbronchial biopsy and epithelial brushing - Chest X-rays - CT scanning (MRI scanning is rarely used) - Scintigraphy and other methods of nuclear medicine - Positron emission tomography (especially in lung cancer) # Treatment Surgical treatment in generally performed by the (cardio)thoracic surgeon, generally after primary evaluation by a pulmonologist. Medication is the most important treatment of most diseases of pulmonology, either by inhalation (bronchodilators and steroids) or in oral form (antibiotics, leukotriene antagonists). Oxygen therapy is often necessary in severe respiratory disease (emphysema and pulmonary fibrosis). When this is insufficient, the patient might require mechanical ventilation. # Training In the United States, pulmonologists are physicians who, after receiving a medical degree MD or DO, complete residency training in internal medicine (3 years), followed by at least 2 additional years of subspeciality fellowship training in pulmonology. Most pulmonologists complete 3 years of combined subspecialty fellowship training in pulmonary medicine and critical care medicine. In the United States, pediatric pulmonologists are physicians who, after receiving a medical degree MD or DO, complete residency training in pediatrics (3 years), followed by at least 3 additional years of subspeciality fellowship training in pulmonology. # Diseases managed by the pulmonologist - Allergic bronchopulmonary aspergillosis - Asthma - Chronic obstructive pulmonary disease: - Chronic bronchitis Emphysema - Chronic bronchitis - Emphysema - Cystic fibrosis (in adults; pediatricians may be involved in the care of children with the disease) - Lung cancer diagnosis - Pneumoconiosis - Pneumonia - Pneumothorax - Psittacosis - Pulmonary embolism - Pulmonary fibrosis - Pulmonary hypertension - Pulmonary sequestration - Sarcoidosis - Sleep apnea - Tuberculosis # Scientific research Pulmonologists are involved in both clinical and basic research of the respiratory system, ranging from the anatomy of the bronchial epithelium to the most effective treatment of pulmonary hypertension (a disease notoriously resistant to therapy). ar:طب الأمراض الصدرية bn:ফুসফুসবিদ্যা bg:Пулмология ca:Pneumologia de:Pneumologie eu:Pneumologia it:Pneumologia he:פולמונולוגיה la:Pulmonologia nl:Pneumologie ne:फोक्सोशास्त्र nn:Pulmonologi sq:Pneumologjia sk:Pneumológia sl:Pulmologija	Pulmonology Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview In medicine, pulmonology (aka pneumology) is the specialty that deals with diseases of the lungs and the respiratory tract. It is called chest medicine and respiratory medicine in some countries and areas. Pulmonology is generally considered a branch of internal medicine, although it is closely related to intensive care medicine when dealing with patients requiring mechanical ventilation. Surgery of the respiratory tract is generally performed by specialists in cardiothoracic surgery (or thoracic surgery). Chest medicine is not a specialty in itself but is an inclusive term which pertains to the treatment of diseases of the chest and contains the fields of pulmonology, thoracic surgery, and intensive care medicine. Pulmonology is concerned with the diagnosis and treatment of lung diseases, as well as secondary prevention (tuberculosis). Physicians specializing in this area are called pulmonologists. # Diagnosis In medicine, 50% of all diagnoses can be made by a thorough medical history, and lung diseases are no different. The pulmonologist will conduct a general review and focus on: - hereditary diseases affecting the lungs (cystic fibrosis, alpha 1-antitrypsin deficiency) - exposure to toxins (tobacco smoke, asbestos, exhaust fumes, coal mining fumes) - exposure to infectious agents (certain types of birds, malt processing) - an autoimmune diathesis that might predispose to certain conditions (pulmonary fibrosis, pulmonary hypertension) Physical diagnostics are as important as in the other fields of medicine. - Inspection of the hands for signs of cyanosis or clubbing, chest wall, and respiratory rate. - Palpation of the cervical lymph nodes, trachea and chest wall movement. - Percussion of the lung fields for dullness or hyperresonance. - Auscultation (with a stethoscope) of the lung fields for diminished or unusual breath sounds. As many heart diseases can give pulmonary signs, a thorough cardiac investigation is usually included. Other tools include: - Laboratory investigation of blood (blood tests). Sometimes arterial blood gas measurements are also required. - Spirometry (the determination of lung volumes in time by breathing into a dedicated machine; response to bronchodilatators and diffusion of carbon monoxide) - Bronchoscopy with bronchoalveolar lavage (BAL), endobronchial and transbronchial biopsy and epithelial brushing - Chest X-rays - CT scanning (MRI scanning is rarely used) - Scintigraphy and other methods of nuclear medicine - Positron emission tomography (especially in lung cancer) # Treatment Surgical treatment in generally performed by the (cardio)thoracic surgeon, generally after primary evaluation by a pulmonologist. Medication is the most important treatment of most diseases of pulmonology, either by inhalation (bronchodilators and steroids) or in oral form (antibiotics, leukotriene antagonists). Oxygen therapy is often necessary in severe respiratory disease (emphysema and pulmonary fibrosis). When this is insufficient, the patient might require mechanical ventilation. # Training In the United States, pulmonologists are physicians who, after receiving a medical degree MD or DO, complete residency training in internal medicine (3 years), followed by at least 2 additional years of subspeciality fellowship training in pulmonology. Most pulmonologists complete 3 years of combined subspecialty fellowship training in pulmonary medicine and critical care medicine. In the United States, pediatric pulmonologists are physicians who, after receiving a medical degree MD or DO, complete residency training in pediatrics (3 years), followed by at least 3 additional years of subspeciality fellowship training in pulmonology. # Diseases managed by the pulmonologist - Allergic bronchopulmonary aspergillosis - Asthma - Chronic obstructive pulmonary disease: - Chronic bronchitis Emphysema - Chronic bronchitis - Emphysema - Cystic fibrosis (in adults; pediatricians may be involved in the care of children with the disease) - Lung cancer diagnosis - Pneumoconiosis - Pneumonia - Pneumothorax - Psittacosis - Pulmonary embolism - Pulmonary fibrosis - Pulmonary hypertension - Pulmonary sequestration - Sarcoidosis - Sleep apnea - Tuberculosis # Scientific research Pulmonologists are involved in both clinical and basic research of the respiratory system, ranging from the anatomy of the bronchial epithelium to the most effective treatment of pulmonary hypertension (a disease notoriously resistant to therapy). Template:SIB ar:طب الأمراض الصدرية bn:ফুসফুসবিদ্যা bg:Пулмология ca:Pneumologia de:Pneumologie eu:Pneumologia it:Pneumologia he:פולמונולוגיה la:Pulmonologia nl:Pneumologie ne:फोक्सोशास्त्र nn:Pulmonologi sq:Pneumologjia sk:Pneumológia sl:Pulmologija Template:WS	https://www.wikidoc.org/index.php/Chest_medicine
a65b5576beb309e239ff9287cd6fff63f347b946	wikidoc	Mastication	Mastication Mastication or chewing is the process by which food is mashed and crushed by teeth. It is the first step of digestion and it increases the surface area of foods to allow more efficient break down by enzymes. During the mastication process, the food is positioned between the teeth for grinding by the cheek and tongue. As chewing continues, the food is made softer and warmer, and the enzymes in saliva begin to break down carbohydrates in the food. After chewing, the food (now called a bolus) is swallowed. It enters the esophagus and continues on to the stomach, where the next step of digestion occurs. # Muscles of mastication Mastication is accomplished through the activity of the four muscles of mastication. - The masseter - The temporalis - The medial pterygoid - The lateral pterygoid Unlike most of the other facial muscles, which are innervated by the facial nerve, or CN VII, the muscles of mastication are all innervated by the trigeminal nerve, or CN V. More specifically, they are innervated by the mandibular branch, or V3. This is a testament to their shared embryological origin from the first branchial arch. The muscles of facial expression, on the other hand, derive from the second branchial arch. In humans, the mandible, or lower jaw, is connected to the temporal bone of the skull via the temporomandibular joint, an extremely complex joint which permits movement in all planes. The muscles of mastication originate on the skull and insert into the mandible, thereby allowing for jaw movements during contraction. The mandible is the only bone that moves during mastication and other activities, such as talking. Each of these primary muscles of mastication is paired, with each side of the mandible possessing one of the four. While these four muscles are the primary participants in mastication, other muscles are usually if not always helping the process, such as those of the tongue and the cheeks. # The chewing cycle Mastication is a repetitive sequence of jaw opening and closing with a profile in the vertical plane called the chewing cycle. Mastication consists of a number of chewing cycles. The human chewing cycle consists of three phases: 1. Opening phase: the mouth is opened and the mandible is depressed. 2. Closing phase: the mandible is raised towards the maxilla. 3. Occlusal or intercuspal phase: the mandible is stationary and the teeth from both upper and lower arches approximate. # Mastication motor program Mastication is primarily an unconscious act, but can be mediated by higher conscious input. The motor program for mastication is an hypothesized central nervous system function by which the complex patterns governing mastication are created and controlled. It is thought that feedback from proprioceptive nerves in teeth and the temporomandibular joints govern the creation of neural pathways, which in turn determine duration and force of individual muscle activation (and in some cases muscle fiber groups as in the masseter and temporalis). The motor program continuously adapts to changes in food type or occlusion . It is thought that conscious mediation is important in the limitation of parafunctional habits as most commonly, the motor program can be excessively engaged during periods of sleep and times of stress. It is also theorized that excessive input to the motor program from myofascial pain or occlusal imbalance can contribute to parafunctional habits. # In other animals Chewing is largely an adaptation for mammalian herbivory. Carnivores generally chew very little or swallow their food whole or in chunks, a fact to which many dog and cat owners can attest. This act of gulping food without chewing has inspired the English idiom "wolfing it down". Ornithopods, a group of dinosaurs including the Hadrosaurids ("duck-bills"), developed teeth analagous to mammalian molars and incisors during the Cretaceous period; this advanced, cow-like dentition allowed the creatures to obtain more nutrients from the tough plant life. This may have given them the advantage needed to usurp the formidable sauropods, who depended on gastroliths for grinding food, from their ecological niches. They eventually became some of the most successful animals on the planet until the Cretaceous–Tertiary extinction event wiped them out. # Notes - - Influence of age on adaptability of human mastication.	Mastication Template:Redirect3 Mastication or chewing is the process by which food is mashed and crushed by teeth. It is the first step of digestion and it increases the surface area of foods to allow more efficient break down by enzymes. During the mastication process, the food is positioned between the teeth for grinding by the cheek and tongue. As chewing continues, the food is made softer and warmer, and the enzymes in saliva begin to break down carbohydrates in the food. After chewing, the food (now called a bolus) is swallowed. It enters the esophagus and continues on to the stomach, where the next step of digestion occurs. # Muscles of mastication Mastication is accomplished through the activity of the four muscles of mastication. - The masseter - The temporalis - The medial pterygoid - The lateral pterygoid Unlike most of the other facial muscles, which are innervated by the facial nerve, or CN VII, the muscles of mastication are all innervated by the trigeminal nerve, or CN V. More specifically, they are innervated by the mandibular branch, or V3. This is a testament to their shared embryological origin from the first branchial arch. The muscles of facial expression, on the other hand, derive from the second branchial arch. In humans, the mandible, or lower jaw, is connected to the temporal bone of the skull via the temporomandibular joint, an extremely complex joint which permits movement in all planes. The muscles of mastication originate on the skull and insert into the mandible, thereby allowing for jaw movements during contraction. The mandible is the only bone that moves during mastication and other activities, such as talking. Each of these primary muscles of mastication is paired, with each side of the mandible possessing one of the four. While these four muscles are the primary participants in mastication, other muscles are usually if not always helping the process, such as those of the tongue and the cheeks. # The chewing cycle Mastication is a repetitive sequence of jaw opening and closing with a profile in the vertical plane called the chewing cycle. Mastication consists of a number of chewing cycles. The human chewing cycle consists of three phases: 1. Opening phase: the mouth is opened and the mandible is depressed. 2. Closing phase: the mandible is raised towards the maxilla. 3. Occlusal or intercuspal phase: the mandible is stationary and the teeth from both upper and lower arches approximate. # Mastication motor program Mastication is primarily an unconscious act, but can be mediated by higher conscious input. The motor program for mastication is an hypothesized central nervous system function by which the complex patterns governing mastication are created and controlled. It is thought that feedback from proprioceptive nerves in teeth and the temporomandibular joints govern the creation of neural pathways, which in turn determine duration and force of individual muscle activation (and in some cases muscle fiber groups as in the masseter and temporalis). The motor program continuously adapts to changes in food type or occlusion [1]. It is thought that conscious mediation is important in the limitation of parafunctional habits as most commonly, the motor program can be excessively engaged during periods of sleep and times of stress. It is also theorized that excessive input to the motor program from myofascial pain or occlusal imbalance can contribute to parafunctional habits. # In other animals Chewing is largely an adaptation for mammalian herbivory. Carnivores generally chew very little or swallow their food whole or in chunks, a fact to which many dog and cat owners can attest. This act of gulping food without chewing has inspired the English idiom "wolfing it down". Ornithopods, a group of dinosaurs including the Hadrosaurids ("duck-bills"), developed teeth analagous to mammalian molars and incisors during the Cretaceous period; this advanced, cow-like dentition allowed the creatures to obtain more nutrients from the tough plant life. This may have given them the advantage needed to usurp the formidable sauropods, who depended on gastroliths for grinding food, from their ecological niches. They eventually became some of the most successful animals on the planet until the Cretaceous–Tertiary extinction event wiped them out. # Notes - http://jn.physiology.org/cgi/content/full/92/2/773 - Influence of age on adaptability of human mastication. # External links - Template:MeshNumber - Neuromuscular dentistry de:Kaumuskulatur el:Μάσηση it:Masticazione Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Chew
09418d7420bf1cb93775f2bfa8e04bb3ab11d5a3	wikidoc	Tzanck test	Tzanck test Synonyms and keywords: Tzanck smear, Chickenpox skin test, herpes skin test # Overview In dermatopathology, the Tzanck test, also Tzanck smear, is scraping of an ulcer base to look for Tzanck cells. It is sometimes also called the Chickenpox skin test and the herpes skin test. The test is named after Arnault Tzanck (1886-1954), a Russian dermatologist. Atypical Tzanck cell is a large round keratinocyte with a hypertrophic nucleus, hazy or absent nucleoli, and abundant basophilic cytoplasm. The basophilic staining is deeper peripherally on the cell membrane due to the cytoplasm's tendency to get condensed at the periphery, leading to a perinuclear halo. Tzanck cells commonly are found in: herpes simplex, varicella, herpes zoster and pemphigus vulgaris. # Historical Perspective - Diagnostic cytology is the study of individual cells and their characteristics and functions. - George Papanicolaou is considered the father of exfoliative cytology. - Cytology technique was first used by Tzanck for the diagnosis dermatological disorders such as herpes and other vesico-bullous lesions. - The test is named after Arnault Tzanck (1886-1954), a Russian dermatologist. - The different techniques of cytological studies include aspiration cytology, imprint smear, exudate smear, skin scraping smear, and Tzanck smear. # Tzanck Smear ## Sample Collection - In patients with suspected viral lesions the sample must be collected from fresh vesicular lesions rather than the healing crusted lesions, to have a sample with adequate number of virus infected cells. - The vesicle should be un-roofed and the base of the ulcer must be scraped with a scalpel or with a scapula. - The obtained material should be then transferred on to a clean glass slide. - Care should should be taken that the glass slide is clean and has no finger prints as the specimen will not stay on the glass slide with finger prints. ## Fixation of the Smear - A fixative fluid contains reactive chemicals and is useful for the preservation of the specimens. The fixative fluid prevents the denaturation of the proteins and autolysis and helps in maintaining the cellular morphology and its contents. - Fixatives usually contain chemicals like formalin, glutaraldehyde, methanol, ethanol, acetone, acetic acid, chromates, and picric acid. - Once the sample is transferred on to the glass slide it should be fixed immediately using a fixative fluid to prevent drying of the tissue. ## Staining of the Smear - Many stains can be used for the fixation of the Tzanck smear must the most commonly used stain is the Giemsa stain. - Other stains that can be used include the following: Hematoxylin and eosin Wright's stain Methylene blue Papanicolaou Toluidine blue - Hematoxylin and eosin - Wright's stain - Methylene blue - Papanicolaou - Toluidine blue ## Tzanck Smear Findings - A typical Tzanck cell is a large round keratinocyte with a hypertrophic nucleus, hazy or absent nucleoli, and abundant basophilic cytoplasm. The basophilic staining is deeper peripherally on the cell membrane due to the cytoplasm's tendency to get condensed at the periphery, leading to a perinuclear halo. The following are the list of cutaneous diseases which can be differentiated based on the findings on the Tzanck smear:	Tzanck test Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2] Synonyms and keywords: Tzanck smear, Chickenpox skin test, herpes skin test # Overview In dermatopathology, the Tzanck test, also Tzanck smear, is scraping of an ulcer base to look for Tzanck cells. It is sometimes also called the Chickenpox skin test and the herpes skin test. The test is named after Arnault Tzanck (1886-1954), a Russian dermatologist. Atypical Tzanck cell is a large round keratinocyte with a hypertrophic nucleus, hazy or absent nucleoli, and abundant basophilic cytoplasm. The basophilic staining is deeper peripherally on the cell membrane due to the cytoplasm's tendency to get condensed at the periphery, leading to a perinuclear halo. Tzanck cells commonly are found in: herpes simplex, varicella, herpes zoster and pemphigus vulgaris.[1] # Historical Perspective - Diagnostic cytology is the study of individual cells and their characteristics and functions. - George Papanicolaou is considered the father of exfoliative cytology. - Cytology technique was first used by Tzanck for the diagnosis dermatological disorders such as herpes and other vesico-bullous lesions.[2] - The test is named after Arnault Tzanck (1886-1954), a Russian dermatologist. - The different techniques of cytological studies include aspiration cytology, imprint smear, exudate smear, skin scraping smear, and Tzanck smear. # Tzanck Smear ## Sample Collection - In patients with suspected viral lesions the sample must be collected from fresh vesicular lesions rather than the healing crusted lesions, to have a sample with adequate number of virus infected cells.[3] - The vesicle should be un-roofed and the base of the ulcer must be scraped with a scalpel or with a scapula. - The obtained material should be then transferred on to a clean glass slide. - Care should should be taken that the glass slide is clean and has no finger prints as the specimen will not stay on the glass slide with finger prints. ## Fixation of the Smear - A fixative fluid contains reactive chemicals and is useful for the preservation of the specimens. The fixative fluid prevents the denaturation of the proteins and autolysis and helps in maintaining the cellular morphology and its contents. - Fixatives usually contain chemicals like formalin, glutaraldehyde, methanol, ethanol, acetone, acetic acid, chromates, and picric acid. - Once the sample is transferred on to the glass slide it should be fixed immediately using a fixative fluid to prevent drying of the tissue. ## Staining of the Smear - Many stains can be used for the fixation of the Tzanck smear must the most commonly used stain is the Giemsa stain. - Other stains that can be used include the following: Hematoxylin and eosin Wright's stain Methylene blue Papanicolaou Toluidine blue - Hematoxylin and eosin - Wright's stain - Methylene blue - Papanicolaou - Toluidine blue ## Tzanck Smear Findings - A typical Tzanck cell is a large round keratinocyte with a hypertrophic nucleus, hazy or absent nucleoli, and abundant basophilic cytoplasm. The basophilic staining is deeper peripherally on the cell membrane due to the cytoplasm's tendency to get condensed at the periphery, leading to a perinuclear halo. The following are the list of cutaneous diseases which can be differentiated based on the findings on the Tzanck smear:[4]	https://www.wikidoc.org/index.php/Chickenpox_skin_test
5da77151cc1c08115babc84f0b4ca09ef5da2a03	wikidoc	Chigoe flea	Chigoe flea The chigoe flea (Tunga penetrans) is a parasitic arthropod found in tropical climates, especially South America and the West Indies. At 1 mm long, the chigoe flea is the smallest known flea. Breeding female chigoes burrow into exposed skin and lay eggs, causing intense irritation. After this point, the skin lesion looks like a 5 to 10 mm white spot with a central black dot, which are the flea's exposed hind legs, respiratory spiracles and reproductive organs. If the flea is left within the skin, infection and/or other dangerous complications may ensue. The free-living flea is a poor jumper and can only reach a height of around 20 cm; therefore the use of closed shoes (as opposed to sandals or slippers) is an effective way of preventing infection. The parasitic flea lives in soil and sand, and feeds intermittently on warm-blooded hosts such as humans, cattle, sheep, dogs, mice, and other animals. In order to reproduce, the female flea burrows head-first into the hosts' skin, often leaving the caudal tip of its abdomen visible through an orifice in a skin lesion. This orifice allows the chigoe flea to breathe while feeding on blood vessels in the cutaneous and subcutaneous dermal layer. In the next two weeks, the flea releases about 100 eggs through the orifice, which fall to the ground. The flea then dies and is sloughed by the host's skin. Within the next three to four days, the eggs hatch and mature into adult fleas within three to four weeks. # Synonyms - Sarcopsylla penetrans - Pulex penetrans The chigoe is sometimes called a "chigger," a term also used for the harvest mite in North America.	Chigoe flea The chigoe flea (Tunga penetrans) is a parasitic arthropod found in tropical climates, especially South America and the West Indies. At 1 mm long, the chigoe flea is the smallest known flea. Breeding female chigoes burrow into exposed skin and lay eggs, causing intense irritation. After this point, the skin lesion looks like a 5 to 10 mm white spot with a central black dot, which are the flea's exposed hind legs, respiratory spiracles and reproductive organs. If the flea is left within the skin, infection and/or other dangerous complications may ensue. The free-living flea is a poor jumper and can only reach a height of around 20 cm; therefore the use of closed shoes (as opposed to sandals or slippers) is an effective way of preventing infection.[1] The parasitic flea lives in soil and sand, and feeds intermittently on warm-blooded hosts such as humans, cattle, sheep, dogs, mice, and other animals. In order to reproduce, the female flea burrows head-first into the hosts' skin, often leaving the caudal tip of its abdomen visible through an orifice in a skin lesion. This orifice allows the chigoe flea to breathe while feeding on blood vessels in the cutaneous and subcutaneous dermal layer. In the next two weeks, the flea releases about 100 eggs through the orifice, which fall to the ground. The flea then dies and is sloughed by the host's skin. Within the next three to four days, the eggs hatch and mature into adult fleas within three to four weeks. # Synonyms - Sarcopsylla penetrans - Pulex penetrans The chigoe is sometimes called a "chigger," a term also used for the harvest mite in North America.	https://www.wikidoc.org/index.php/Chigoe_flea
0e4c6d05d1ac8817a4fd991ce4417aaad119633e	wikidoc	Rodenticide	Rodenticide Rodenticides are a category of pest control chemicals intended to kill rodents. Single feed baits are chemicals sufficiently dangerous that the first dose is sufficient to kill. Rodents are difficult to kill with poisons because their feeding habits reflect their place as scavengers. They will eat a small bit of something and wait, and if they don't get sick, they continue. An effective rodenticide must be tasteless and odorless in lethal concentrations, and have a delayed effect. # Poisonous chemicals ## Anticoagulants Anticoagulants are defined as chronic (death occurs after 1 - 2 weeks post ingestion of the lethal dose, rarely sooner), single-dose (second generation) or multiple dose (first generation) cumulative rodenticides. Fatal internal bleeding is caused by lethal dose of anticoagulants such as brodifacoum, coumatetralyl or warfarin. These substances, in effective doses are antivitamins K, blocking the enzymes K1-2,3-epoxide-reductase (this enzyme is preferentially blocked by 4-hydroxycoumarin/4-hydroxythiacoumarin derivatives) and K1-quinone-reductase (this enzyme is preferentially blocked by indandione derivatives), depriving the organism of its source of active vitamin K1. This leads to disruption of the vitamin K cycle, resulting in inability of production of essential blood-clotting factors (mainly coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor) and X (Stuart factor)). In addition to this specific metabolic disruption, toxic doses of 4-hydroxycoumarin/4-hydroxythiacoumarin and indandione anticoagulants cause damage to tiny blood vessels (capillaries), increasing their permeability, causing diffuse internal bleedings (haemorrhagias). These effects are gradual, they develop in course of days and are not accompanied by any nociceptive perceptions, such as pain or agony. In final phase of the intoxication, the exhausted rodent collapses in hypovolemic circulatory shock or severe anemia and dies calmly. Rodenticidal anticoagulants are either first generation agents (4-hydroxycoumarin type: warfarin, coumatetralyl; indandione type: pindone, diphacinone, chlorophacinone), generally requiring higher concentrations (usually between 0.005 and 0.1%), consecutive intake over days in order to accumulate the lethal dose, poor active or inactive after single feeding and less toxic than second generation agents, which are derivatives of 4-hydroxycoumarin (difenacoum, brodifacoum, bromadiolone and flocoumafen) or 4-hydroxy-1-benzothiin-2-one (4-hydroxy-1-thiacoumarin, sometimes incorrectly referred to as 4-hydroxy-1-thiocoumarin, for reason see heterocyclic compounds), namely difethialone. Second generation agents are far more toxic than first generation, they are generally applied in lower concentrations in baits (usually in order 0.001 - 0.005%), are lethal after single ingestion of bait and are effective also against strains of rodents that became resistant against first generation anticoagulants; thus, the second generation anticoagulants are sometimes referred to as "superwarfarins". Sometimes, anticoagulant rodenticides are potentiated by an antibiotic, most common the sulfaquinoxaline. The aim of this association (e.g. warfarin 0.05% + sulfaquinoxaline 0.02%, or difenacoum 0.005% + sulfaquinoxaline 0.02% etc.) is, that the antibiotic/bacteriostatic agent suppresses intestinal/gut symbiotic microflora, that represents a source of vitamin K. Thus, the symbiotic bacterias are killed, or their metabolism is impaired and the production of vitamin K by them is diminuted, an effect, which logically contributes to the action of anticoagulants. Antibiotic agents other than sulfaquinoxaline may be used, f.e. co-trimoxazole, tetracycline, neomycin or metronidazole. Further synergism used in rodenticidal baits is that of an association of an anticoagulant with a compound with vitamin D-activity, i.e. cholecalciferol or ergocalciferol, see below. Typical formulas used are f.e. warfarin 0.025 - 0.05% + cholecalciferol 0.01%. In some lands, there are even fixed three-component rodenticides, i.e. anticoagulant + antibiotic + vitamin D, f.e. difenacoum 0.005% + sulfaquinoxaline 0.02% + cholecalciferol 0.01%. Associations of a second-generation anticoagulant with an antibiotic and/or vitamin D are considered to be effective even against most resistant strains of rodents, though some second generation anticoagulants (namely brodifacoum and difethialone), in bait concentrations of 0.0025 - 0.005% are so toxic, that no known resistant strains of rodents exists, and even rodents resistant against other derivatives are reliably exterminated by application of these most toxic anticoagulants. Vitamin K1 has been suggested, and successfully used, as antidote for pets or humans accidentally or intentionally (poison assaults on pets, suicidal attempts) exposed to anticoagulant poisons. In addition, since some of these poisons act by inhibiting liver functions and in progressed stage of poisoning, several blood-clotting factors as well as the whole volume of circulating blood lacks, a blood transfusion (optionally with the clotting factors present) can save a person who inadvertently takes them, an advantage over some older poisons. The main benefit of anticoagulants is the time taken for the poison to induce death means that the rats do not associate death with eating the poison. In fact the rat will often die from being bitten by a fellow rat, which can lead to the offending rodent to be outcast from the group. ## Metal phosphides Metal phosphides have been used as a means of killing rodents and are considered single-dose fast acting rodenticides (death occurs commonly within 1-3 days after single bait ingestion). A bait consisting of food and a phosphide (usually zinc phosphide) is left where the rodents can eat it. The acid in the digestive system of the rodent reacts with the phosphide to generate the toxic phosphine gas. This method of vermin control has possible use in places where rodents are resistant to some of the anticoagulants, particularly for control of house and field mice; zinc phosphide baits are also cheaper than most second-generation anticoagulants, so that sometimes, in the case of large infestation by rodents, their population is initially reduced by copious amounts of zinc phosphide bait applied, and the rest of population that survived the initial fast-acting poison is then eradicated by prolonged feeding on anticoagulant bait. Inversely, the individual rodents, that survived anticoagulant bait poisoning (rest population) can be eradicated by pre-baiting them with nontoxic bait for a week or two (this is important to overcome bait shyness, and to get rodents used to feeding in specific areas by specific food, especially in eradicating rats) and subsequently applying poisoned bait of the same sort as used for pre-baiting until all consumption of the bait ceases (usually within 2-4 days). These methods of alterning rodenticides with different modes of action gives actual or almost 100% eradications of the rodent population in the area, if the acceptance/palatability of baits are good (i.e., rodents feed on it readily). Zinc phosphide is typically added to rodent baits in amount of around 0.75-2%. The baits have strong, pungent garlic-like odor characteristic for phosphine liberated by hydrolysis. The odor attracts (or, at least, does not repulse) rodents, but has repulsive effect on other mammals. Birds(notably wild turkeys) are not sensitive to the smell, and will feed on the bait, and thus become collateral damage. The tablets or pellets (usually aluminium, calcium or magnesium phopsphide for fumigation/gassing) may also contain other chemicals which evolve ammonia which helps to reduce the potential for spontaneous ignition or explosion of the phosphine gas. Phosphides do not accumulate in the tissues of poisoned animals, therefore the risk of secondary poisoning is low. Before the advent of anticoagulants, phosphides were the favored kind of rat poison. During the World War II, they came in use in United States because of shortage of strychnine due to the Japanese occupation of the territories, where strychnine-producing plants are grown (Strychnos nux-vomica, in south-east Asia). Phosphides are rather fast acting rat poisons, resulting in the rats dying usually in open areas instead of in the affected buildings. Phosphides used as rodenticides are: - aluminium phosphide (fumigant only) - calcium phosphide (fumigant only) - magnesium phosphide (fumigant only) - zinc phosphide (in baits) ## Hypercalcemia Calciferols (vitamins D), cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are used as rodenticides. They are toxic to rodents for the same reason they are beneficial to mammals: they affect calcium and phosphate homeostasis in the body. Vitamins D are essential in minute quantities (few IUs per kilogram body weight daily, only a fraction of a miligram), and like most fat soluble vitamins, they are toxic in larger doses, causing hypervitaminosis. If the poisoning is severe enough (that is, if the dose of the toxin is high enough), it leads to death. In rodents that consume the rodenticidal bait, it causes hypercalcemia, raising the calcium level, mainly by increasing calcium absorption from food, mobilising bone-matrix-fixed calcium into ionised form (mainly monohydrogencarbonate calcium cation, partially bound to plasma proteins, +), which circulates dissolved in the blood plasma. After ingestion of a lethal dose, the free calcium levels are raised sufficiently that blood vessels, kidneys, the stomach wall and lungs are mineralised/calcificated (formation of calcificates, crystals of calcium salts/complexes in the tissues, damaging them), leading further to heart problems (myocard is sensitive to variations of free calcium levels, affecting both myocardial contractibility and excitation propagation between atrias and ventriculas), bleeding (due to capillary damage) and possibly kidney failure. It is considered to be single-dose, or cumulative (depending on concentration used; the common 0.075% bait concentration is lethal to most rodents after a single intake of larger portions of the bait), sub-chronic (death occurring usually within days to one week after ingestion of the bait). Applied concentrations are 0.075% cholecalciferol and 0.1% ergocalciferol when used alone. There is an important feature of calciferols toxicology, that they are synergistic with anticoagulant toxicants, that means, that mixtures of anticoagulants and calciferols in same bait are more toxic than a sum of toxicities of the anticoagulant and the calciferol in the bait, so that a massive hypercalcemic effect can be achieved by a substantially lower calciferol content in the bait, and vice-versa, a more pronounced anticoagulant/hemorrhagic effects are observed if the calciferol is present. This synergism is mostly used in calciferol low concetration baits, because effective concentrations of calciferols are more expensive, than effective concentrations of the most anticoagulants. The historically very first application of a calciferol in rodenticidal bait was in fact the Sorex product Sorexa® D (with a different formula than today's Sorexa® D) back in early 1970s, containing warfarin 0.025% + ergocalciferol 0.1%. Today, Sorexa® CD contains a 0.0025% difenacoum + 0.075% cholecalciferol combination. Numerous other brand products containing either calciferols 0.075 - 0.1% (f.e. Quintox®, containing 0.075% cholecalciferol) alone, or a combination of calciferol 0.01 - 0.075% with an anticoagulant are marketed. In family pets, accidental ingestion is generally considered safe for cats but dangerous for dogs. Additional anticoagulant renders the bait more toxic to pets as well as human. Upon single ingestion, solely calciferol-based baits are considered generally safer to birds than second generation anticoagulants or acute toxicants (zinc phosphide, bromethalin, f.e.). Specific antidote for calciferol intoxication is calcitonin, a hormone, that lowers the blood levels of calcium. The therapy with commercially available calcitonin preparations is, however, expensive. ## Other Other chemical poisons include: - ANTU (α-naphtylthiourea; specific against Norway rat, Rattus norvegicus) - Arsenic - Barium (a toxic metal) compound Barium carbonate - Barium carbonate - Bromethalin (which affects the nervous system, no antidote) - Chloralose (narcotic acting condensation product of chloral and glucose) - Crimidine (2-chloro-N, N,6-trimethylpyrimidin-4-amine; a synthetic convulsant poison, antivitamin B6) - 1,3-Difluoro-2-propanol ("Gliftor" in the former USSR) - Endrin (organochlorine cyclodiene insecticide, used in the past for extermination of voles in fields during winter by aircraft spraying) - Fluoroacetamide ("1081") - Phosacetim (a delayed-action organophosphorous rodenticide) - White phosphorus - Pyrinuron (an urea derivative) - Scilliroside - Sodium fluoroacetate ("1080") - Strychnine - Tetramethylenedisulfotetramine ("tetramine") - Thallium (a toxic heavy metal) compounds - Zyklon B (hydrogen cyanide absorbed in an inert carrier) # Alternatives Mechanical rat traps are one possible alternative to poisons; another alternative is to have a dog. Both of these methods have a disadvantage of being comparatively messy, a particular problem when the building with a rat problem is to be uninhabited for some months. Anticoagulants have the advantage that their first effect is dehydration from blood loss, causing the unfortunate rodent to leave the building in search of water. Another alternative is the use of biological, non-toxic, yet lethal baits, consisting of anhydrous powdered maize/corn cobs, containing high fractions (over 40%) of α-cellulose, which is incorporated into a solid, gastric-resistant matrix, that is dissolved in the gut. The α-cellulose anhydrous powder released in the gut of the rodent disrupts water and electrolyte balance and so kills the rodent. This material is commonly formulated with taste and flavour additives to increase its palatability, and is compressed into granulate of appropriate size (granules of bigger size for rats, smaller granules for mice). This material is completely non-toxic, leaves no harmful residues, is environmentally friendly and accidental ingestion of it by pets or children is simply treated by giving laxatives, plenty of water and electrolytes. Dead rodents killed by this mean pose no risk of secondary poisoning. Newer rodenticides have been developed to work with by reducing the sperm count in males to deprive them of the ability to procreate rather than to kill rodents outright. They are usually administered in the breeding seasons of most rodents.	Rodenticide Rodenticides are a category of pest control chemicals intended to kill rodents. Single feed baits are chemicals sufficiently dangerous that the first dose is sufficient to kill. Rodents are difficult to kill with poisons because their feeding habits reflect their place as scavengers. They will eat a small bit of something and wait, and if they don't get sick, they continue. An effective rodenticide must be tasteless and odorless in lethal concentrations, and have a delayed effect. # Poisonous chemicals ## Anticoagulants Anticoagulants are defined as chronic (death occurs after 1 - 2 weeks post ingestion of the lethal dose, rarely sooner), single-dose (second generation) or multiple dose (first generation) cumulative rodenticides. Fatal internal bleeding is caused by lethal dose of anticoagulants such as brodifacoum, coumatetralyl or warfarin. These substances, in effective doses are antivitamins K, blocking the enzymes K1-2,3-epoxide-reductase (this enzyme is preferentially blocked by 4-hydroxycoumarin/4-hydroxythiacoumarin derivatives) and K1-quinone-reductase (this enzyme is preferentially blocked by indandione derivatives), depriving the organism of its source of active vitamin K1. This leads to disruption of the vitamin K cycle, resulting in inability of production of essential blood-clotting factors (mainly coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor) and X (Stuart factor)). In addition to this specific metabolic disruption, toxic doses of 4-hydroxycoumarin/4-hydroxythiacoumarin and indandione anticoagulants cause damage to tiny blood vessels (capillaries), increasing their permeability, causing diffuse internal bleedings (haemorrhagias). These effects are gradual, they develop in course of days and are not accompanied by any nociceptive perceptions, such as pain or agony. In final phase of the intoxication, the exhausted rodent collapses in hypovolemic circulatory shock or severe anemia and dies calmly. Rodenticidal anticoagulants are either first generation agents (4-hydroxycoumarin type: warfarin, coumatetralyl; indandione type: pindone, diphacinone, chlorophacinone), generally requiring higher concentrations (usually between 0.005 and 0.1%), consecutive intake over days in order to accumulate the lethal dose, poor active or inactive after single feeding and less toxic than second generation agents, which are derivatives of 4-hydroxycoumarin (difenacoum, brodifacoum, bromadiolone and flocoumafen) or 4-hydroxy-1-benzothiin-2-one (4-hydroxy-1-thiacoumarin, sometimes incorrectly referred to as 4-hydroxy-1-thiocoumarin, for reason see heterocyclic compounds), namely difethialone. Second generation agents are far more toxic than first generation, they are generally applied in lower concentrations in baits (usually in order 0.001 - 0.005%), are lethal after single ingestion of bait and are effective also against strains of rodents that became resistant against first generation anticoagulants; thus, the second generation anticoagulants are sometimes referred to as "superwarfarins". Sometimes, anticoagulant rodenticides are potentiated by an antibiotic, most common the sulfaquinoxaline. The aim of this association (e.g. warfarin 0.05% + sulfaquinoxaline 0.02%, or difenacoum 0.005% + sulfaquinoxaline 0.02% etc.) is, that the antibiotic/bacteriostatic agent suppresses intestinal/gut symbiotic microflora, that represents a source of vitamin K. Thus, the symbiotic bacterias are killed, or their metabolism is impaired and the production of vitamin K by them is diminuted, an effect, which logically contributes to the action of anticoagulants. Antibiotic agents other than sulfaquinoxaline may be used, f.e. co-trimoxazole, tetracycline, neomycin or metronidazole. Further synergism used in rodenticidal baits is that of an association of an anticoagulant with a compound with vitamin D-activity, i.e. cholecalciferol or ergocalciferol, see below. Typical formulas used are f.e. warfarin 0.025 - 0.05% + cholecalciferol 0.01%. In some lands, there are even fixed three-component rodenticides, i.e. anticoagulant + antibiotic + vitamin D, f.e. difenacoum 0.005% + sulfaquinoxaline 0.02% + cholecalciferol 0.01%. Associations of a second-generation anticoagulant with an antibiotic and/or vitamin D are considered to be effective even against most resistant strains of rodents, though some second generation anticoagulants (namely brodifacoum and difethialone), in bait concentrations of 0.0025 - 0.005% are so toxic, that no known resistant strains of rodents exists, and even rodents resistant against other derivatives are reliably exterminated by application of these most toxic anticoagulants. Vitamin K1 has been suggested, and successfully used, as antidote for pets or humans accidentally or intentionally (poison assaults on pets, suicidal attempts) exposed to anticoagulant poisons. In addition, since some of these poisons act by inhibiting liver functions and in progressed stage of poisoning, several blood-clotting factors as well as the whole volume of circulating blood lacks, a blood transfusion (optionally with the clotting factors present) can save a person who inadvertently takes them, an advantage over some older poisons. The main benefit of anticoagulants is the time taken for the poison to induce death means that the rats do not associate death with eating the poison. In fact the rat will often die from being bitten by a fellow rat, which can lead to the offending rodent to be outcast from the group. ## Metal phosphides Metal phosphides have been used as a means of killing rodents and are considered single-dose fast acting rodenticides (death occurs commonly within 1-3 days after single bait ingestion). A bait consisting of food and a phosphide (usually zinc phosphide) is left where the rodents can eat it. The acid in the digestive system of the rodent reacts with the phosphide to generate the toxic phosphine gas. This method of vermin control has possible use in places where rodents are resistant to some of the anticoagulants, particularly for control of house and field mice; zinc phosphide baits are also cheaper than most second-generation anticoagulants, so that sometimes, in the case of large infestation by rodents, their population is initially reduced by copious amounts of zinc phosphide bait applied, and the rest of population that survived the initial fast-acting poison is then eradicated by prolonged feeding on anticoagulant bait. Inversely, the individual rodents, that survived anticoagulant bait poisoning (rest population) can be eradicated by pre-baiting them with nontoxic bait for a week or two (this is important to overcome bait shyness, and to get rodents used to feeding in specific areas by specific food, especially in eradicating rats) and subsequently applying poisoned bait of the same sort as used for pre-baiting until all consumption of the bait ceases (usually within 2-4 days). These methods of alterning rodenticides with different modes of action gives actual or almost 100% eradications of the rodent population in the area, if the acceptance/palatability of baits are good (i.e., rodents feed on it readily). Zinc phosphide is typically added to rodent baits in amount of around 0.75-2%. The baits have strong, pungent garlic-like odor characteristic for phosphine liberated by hydrolysis. The odor attracts (or, at least, does not repulse) rodents, but has repulsive effect on other mammals. Birds(notably wild turkeys) are not sensitive to the smell, and will feed on the bait, and thus become collateral damage. The tablets or pellets (usually aluminium, calcium or magnesium phopsphide for fumigation/gassing) may also contain other chemicals which evolve ammonia which helps to reduce the potential for spontaneous ignition or explosion of the phosphine gas. Phosphides do not accumulate in the tissues of poisoned animals, therefore the risk of secondary poisoning is low. Before the advent of anticoagulants, phosphides were the favored kind of rat poison. During the World War II, they came in use in United States because of shortage of strychnine due to the Japanese occupation of the territories, where strychnine-producing plants are grown (Strychnos nux-vomica, in south-east Asia). Phosphides are rather fast acting rat poisons, resulting in the rats dying usually in open areas instead of in the affected buildings. Phosphides used as rodenticides are: - aluminium phosphide (fumigant only) - calcium phosphide (fumigant only) - magnesium phosphide (fumigant only) - zinc phosphide (in baits) ## Hypercalcemia Calciferols (vitamins D), cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are used as rodenticides. They are toxic to rodents for the same reason they are beneficial to mammals: they affect calcium and phosphate homeostasis in the body. Vitamins D are essential in minute quantities (few IUs per kilogram body weight daily, only a fraction of a miligram), and like most fat soluble vitamins, they are toxic in larger doses, causing hypervitaminosis. If the poisoning is severe enough (that is, if the dose of the toxin is high enough), it leads to death. In rodents that consume the rodenticidal bait, it causes hypercalcemia, raising the calcium level, mainly by increasing calcium absorption from food, mobilising bone-matrix-fixed calcium into ionised form (mainly monohydrogencarbonate calcium cation, partially bound to plasma proteins, [CaHCO3]+), which circulates dissolved in the blood plasma. After ingestion of a lethal dose, the free calcium levels are raised sufficiently that blood vessels, kidneys, the stomach wall and lungs are mineralised/calcificated (formation of calcificates, crystals of calcium salts/complexes in the tissues, damaging them), leading further to heart problems (myocard is sensitive to variations of free calcium levels, affecting both myocardial contractibility and excitation propagation between atrias and ventriculas), bleeding (due to capillary damage) and possibly kidney failure. It is considered to be single-dose, or cumulative (depending on concentration used; the common 0.075% bait concentration is lethal to most rodents after a single intake of larger portions of the bait), sub-chronic (death occurring usually within days to one week after ingestion of the bait). Applied concentrations are 0.075% cholecalciferol and 0.1% ergocalciferol when used alone. There is an important feature of calciferols toxicology, that they are synergistic with anticoagulant toxicants, that means, that mixtures of anticoagulants and calciferols in same bait are more toxic than a sum of toxicities of the anticoagulant and the calciferol in the bait, so that a massive hypercalcemic effect can be achieved by a substantially lower calciferol content in the bait, and vice-versa, a more pronounced anticoagulant/hemorrhagic effects are observed if the calciferol is present. This synergism is mostly used in calciferol low concetration baits, because effective concentrations of calciferols are more expensive, than effective concentrations of the most anticoagulants. The historically very first application of a calciferol in rodenticidal bait was in fact the Sorex product Sorexa® D (with a different formula than today's Sorexa® D) back in early 1970s, containing warfarin 0.025% + ergocalciferol 0.1%. Today, Sorexa® CD contains a 0.0025% difenacoum + 0.075% cholecalciferol combination. Numerous other brand products containing either calciferols 0.075 - 0.1% (f.e. Quintox®, containing 0.075% cholecalciferol) alone, or a combination of calciferol 0.01 - 0.075% with an anticoagulant are marketed. In family pets, accidental ingestion is generally considered safe for cats but dangerous for dogs.[1] Additional anticoagulant renders the bait more toxic to pets as well as human. Upon single ingestion, solely calciferol-based baits are considered generally safer to birds than second generation anticoagulants or acute toxicants (zinc phosphide, bromethalin, f.e.). Specific antidote for calciferol intoxication is calcitonin, a hormone, that lowers the blood levels of calcium. The therapy with commercially available calcitonin preparations is, however, expensive. ## Other Other chemical poisons include: - ANTU (α-naphtylthiourea; specific against Norway rat, Rattus norvegicus) - Arsenic - Barium (a toxic metal) compound Barium carbonate - Barium carbonate - Bromethalin (which affects the nervous system, no antidote) - Chloralose (narcotic acting condensation product of chloral and glucose) - Crimidine (2-chloro-N, N,6-trimethylpyrimidin-4-amine; a synthetic convulsant poison, antivitamin B6) - 1,3-Difluoro-2-propanol ("Gliftor" in the former USSR) - Endrin (organochlorine cyclodiene insecticide, used in the past for extermination of voles in fields during winter by aircraft spraying) - Fluoroacetamide ("1081") - Phosacetim (a delayed-action organophosphorous rodenticide) - White phosphorus - Pyrinuron (an urea derivative) - Scilliroside - Sodium fluoroacetate ("1080") - Strychnine - Tetramethylenedisulfotetramine ("tetramine") - Thallium (a toxic heavy metal) compounds - Zyklon B (hydrogen cyanide absorbed in an inert carrier) # Alternatives Mechanical rat traps are one possible alternative to poisons; another alternative is to have a dog. Both of these methods have a disadvantage of being comparatively messy, a particular problem when the building with a rat problem is to be uninhabited for some months. Anticoagulants have the advantage that their first effect is dehydration from blood loss, causing the unfortunate rodent to leave the building in search of water. Another alternative is the use of biological, non-toxic, yet lethal baits, consisting of anhydrous powdered maize/corn cobs, containing high fractions (over 40%) of α-cellulose, which is incorporated into a solid, gastric-resistant matrix, that is dissolved in the gut. The α-cellulose anhydrous powder released in the gut of the rodent disrupts water and electrolyte balance and so kills the rodent. This material is commonly formulated with taste and flavour additives to increase its palatability, and is compressed into granulate of appropriate size (granules of bigger size for rats, smaller granules for mice). This material is completely non-toxic, leaves no harmful residues, is environmentally friendly and accidental ingestion of it by pets or children is simply treated by giving laxatives, plenty of water and electrolytes. Dead rodents killed by this mean pose no risk of secondary poisoning. Newer rodenticides have been developed to work with by reducing the sperm count in males to deprive them of the ability to procreate rather than to kill rodents outright. They are usually administered in the breeding seasons of most rodents.	https://www.wikidoc.org/index.php/Chlorophacinone_rodenticide_poisoning
c331e7987cb2bc5883dae381d7700af91fd7b40f	wikidoc	Chlorophyll	Chlorophyll # Overview Chlorophyll (also chlorophyl) is a term used for several closely related green pigments found in cyanobacteria and the chloroplasts of algae and plants. Its name is derived from the Greek words χλωρός, chloros ("green") and φύλλον, phyllon ("leaf"). Chlorophyll is an extremely important biomolecule, critical in photosynthesis, which allows plants to absorb energy from light. Chlorophyll absorbs light most strongly in the blue portion of the electromagnetic spectrum, followed by the red portion. Conversely, it is a poor absorber of green and near-green portions of the spectrum, hence the green color of chlorophyll-containing tissues. Chlorophyll was first isolated by Joseph Bienaimé Caventou and Pierre Joseph Pelletier in 1817. # Gallery - Chlorophyll gives leaves their green color and absorbs light that is used in photosynthesis. - Chlorophyll is found in high concentrations in chloroplasts of plant cells. - Absorption maxima of chlorophylls against the spectrum of white light. - SeaWiFS-derived average sea surface chlorophyll for the period 1998 to 2006. # Chlorophyll and photosynthesis Chlorophyll is vital for photosynthesis, which allows plants to absorb energy from light. Chlorophyll molecules are specifically arranged in and around photosystems that are embedded in the thylakoid membranes of chloroplasts. In these complexes, chlorophyll serves two primary functions. The function of the vast majority of chlorophyll (up to several hundred molecules per photosystem) is to absorb light and transfer that light energy by resonance energy transfer to a specific chlorophyll pair in the reaction center of the photosystems. The two currently accepted photosystem units are Photosystem II and Photosystem I, which have their own distinct reaction centres, named P680 and P700, respectively. These centres are named after the wavelength (in nanometers) of their red-peak absorption maximum. The identity, function and spectral properties of the types of chlorophyll in each photosystem are distinct and determined by each other and the protein structure surrounding them. Once extracted from the protein into a solvent (such as acetone or methanol), these chlorophyll pigments can be separated in a simple paper chromatography experiment and, based on the number of polar groups between chlorophyll a and chlorophyll b, will chemically separate out on the paper. The function of the reaction center chlorophyll is to use the energy absorbed by and transferred to it from the other chlorophyll pigments in the photosystems to undergo a charge separation, a specific redox reaction in which the chlorophyll donates an electron into a series of molecular intermediates called an electron transport chain. The charged reaction center chlorophyll (P680+) is then reduced back to its ground state by accepting an electron. In Photosystem II, the electron that reduces P680+ ultimately comes from the oxidation of water into O2 and H+ through several intermediates. This reaction is how photosynthetic organisms such as plants produce O2 gas, and is the source for practically all the O2 in Earth's atmosphere. Photosystem I typically works in series with Photosystem II; thus the P700+ of Photosystem I is usually reduced, via many intermediates in the thylakoid membrane, by electrons ultimately from Photosystem II. Electron transfer reactions in the thylakoid membranes are complex, however, and the source of electrons used to reduce P700+ can vary. The electron flow produced by the reaction center chlorophyll pigments is used to shuttle H+ ions across the thylakoid membrane, setting up a chemiosmotic potential used mainly to produce ATP chemical energy; and those electrons ultimately reduce NADP+ to NADPH, a universal reductant used to reduce CO2 into sugars as well as for other biosynthetic reductions. Reaction center chlorophyll–protein complexes are capable of directly absorbing light and performing charge separation events without other chlorophyll pigments, but the absorption cross section (the likelihood of absorbing a photon under a given light intensity) is small. Thus, the remaining chlorophylls in the photosystem and antenna pigment protein complexes associated with the photosystems all cooperatively absorb and funnel light energy to the reaction center. Besides chlorophyll a, there are other pigments, called accessory pigments, which occur in these pigment–protein antenna complexes. # Chemical structure Chlorophyll is a chlorin pigment, which is structurally similar to and produced through the same metabolic pathway as other porphyrin pigments such as heme. At the center of the chlorin ring is a magnesium ion. This was discovered in 1906, and was the first time that magnesium had been detected in living tissue. For the structures depicted in this article, some of the ligands attached to the Mg2+ center are omitted for clarity. The chlorin ring can have several different side chains, usually including a long phytol chain. There are a few different forms that occur naturally, but the most widely distributed form in terrestrial plants is chlorophyll a. After initial work done by German chemist Richard Willstätter spanning from 1905 to 1915, the general structure of chlorophyll a was elucidated by Hans Fischer in 1940. By 1960, when most of the stereochemistry of chlorophyll a was known, Robert Burns Woodward published a total synthesis of the molecule. In 1967, the last remaining stereochemical elucidation was completed by Ian Fleming, and in 1990 Woodward and co-authors published an updated synthesis. Chlorophyll f was announced to be present in cyanobacteria and other oxygenic microorganisms that form stromatolites in 2010; a molecular formula of C55H70O6N4Mg and a structure of (2-formyl)-chlorophyll a were deduced based on NMR, optical and mass spectra. The different structures of chlorophyll are summarized below: When leaves degreen in the process of plant senescence, chlorophyll is converted to a group of colourless tetrapyrroles known as nonfluorescent chlorophyll catabolites (NCC's) with the general structure: These compounds have also been identified in several ripening fruits. # Spectrophotometry Measurement of the absorption of light is complicated by the solvent used to extract it from plant material, which affects the values obtained, - In diethyl ether, chlorophyll a has approximate absorbance maxima of 430 nm and 662 nm, while chlorophyll b has approximate maxima of 453 nm and 642 nm. - The absorption peaks of chlorophyll a are at 665 nm and 465 nm. Chlorophyll a fluoresces at 673 nm (maximum) and 726 nm. The peak molar absorption coefficient of chlorophyll a exceeds 105 M−1 cm−1, which is among the highest for small-molecule organic compounds. - In 90% acetone-water, the peak absorption wavelengths of chlorophyll a are 430 nm and 664 nm; peaks for chlorophyll b are 460 nm and 647 nm; peaks for chlorophyll c1 are 442 nm and 630 nm; peaks for chlorophyll c2 are 444 nm and 630 nm; peaks for chlorophyll d are 401 nm, 455 nm and 696 nm. By measuring the absorption of light in the red and far red regions it is possible to estimate the concentration of chlorophyll within a leaf. In his scientific paper Gitelson (1999) states, "The ratio between chlorophyll fluorescence, at 735 nm and the wavelength range 700nm to 710 nm, F735/F700 was found to be linearly proportional to the chlorophyll content (with determination coefficient, r2, more than 0.95) and thus this ratio can be used as a precise indicator of chlorophyll content in plant leaves." The fluorescent ratio chlorophyll content meters use this technique. # Biosynthesis In plants, chlorophyll may be synthesized from succinyl-CoA and glycine, although the immediate precursor to chlorophyll a and b is protochlorophyllide. In Angiosperm plants, the last step, conversion of protochlorophyllide to chlorophyll, is light-dependent and such plants are pale (etiolated) if grown in the darkness. Non-vascular plants and green algae have an additional light-independent enzyme and grow green in the darkness instead. Chlorophyll itself is bound to proteins and can transfer the absorbed energy in the required direction. Protochlorophyllide occurs mostly in the free form and, under light conditions, acts as a photosensitizer, forming highly toxic free radicals. Hence, plants need an efficient mechanism of regulating the amount of chlorophyll precursor. In angiosperms, this is done at the step of aminolevulinic acid (ALA), one of the intermediate compounds in the biosynthesis pathway. Plants that are fed by ALA accumulate high and toxic levels of protochlorophyllide; so do the mutants with the damaged regulatory system. Chlorosis is a condition in which leaves produce insufficient chlorophyll, turning them yellow. Chlorosis can be caused by a nutrient deficiency of iron—called iron chlorosis—or by a shortage of magnesium or nitrogen. Soil pH sometimes plays a role in nutrient-caused chlorosis; many plants are adapted to grow in soils with specific pH levels and their ability to absorb nutrients from the soil can be dependent on this. Chlorosis can also be caused by pathogens including viruses, bacteria and fungal infections, or sap-sucking insects. # Complementary light absorbance of anthocyanins with chlorophylls Anthocyanins are other plant pigments. The absorbance pattern responsible for the red color of anthocyanins may be complementary to that of green chlorophyll in photosynthetically active tissues such as young Quercus coccifera leaves. It may protect the leaves from attacks by plant eaters that may be attracted by green color. # Culinary use Chlorophyll is registered as a food additive (colorant), and its E number is E140. Chefs use chlorophyll to color a variety of foods and beverages green, such as pasta and absinthe. Chlorophyll is not soluble in water, and it is first mixed with a small quantity of vegetable oil to obtain the desired solution. Extracted liquid chlorophyll was considered to be unstable and always denatured until 1997, when Frank S. & Lisa Sagliano used freeze-drying of liquid chlorophyll at the University of Florida and stabilized it as a powder, preserving it for future use. # Alternative medicine Many claims are made about the healing properties of chlorophyll, but most have been disproved or are exaggerated by the companies that are marketing them. Quackwatch, a website dedicated to debunking false medical claims, has a quote from Toledo Blade (1952) which claims "Chlorophyll Held Useless As Body Deodorant", but later has John C. Kephart pointing out "No deodorant effect can possibly occur from the quantities of chlorophyll put in products such as gum, foot powder, cough drops, etc. To be effective, large doses must be given internally".	Chlorophyll Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Chlorophyll (also chlorophyl) is a term used for several closely related green pigments found in cyanobacteria and the chloroplasts of algae and plants.[2] Its name is derived from the Greek words χλωρός, chloros ("green") and φύλλον, phyllon ("leaf").[3] Chlorophyll is an extremely important biomolecule, critical in photosynthesis, which allows plants to absorb energy from light. Chlorophyll absorbs light most strongly in the blue portion of the electromagnetic spectrum, followed by the red portion. Conversely, it is a poor absorber of green and near-green portions of the spectrum, hence the green color of chlorophyll-containing tissues.[4] Chlorophyll was first isolated by Joseph Bienaimé Caventou and Pierre Joseph Pelletier in 1817.[5] # Gallery - Chlorophyll gives leaves their green color and absorbs light that is used in photosynthesis. - Chlorophyll is found in high concentrations in chloroplasts of plant cells. - Absorption maxima of chlorophylls against the spectrum of white light. - SeaWiFS-derived average sea surface chlorophyll for the period 1998 to 2006. # Chlorophyll and photosynthesis Chlorophyll is vital for photosynthesis, which allows plants to absorb energy from light.[6] Chlorophyll molecules are specifically arranged in and around photosystems that are embedded in the thylakoid membranes of chloroplasts.[7] In these complexes, chlorophyll serves two primary functions. The function of the vast majority of chlorophyll (up to several hundred molecules per photosystem) is to absorb light and transfer that light energy by resonance energy transfer to a specific chlorophyll pair in the reaction center of the photosystems. The two currently accepted photosystem units are Photosystem II and Photosystem I, which have their own distinct reaction centres, named P680 and P700, respectively. These centres are named after the wavelength (in nanometers) of their red-peak absorption maximum. The identity, function and spectral properties of the types of chlorophyll in each photosystem are distinct and determined by each other and the protein structure surrounding them. Once extracted from the protein into a solvent (such as acetone or methanol),[8][9][10] these chlorophyll pigments can be separated in a simple paper chromatography experiment and, based on the number of polar groups between chlorophyll a and chlorophyll b, will chemically separate out on the paper. The function of the reaction center chlorophyll is to use the energy absorbed by and transferred to it from the other chlorophyll pigments in the photosystems to undergo a charge separation, a specific redox reaction in which the chlorophyll donates an electron into a series of molecular intermediates called an electron transport chain. The charged reaction center chlorophyll (P680+) is then reduced back to its ground state by accepting an electron. In Photosystem II, the electron that reduces P680+ ultimately comes from the oxidation of water into O2 and H+ through several intermediates. This reaction is how photosynthetic organisms such as plants produce O2 gas, and is the source for practically all the O2 in Earth's atmosphere. Photosystem I typically works in series with Photosystem II; thus the P700+ of Photosystem I is usually reduced, via many intermediates in the thylakoid membrane, by electrons ultimately from Photosystem II. Electron transfer reactions in the thylakoid membranes are complex, however, and the source of electrons used to reduce P700+ can vary. The electron flow produced by the reaction center chlorophyll pigments is used to shuttle H+ ions across the thylakoid membrane, setting up a chemiosmotic potential used mainly to produce ATP chemical energy; and those electrons ultimately reduce NADP+ to NADPH, a universal reductant used to reduce CO2 into sugars as well as for other biosynthetic reductions. Reaction center chlorophyll–protein complexes are capable of directly absorbing light and performing charge separation events without other chlorophyll pigments, but the absorption cross section (the likelihood of absorbing a photon under a given light intensity) is small. Thus, the remaining chlorophylls in the photosystem and antenna pigment protein complexes associated with the photosystems all cooperatively absorb and funnel light energy to the reaction center. Besides chlorophyll a, there are other pigments, called accessory pigments, which occur in these pigment–protein antenna complexes. # Chemical structure Chlorophyll is a chlorin pigment, which is structurally similar to and produced through the same metabolic pathway as other porphyrin pigments such as heme. At the center of the chlorin ring is a magnesium ion. This was discovered in 1906, and was the first time that magnesium had been detected in living tissue.[11] For the structures depicted in this article, some of the ligands attached to the Mg2+ center are omitted for clarity. The chlorin ring can have several different side chains, usually including a long phytol chain. There are a few different forms that occur naturally, but the most widely distributed form in terrestrial plants is chlorophyll a. After initial work done by German chemist Richard Willstätter spanning from 1905 to 1915, the general structure of chlorophyll a was elucidated by Hans Fischer in 1940. By 1960, when most of the stereochemistry of chlorophyll a was known, Robert Burns Woodward published a total synthesis of the molecule.[11][12] In 1967, the last remaining stereochemical elucidation was completed by Ian Fleming,[13] and in 1990 Woodward and co-authors published an updated synthesis.[14] Chlorophyll f was announced to be present in cyanobacteria and other oxygenic microorganisms that form stromatolites in 2010;[15][16] a molecular formula of C55H70O6N4Mg and a structure of (2-formyl)-chlorophyll a were deduced based on NMR, optical and mass spectra.[17] The different structures of chlorophyll are summarized below:[citation needed] When leaves degreen in the process of plant senescence, chlorophyll is converted to a group of colourless tetrapyrroles known as nonfluorescent chlorophyll catabolites (NCC's) with the general structure: These compounds have also been identified in several ripening fruits.[18] # Spectrophotometry Measurement of the absorption of light is complicated by the solvent used to extract it from plant material, which affects the values obtained, - In diethyl ether, chlorophyll a has approximate absorbance maxima of 430 nm and 662 nm, while chlorophyll b has approximate maxima of 453 nm and 642 nm.[19] - The absorption peaks of chlorophyll a are at 665 nm and 465 nm. Chlorophyll a fluoresces at 673 nm (maximum) and 726 nm. The peak molar absorption coefficient of chlorophyll a exceeds 105 M−1 cm−1, which is among the highest for small-molecule organic compounds.[citation needed] - In 90% acetone-water, the peak absorption wavelengths of chlorophyll a are 430 nm and 664 nm; peaks for chlorophyll b are 460 nm and 647 nm; peaks for chlorophyll c1 are 442 nm and 630 nm; peaks for chlorophyll c2 are 444 nm and 630 nm; peaks for chlorophyll d are 401 nm, 455 nm and 696 nm.[20] By measuring the absorption of light in the red and far red regions it is possible to estimate the concentration of chlorophyll within a leaf.[21] In his scientific paper Gitelson (1999) states, "The ratio between chlorophyll fluorescence, at 735 nm and the wavelength range 700nm to 710 nm, F735/F700 was found to be linearly proportional to the chlorophyll content (with determination coefficient, r2, more than 0.95) and thus this ratio can be used as a precise indicator of chlorophyll content in plant leaves."[22] The fluorescent ratio chlorophyll content meters use this technique. # Biosynthesis In plants, chlorophyll may be synthesized from succinyl-CoA and glycine, although the immediate precursor to chlorophyll a and b is protochlorophyllide. In Angiosperm plants, the last step, conversion of protochlorophyllide to chlorophyll, is light-dependent and such plants are pale (etiolated) if grown in the darkness. Non-vascular plants and green algae have an additional light-independent enzyme and grow green in the darkness instead. Chlorophyll itself is bound to proteins and can transfer the absorbed energy in the required direction. Protochlorophyllide occurs mostly in the free form and, under light conditions, acts as a photosensitizer, forming highly toxic free radicals. Hence, plants need an efficient mechanism of regulating the amount of chlorophyll precursor. In angiosperms, this is done at the step of aminolevulinic acid (ALA), one of the intermediate compounds in the biosynthesis pathway. Plants that are fed by ALA accumulate high and toxic levels of protochlorophyllide; so do the mutants with the damaged regulatory system.[23] Chlorosis is a condition in which leaves produce insufficient chlorophyll, turning them yellow. Chlorosis can be caused by a nutrient deficiency of iron—called iron chlorosis—or by a shortage of magnesium or nitrogen. Soil pH sometimes plays a role in nutrient-caused chlorosis; many plants are adapted to grow in soils with specific pH levels and their ability to absorb nutrients from the soil can be dependent on this.[24] Chlorosis can also be caused by pathogens including viruses, bacteria and fungal infections, or sap-sucking insects. # Complementary light absorbance of anthocyanins with chlorophylls Anthocyanins are other plant pigments. The absorbance pattern responsible for the red color of anthocyanins may be complementary to that of green chlorophyll in photosynthetically active tissues such as young Quercus coccifera leaves. It may protect the leaves from attacks by plant eaters that may be attracted by green color.[25] # Culinary use Chlorophyll is registered as a food additive (colorant), and its E number is E140. Chefs use chlorophyll to color a variety of foods and beverages green, such as pasta and absinthe.[26] Chlorophyll is not soluble in water, and it is first mixed with a small quantity of vegetable oil to obtain the desired solution. Extracted liquid chlorophyll was considered to be unstable and always denatured until 1997,[citation needed] when Frank S. & Lisa Sagliano used freeze-drying of liquid chlorophyll at the University of Florida and stabilized it as a powder, preserving it for future use.[27] # Alternative medicine Many claims are made about the healing properties of chlorophyll, but most have been disproved or are exaggerated by the companies that are marketing them. Quackwatch, a website dedicated to debunking false medical claims, has a quote from Toledo Blade (1952) which claims [28] "Chlorophyll Held Useless As Body Deodorant",[29] but later has John C. Kephart pointing out "No deodorant effect can possibly occur from the quantities of chlorophyll put in products such as gum, foot powder, cough drops, etc. To be effective, large doses must be given internally".[30]	https://www.wikidoc.org/index.php/Chlorophyll
34cedef47deffa63f7436be3f31a4cc15ecf52ed	wikidoc	Chloroplast	Chloroplast # Overview Chloroplasts are organelles found in plant cells and eukaryotic algae that conduct photosynthesis. Chloroplasts absorb light and use it in conjunction with water and carbon dioxide to produce sugars, the raw material for energy and biomass production in all green plants and the animals that depend on them, directly or indirectly, for food. Chloroplasts capture light energy to conserve free energy in the form of ATP and reduce NADP to NADPH through a complex set of processes called photosynthesis. It is derived from the Greek words chloros which means green and plast which means form or entity. Chloroplasts are members of a class of organelles known as plastids. # Evolutionary origin Chloroplasts are one of the many unique organelles in the plant cell. They are generally considered to have originated as endosymbiotic cyanobacteria (i.e. blue-green algae). This was first suggested by Mereschkowsky in 1905 after an observation by Schimper in 1883 that chloroplasts closely resemble cyanobacteria. All eukaryote chloroplasts are thought to derive directly or indirectly from a single endosymbiotic event (in the Archaeplastida), except for Paulinella chromatophora, which has recently acquired a photosynthetic cyanobacterial endosymbiont which is not closely related to chloroplasts of other eukaryotes. In that they derive from an endosymbiotic event, chloroplasts are similar to mitochondria but chloroplasts are found only in plants and protista. The chloroplast is surrounded by a double-layered composite membrane with an intermembrane space; it has its own DNA and is involved in energy metabolism. Further, it has reticulations, or many infoldings, filling the inner spaces. In green plants, chloroplasts are surrounded by two lipid-bilayer membranes. The inner membrane is now believed to correspond to the outer membrane of the ancestral cyanobacterium. Chloroplasts have their own genome, which is considerably reduced compared to that of free-living cyanobacteria, but the parts that are still present show clear similarities with the cyanobacterial genome. Plastids may contain 60-100 genes whereas cyanobacteria often contain more than 1500 genes. Many of the missing genes are encoded in the nuclear genome of the host. The transfer of nuclear information has been estimated in tobacco plants at one gene for every 16000 pollen grains. In some algae (such as the heterokonts and other protists such as Euglenozoa and Cercozoa), chloroplasts seem to have evolved through a secondary event of endosymbiosis, in which a eukaryotic cell engulfed a second eukaryotic cell containing chloroplasts, forming chloroplasts with three or four membrane layers. In some cases, such secondary endosymbionts may have themselves been engulfed by still other eukaryotes, thus forming tertiary endosymbionts. # Structure Chloroplasts are observable morphologically as flat discs usually 2 to 10 micrometer in diameter and 1 micrometer thick. The chloroplast is contained by an envelope that consists of an inner and an outer phospholipid membrane. Between these two layers is the intermembrane space. The material within the chloroplast is called the stroma, corresponding to the cytosol of the original bacterium, and contains one or more molecules of small circular DNA. It also contains ribosomes, although most of its proteins are encoded by genes contained in the host cell nucleus, with the protein products transported to the chloroplast. Within the stroma are stacks of thylakoids, the sub-organelles which are the site of photosynthesis. The thylakoids are arranged in stacks called grana (singular: granum). A thylakoid has a flattened disk shape. Inside it is an empty area called the thylakoid space or lumen. Photosynthesis takes place on the thylakoid membrane; as in mitochondrial oxidative phosphorylation, it involves the coupling of cross-membrane fluxes with biosynthesis via the dissipation of a proton electrochemical gradient. Embedded in the thylakoid membrane is the antenna complex, which consists of proteins, and light-absorbing pigments, including chlorophyll and carotenoids. This complex both increases the surface area for light capture, and allows capture of photons with a wider range of wavelengths. The energy of the incident photons is absorbed by the pigments and funneled to the reaction centre of this complex through resonance energy transfer. Two chlorophyll molecules are then ionised, producing an excited electron which then passes onto the photochemical reaction centre. # Transplastomic plants Recently, chloroplasts have caught attention by developers of genetically modified plants. In certain plant species, such as tobacco, chloroplasts are not inherited from the male, and therefore, transgenes in these plastids cannot be disseminated by pollen. This makes plastid transformation a valuable tool for the creation and cultivation of genetically modified plants that are biologically contained, thus posing significantly lower environmental risks. This biological containment strategy is therefore suitable for establishing the coexistence of conventional and organic agriculture. The reliability of this mechanism has not yet been studied for all relevant crop species. However, the research programme Co-Extra recently published results for tobacco plants, demonstrating that the containment of transplastomic plants is highly reliable with a tiny failure rate of 3 in 1,000,000.	Chloroplast # Overview Chloroplasts are organelles found in plant cells and eukaryotic algae that conduct photosynthesis. Chloroplasts absorb light and use it in conjunction with water and carbon dioxide to produce sugars, the raw material for energy and biomass production in all green plants and the animals that depend on them, directly or indirectly, for food. Chloroplasts capture light energy to conserve free energy in the form of ATP and reduce NADP to NADPH through a complex set of processes called photosynthesis. It is derived from the Greek words chloros which means green and plast which means form or entity. Chloroplasts are members of a class of organelles known as plastids. # Evolutionary origin Chloroplasts are one of the many unique organelles in the plant cell. They are generally considered to have originated as endosymbiotic cyanobacteria (i.e. blue-green algae). This was first suggested by Mereschkowsky in 1905 [1] after an observation by Schimper in 1883 that chloroplasts closely resemble cyanobacteria. [2] All eukaryote chloroplasts are thought to derive directly or indirectly from a single endosymbiotic event (in the Archaeplastida), except for Paulinella chromatophora, which has recently acquired a photosynthetic cyanobacterial endosymbiont which is not closely related to chloroplasts of other eukaryotes.[3] In that they derive from an endosymbiotic event, chloroplasts are similar to mitochondria but chloroplasts are found only in plants and protista. The chloroplast is surrounded by a double-layered composite membrane with an intermembrane space; it has its own DNA and is involved in energy metabolism. Further, it has reticulations, or many infoldings, filling the inner spaces. In green plants, chloroplasts are surrounded by two lipid-bilayer membranes. The inner membrane is now believed to correspond to the outer membrane of the ancestral cyanobacterium. Chloroplasts have their own genome, which is considerably reduced compared to that of free-living cyanobacteria, but the parts that are still present show clear similarities with the cyanobacterial genome. Plastids may contain 60-100 genes whereas cyanobacteria often contain more than 1500 genes.[4] Many of the missing genes are encoded in the nuclear genome of the host. The transfer of nuclear information has been estimated in tobacco plants at one gene for every 16000 pollen grains.[5] In some algae (such as the heterokonts and other protists such as Euglenozoa and Cercozoa), chloroplasts seem to have evolved through a secondary event of endosymbiosis, in which a eukaryotic cell engulfed a second eukaryotic cell containing chloroplasts, forming chloroplasts with three or four membrane layers. In some cases, such secondary endosymbionts may have themselves been engulfed by still other eukaryotes, thus forming tertiary endosymbionts. # Structure Chloroplasts are observable morphologically as flat discs usually 2 to 10 micrometer in diameter and 1 micrometer thick. The chloroplast is contained by an envelope that consists of an inner and an outer phospholipid membrane. Between these two layers is the intermembrane space. The material within the chloroplast is called the stroma, corresponding to the cytosol of the original bacterium, and contains one or more molecules of small circular DNA. It also contains ribosomes, although most of its proteins are encoded by genes contained in the host cell nucleus, with the protein products transported to the chloroplast. Within the stroma are stacks of thylakoids, the sub-organelles which are the site of photosynthesis. The thylakoids are arranged in stacks called grana (singular: granum). A thylakoid has a flattened disk shape. Inside it is an empty area called the thylakoid space or lumen. Photosynthesis takes place on the thylakoid membrane; as in mitochondrial oxidative phosphorylation, it involves the coupling of cross-membrane fluxes with biosynthesis via the dissipation of a proton electrochemical gradient. Embedded in the thylakoid membrane is the antenna complex, which consists of proteins, and light-absorbing pigments, including chlorophyll and carotenoids. This complex both increases the surface area for light capture, and allows capture of photons with a wider range of wavelengths. The energy of the incident photons is absorbed by the pigments and funneled to the reaction centre of this complex through resonance energy transfer. Two chlorophyll molecules are then ionised, producing an excited electron which then passes onto the photochemical reaction centre. # Transplastomic plants Recently, chloroplasts have caught attention by developers of genetically modified plants. In certain plant species, such as tobacco, chloroplasts are not inherited from the male, and therefore, transgenes in these plastids cannot be disseminated by pollen. This makes plastid transformation a valuable tool for the creation and cultivation of genetically modified plants that are biologically contained, thus posing significantly lower environmental risks. This biological containment strategy is therefore suitable for establishing the coexistence of conventional and organic agriculture. The reliability of this mechanism has not yet been studied for all relevant crop species. However, the research programme Co-Extra recently published results for tobacco plants, demonstrating that the containment of transplastomic plants is highly reliable with a tiny failure rate of 3 in 1,000,000.[6]	https://www.wikidoc.org/index.php/Chloroplast
69f2a8958ff45f3d5f4cf5c3824dfed2c591741e	wikidoc	Chloroprene	Chloroprene # Overview Chloroprene is the common name for the organic compound 2-chloro-1,3-butadiene, which has the chemical formula C4H5Cl. The chemical structure is shown at right. It is used as monomer for the production of the polymer polychloroprene, a type of synthetic rubber. Polychloroprene is better known to the public as Neoprene, the trade name DuPont gave it when the company first developed it and currently used by DuPont Dow. # Production of chloroprene The acetylene process was used to produce chloroprene until the 1960s. In this process, acetylene and hydrogen chloride were used as shown here: This process had disadvantages in that it was very energy-intensive and had high investment costs. The modern chloroprene process which is currently used by nearly all makers uses butadiene differently. 1,3-Butadiene undergoes addition of chlorine across one of its double bonds in its molecule to give 3,4-dichloro-1-butene. Then this compound undergoes an elimination of a hydrogen atom in the #3 position and the chlorine atom in the #4 position as HCl forming a double bond between the #3 and #4 carbon atoms in the molecule, yielding chloroprene.	Chloroprene Template:Chembox new # Overview Chloroprene is the common name for the organic compound 2-chloro-1,3-butadiene, which has the chemical formula C4H5Cl. The chemical structure is shown at right. It is used as monomer for the production of the polymer polychloroprene, a type of synthetic rubber. Polychloroprene is better known to the public as Neoprene, the trade name DuPont gave it when the company first developed it and currently used by DuPont Dow. # Production of chloroprene The acetylene process was used to produce chloroprene until the 1960s. In this process, acetylene and hydrogen chloride were used as shown here: This process had disadvantages in that it was very energy-intensive and had high investment costs. The modern chloroprene process which is currently used by nearly all makers uses butadiene differently. 1,3-Butadiene undergoes addition of chlorine across one of its double bonds in its molecule to give 3,4-dichloro-1-butene. Then this compound undergoes an elimination of a hydrogen atom in the #3 position and the chlorine atom in the #4 position as HCl forming a double bond between the #3 and #4 carbon atoms in the molecule, yielding chloroprene.	https://www.wikidoc.org/index.php/Chloroprene
7e0c77db0dfda49b281fb6ce25781ac6d7782850	wikidoc	Chlorotoxin	Chlorotoxin # Overview Chlorotoxin is a 36-amino acid peptide found in the venom of the deathstalker scorpion (Leiurus quinquestriatus). A synthetically modified version, 131I-chlorotoxin or TM-601, is under investigation for the treatment of gliomas, because it specifically binds to glial tumor cells, but not normal cells. Researchers at Seattle Children’s Hospital Research Institute and Fred Hutchinson Cancer Research Center have recently used Chlorotoxin in combination with fluorescent material named, Cy5.5 to first ever demarcate cancer cells from surrounding normal cells. Chlorotoxin:Cy5.5 is a fluorescent molecular material emitting photons in the near infrared spectrum and hence, can be visualized in operating room with the aid of infrared glasses. This illumination gives surgeons a better chance of removing all of the cancerous cells during surgery without injuring surrounding healthy tissue. Team has conducted pre-clinical study in mouse models where they showed positive results in brain tumors. To note, approximately 80% of malignant cancers of brain recur at the edges of the surgical site. Current technology (such as MRI with contrast agent) can distinguish tumors from healthy tissue only if more than 1 million cancer cells are present. But Cy5.5 can identify tumors with as few as 2000 cancer cells, making it 500 times more sensitive than MRI. Chlorotoxin:Cy5.5 could be used in operating rooms in as little as 18 months as team is planning to conduct clinical trial in coming months. Original article can be found in July 15, 2007 issue of Cancer Research # Reference - ↑ "Tumor painting revolutionizes fight against cancer (Researchers develop Chlorotoxin:Cy5.5 enabling surgeons to see cancer cells 500 times better than an MRI)" (Press release). Children's Hospital and Regional Medical Center of Seattle at EurekAlert!. 2007-07-12. Retrieved 2006-07-15. Check date values in: \|date= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	Chlorotoxin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Chlorotoxin is a 36-amino acid peptide found in the venom of the deathstalker scorpion (Leiurus quinquestriatus). A synthetically modified version, 131I-chlorotoxin or TM-601, is under investigation for the treatment of gliomas, because it specifically binds to glial tumor cells, but not normal cells. Researchers at Seattle Children’s Hospital Research Institute and Fred Hutchinson Cancer Research Center have recently used Chlorotoxin in combination with fluorescent material named, Cy5.5 to first ever demarcate cancer cells from surrounding normal cells. Chlorotoxin:Cy5.5 is a fluorescent molecular material emitting photons in the near infrared spectrum and hence, can be visualized in operating room with the aid of infrared glasses. This illumination gives surgeons a better chance of removing all of the cancerous cells during surgery without injuring surrounding healthy tissue. Team has conducted pre-clinical study in mouse models where they showed positive results in brain tumors. To note, approximately 80% of malignant cancers of brain recur at the edges of the surgical site. Current technology (such as MRI with contrast agent) can distinguish tumors from healthy tissue only if more than 1 million cancer cells are present. But Cy5.5 can identify tumors with as few as 2000 cancer cells, making it 500 times more sensitive than MRI. Chlorotoxin:Cy5.5 could be used in operating rooms in as little as 18 months as team is planning to conduct clinical trial in coming months. Original article can be found in July 15, 2007 issue of Cancer Research[1] # Reference - ↑ "Tumor painting revolutionizes fight against cancer (Researchers develop Chlorotoxin:Cy5.5 enabling surgeons to see cancer cells 500 times better than an MRI)" (Press release). Children's Hospital and Regional Medical Center of Seattle at EurekAlert!. 2007-07-12. Retrieved 2006-07-15. 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62ef813e7241b39a524a1d3c45ca5acfb6a66b15	wikidoc	Chokecherry	Chokecherry The Chokecherry (Prunus virginiana) is a species of bird cherry (Prunus subgenus Padus) native to North America, where it is found almost throughout the continent except for the deep south and the far north. It is a suckering shrub or small tree growing to 5 m tall. The leaves are oval, 3-10 cm long, with a coarsely serrated margin. The flowers are produced in racemes of 15-30 in late spring (well after leaf emergence). The fruit are about 1 cm diameter, bright red, with a very astringent, sour taste. Like chokeberries, chokecherries are very high in antioxidant pigment compounds, like anthocyanins. There are two varieties: - Common Chokecherry Prunus virginiana var. virginiana. Eastern North America. Leaves hairless underneath or downy only in the vein axils. - Western Chokecherry Prunus virginiana var. demissa. Western North America. Leaves downy underneath. The wild Chokecherry is often considered a pest, as it is a host for the tent caterpillar, a threat to other fruit plants. However, there are more appreciated cultivars of the chokecherry, such as 'Goertz', which has a non-astringent, and therefore palatable, fruit. Research is being done at the University of Saskatchewan to find and create new cultivars to increase production and processing . Chokecherry is closely related to the Black Cherry (Prunus serotina) of eastern North America; it is most readily distinguished from that by its smaller size (Black Cherry can reach 30 m tall), smaller leaves, and red (not black) ripe fruit. The name chokecherry has also been used (as 'Amur Chokecherry') for the related Manchurian Cherry or Amur Cherry (Prunus maackii). Chokecherry is toxic to horses, especially after the leaves have wilted (such as after a frost or after branches have been broken) because wilting releases cyanide and makes the plant sweet. About 5-10 kg of foliage can be fatal. Symptoms of a horse that has been poisoned include heavy breathing, agitation, and weakness. The leaves of the chokecherry serve as food for caterpillars of various Lepidoptera. See List of Lepidoptera which feed on Prunus. The chokeberries, genus Aronia, are often mistakenly called chokecherries . This naming confusion is easy to understand considering there is a cultivar of the chokecherry Prunus virginiana 'Melanocarpa' , , and a species of chokeberry named Aronia melanocarpa . # Sources - [ Michigan State University Extension Information Management Progam	Chokecherry The Chokecherry (Prunus virginiana) is a species of bird cherry (Prunus subgenus Padus) native to North America, where it is found almost throughout the continent except for the deep south and the far north. It is a suckering shrub or small tree growing to 5 m tall. The leaves are oval, 3-10 cm long, with a coarsely serrated margin. The flowers are produced in racemes of 15-30 in late spring (well after leaf emergence). The fruit are about 1 cm diameter, bright red, with a very astringent, sour taste. Like chokeberries, chokecherries are very high in antioxidant pigment compounds, like anthocyanins. There are two varieties: - Common Chokecherry Prunus virginiana var. virginiana. Eastern North America. Leaves hairless underneath or downy only in the vein axils. - Western Chokecherry Prunus virginiana var. demissa. Western North America. Leaves downy underneath. The wild Chokecherry is often considered a pest, as it is a host for the tent caterpillar, a threat to other fruit plants. However, there are more appreciated cultivars of the chokecherry, such as 'Goertz', which has a non-astringent, and therefore palatable, fruit. Research is being done at the University of Saskatchewan to find and create new cultivars to increase production and processing [1]. Chokecherry is closely related to the Black Cherry (Prunus serotina) of eastern North America; it is most readily distinguished from that by its smaller size (Black Cherry can reach 30 m tall), smaller leaves, and red (not black) ripe fruit. The name chokecherry has also been used (as 'Amur Chokecherry') for the related Manchurian Cherry or Amur Cherry (Prunus maackii). Chokecherry is toxic to horses, especially after the leaves have wilted (such as after a frost or after branches have been broken) because wilting releases cyanide and makes the plant sweet. About 5-10 kg of foliage can be fatal. Symptoms of a horse that has been poisoned include heavy breathing, agitation, and weakness. The leaves of the chokecherry serve as food for caterpillars of various Lepidoptera. See List of Lepidoptera which feed on Prunus. The chokeberries, genus Aronia, are often mistakenly called chokecherries . This naming confusion is easy to understand considering there is a cultivar of the chokecherry Prunus virginiana 'Melanocarpa' [2], [3], and a species of chokeberry named Aronia melanocarpa [4]. # Sources - [http://www.msue.msu.edu/msue/imp/modzz/modzzo.html Michigan State University Extension Information Management Progam	https://www.wikidoc.org/index.php/Chokecherry
80bdba792e6f049fe2498b946ce0f999c018ecc8	wikidoc	Cholesterol	Cholesterol For patient information on Hypercholesterolemia click here For WikiDoc information on Hypercholesterolemia click here For patient information on Coronary Risk Profile click here # Overview Cholesterol is a sterol (a combination steroid and alcohol). Cholesterol is a lipid found in the cell membranes of all tissues, and it is transported in the blood plasma of all animals. Because cholesterol is synthesized by all eukaryotes, trace amounts of cholesterol are also found in membranes of plants and fungi. # Background The name cholesterol originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as researchers first identified cholesterol in solid form in gallstones by François Poulletier de la Salle in 1769. However, it is only in 1815 that chemist Eugène Chevreul named the compound "cholesterine". Most of the cholesterol is synthesized by the body and some has dietary origin. Cholesterol is more abundant in tissues which either synthesize more or have more abundant densely-packed membranes, for example, the liver, spinal cord and brain. It plays a central role in many biochemical processes, such as the composition of cell membranes and the synthesis of steroid hormones. Cholesterol is insoluble in blood, but is transported in the circulatory system bound to one of the varieties of lipoprotein, spherical particles which have an exterior composed mainly of water-soluble proteins. The main types, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) carry cholesterol from and to the liver. According to the lipid hypothesis, abnormally high cholesterol levels (hypercholesterolemia) and abnormal proportions of LDL and HDL are associated with cardiovascular disease by promoting atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke and peripheral vascular disease. As high LDL contributes to this process, it is termed "bad cholesterol", while high levels of HDL ("good cholesterol") offer a degree of protection. The balance can be redressed with exercise, a healthy diet, and sometimes medication. # Physiology ## Function Cholesterol is required to build and maintain cell membranes; it regulates membrane fluidity over a wide range of temperatures. The hydroxyl group on cholesterol interacts with the phosphate head of the membrane, while the bulky steroid and the hydrocarbon chain is embedded in the membrane. Some research indicates that cholesterol may act as an antioxidant. Cholesterol also aids in the manufacture of bile (which is stored in the gallbladder and helps digest fats), and is also important for the metabolism of fat soluble vitamins, including vitamins A, D, E and K. It is the major precursor for the synthesis of vitamin D and of the various steroid hormones (which include cortisol and aldosterone in the adrenal glands, and the sex hormones progesterone, the various estrogens, testosterone, and derivatives). Recently, cholesterol has also been implicated in cell signalling processes, where it has been suggested that it forms lipid rafts in the plasma membrane. It also reduces the permeability of the plasma membrane to hydrogen ions (protons) and sodium ions. Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including the caveolae-dependent endocytosis and clathrin-dependent endocytosis. The role of cholesterol in caveolae-dependent and clathrin-dependent endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane. ## Synthesis and intake Cholesterol is required in the membrane of mammalian cells for normal cellular function, and is either synthesized in the endoplasmic reticulum, or derived from the diet, in which case it is delivered by the bloodstream in low-density lipoproteins. These are taken into the cell by LDL receptor-mediated endocytosis in clathrin-coated pits, and then hydrolysed in lysosomes. Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells and tissues. About 20 – 25% of total daily production (~1 g/day) occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands and reproductive organs. For a person of about 150 pounds (68 kg), typical total body content is about 35 g, typical daily internal production is about 1 g and typical daily dietary intake is 200 to 300 mg in the United States and societies adopting its dietary patterns. Of the cholesterol input to the intestines via bile production, 92-97% is reabsorbed in the intestines and recycled via enterohepatic circulation. Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism. ## Regulation Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, while lower intake from food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (Sterol Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site 1/2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the SRE (sterol regulatory element) of a number of genes to stimulate their transcription. Among the genes transcribed are the LDL receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol. A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L. Goldstein in the 1970s. They received the Nobel Prize in Physiology or Medicine for their work in 1985. The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60 years old. There appear to be seasonal variations in cholesterol levels in humans, more, on average, in winter. ## Excretion Cholesterol is excreted from the liver in bile and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the gallbladder, it crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently. ## Body fluids Cholesterol is minimally soluble in water; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by lipoproteins - protein "molecular-suitcases" that are water-soluble and carry cholesterol and triglycerides internally. The apolipoproteins forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied. The largest lipoproteins, which primarily transport fats from the intestinal mucosa to the liver, are called chylomicrons. They carry mostly fats in the form of triglycerides and cholesterol. In the liver, chylomicron particles release triglycerides and some cholesterol. The liver converts unburned food metabolites into very low density lipoproteins (VLDL) and secretes them into plasma where they are converted to low-density lipoprotein (LDL) particles and non-esterified fatty acids, which can affect other body cells. In healthy individuals, the relatively few LDL particles are large. In contrast, large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of atheromatous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol". The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be: 240 mg/dl high cholesterol. High-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes, and hence it is commonly called "good cholesterol". In contrast, having small amounts of large HDL particles is independently associated with atheromatous disease progression within the arteries. # Clinical significance ## Hypercholesterolemia Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated with atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have been identified as a mechanism by which cholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression. The relation of cholesterol to CHD, termed the "lipid hypothesis," is still hotly debated. Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration. Multiple human trials utilizing HMG-CoA reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults. As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels, and in men without cardiovascular disease there is benefit from lowering abnormally high cholesterol levels ("primary prevention"). Primary prevention in women is practiced only by extension of the findings in studies on men, since in women, none of the large statin trials has shown a reduction in overall mortality or in cardiovascular end points. The American Heart Association provides a set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease: However, as today's testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, this simplistic view has become somewhat outdated. The desirable LDL level is considered to be less than 100 mg/dL (2.6 mmol/L), although a newer target of <70 mg/dL can be considered in higher risk individuals based on some of the above-mentioned trials. A ratio of total cholesterol to HDL — another useful measure — of far less than 5:1 is thought to be healthier. Of note, typical LDL values for children before fatty streaks begin to develop is 35 mg/dL. Most testing methods for LDL do not actually measure LDL in their blood, much less particle size. For cost reasons, LDL values have long been estimated using the Friedewald formula: − − 20% of the triglyceride value = estimated LDL. The basis of this is that Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Ordinarily just the total, HDL, and triglycerides are actually measured. The VLDL is estimated as one-fifth of the triglycerides. It is important to fast for at least 8-12 hours before the blood test because the triglyceride level varies significantly with food intake. Given the well-recognized role of cholesterol in cardiovascular disease, it is surprising that some studies have shown an inverse correlation between cholesterol levels and mortality in subjects over 50 years of age — an 11% increase overall and 14% increase in CVD mortality per 1 mg/dL per year drop in cholesterol levels. In the Framingham Heart Study, the researchers attributed this phenomenon to the fact that people with severe chronic diseases or cancer tend to have below-normal cholesterol levels. This explanation is not supported by the Vorarlberg Health Monitoring and Promotion Programme, in which men of all ages and women over 50 lower cholesterol levels with very low cholesterol were increasingly likely to die of cancer, liver diseases, and mental diseases. This result indicates that the low cholesterol effect occurs even among younger respondents, contradicting the previous assessment among cohorts of older people that this is a proxy or marker for frailty occurring with age. A small group of scientists, united in The International Network of Cholesterol Skeptics, continues to question the link between cholesterol and atherosclerosis. However, the vast majority of doctors and medical scientists accepts the link as fact. ## Hypocholesterolemia Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, and while some studies suggest a link with depression, cancer and cerebral hemorrhage it is unclear whether the low cholesterol levels are a cause for these conditions or an epiphenomenon. # Food sources Cholesterol is found in animal fats: all food containing animal fats contains cholesterol; food not containing animal fats either contains no cholesterol or negligible amounts. Major dietary sources of cholesterol include eggs, beef and poultry. Plants have trace amounts of cholesterol, so even a vegan diet, which includes no animal foods, has traces of cholesterol. However, the amounts are very small. For example, to ingest the amount of cholesterol in one egg, one would need to drink about 9.6 litres (19.57 pounds) of pure peanut oil. Plant products (e.g. flax seed, peanut), also contain cholesterol-like compounds, phytosterols, which are suggested to help lower serum cholesterol. # Cholesteric liquid crystals Some cholesterol derivatives, (among other simple cholesteric lipids) are known to generate the liquid crystalline cholesteric phase. The cholesteric phase is in fact a chiral nematic phase, and changes colour when its temperature changes. Therefore, cholesterol derivatives are commonly used as temperature-sensitive dyes, in liquid crystal thermometers and temperature-sensitive paints.	Cholesterol Template:Chembox new For patient information on Hypercholesterolemia click here For WikiDoc information on Hypercholesterolemia click here For patient information on Coronary Risk Profile click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cholesterol is a sterol (a combination steroid and alcohol). Cholesterol is a lipid found in the cell membranes of all tissues, and it is transported in the blood plasma of all animals. Because cholesterol is synthesized by all eukaryotes, trace amounts of cholesterol are also found in membranes of plants and fungi. # Background The name cholesterol originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as researchers first identified cholesterol in solid form in gallstones by François Poulletier de la Salle in 1769. However, it is only in 1815 that chemist Eugène Chevreul named the compound "cholesterine".[1] Most of the cholesterol is synthesized by the body and some has dietary origin. Cholesterol is more abundant in tissues which either synthesize more or have more abundant densely-packed membranes, for example, the liver, spinal cord and brain. It plays a central role in many biochemical processes, such as the composition of cell membranes and the synthesis of steroid hormones. Cholesterol is insoluble in blood, but is transported in the circulatory system bound to one of the varieties of lipoprotein, spherical particles which have an exterior composed mainly of water-soluble proteins. The main types, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) carry cholesterol from and to the liver. According to the lipid hypothesis, abnormally high cholesterol levels (hypercholesterolemia) and abnormal proportions of LDL and HDL are associated with cardiovascular disease by promoting atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke and peripheral vascular disease. As high LDL contributes to this process, it is termed "bad cholesterol", while high levels of HDL ("good cholesterol") offer a degree of protection. The balance can be redressed with exercise, a healthy diet, and sometimes medication. # Physiology ## Function Cholesterol is required to build and maintain cell membranes; it regulates membrane fluidity over a wide range of temperatures. The hydroxyl group on cholesterol interacts with the phosphate head of the membrane, while the bulky steroid and the hydrocarbon chain is embedded in the membrane. Some research indicates that cholesterol may act as an antioxidant.[2] Cholesterol also aids in the manufacture of bile (which is stored in the gallbladder and helps digest fats), and is also important for the metabolism of fat soluble vitamins, including vitamins A, D, E and K. It is the major precursor for the synthesis of vitamin D and of the various steroid hormones (which include cortisol and aldosterone in the adrenal glands, and the sex hormones progesterone, the various estrogens, testosterone, and derivatives). Recently, cholesterol has also been implicated in cell signalling processes, where it has been suggested that it forms lipid rafts in the plasma membrane. It also reduces the permeability of the plasma membrane to hydrogen ions (protons) and sodium ions.[3] Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including the caveolae-dependent endocytosis and clathrin-dependent endocytosis. The role of cholesterol in caveolae-dependent and clathrin-dependent endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane. ## Synthesis and intake Cholesterol is required in the membrane of mammalian cells for normal cellular function, and is either synthesized in the endoplasmic reticulum, or derived from the diet, in which case it is delivered by the bloodstream in low-density lipoproteins. These are taken into the cell by LDL receptor-mediated endocytosis in clathrin-coated pits, and then hydrolysed in lysosomes. Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells and tissues. About 20 – 25% of total daily production (~1 g/day) occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands and reproductive organs. For a person of about 150 pounds (68 kg), typical total body content is about 35 g, typical daily internal production is about 1 g and typical daily dietary intake is 200 to 300 mg in the United States and societies adopting its dietary patterns. Of the cholesterol input to the intestines via bile production, 92-97% is reabsorbed in the intestines and recycled via enterohepatic circulation. Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism. ## Regulation Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, while lower intake from food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (Sterol Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site 1/2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the SRE (sterol regulatory element) of a number of genes to stimulate their transcription. Among the genes transcribed are the LDL receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol.[4] A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L. Goldstein in the 1970s. They received the Nobel Prize in Physiology or Medicine for their work in 1985.[4] The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60 years old. There appear to be seasonal variations in cholesterol levels in humans, more, on average, in winter.[5] ## Excretion Cholesterol is excreted from the liver in bile and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the gallbladder, it crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently. ## Body fluids Cholesterol is minimally soluble in water; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by lipoproteins - protein "molecular-suitcases" that are water-soluble and carry cholesterol and triglycerides internally. The apolipoproteins forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied. The largest lipoproteins, which primarily transport fats from the intestinal mucosa to the liver, are called chylomicrons. They carry mostly fats in the form of triglycerides and cholesterol. In the liver, chylomicron particles release triglycerides and some cholesterol. The liver converts unburned food metabolites into very low density lipoproteins (VLDL) and secretes them into plasma where they are converted to low-density lipoprotein (LDL) particles and non-esterified fatty acids, which can affect other body cells. In healthy individuals, the relatively few LDL particles are large. In contrast, large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of atheromatous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol". The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be: <200 mg/dl normal blood cholesterol, 200-239 mg/dl borderline-high, >240 mg/dl high cholesterol.[6] High-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes, and hence it is commonly called "good cholesterol". In contrast, having small amounts of large HDL particles is independently associated with atheromatous disease progression within the arteries. # Clinical significance ## Hypercholesterolemia Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated with atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have been identified as a mechanism by which cholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression. The relation of cholesterol to CHD, termed the "lipid hypothesis," is still hotly debated. Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration. Multiple human trials utilizing HMG-CoA reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults. As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels,[7] and in men without cardiovascular disease there is benefit from lowering abnormally high cholesterol levels ("primary prevention").[8] Primary prevention in women is practiced only by extension of the findings in studies on men,[9] since in women, none of the large statin trials has shown a reduction in overall mortality or in cardiovascular end points.[10] The American Heart Association provides a set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:[11] However, as today's testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, this simplistic view has become somewhat outdated. The desirable LDL level is considered to be less than 100 mg/dL (2.6 mmol/L), although a newer target of <70 mg/dL can be considered in higher risk individuals based on some of the above-mentioned trials. A ratio of total cholesterol to HDL — another useful measure — of far less than 5:1 is thought to be healthier. Of note, typical LDL values for children before fatty streaks begin to develop is 35 mg/dL. Most testing methods for LDL do not actually measure LDL in their blood, much less particle size. For cost reasons, LDL values have long been estimated using the Friedewald formula: [total cholesterol] − [total HDL] − 20% of the triglyceride value = estimated LDL. The basis of this is that Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Ordinarily just the total, HDL, and triglycerides are actually measured. The VLDL is estimated as one-fifth of the triglycerides. It is important to fast for at least 8-12 hours before the blood test because the triglyceride level varies significantly with food intake. Given the well-recognized role of cholesterol in cardiovascular disease, it is surprising that some studies have shown an inverse correlation between cholesterol levels and mortality in subjects over 50 years of age — an 11% increase overall and 14% increase in CVD mortality per 1 mg/dL per year drop in cholesterol levels. In the Framingham Heart Study, the researchers attributed this phenomenon to the fact that people with severe chronic diseases or cancer tend to have below-normal cholesterol levels.[12] This explanation is not supported by the Vorarlberg Health Monitoring and Promotion Programme, in which men of all ages and women over 50 lower cholesterol levels with very low cholesterol were increasingly likely to die of cancer, liver diseases, and mental diseases. This result indicates that the low cholesterol effect occurs even among younger respondents, contradicting the previous assessment among cohorts of older people that this is a proxy or marker for frailty occurring with age.[13] A small group of scientists, united in The International Network of Cholesterol Skeptics, continues to question the link between cholesterol and atherosclerosis.[14] However, the vast majority of doctors and medical scientists accepts the link as fact.[15] ## Hypocholesterolemia Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, and while some studies suggest a link with depression, cancer and cerebral hemorrhage it is unclear whether the low cholesterol levels are a cause for these conditions or an epiphenomenon. # Food sources Cholesterol is found in animal fats: all food containing animal fats contains cholesterol; food not containing animal fats either contains no cholesterol or negligible amounts. Major dietary sources of cholesterol include eggs, beef and poultry.[16] Plants have trace amounts of cholesterol, so even a vegan diet, which includes no animal foods, has traces of cholesterol. However, the amounts are very small. For example, to ingest the amount of cholesterol in one egg, one would need to drink about 9.6 litres (19.57 pounds) of pure peanut oil.[11] [17] Plant products (e.g. flax seed, peanut), also contain cholesterol-like compounds, phytosterols, which are suggested to help lower serum cholesterol.[18] # Cholesteric liquid crystals Some cholesterol derivatives, (among other simple cholesteric lipids) are known to generate the liquid crystalline cholesteric phase. The cholesteric phase is in fact a chiral nematic phase, and changes colour when its temperature changes. Therefore, cholesterol derivatives are commonly used as temperature-sensitive dyes, in liquid crystal thermometers and temperature-sensitive paints.	https://www.wikidoc.org/index.php/Cholesterine
d391dd5b821b741d3f43f975b14144044cefee3a	wikidoc	Cholic acid	Cholic acid # 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 Cholic acid is a bile acid that is FDA approved for the treatment of patients with bile acid synthesis disorders due to single enzyme defects (SEDs) and as an adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. Common adverse reactions include diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp , urinary tract infection, and peripheral neuropathy (≥1%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Bile Acid Synthesis Disorders due to Single Enzyme Defects Cholic acid is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects (SEDs). - Peroxisomal Disorders Including Zellweger Spectrum Disorders Cholic acid is indicated for adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. Limitation of Use: The safety and effectiveness of cholic acid on extrahepatic manifestations of bile acid synthesis disorders due to SEDs or PDs including Zellweger spectrum disorders have not been established. - Dosage Regimen for Bile Acid Synthesis Disorders due to Single Enzyme Defects and Peroxisomal Disorders including Zellweger Spectrum Disorders The recommended dosage of cholic acid is 10 to 15 mg/kg administered orally once daily, or in two divided doses, in pediatric patients and in adults. Tables 1 and 2 show the number of capsules that should be administered daily to approximate a 10 mg/kg/day and 15 mg/kg/day dosage, respectively, using the available 50 mg and 250 mg capsules alone or in combination. - Table 1: Number of cholic acid capsules Needed to Achieve a Recommended Dosage of 10 mg/kg/day - Table 2: Number of cholic acid capsules Needed to Achieve a Recommended Dosage of 15 mg/kg/day Patients with newly diagnosed, or a family history of, familial hypertriglyceridemia may have poor absorption of cholic acid from the intestine and require a 10% increase in the recommended dosage to account for losses due to malabsorption. The recommended dosage of cholic acid in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg orally once daily, or in two divided doses. Adequacy of the dosage regimen can be determined by monitoring of patients' clinical response including steatorrhea, and laboratory values including transaminases, bilirubin and PT/INR. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cholic acid in adult patients ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cholic acid in adult patients # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of cholic acid has been established in pediatric patients 3 weeks of age and older for the treatment of bile acid synthesis disorders due to SEDs, and for adjunctive treatment of patients with PDs including Zellweger spectrum disorders who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. - Dosage Regimen for Bile Acid Synthesis Disorders due to Single Enzyme Defects and Peroxisomal Disorders including Zellweger Spectrum Disorders The recommended dosage of cholic acid is 10 to 15 mg/kg administered orally once daily, or in two divided doses, in pediatric patients and in adults. Tables 1 and 2 show the number of capsules that should be administered daily to approximate a 10 mg/kg/day and 15 mg/kg/day dosage, respectively, using the available 50 mg and 250 mg capsules alone or in combination. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cholic acid in pediatric patients ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cholic acid in pediatric patients # Contraindications None # Warnings Monitor liver function and discontinue cholic acid in patients who develop worsening of liver function while on treatment. Concurrent elevations of serum gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) may indicate cholic acid overdose. Discontinue treatment with cholic acid at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis. Evidence of liver impairment was present before treatment with cholic acid in approximately 86% (44/51) of patients with bile acid synthesis disorders due to SEDs and in approximately 50% (14/28) of patients with PDs including Zellweger spectrum disorders. Five of the patients (3 SED and 2 PD) with liver impairment at baseline experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy following treatment. An additional 5 patients (2 SED and 3 PD) who did not have baseline cholestasis experienced an exacerbation of their liver disease while on treatment. Exacerbation of liver impairment by cholic acid in these patients cannot be ruled out. Six patients with single enzyme defects underwent liver transplant, including four patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency. # 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. Clinical safety experience with cholic acid consists of: - Trial 1: a non-randomized, open-label, single-arm trial of 50 patients with bile acid synthesis disorders due to SEDs and 29 patients with PDs including Zellweger spectrum disorders. Safety data are available over the 18 years of the trial. - Trial 2: an extension trial of 12 new patients (10 SED and 2 PD) along with 31 (21 SED and 10 PD) patients who rolled-over from Trial 1. Safety data are available for 3 years and 11 months of treatment. Adverse events were not collected systematically in either of these trials. Most patients received an oral dose of 10 to 15 mg/kg/day of cholic acid. Deaths In Trial 1, among the 50 patients with SEDs, 5 patients aged 1 year or less died, which included three patients originally diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency and one with CYP7A1 deficiency. The cause of death was attributed to progression of underlying liver disease in every patient. Of the 29 patients in Trial 1 with PDs including Zellweger spectrum disorders, 12 patients between the ages of 7 months and 2.5 years died. In the majority of these patients (8/12), the cause of death was attributed to progression of underlying liver disease or to a worsening of their primary illness. Two additional patients in Trial 1 (1 SED and 1 PD) died who had been off study medication for more than one year with the cause of death most likely being a progression of their underlying liver disease. Of the patients who died with disease progression, laboratory testing showed abnormal serum transaminases, bilirubin, or cholestasis on liver biopsy suggesting worsening of their underlying cholestasis. In Trial 2, among the 31 patients with SED, two patients (1 new patient and 1 who rolled over from Trial 1) died. The cause of death in both cases was unrelated to their primary treatment or progression of their underlying liver disease. Of the 12 patients with PD in Trial 2, four patients died between the ages of 4 and 8 years (1 new patient and 3 who rolled over from Trial 1). The cause of death in three of these patients was attributed to progression of underlying liver disease or to a worsening of their primary illness. Worsening Liver Impairment Seven patients in Trial 1(4 SED and 3 PD) and 3 patients in Trial 2 (1 SED and 2 PD) experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy during treatment. Common Adverse Reactions There were 12 adverse reactions reported across 9 patients in the trials, with diarrhea being the most common reaction in approximately 2% of the patient population. All other adverse reactions represented 1% of the patient population. The breakdown by trial follows: - Table 3: Most Common Adverse Reactions in Trials 1 and 2 Only one of the reactions (peripheral neuropathy) resulted in discontinuation of medication for a patient in Trial 2. An additional five SED patients (3 from Trial 1 and 2 from Trial 2) and 1 PD patient (Trial 1) discontinued medication and withdrew from the study due to a worsening of their primary disease. The development of symptomatic cholelithiasis requiring cholecystectomy has been reported in a single patient with 3β-HSD deficiency. ## Postmarketing Experience There is limited information regarding Cholic acid Postmarketing Experience in the drug label. # Drug Interactions Drug interactions with cholic acid mainly relate to agents capable of interrupting the enterohepatic circulation of bile acids. - Inhibitors of Bile Acid Transporters Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitoring of serum transaminases and bilirubin is recommended. - Bile Acid Binding Resins Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the efficacy of cholic acid. Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin. - Aluminum-Based Antacids Aluminum-based antacids have been shown to adsorb bile acids in vitro and can reduce the bioavailability of cholic acid. Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after an aluminum-based antacid. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Pregnancy Exposure Registry There is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to cholic acid during pregnancy . Women who become pregnant during cholic acid treatment are encouraged to enroll. Patients or their health care provider should call 1-844-20C-OCOA or 1-844-202-6262 to enroll. - Risk Summary No studies in pregnant women or animal reproduction studies have been conducted with cholic acid. Limited published case reports discuss pregnancies in women taking cholic acid for 3β-HSD deficiency resulting in healthy infants. These reports may not adequately inform the presence or absence of drug-associated risk with the use of cholic acid during pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cholic acid in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cholic acid during labor and delivery. ### Nursing Mothers Endogenous cholic acid is present in human milk. Clinical lactation studies have not been conducted to assess the presence of cholic acid in human milk, the effects of cholic acid on the breastfed infant, or the effects of cholic acid on milk production. There are no animal lactation data and no data from case reports available in the published literature. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for cholic acid and any potential adverse effects on the breastfed infant from cholic acid or from the underlying maternal condition. ### Pediatric Use The safety and effectiveness of cholic acid has been established in pediatric patients 3 weeks of age and older for the treatment of bile acid synthesis disorders due to SEDs, and for adjunctive treatment of patients with PDs including Zellweger spectrum disorders who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. ### Geriatic Use Clinical studies of cholic acid did not include any patients aged 65 years and over. It is not known if elderly patients respond differently from younger patients. ### Gender There is no FDA guidance on the use of Cholic acid with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cholic acid with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Cholic acid in patients with renal impairment. ### Hepatic Impairment Discontinue treatment with cholic acid if liver function does not improve within 3 months of the start of treatment. Discontinue treatment with cholic acid at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cholic acid in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cholic acid in patients who are immunocompromised. # Administration and Monitoring ### Administration - Take cholic acid with food. - Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacid. - Do not crush or chew the capsules. - For patients unable to swallow the capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste: - Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food. - Mix the entire capsule contents with one or two tablespoons (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree. - Stir for 30 seconds. - The capsule contents will remain as fine granules in the milk or food, and will not dissolve. - Administer the mixture immediately ### Monitoring Treatment with cholic acid should be initiated and monitored by an experienced hepatologist or pediatric gastroenterologist. Monitor serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the subsequent three years and annually thereafter. Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy. Administer the lowest dose of cholic acid that effectively maintains liver function. Discontinue treatment with cholic acid if liver function does not improve within 3 months of the start of treatment or complete biliary obstruction develops. Discontinue treatment with cholic acid at any time if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis. Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate cholic acid overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline. Assessment of serum or urinary bile acid levels using mass spectrometry is used in the diagnosis of bile acid synthesis disorders due to SEDs and PDs including Zellweger spectrum disorders. The utility of bile acid measurements in monitoring the clinical course of patients and in decisions regarding dose adjustment has not been demonstrated. # IV Compatibility There is limited information regarding the compatibility of Cholic acid and IV administrations. # Overdosage Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate cholic acid overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline. In the event of overdose the patient should be monitored and treated symptomatically. # Pharmacology ## Mechanism of Action Cholic acid is a primary bile acid synthesized from cholesterol in the liver. In bile acid synthesis disorders due to SEDs in the biosynthetic pathway, and in PDs including Zellweger spectrum disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixed micelles, and facilitate absorption of fat-soluble vitamins in the intestine. Endogenous bile acids including cholic acid enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis. The mechanism of action of cholic acid has not been fully established; however, it is known that cholic acid and its conjugates are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR). FXR regulates enzymes and transporters that are involved in bile acid synthesis and in the enterohepatic circulation to maintain bile acid homeostasis under normal physiologic conditions. ## Structure Cholic acid is a white to off-white powder. It is practically insoluble in water and in 0.1 M HCl at 20°C and is sparingly soluble in 0.1 M NaOH at 20°C. It is soluble in glacial acetic acid, alcohols and acetone. A saturated solution in water at 20°C has a pH of 4.4. The chemical formula is C24H40O5, the molecular weight is 408.57. Cholic acid capsules contain 50 mg or 250 mg of cholic acid as the active ingredient in size 2 Swedish orange or size 0 white opaque gelatin capsules, respectively. Inactive ingredients in cholic acid include silicified microcrystalline cellulose, magnesium stearate and hard gelatin capsules. The size 2 shells contain gelatin, red iron oxide and titanium dioxide and the size 0 shells contain gelatin and titanium dioxide. Cholic acid is administered orally. ## Pharmacodynamics There is limited information regarding Cholic acid Pharmacodynamics in the drug label. ## Pharmacokinetics Orally administered cholic acid is subject to the same metabolic pathway as endogenous cholic acid. Cholic acid is absorbed by passive diffusion along the length of the gastrointestinal tract. Once absorbed, cholic acid enters into the body's bile acid pool and undergoes enterohepatic circulation mainly in conjugated forms. In the liver, cholic acid is conjugated with glycine or taurine by bile acid-CoA synthetase and bile acid-CoA: amino acid N-acetyltransferase. Conjugated cholic acid is actively secreted into bile mainly by the Bile Salt Efflux Pump (BSEP), and then released into the small intestine, along with other components of bile. Conjugated cholic acid is mostly re-absorbed in the ileum mainly by the apical-sodium-dependent-bile acid transporter, passed back to the liver by transporters including sodium-taurocholate cotransporting polypeptide and organic anion transport protein and enters another cycle of enterohepatic circulation. Any conjugated cholic acid not absorbed in the ileum passes into the colon where deconjugation and 7-dehydroxylation are mediated by bacteria to form cholic acid and deoxycholic acid which may be re-absorbed in the colon or excreted in the feces. The loss of cholic acid is compensated by de-novo synthesis of cholic acids from cholesterol to maintain the bile acid pool in healthy subjects. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, genetic toxicology, and nonclinical fertility studies have not been performed with cholic acid. - Animal Toxicology and/or Pharmacology In the PEX2-/- mouse model of peroxisomal disorders, feeding with a combination of cholic acid and ursodeoxycholic acid normalized C24 bile acid concentrations in bile to that of untreated control animals. Although growth was only mildly improved, there was near complete normalization of stool fat content, resolution of steatorrhea, and improved survival. Bile acid feeding reduced the number of cholestatic deposits in bile ducts and alleviated cholangitis, but exacerbated the degree of hepatic steatosis and mitochondrial and cellular damage in the peroxisome-deficient livers of these animals. # Clinical Studies The effectiveness of cholic acid at dosages of 10 to 15 mg/kg per day in patients with SEDs was assessed in: - Trial 1: a non-randomized, open-label, single-arm trial in 50 patients over an 18 year period. - Trial 2: an extension trial of 12 new patients along with 21 patients who rolled-over from Trial 1 (n=33 total). Efficacy data are available for 21 months of treatment. - A published case series of 15 patients. Enrollment criteria in Trials 1 and 2 were based on abnormal urinary bile acid by Fast Atom Bombardment ionization - Mass Spectrometry (FAB-MS) analysis. Pre- and post-treatment liver biopsies were performed in a limited number of patients. Documentation of adherence to treatment, concomitant medications and response to treatment were incomplete during Trial 1. Additional interventions in some patients included supplementation with fat-soluble vitamins, as dictated by the patient's clinical signs and symptoms. - Trials 1 and 2 On average, patients were 4 years of age at the start of cholic acid treatment (range three weeks to 36 years). The majority of patients were treated for an average of 310 weeks (6 years). Patient ages at the end of treatment ranged from 19 to 36 years. These trials were carried out over many years and data are not available on all patients. Thirty-nine patients in Trial 1 and 5 new patients in Trial 2 received at least one dose of cholic acid and had sufficient data available to assess baseline liver function and effects of cholic acid treatment. A responder analysis was performed to determine the response to treatment with cholic acid. Response to cholic acid treatment was assessed by the following laboratory criteria: (1)ALT or AST values reduced to less than 50 U/L, or baseline levels reduced by 80%; (2)total bilirubin values reduced to less than or equal to 1 mg/dL; and (3)no evidence of cholestasis on liver biopsy; and the following clinical criteria: (1)body weight increased by 10% or stable at greater than the 50th percentile; and (2)survival for greater than 3 years on treatment or alive at the end of Trial 2 Cholic acid responders were defined as patients who either: (1)met at least two laboratory criteria and were alive at the last follow-up; or (2)met at least one laboratory criterion, had increased body weight and were alive at the last follow-up. Overall, 28 of 44 patients (64%) were responders. The breakdown by defect type is as follows: - Table 4: Response to Cholic acid Treatment by Type of Single Enzyme Defect Among SED responsive patients, 45% of the responders met the two clinical criteria plus 1 to 3 laboratory criteria and 55% met the weight criteria. Only six patients had pre- and post-treatment liver biopsies in Trial 1. Where biopsies were available, pre-treatment biopsies showed varying degrees of inflammation, bridging fibrosis, and giant cell formation. Post-treatment biopsies generally showed reduced or absent inflammation and reduced or absent giant cell formation. Fibrosis remained but did not progress. It is difficult to evaluate long term survival in patients with SEDs since there is little natural history survival data for comparison. Overall, 41 of 62, or 67%, of patients with SEDs survived greater than 3 years from trial entry. Thirteen of these 41 patients, or 32%, were "long-term" survivors (range of 10 to 24 years on treatment). Four patients in Trial 1 underwent liver transplant, including two patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency and two patients in Trial 2, both with AKR1D1. Cholic acid's effects on extrahepatic manifestations of SEDs, such as neurologic symptoms are not established. - Case Series A published report of a case series described 15 patients with SEDs; thirteen were diagnosed with 3β-HSD deficiency and two with AKR1D1 deficiency by mass spectrometry and gene sequencing. All patients were treated with cholic acid with a median duration of treatment of 12.4 years (range 5.6 to 15 years). Therapy started at a median age of 3.9 years (range 0.3 to 13.1 years). The mean dose at the start of cholic acid treatment was 13 mg/kg and the mean dose at last follow up was 6 mg/kg. Eight patients were initially treated with oral ursodeoxycholic acid prior to receiving a diagnosis of bile acid synthesis defect, after which they were switched to cholic acid. Initial signs and symptoms included jaundice, hepatosplenomegaly, steatorrhea, or symptoms related to deficiency of a fat soluble vitamin (K, D or E). Of the 8 patients who received ursodeoxycholic acid initially, the six with 3β-HSD deficiency demonstrated mild clinical improvement. Following treatment with cholic acid, all patients experienced resolution of their pre-existing jaundice and steatorrhea, and all but one experienced resolution of hepatosplenomegaly. Weight and height improved and sexual maturation progressed normally in all patients. Liver biopsies were performed in 14 patients after at least 5 years of cholic acid treatment and all showed resolution of cholestasis. In one patient with 3β-HSD deficiency, biliary bile acid analysis while on cholic acid therapy showed enrichment of the bile with cholic acid. The effectiveness of cholic acid at a dosage of 10 to 15 mg/kg per day in patients with PDs including Zellweger spectrum disorders was assessed in patients in the same trials described in the section above. - Trial 1 treated 29 patients with PDs over an 18 year period. - Trial 2 treated 2 new patients along with 10 patients who rolled-over from Trial 1 (n=12 total). Efficacy data are available from Trial 2 for 21 months of treatment. - Additional efficacy data were obtained from published case reports of 3 patients. Enrollment criteria in Trials 1 and 2 were based on abnormal urinary bile acids analysis by Fast Atom Bombardment ionization - Mass Spectrometry (FAB-MS) and a neurologic exam. Most patients received concomitant DHA () and Vitamins A, D, E and K. Documentation of adherence to treatment, concomitant medications and response to treatment were incomplete during Trial 1. - Trials 1 and 2 The majority of patients (80%, 25/31) were less than 2 years of age at the start of cholic acid treatment (range 3 weeks to 10 years). The majority of patients were treated for an average of 254 weeks (4.8 years). Sufficient data were available to assess baseline liver function and effects of cholic acid treatment in 23 patients in Trial 1 and in one new patient in Trial 2. A responder analysis was performed in the patients who had received at least one dose of cholic acid and had sufficient data available to assess baseline liver impairment. Response to cholic acid treatment was assessed by the following laboratory criteria: (1)ALT or AST values reduced to less than 50 U/L, or baseline levels reduced by 80%; (2)total bilirubin values reduced to less than or equal to 1 mg/dL; and (3)no evidence of cholestasis on liver biopsy; and the following clinical criteria: (1)body weight increased by 10% or stable at greater than the 50th percentile; and (2)survival for greater than 3 years on treatment or alive at the end of Trial 2 Cholic acid responders were defined as patients who either: (1)met at least two laboratory criteria and were alive at the last follow-up; or (2)met at least one laboratory criterion, had increased body weight and were alive at the last follow-up. Overall, 11 of 24 patients (46%) were responders. The breakdown by disorder is as follows: - Table 5: Response to Cholic acid Treatment by Type of Peroxisomal Disorders including Zellweger Spectrum Disorders Among responsive patients with PDs, 38% of the responders met the two clinical criteria plus 1 to 3 laboratory criteria and 63% met the weight criteria. There were no PD patients that underwent liver transplant. No evidence of improvement in survival over that seen in historical controls could be demonstrated from the data presented. Overall, 13 of 31, or 42%, of patients survived greater than 3 years from the time of trial entry. Eight of these 13 patients, or 62% were "long-term" survivors (range of 10 to 17 years on treatment). Nine patients had both pre- and post-treatment liver biopsies. One patient showed improvement in histology, while the majority of patients remained unchanged. Two patients demonstrated worsening histology, which was consistent with a worsening of other liver laboratory parameters (bilirubin, serum transaminase values). Cholic acid's effects on extrahepatic manifestations of PDs including Zellweger spectrum disorders, such as neurologic symptoms are not established. One patient, who did not have cholestasis on pre-treatment liver biopsy, developed cholestasis on treatment with cholic acid and subsequently died. - Case Reports In case reports from the literature, a 6 month old patient with Zellweger syndrome treated with a combination of cholic and chenodeoxycholic acids experienced normalization of serum transaminases and bilirubin, improvement in liver histology, reduced serum and urinary atypical bile acid intermediates, and improvement in steatorrhea and growth. Two patients with Zellweger syndrome treated with oral bile acids showed decreased serum transaminases. # How Supplied - 50 mg Capsules Cholic acid capsules are available as two-piece gelatin capsules with a Swedish orange cap imprinted with "50mg" and Swedish orange body with imprinted with "ASK001". The capsules contain a white or off-white powder and are supplied in bottles of: 90 capsules (NDC 45043-001-02) - 250 mg Capsules Cholic acid capsules are available as two-piece gelatin capsules with a white cap imprinted with "250mg" and white body with imprinted with "ASK002". The capsules contain a white or off-white powder and are supplied in bottles of: 90 capsules (NDC 45043-002-02) ## Storage Store at 20–25°C (69-77°F), excursions permitted between 15-30°C (59-86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients that they will need to undergo laboratory testing periodically while on treatment to assess liver function. - Advise patients that cholic acid may worsen liver impairment and that they should immediately report to their health care provider any symptoms associated with liver impairment (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown , pain on the right side of stomach, bleeding or bruising occurs more easily than normal, or increased lethargy) Advise patients: - to take cholic acid with food. - to take cholic acid at least one hour before or 4 to 6 hours after taking a bile acid binding resin or an aluminum-based antacid. - not to crush or chew the capsules. - for infants and children who cannot swallow capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste: - Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food. - Mix the entire capsule contents with one or two tablespoonfuls (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree. - Stir for 30 seconds. - The capsule contents will remain as fine granules in the milk or food, and will not dissolve. - Administer the mixture immediately. Advise patients there is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to cholic acid during pregnancy # Precautions with Alcohol Alcohol-Cholic acid interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names CHOLBAM™ # Look-Alike Drug Names There is limited information regarding Cholic acid Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cholic acid Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Cholic acid is a bile acid that is FDA approved for the treatment of patients with bile acid synthesis disorders due to single enzyme defects (SEDs) and as an adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. Common adverse reactions include diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp , urinary tract infection, and peripheral neuropathy (≥1%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Bile Acid Synthesis Disorders due to Single Enzyme Defects Cholic acid is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects (SEDs). - Peroxisomal Disorders Including Zellweger Spectrum Disorders Cholic acid is indicated for adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. Limitation of Use: The safety and effectiveness of cholic acid on extrahepatic manifestations of bile acid synthesis disorders due to SEDs or PDs including Zellweger spectrum disorders have not been established. - Dosage Regimen for Bile Acid Synthesis Disorders due to Single Enzyme Defects and Peroxisomal Disorders including Zellweger Spectrum Disorders The recommended dosage of cholic acid is 10 to 15 mg/kg administered orally once daily, or in two divided doses, in pediatric patients and in adults. Tables 1 and 2 show the number of capsules that should be administered daily to approximate a 10 mg/kg/day and 15 mg/kg/day dosage, respectively, using the available 50 mg and 250 mg capsules alone or in combination. - Table 1: Number of cholic acid capsules Needed to Achieve a Recommended Dosage of 10 mg/kg/day - Table 2: Number of cholic acid capsules Needed to Achieve a Recommended Dosage of 15 mg/kg/day Patients with newly diagnosed, or a family history of, familial hypertriglyceridemia may have poor absorption of cholic acid from the intestine and require a 10% increase in the recommended dosage to account for losses due to malabsorption. The recommended dosage of cholic acid in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg orally once daily, or in two divided doses. Adequacy of the dosage regimen can be determined by monitoring of patients' clinical response including steatorrhea, and laboratory values including transaminases, bilirubin and PT/INR. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cholic acid in adult patients ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cholic acid in adult patients # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of cholic acid has been established in pediatric patients 3 weeks of age and older for the treatment of bile acid synthesis disorders due to SEDs, and for adjunctive treatment of patients with PDs including Zellweger spectrum disorders who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. - Dosage Regimen for Bile Acid Synthesis Disorders due to Single Enzyme Defects and Peroxisomal Disorders including Zellweger Spectrum Disorders The recommended dosage of cholic acid is 10 to 15 mg/kg administered orally once daily, or in two divided doses, in pediatric patients and in adults. Tables 1 and 2 show the number of capsules that should be administered daily to approximate a 10 mg/kg/day and 15 mg/kg/day dosage, respectively, using the available 50 mg and 250 mg capsules alone or in combination. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cholic acid in pediatric patients ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cholic acid in pediatric patients # Contraindications None # Warnings Monitor liver function and discontinue cholic acid in patients who develop worsening of liver function while on treatment. Concurrent elevations of serum gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) may indicate cholic acid overdose. Discontinue treatment with cholic acid at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis. Evidence of liver impairment was present before treatment with cholic acid in approximately 86% (44/51) of patients with bile acid synthesis disorders due to SEDs and in approximately 50% (14/28) of patients with PDs including Zellweger spectrum disorders. Five of the patients (3 SED and 2 PD) with liver impairment at baseline experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy following treatment. An additional 5 patients (2 SED and 3 PD) who did not have baseline cholestasis experienced an exacerbation of their liver disease while on treatment. Exacerbation of liver impairment by cholic acid in these patients cannot be ruled out. Six patients with single enzyme defects underwent liver transplant, including four patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency. # 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. Clinical safety experience with cholic acid consists of: - Trial 1: a non-randomized, open-label, single-arm trial of 50 patients with bile acid synthesis disorders due to SEDs and 29 patients with PDs including Zellweger spectrum disorders. Safety data are available over the 18 years of the trial. - Trial 2: an extension trial of 12 new patients (10 SED and 2 PD) along with 31 (21 SED and 10 PD) patients who rolled-over from Trial 1. Safety data are available for 3 years and 11 months of treatment. Adverse events were not collected systematically in either of these trials. Most patients received an oral dose of 10 to 15 mg/kg/day of cholic acid. Deaths In Trial 1, among the 50 patients with SEDs, 5 patients aged 1 year or less died, which included three patients originally diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency and one with CYP7A1 deficiency. The cause of death was attributed to progression of underlying liver disease in every patient. Of the 29 patients in Trial 1 with PDs including Zellweger spectrum disorders, 12 patients between the ages of 7 months and 2.5 years died. In the majority of these patients (8/12), the cause of death was attributed to progression of underlying liver disease or to a worsening of their primary illness. Two additional patients in Trial 1 (1 SED and 1 PD) died who had been off study medication for more than one year with the cause of death most likely being a progression of their underlying liver disease. Of the patients who died with disease progression, laboratory testing showed abnormal serum transaminases, bilirubin, or cholestasis on liver biopsy suggesting worsening of their underlying cholestasis. In Trial 2, among the 31 patients with SED, two patients (1 new patient and 1 who rolled over from Trial 1) died. The cause of death in both cases was unrelated to their primary treatment or progression of their underlying liver disease. Of the 12 patients with PD in Trial 2, four patients died between the ages of 4 and 8 years (1 new patient and 3 who rolled over from Trial 1). The cause of death in three of these patients was attributed to progression of underlying liver disease or to a worsening of their primary illness. Worsening Liver Impairment Seven patients in Trial 1(4 SED and 3 PD) and 3 patients in Trial 2 (1 SED and 2 PD) experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy during treatment. Common Adverse Reactions There were 12 adverse reactions reported across 9 patients in the trials, with diarrhea being the most common reaction in approximately 2% of the patient population. All other adverse reactions represented 1% of the patient population. The breakdown by trial follows: - Table 3: Most Common Adverse Reactions in Trials 1 and 2 Only one of the reactions (peripheral neuropathy) resulted in discontinuation of medication for a patient in Trial 2. An additional five SED patients (3 from Trial 1 and 2 from Trial 2) and 1 PD patient (Trial 1) discontinued medication and withdrew from the study due to a worsening of their primary disease. The development of symptomatic cholelithiasis requiring cholecystectomy has been reported in a single patient with 3β-HSD deficiency. ## Postmarketing Experience There is limited information regarding Cholic acid Postmarketing Experience in the drug label. # Drug Interactions Drug interactions with cholic acid mainly relate to agents capable of interrupting the enterohepatic circulation of bile acids. - Inhibitors of Bile Acid Transporters Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitoring of serum transaminases and bilirubin is recommended. - Bile Acid Binding Resins Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the efficacy of cholic acid. Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin. - Aluminum-Based Antacids Aluminum-based antacids have been shown to adsorb bile acids in vitro and can reduce the bioavailability of cholic acid. Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after an aluminum-based antacid. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Pregnancy Exposure Registry There is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to cholic acid during pregnancy [COCOA Registry (ChOlbam: Child and mOther's heAlth)]. Women who become pregnant during cholic acid treatment are encouraged to enroll. Patients or their health care provider should call 1-844-20C-OCOA or 1-844-202-6262 to enroll. - Risk Summary No studies in pregnant women or animal reproduction studies have been conducted with cholic acid. Limited published case reports discuss pregnancies in women taking cholic acid for 3β-HSD deficiency resulting in healthy infants. These reports may not adequately inform the presence or absence of drug-associated risk with the use of cholic acid during pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cholic acid in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cholic acid during labor and delivery. ### Nursing Mothers Endogenous cholic acid is present in human milk. Clinical lactation studies have not been conducted to assess the presence of cholic acid in human milk, the effects of cholic acid on the breastfed infant, or the effects of cholic acid on milk production. There are no animal lactation data and no data from case reports available in the published literature. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for cholic acid and any potential adverse effects on the breastfed infant from cholic acid or from the underlying maternal condition. ### Pediatric Use The safety and effectiveness of cholic acid has been established in pediatric patients 3 weeks of age and older for the treatment of bile acid synthesis disorders due to SEDs, and for adjunctive treatment of patients with PDs including Zellweger spectrum disorders who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. ### Geriatic Use Clinical studies of cholic acid did not include any patients aged 65 years and over. It is not known if elderly patients respond differently from younger patients. ### Gender There is no FDA guidance on the use of Cholic acid with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cholic acid with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Cholic acid in patients with renal impairment. ### Hepatic Impairment Discontinue treatment with cholic acid if liver function does not improve within 3 months of the start of treatment. Discontinue treatment with cholic acid at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cholic acid in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cholic acid in patients who are immunocompromised. # Administration and Monitoring ### Administration - Take cholic acid with food. - Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacid. - Do not crush or chew the capsules. - For patients unable to swallow the capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste: - Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food. - Mix the entire capsule contents with one or two tablespoons (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree. - Stir for 30 seconds. - The capsule contents will remain as fine granules in the milk or food, and will not dissolve. - Administer the mixture immediately ### Monitoring Treatment with cholic acid should be initiated and monitored by an experienced hepatologist or pediatric gastroenterologist. Monitor serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the subsequent three years and annually thereafter. Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy. Administer the lowest dose of cholic acid that effectively maintains liver function. Discontinue treatment with cholic acid if liver function does not improve within 3 months of the start of treatment or complete biliary obstruction develops. Discontinue treatment with cholic acid at any time if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis. Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate cholic acid overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline. Assessment of serum or urinary bile acid levels using mass spectrometry is used in the diagnosis of bile acid synthesis disorders due to SEDs and PDs including Zellweger spectrum disorders. The utility of bile acid measurements in monitoring the clinical course of patients and in decisions regarding dose adjustment has not been demonstrated. # IV Compatibility There is limited information regarding the compatibility of Cholic acid and IV administrations. # Overdosage Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate cholic acid overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline. In the event of overdose the patient should be monitored and treated symptomatically. # Pharmacology ## Mechanism of Action Cholic acid is a primary bile acid synthesized from cholesterol in the liver. In bile acid synthesis disorders due to SEDs in the biosynthetic pathway, and in PDs including Zellweger spectrum disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixed micelles, and facilitate absorption of fat-soluble vitamins in the intestine. Endogenous bile acids including cholic acid enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis. The mechanism of action of cholic acid has not been fully established; however, it is known that cholic acid and its conjugates are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR). FXR regulates enzymes and transporters that are involved in bile acid synthesis and in the enterohepatic circulation to maintain bile acid homeostasis under normal physiologic conditions. ## Structure Cholic acid is a white to off-white powder. It is practically insoluble in water and in 0.1 M HCl at 20°C and is sparingly soluble in 0.1 M NaOH at 20°C. It is soluble in glacial acetic acid, alcohols and acetone. A saturated solution in water at 20°C has a pH of 4.4. The chemical formula is C24H40O5, the molecular weight is 408.57. Cholic acid capsules contain 50 mg or 250 mg of cholic acid as the active ingredient in size 2 Swedish orange or size 0 white opaque gelatin capsules, respectively. Inactive ingredients in cholic acid include silicified microcrystalline cellulose, magnesium stearate and hard gelatin capsules. The size 2 shells contain gelatin, red iron oxide and titanium dioxide and the size 0 shells contain gelatin and titanium dioxide. Cholic acid is administered orally. ## Pharmacodynamics There is limited information regarding Cholic acid Pharmacodynamics in the drug label. ## Pharmacokinetics Orally administered cholic acid is subject to the same metabolic pathway as endogenous cholic acid. Cholic acid is absorbed by passive diffusion along the length of the gastrointestinal tract. Once absorbed, cholic acid enters into the body's bile acid pool and undergoes enterohepatic circulation mainly in conjugated forms. In the liver, cholic acid is conjugated with glycine or taurine by bile acid-CoA synthetase and bile acid-CoA: amino acid N-acetyltransferase. Conjugated cholic acid is actively secreted into bile mainly by the Bile Salt Efflux Pump (BSEP), and then released into the small intestine, along with other components of bile. Conjugated cholic acid is mostly re-absorbed in the ileum mainly by the apical-sodium-dependent-bile acid transporter, passed back to the liver by transporters including sodium-taurocholate cotransporting polypeptide and organic anion transport protein and enters another cycle of enterohepatic circulation. Any conjugated cholic acid not absorbed in the ileum passes into the colon where deconjugation and 7-dehydroxylation are mediated by bacteria to form cholic acid and deoxycholic acid which may be re-absorbed in the colon or excreted in the feces. The loss of cholic acid is compensated by de-novo synthesis of cholic acids from cholesterol to maintain the bile acid pool in healthy subjects. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, genetic toxicology, and nonclinical fertility studies have not been performed with cholic acid. - Animal Toxicology and/or Pharmacology In the PEX2-/- mouse model of peroxisomal disorders, feeding with a combination of cholic acid and ursodeoxycholic acid normalized C24 bile acid concentrations in bile to that of untreated control animals. Although growth was only mildly improved, there was near complete normalization of stool fat content, resolution of steatorrhea, and improved survival. Bile acid feeding reduced the number of cholestatic deposits in bile ducts and alleviated cholangitis, but exacerbated the degree of hepatic steatosis and mitochondrial and cellular damage in the peroxisome-deficient livers of these animals. # Clinical Studies The effectiveness of cholic acid at dosages of 10 to 15 mg/kg per day in patients with SEDs was assessed in: - Trial 1: a non-randomized, open-label, single-arm trial in 50 patients over an 18 year period. - Trial 2: an extension trial of 12 new patients along with 21 patients who rolled-over from Trial 1 (n=33 total). Efficacy data are available for 21 months of treatment. - A published case series of 15 patients. Enrollment criteria in Trials 1 and 2 were based on abnormal urinary bile acid by Fast Atom Bombardment ionization - Mass Spectrometry (FAB-MS) analysis. Pre- and post-treatment liver biopsies were performed in a limited number of patients. Documentation of adherence to treatment, concomitant medications and response to treatment were incomplete during Trial 1. Additional interventions in some patients included supplementation with fat-soluble vitamins, as dictated by the patient's clinical signs and symptoms. - Trials 1 and 2 On average, patients were 4 years of age at the start of cholic acid treatment (range three weeks to 36 years). The majority of patients were treated for an average of 310 weeks (6 years). Patient ages at the end of treatment ranged from 19 to 36 years. These trials were carried out over many years and data are not available on all patients. Thirty-nine patients in Trial 1 and 5 new patients in Trial 2 received at least one dose of cholic acid and had sufficient data available to assess baseline liver function and effects of cholic acid treatment. A responder analysis was performed to determine the response to treatment with cholic acid. Response to cholic acid treatment was assessed by the following laboratory criteria: (1)ALT or AST values reduced to less than 50 U/L, or baseline levels reduced by 80%; (2)total bilirubin values reduced to less than or equal to 1 mg/dL; and (3)no evidence of cholestasis on liver biopsy; and the following clinical criteria: (1)body weight increased by 10% or stable at greater than the 50th percentile; and (2)survival for greater than 3 years on treatment or alive at the end of Trial 2 Cholic acid responders were defined as patients who either: (1)met at least two laboratory criteria and were alive at the last follow-up; or (2)met at least one laboratory criterion, had increased body weight and were alive at the last follow-up. Overall, 28 of 44 patients (64%) were responders. The breakdown by defect type is as follows: - Table 4: Response to Cholic acid Treatment by Type of Single Enzyme Defect Among SED responsive patients, 45% of the responders met the two clinical criteria plus 1 to 3 laboratory criteria and 55% met the weight criteria. Only six patients had pre- and post-treatment liver biopsies in Trial 1. Where biopsies were available, pre-treatment biopsies showed varying degrees of inflammation, bridging fibrosis, and giant cell formation. Post-treatment biopsies generally showed reduced or absent inflammation and reduced or absent giant cell formation. Fibrosis remained but did not progress. It is difficult to evaluate long term survival in patients with SEDs since there is little natural history survival data for comparison. Overall, 41 of 62, or 67%, of patients with SEDs survived greater than 3 years from trial entry. Thirteen of these 41 patients, or 32%, were "long-term" survivors (range of 10 to 24 years on treatment). Four patients in Trial 1 underwent liver transplant, including two patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency and two patients in Trial 2, both with AKR1D1. Cholic acid's effects on extrahepatic manifestations of SEDs, such as neurologic symptoms are not established. - Case Series A published report of a case series described 15 patients with SEDs; thirteen were diagnosed with 3β-HSD deficiency and two with AKR1D1 deficiency by mass spectrometry and gene sequencing. All patients were treated with cholic acid with a median duration of treatment of 12.4 years (range 5.6 to 15 years). Therapy started at a median age of 3.9 years (range 0.3 to 13.1 years). The mean dose at the start of cholic acid treatment was 13 mg/kg and the mean dose at last follow up was 6 mg/kg. Eight patients were initially treated with oral ursodeoxycholic acid prior to receiving a diagnosis of bile acid synthesis defect, after which they were switched to cholic acid. Initial signs and symptoms included jaundice, hepatosplenomegaly, steatorrhea, or symptoms related to deficiency of a fat soluble vitamin (K, D or E). Of the 8 patients who received ursodeoxycholic acid initially, the six with 3β-HSD deficiency demonstrated mild clinical improvement. Following treatment with cholic acid, all patients experienced resolution of their pre-existing jaundice and steatorrhea, and all but one experienced resolution of hepatosplenomegaly. Weight and height improved and sexual maturation progressed normally in all patients. Liver biopsies were performed in 14 patients after at least 5 years of cholic acid treatment and all showed resolution of cholestasis. In one patient with 3β-HSD deficiency, biliary bile acid analysis while on cholic acid therapy showed enrichment of the bile with cholic acid. The effectiveness of cholic acid at a dosage of 10 to 15 mg/kg per day in patients with PDs including Zellweger spectrum disorders was assessed in patients in the same trials described in the section above. - Trial 1 treated 29 patients with PDs over an 18 year period. - Trial 2 treated 2 new patients along with 10 patients who rolled-over from Trial 1 (n=12 total). Efficacy data are available from Trial 2 for 21 months of treatment. - Additional efficacy data were obtained from published case reports of 3 patients. Enrollment criteria in Trials 1 and 2 were based on abnormal urinary bile acids analysis by Fast Atom Bombardment ionization - Mass Spectrometry (FAB-MS) and a neurologic exam. Most patients received concomitant DHA ([docosahexaenoic acid]) and Vitamins A, D, E and K. Documentation of adherence to treatment, concomitant medications and response to treatment were incomplete during Trial 1. - Trials 1 and 2 The majority of patients (80%, 25/31) were less than 2 years of age at the start of cholic acid treatment (range 3 weeks to 10 years). The majority of patients were treated for an average of 254 weeks (4.8 years). Sufficient data were available to assess baseline liver function and effects of cholic acid treatment in 23 patients in Trial 1 and in one new patient in Trial 2. A responder analysis was performed in the patients who had received at least one dose of cholic acid and had sufficient data available to assess baseline liver impairment. Response to cholic acid treatment was assessed by the following laboratory criteria: (1)ALT or AST values reduced to less than 50 U/L, or baseline levels reduced by 80%; (2)total bilirubin values reduced to less than or equal to 1 mg/dL; and (3)no evidence of cholestasis on liver biopsy; and the following clinical criteria: (1)body weight increased by 10% or stable at greater than the 50th percentile; and (2)survival for greater than 3 years on treatment or alive at the end of Trial 2 Cholic acid responders were defined as patients who either: (1)met at least two laboratory criteria and were alive at the last follow-up; or (2)met at least one laboratory criterion, had increased body weight and were alive at the last follow-up. Overall, 11 of 24 patients (46%) were responders. The breakdown by disorder is as follows: - Table 5: Response to Cholic acid Treatment by Type of Peroxisomal Disorders including Zellweger Spectrum Disorders Among responsive patients with PDs, 38% of the responders met the two clinical criteria plus 1 to 3 laboratory criteria and 63% met the weight criteria. There were no PD patients that underwent liver transplant. No evidence of improvement in survival over that seen in historical controls could be demonstrated from the data presented. Overall, 13 of 31, or 42%, of patients survived greater than 3 years from the time of trial entry. Eight of these 13 patients, or 62% were "long-term" survivors (range of 10 to 17 years on treatment). Nine patients had both pre- and post-treatment liver biopsies. One patient showed improvement in histology, while the majority of patients remained unchanged. Two patients demonstrated worsening histology, which was consistent with a worsening of other liver laboratory parameters (bilirubin, serum transaminase values). Cholic acid's effects on extrahepatic manifestations of PDs including Zellweger spectrum disorders, such as neurologic symptoms are not established. One patient, who did not have cholestasis on pre-treatment liver biopsy, developed cholestasis on treatment with cholic acid and subsequently died. - Case Reports In case reports from the literature, a 6 month old patient with Zellweger syndrome treated with a combination of cholic and chenodeoxycholic acids experienced normalization of serum transaminases and bilirubin, improvement in liver histology, reduced serum and urinary atypical bile acid intermediates, and improvement in steatorrhea and growth. Two patients with Zellweger syndrome treated with oral bile acids showed decreased serum transaminases. # How Supplied - 50 mg Capsules Cholic acid capsules are available as two-piece gelatin capsules with a Swedish orange cap imprinted with "50mg" and Swedish orange body with imprinted with "ASK001". The capsules contain a white or off-white powder and are supplied in bottles of: 90 capsules (NDC 45043-001-02) - 250 mg Capsules Cholic acid capsules are available as two-piece gelatin capsules with a white cap imprinted with "250mg" and white body with imprinted with "ASK002". The capsules contain a white or off-white powder and are supplied in bottles of: 90 capsules (NDC 45043-002-02) ## Storage Store at 20–25°C (69-77°F), excursions permitted between 15-30°C (59-86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients that they will need to undergo laboratory testing periodically while on treatment to assess liver function. - Advise patients that cholic acid may worsen liver impairment and that they should immediately report to their health care provider any symptoms associated with liver impairment (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown [tea colored], pain on the right side of stomach, bleeding or bruising occurs more easily than normal, or increased lethargy) Advise patients: - to take cholic acid with food. - to take cholic acid at least one hour before or 4 to 6 hours after taking a bile acid binding resin or an aluminum-based antacid. - not to crush or chew the capsules. - for infants and children who cannot swallow capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste: - Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food. - Mix the entire capsule contents with one or two tablespoonfuls (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree. - Stir for 30 seconds. - The capsule contents will remain as fine granules in the milk or food, and will not dissolve. - Administer the mixture immediately. Advise patients there is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to cholic acid during pregnancy # Precautions with Alcohol Alcohol-Cholic acid interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names CHOLBAM™ # Look-Alike Drug Names There is limited information regarding Cholic acid Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cholic_acid
fce9c31d99de700bb967f09d3f0d7f2a08c4aac6	wikidoc	Cholinergic	Cholinergic # Overview A synapse is cholinergic if it uses acetylcholine as its neurotransmitter. Cholinergic means "related to the neurotransmitter acetylcholine," and is typically used in a neurological perspective. The parasympathetic nervous system is entirely cholinergic. Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes are also cholinergic. A substance is cholinergic if it is capable of producing, altering, or releasing acetylcholine ("indirect-acting") or mimicking its behaviour at one or more of the body's acetylcholine receptor types ("direct-acting"). # Cholinergic drug A cholinergic drug, also known as a cholinergic agent or a parasympathomimetic drug, is any drug that functions to enhance the effects mediated by acetylcholine in the central nervous system, the peripheral nervous system, or both. These include acetylcholine's precursors and cofactors, acetylcholine receptor agonists and cholinergic enzymes: - acetylcholine receptor agonists muscarine (muscarinic receptors) pilocarpine (M3 receptors) nicotine (nicotinic receptors) suxamethonium (muscle type receptors) - muscarine (muscarinic receptors) - pilocarpine (M3 receptors) - nicotine (nicotinic receptors) - suxamethonium (muscle type receptors) - cholinesterase inhibitors physostigmine neostigmine - physostigmine - neostigmine	Cholinergic # Overview A synapse is cholinergic if it uses acetylcholine as its neurotransmitter. Cholinergic means "related to the neurotransmitter acetylcholine," and is typically used in a neurological perspective. The parasympathetic nervous system is entirely cholinergic. Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes are also cholinergic. A substance is cholinergic if it is capable of producing, altering, or releasing acetylcholine ("indirect-acting") or mimicking its behaviour at one or more of the body's acetylcholine receptor types ("direct-acting"). # Cholinergic drug A cholinergic drug, also known as a cholinergic agent or a parasympathomimetic drug, is any drug that functions to enhance the effects mediated by acetylcholine in the central nervous system, the peripheral nervous system, or both. These include acetylcholine's precursors and cofactors, acetylcholine receptor agonists and cholinergic enzymes: - acetylcholine receptor agonists muscarine (muscarinic receptors) pilocarpine (M3 receptors) nicotine (nicotinic receptors) suxamethonium (muscle type receptors) - muscarine (muscarinic receptors) - pilocarpine (M3 receptors) - nicotine (nicotinic receptors) - suxamethonium (muscle type receptors) - cholinesterase inhibitors physostigmine neostigmine - physostigmine - neostigmine	https://www.wikidoc.org/index.php/Cholinergic
5d5c638d5001213575dd0b75361b7da3fc1dd68c	wikidoc	Chromogenic	Chromogenic Chromogenic refers to color photographic processes in which a traditional silver image is first formed, and then later replaced with a colored dye image. Chromogenic film or paper contains one or many layers of silver halide emulsion, along with dye couplers which are capable of forming visible dyes in combination with processing chemistry. In processing, the silver image of each layer is first developed. In concert with the dye couplers in each layer, the process subsequently forms dyes only in those areas where silver is present. In full-color chromogenic materials, multiple layers of emulsion are sensitized to different wavelengths of light. Three layers are usually present, generally sensitive to red, green, and blue colored light. Cyan-colored dye is formed on the red-sensitive layer, magenta-colored dye is formed on the green-sensitive layer, and yellow-colored dye is formed on the blue-sensitive layer, following generally the CMY color model. Some chromogenic black-and-white negative films also exist, mainly to exploit the wide availability of C-41 processing. These films have softer grain and less contrast than traditional silver halide films. In these films, a single emulsion layer has panchromatic sensitivity. The dye image is typically slightly blue because of the choice of dye couplers, and this tends to produce a dark sepia tone when printed on full-color chromogenic paper. Each microscopic point of chromogenic dye formation is called a dye cloud. After the formation of dyes is complete, the silver image is removed in processing by a specialty photographic fixer called bleach fix or blix. A processing variation called skip bleach, most popular in motion picture negative processing, allows the silver image to be left partially or completely intact, yielding a type of contrast enhancement. The most common chromogenic processes are C-41 for color and black-and-white negative film, RA-4 for color negative paper (see Type C print), and E-6 for slide film. A great deal of research effort has been placed by manufacturers, most notably Fujifilm, Ilford, and Kodak, into controlling the color and tonal characteristics of their chromogenic film and paper. The sensitization of the silver halide emulsions, the composition and mixture of the dye couplers, and the chemical interactions of layers upon one another during processing (called interlayer effects), are the subjects of numerous patents. Fujifilm is apparently unique in its use of a fourth (cyan-sensitive) color layer in certain of its negative films. Like the traditional silver halide process, the main hazardous waste product of chromogenic processing consists of silver compounds dissolved in the photographic fixer.	Chromogenic Chromogenic refers to color photographic processes in which a traditional silver image is first formed, and then later replaced with a colored dye image. Chromogenic film or paper contains one or many layers of silver halide emulsion, along with dye couplers which are capable of forming visible dyes in combination with processing chemistry. In processing, the silver image of each layer is first developed. In concert with the dye couplers in each layer, the process subsequently forms dyes only in those areas where silver is present. In full-color chromogenic materials, multiple layers of emulsion are sensitized to different wavelengths of light. Three layers are usually present, generally sensitive to red, green, and blue colored light. Cyan-colored dye is formed on the red-sensitive layer, magenta-colored dye is formed on the green-sensitive layer, and yellow-colored dye is formed on the blue-sensitive layer, following generally the CMY color model. Some chromogenic black-and-white negative films also exist, mainly to exploit the wide availability of C-41 processing. These films have softer grain and less contrast than traditional silver halide films. In these films, a single emulsion layer has panchromatic sensitivity. The dye image is typically slightly blue because of the choice of dye couplers, and this tends to produce a dark sepia tone when printed on full-color chromogenic paper. Each microscopic point of chromogenic dye formation is called a dye cloud. After the formation of dyes is complete, the silver image is removed in processing by a specialty photographic fixer called bleach fix or blix. A processing variation called skip bleach, most popular in motion picture negative processing, allows the silver image to be left partially or completely intact, yielding a type of contrast enhancement. The most common chromogenic processes are C-41 for color and black-and-white negative film, RA-4 for color negative paper (see Type C print), and E-6 for slide film. A great deal of research effort has been placed by manufacturers, most notably Fujifilm, Ilford, and Kodak, into controlling the color and tonal characteristics of their chromogenic film and paper. The sensitization of the silver halide emulsions, the composition and mixture of the dye couplers, and the chemical interactions of layers upon one another during processing (called interlayer effects), are the subjects of numerous patents. Fujifilm is apparently unique in its use of a fourth (cyan-sensitive) color layer in certain of its negative films. Like the traditional silver halide process, the main hazardous waste product of chromogenic processing consists of silver compounds dissolved in the photographic fixer. Template:WH Template:WS	https://www.wikidoc.org/index.php/Chromogenic
034f17f69c12cf52d62efafc9d15473f19e7bbb0	wikidoc	Chromophobe	Chromophobe The term chromophobe refers to histological structures which do not take up colored dye readily, and thus appear more relatively pale under the microscope -- hence their "fear" ("phobia") of "color" ("chrome"). # Pituitary The term is most commonly associated with the anterior pituitary, where approximately half of the cells are considered chromophobes. (Of the remaining cells, about a third are basophils, and the other two thirds acidophils.) The chromophobe cells do not actually appear clear, but rather a light blue (in contrast to the deep blue of the basophils.) # Cancer "Chromophobe" also refers to a type of renal cell carcinoma (distinct from "clear cell").	Chromophobe The term chromophobe refers to histological structures which do not take up colored dye readily, and thus appear more relatively pale under the microscope -- hence their "fear" ("phobia") of "color" ("chrome"). # Pituitary The term is most commonly associated with the anterior pituitary, where approximately half of the cells are considered chromophobes. (Of the remaining cells, about a third are basophils, and the other two thirds acidophils.) The chromophobe cells do not actually appear clear, but rather a light blue (in contrast to the deep blue of the basophils.)[1] # Cancer "Chromophobe" also refers to a type of renal cell carcinoma (distinct from "clear cell").[2]	https://www.wikidoc.org/index.php/Chromophobe
dfd36c8d9c6d6c6fda26d073af9ff6fb555bee6a	wikidoc	Chylothorax	Chylothorax Synonyms and keywords: Chylothorax # Overview Chylothorax, a type of pleural effusion is the accumulation of chyle in the pleural cavity secondary to destruction or obstruction of the thoracic duct or its tributaries. Depending on the etiology, chylothorax could be exudative ( tuberculosis) or transudative (svc obstruction). It is an uncommon but established complication of thoracic surgery. Chylothorax is most commonly right-sided (50%) because of the anatomic location of the thoracic duct, left-sided (33.3%), or bilateral (16.66%). Thoracic duct damage above the fifth thoracic vertebra results in a left-sided chylothorax whereas damage to the thoracic duct below fifth thoracic vertebra leads to a right-sided effusion. Some common symptoms of chylothorax include dyspnea, cough, and severe chest pain. Some physical exams finding include decreased breath sounds and dullness to percussion depending on the size and location of fluid. The definitive diagnosis of chylothorax is with thoracentesis and analysis of the pleural fluid showing a reduced concentration of cholesterol 110 mg/dl. Management of chylothorax may be conservative or surgical. Conservative management include total parenteral nutrition, oral low-fat medium-chain triglyceride, and octreotide injections. Surgical management include tube thoracostomy, pleurodesis, pleurectomy, pleuroperitoneal shunt, and thoracic duct ligation. # Historical Perspective - Chylothorax was first described in 1633 by Bartolet, and Quincke reported the first case in 1875. - In 1917, Brandt was the first to discover the association between tuberculosis and the development of chylothorax. # Classification Chylothorax may be classified as - Non-traumatic Malignacy Idopathic Disease Sarcoidosis Haemangiomatosis Tuberculosis Heart failure Benign tumor Amyloidosis Lymphangioleiomyomatosis Filariasis Transdiaphrgmatic movement of chylous ascitic fluid SVC obstruction - Malignacy - Idopathic - Disease Sarcoidosis Haemangiomatosis Tuberculosis Heart failure Benign tumor Amyloidosis Lymphangioleiomyomatosis Filariasis Transdiaphrgmatic movement of chylous ascitic fluid SVC obstruction - Sarcoidosis - Haemangiomatosis - Tuberculosis - Heart failure - Benign tumor - Amyloidosis - Lymphangioleiomyomatosis - Filariasis - Transdiaphrgmatic movement of chylous ascitic fluid - SVC obstruction - Traumatic Iatrogenic Radiation Thoracic surgery Head and neck surgery Non-iatrogenic Knife injury Childbirth Forceful cough or emesis Blunt trauma to the thorax Bullet wound - Iatrogenic Radiation Thoracic surgery Head and neck surgery - Radiation - Thoracic surgery - Head and neck surgery - Non-iatrogenic Knife injury Childbirth Forceful cough or emesis Blunt trauma to the thorax Bullet wound - Knife injury - Childbirth - Forceful cough or emesis - Blunt trauma to the thorax - Bullet wound # Pathophysiology - It is thought that chylothorax is the result of obstruction, difficulty in drainage of lymph, lymphatic malformation or laceration of the thoracic duct leading to leakage of chyle into the pleural cavity. - Chylothorax as a result of tuberculosis is thought to be produced by the enlargement of the lumbar and the iliac lymph nodes producing obstruction of the cisterna chyli and thoracic duct. This leads to dilatation of the lumbar channels, followed by the opening of collateral anastomosis. With the many lymphaticovenous anastomosis existing between the thoracic duct, and the azygos, intercostal, and Lumbar veins. The increased pressure in the system results in the transudation of chyle into the pleural cavity. # Causes - Common causes of chylothorax include Congenital Down syndrome Noonan syndrome Turner syndrome Malignacy Sarcoidosis Tuberculosis Cirrhosis Heart failure Benign tumor SVC obstruction Thoracic surgery Knife injury Bullet wound Blunt trauma to the thorax Head and neck surgery Transdiaphrgmatic movement of chylous ascitic fluid - Congenital Down syndrome Noonan syndrome Turner syndrome - Down syndrome - Noonan syndrome - Turner syndrome - Malignacy - Sarcoidosis - Tuberculosis - Cirrhosis - Heart failure - Benign tumor - SVC obstruction - Thoracic surgery - Knife injury - Bullet wound - Blunt trauma to the thorax - Head and neck surgery - Transdiaphrgmatic movement of chylous ascitic fluid # Differentiating chylothorax from other Diseasess Chylothorax must be differentiated from - Empyema - Pseudochylothorax - Cholesterol pleural effusions - Tuberculosis - Chronic pneumothorax - Rheumatoid pleurisy - Chronic hemothorax - Cirrhosis - Nephrotic syndrome - Lymphoma - Congestive heart failure - Constrictive pericarditis # Epidemiology and Demographics - The prevalence of is approximately per 100,000 individuals worldwide. - In 2011, the incidence of pediatric chylothorax was estimated to be 3.7% - Incidence post cardiothoracic surgeries are between 0.9% and 6.6%. Incidence post congenital cardiac anomalies repair is 2.8%. - Incidence post congenital cardiac anomalies repair is 2.8%. - Incidence post esophageal surgeries range from 0.2% to 10%. ## Age - Patients of all age groups may develop chylothorax. ## Gender - Chylothorax affects men and women equally. ## Race - There is no racial predilection for chylothorax. # Risk Factors Common risk factors in the development of Chylothorax] are - Surgery Hepatectomy Esophagectomy Lung surgery Cardiac surgery Fontan procedure Retroperitoneal surgery around the cisterna chyli, example AAA repair - Hepatectomy - Esophagectomy - Lung surgery - Cardiac surgery - Fontan procedure - Retroperitoneal surgery around the cisterna chyli, example AAA repair - Dasatinib therapy - Rib fracture - Tuberculosis - Gastric cancer - Malignant pleural mesothelioma - Malignant lymphoproliferative disorders # Screening - There is insufficient evidence to recommend routine screening for chylothorax. # Natural History, Complications and Prognosis - If left untreated, 100% of patients with chylothorax may progress to develop Hypovolaemia Hypoalbuminemia Malnutrition; as a result of protein, fats and vitamins loss with weight loss and muscle wasting. Hyponatremia and hypocalcemia due to electrolyte loss. Opportunistic infections as a result of immunoglobulins loss. Subtherapeutic effects of medications like digoxin and amiodarone as they are lost through the leaking chyle. - Hypovolaemia - Hypoalbuminemia - Malnutrition; as a result of protein, fats and vitamins loss with weight loss and muscle wasting. - Hyponatremia and hypocalcemia due to electrolyte loss. - Opportunistic infections as a result of immunoglobulins loss. - Subtherapeutic effects of medications like digoxin and amiodarone as they are lost through the leaking chyle. - Common complications of chylothorax include malnutrition, immunosuppression and respiratory distress. - Prognosis is generally good and the mortality rate from chylothorax has considerably improved from approximately 50% as described in 1948. This is due to the more aggressive management plans implemented. Currently, the worst prognosis is seen in malignant and bilateral chylothoraces. # Diagnosis ## Diagnostic Study of Choice - The diagnosis of chylothorax is with thoracentesis and analysis of the pleural fluid showing a reduced concentration of cholesterol 110 mg/dl. In centres with available facilities, lipoprotein analysis showing the presence of chylomicrons is the gold standard. ## History and Symptoms - Symptoms of chylothorax depends on the rate of chyle accumulation and etiology. In traumatic or surgically induced chylothorax, there is usually a latency period of two to ten days before symptoms become clinically evident. This is due to the restricted diet offered to critically ill or surgical patients, thereby reducing the lymphatic flow through the thoracic duct. - Symptoms may include the following - Dyspnea - Cough - Pleuritic chest pain - Fever - Swelling in the supraclavicular fossa - Weight loss - Muscle wasting - Immunodeficiency - Malnutrition ## Physical Examination - Patients with chylothorax usually appear to be in respiratory distress - Physical examination may be remarkable for - Decreased breath sounds on the affected side - Tachypnea - Apneic episodes - Tachycardia - Hypotension - Enlarged axillary lymph nodes ## Laboratory Findings - An elevated concentration of pleural fluid triglyceride >110 mg/dL is diagnostic of chylothorax. - A reduced concentration of cholesterol <200mg/dl is diagnostic of chylothorax. - Leukocyte cell count ˃1000, with > 90% lymphocytic predominance. - Hypoalbuminemia ## Electrocardiogram - There are no ECG findings associated with chylothorax. ## X-ray - An x-ray may be helpful in the diagnosis of chylothorax. Findings on an x-ray suggestive of chylothorax include. - Pleural effusion - Pleural thickening - Blunting of the Costophrenic angle ## Ultrasound Transthoracic ultrasound may be helpful in the diagnosis of chylothorax. Finding loculated fluid collection is suggestive of chylothorax. ## CT scan Thoracic CT scan may be helpful in the diagnosis of chylothorax.CT scan is valuable in the location and treatment decision of chylothorax Findings on CT scan suggestive of chylothorax include pleural effusion ## MRI - There are no MRI findings associated with chylothorax. ## Other Imaging Findings Other diagnostic studies for chylothorax include - Lymphangiography with Lipiodol (ethiodized oil) which demonstrates the site of extravasation into the pleural cavity. - lymphoscintigraphy; identify chyle leakage but not the exact site. ## Other Diagnostic Studies - There are no other diagnostic studies associated with chylothorax. # Treatment ## Medical Therapy Chylothorax is a medical emergency and requires prompt treatment. Medical therapy for chylothorax include Conservative therapy aims at minimizing lymph flow through the damaged thoracic duct. - Total parenteral nutrition with oral fasting - Oral low-fat medium-chain triglyceride - Octreotide injections - Treatment of the underlying condition Sarcoidosis with steroids Tuberculosis with RIPE Congestive heart failure with diuretics - Sarcoidosis with steroids - Tuberculosis with RIPE - Congestive heart failure with diuretics - Intravenous etilefrine ## Surgery Surgery is the mainstay of therapy for chylothorax. Surgery is recommended where despite conservative management, patient drains more than 1.5 l/day in an adult or >100 ml/kg body weight per day in a child, leaks chyle at >1 l/day× 5 days or has persistent chyle flow for >2 weeks. It is also recommended if there is a rapid decline in nutritional status despite conservative management. - Thoracentesis - Tube thoracostomy - Thoracoscopy - Pleurodesis with Talc Tetracycline Bleomycin Povidone - Talc - Tetracycline - Bleomycin - Povidone - Pleurectomy - pleuroperitoneal shunt - Thoracic duct ligation - Ligation of cisterna chyli - Lymphatic embolization ## Primary Prevention - There are no established measures for the primary prevention of chylothorax. ## Secondary Prevention - There are no established measures for the secondary prevention of chylothorax.	Chylothorax Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor: Joanna Ekabua, M.D. [2] Synonyms and keywords: Chylothorax # Overview Chylothorax, a type of pleural effusion is the accumulation of chyle in the pleural cavity secondary to destruction or obstruction of the thoracic duct or its tributaries. Depending on the etiology, chylothorax could be exudative ( tuberculosis) or transudative (svc obstruction). It is an uncommon but established complication of thoracic surgery. Chylothorax is most commonly right-sided (50%) because of the anatomic location of the thoracic duct, left-sided (33.3%), or bilateral (16.66%). Thoracic duct damage above the fifth thoracic vertebra results in a left-sided chylothorax whereas damage to the thoracic duct below fifth thoracic vertebra leads to a right-sided effusion. Some common symptoms of chylothorax include dyspnea, cough, and severe chest pain. Some physical exams finding include decreased breath sounds and dullness to percussion depending on the size and location of fluid. The definitive diagnosis of chylothorax is with thoracentesis and analysis of the pleural fluid showing a reduced concentration of cholesterol <200mg/dl, and an elevated concentration of triglyceride >110 mg/dl. Management of chylothorax may be conservative or surgical. Conservative management include total parenteral nutrition, oral low-fat medium-chain triglyceride, and octreotide injections. Surgical management include tube thoracostomy, pleurodesis, pleurectomy, pleuroperitoneal shunt, and thoracic duct ligation. # Historical Perspective - Chylothorax was first described in 1633 by Bartolet, and Quincke reported the first case in 1875. [1] - In 1917, Brandt was the first to discover the association between tuberculosis and the development of chylothorax. [1] # Classification Chylothorax may be classified as[2][3] - Non-traumatic Malignacy Idopathic Disease Sarcoidosis Haemangiomatosis Tuberculosis Heart failure Benign tumor Amyloidosis Lymphangioleiomyomatosis Filariasis Transdiaphrgmatic movement of chylous ascitic fluid SVC obstruction - Malignacy - Idopathic - Disease Sarcoidosis Haemangiomatosis Tuberculosis Heart failure Benign tumor Amyloidosis Lymphangioleiomyomatosis Filariasis Transdiaphrgmatic movement of chylous ascitic fluid SVC obstruction - Sarcoidosis - Haemangiomatosis - Tuberculosis - Heart failure - Benign tumor - Amyloidosis - Lymphangioleiomyomatosis - Filariasis - Transdiaphrgmatic movement of chylous ascitic fluid - SVC obstruction - Traumatic Iatrogenic Radiation Thoracic surgery Head and neck surgery Non-iatrogenic Knife injury Childbirth Forceful cough or emesis Blunt trauma to the thorax Bullet wound - Iatrogenic Radiation Thoracic surgery Head and neck surgery - Radiation - Thoracic surgery - Head and neck surgery - Non-iatrogenic Knife injury Childbirth Forceful cough or emesis Blunt trauma to the thorax Bullet wound - Knife injury - Childbirth - Forceful cough or emesis - Blunt trauma to the thorax - Bullet wound # Pathophysiology - It is thought that chylothorax is the result of obstruction, difficulty in drainage of lymph, lymphatic malformation or laceration of the thoracic duct leading to leakage of chyle into the pleural cavity.[4] - Chylothorax as a result of tuberculosis is thought to be produced by the enlargement of the lumbar and the iliac lymph nodes producing obstruction of the cisterna chyli and thoracic duct. This leads to dilatation of the lumbar channels, followed by the opening of collateral anastomosis. With the many lymphaticovenous anastomosis existing between the thoracic duct, and the azygos, intercostal, and Lumbar veins. The increased pressure in the system results in the transudation of chyle into the pleural cavity.[1] # Causes - Common causes of chylothorax include[1][2][3][4][5][6][7] Congenital Down syndrome Noonan syndrome Turner syndrome Malignacy Sarcoidosis Tuberculosis Cirrhosis Heart failure Benign tumor SVC obstruction Thoracic surgery Knife injury Bullet wound Blunt trauma to the thorax Head and neck surgery Transdiaphrgmatic movement of chylous ascitic fluid - Congenital Down syndrome Noonan syndrome Turner syndrome - Down syndrome - Noonan syndrome - Turner syndrome - Malignacy - Sarcoidosis - Tuberculosis - Cirrhosis - Heart failure - Benign tumor - SVC obstruction - Thoracic surgery - Knife injury - Bullet wound - Blunt trauma to the thorax - Head and neck surgery - Transdiaphrgmatic movement of chylous ascitic fluid # Differentiating chylothorax from other Diseasess Chylothorax must be differentiated from[3] [8] [9][4] - Empyema - Pseudochylothorax - Cholesterol pleural effusions - Tuberculosis - Chronic pneumothorax - Rheumatoid pleurisy - Chronic hemothorax - Cirrhosis - Nephrotic syndrome - Lymphoma - Congestive heart failure - Constrictive pericarditis # Epidemiology and Demographics - The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide. - In 2011, the incidence of pediatric chylothorax was estimated to be 3.7%[10] [11] - Incidence post cardiothoracic surgeries are between 0.9% and 6.6%. Incidence post congenital cardiac anomalies repair is 2.8%. - Incidence post congenital cardiac anomalies repair is 2.8%. - Incidence post esophageal surgeries range from 0.2% to 10%. ## Age - Patients of all age groups may develop chylothorax.[11][10] ## Gender - Chylothorax affects men and women equally. ## Race - There is no racial predilection for chylothorax. # Risk Factors Common risk factors in the development of Chylothorax] are[2][3][12][13][10][14][15][16][17][5][18][19] - Surgery Hepatectomy Esophagectomy Lung surgery Cardiac surgery Fontan procedure Retroperitoneal surgery around the cisterna chyli, example AAA repair - Hepatectomy - Esophagectomy - Lung surgery - Cardiac surgery - Fontan procedure - Retroperitoneal surgery around the cisterna chyli, example AAA repair - Dasatinib therapy - Rib fracture - Tuberculosis - Gastric cancer - Malignant pleural mesothelioma - Malignant lymphoproliferative disorders # Screening - There is insufficient evidence to recommend routine screening for chylothorax. # Natural History, Complications and Prognosis - If left untreated, 100% of patients with chylothorax may progress to develop[3][20] Hypovolaemia Hypoalbuminemia Malnutrition; as a result of protein, fats and vitamins loss with weight loss and muscle wasting. Hyponatremia and hypocalcemia due to electrolyte loss. Opportunistic infections as a result of immunoglobulins loss. Subtherapeutic effects of medications like digoxin and amiodarone as they are lost through the leaking chyle. - Hypovolaemia - Hypoalbuminemia - Malnutrition; as a result of protein, fats and vitamins loss with weight loss and muscle wasting. - Hyponatremia and hypocalcemia due to electrolyte loss. - Opportunistic infections as a result of immunoglobulins loss. - Subtherapeutic effects of medications like digoxin and amiodarone as they are lost through the leaking chyle. - Common complications of chylothorax include malnutrition, immunosuppression and respiratory distress.[3][4] - Prognosis is generally good and the mortality rate from chylothorax has considerably improved from approximately 50% as described in 1948. This is due to the more aggressive management plans implemented. Currently, the worst prognosis is seen in malignant and bilateral chylothoraces.[3][4][14] # Diagnosis ## Diagnostic Study of Choice - The diagnosis of chylothorax is with thoracentesis and analysis of the pleural fluid showing a reduced concentration of cholesterol <200mg/dl, and an elevated concentration of triglyceride >110 mg/dl. In centres with available facilities, lipoprotein analysis showing the presence of chylomicrons is the gold standard.[2][3][16][1][4] ## History and Symptoms - Symptoms of chylothorax depends on the rate of chyle accumulation and etiology. In traumatic or surgically induced chylothorax, there is usually a latency period of two to ten days before symptoms become clinically evident. This is due to the restricted diet offered to critically ill or surgical patients, thereby reducing the lymphatic flow through the thoracic duct. - Symptoms may include the following[2][3][5][19] - Dyspnea - Cough - Pleuritic chest pain - Fever - Swelling in the supraclavicular fossa - Weight loss - Muscle wasting - Immunodeficiency - Malnutrition ## Physical Examination - Patients with chylothorax usually appear to be in respiratory distress - Physical examination may be remarkable for[16][11][19][4] - Decreased breath sounds on the affected side - Tachypnea - Apneic episodes - Tachycardia - Hypotension - Enlarged axillary lymph nodes ## Laboratory Findings - An elevated concentration of pleural fluid triglyceride >110 mg/dL is diagnostic of chylothorax.[2][3][16][4] - A reduced concentration of cholesterol <200mg/dl is diagnostic of chylothorax.[3] - Leukocyte cell count ˃1000, with > 90% lymphocytic predominance.[11] - Hypoalbuminemia[1] ## Electrocardiogram - There are no ECG findings associated with chylothorax. ## X-ray - An x-ray may be helpful in the diagnosis of chylothorax. Findings on an x-ray suggestive of chylothorax include.[16][5][11] - Pleural effusion - Pleural thickening - Blunting of the Costophrenic angle ## Ultrasound Transthoracic ultrasound may be helpful in the diagnosis of chylothorax. Finding loculated fluid collection is suggestive of chylothorax. [11] ## CT scan Thoracic CT scan may be helpful in the diagnosis of chylothorax.CT scan is valuable in the location and treatment decision of chylothorax Findings on CT scan suggestive of chylothorax include[2] pleural effusion ## MRI - There are no MRI findings associated with chylothorax. ## Other Imaging Findings Other diagnostic studies for chylothorax include - Lymphangiography with Lipiodol (ethiodized oil) [2] which demonstrates the site of extravasation into the pleural cavity. - lymphoscintigraphy; identify chyle leakage but not the exact site.[14][20][21][4] ## Other Diagnostic Studies - There are no other diagnostic studies associated with chylothorax. # Treatment ## Medical Therapy Chylothorax is a medical emergency and requires prompt treatment. Medical therapy for chylothorax include[2][3][10] Conservative therapy aims at minimizing lymph flow through the damaged thoracic duct.[20][11][6][4] - Total parenteral nutrition with oral fasting - Oral low-fat medium-chain triglyceride - Octreotide injections - Treatment of the underlying condition Sarcoidosis with steroids Tuberculosis with RIPE Congestive heart failure with diuretics - Sarcoidosis with steroids - Tuberculosis with RIPE - Congestive heart failure with diuretics - Intravenous etilefrine ## Surgery Surgery is the mainstay of therapy for chylothorax. Surgery is recommended where despite conservative management, patient drains more than 1.5 l/day in an adult or >100 ml/kg body weight per day in a child, leaks chyle at >1 l/day× 5 days or has persistent chyle flow for >2 weeks. It is also recommended if there is a rapid decline in nutritional status despite conservative management.[2] [3][4][12][10][20][15][6][18][22] - Thoracentesis - Tube thoracostomy - Thoracoscopy - Pleurodesis with Talc Tetracycline Bleomycin Povidone - Talc - Tetracycline - Bleomycin - Povidone - Pleurectomy - pleuroperitoneal shunt - Thoracic duct ligation - Ligation of cisterna chyli - Lymphatic embolization ## Primary Prevention - There are no established measures for the primary prevention of chylothorax. ## Secondary Prevention - There are no established measures for the secondary prevention of chylothorax.	https://www.wikidoc.org/index.php/Chylothorax
074efbc062a7d7997fef1fcbd842ebb0fac3bc7e	wikidoc	Chymopapain	Chymopapain # Overview Chymopapain (EC 3.4.22.6, chymopapain A, chymopapain B, chymopapain S, brand name Chymodiactin) is a proteolytic enzyme isolated from the latex of papaya (Carica papaya). It is a medication used to treat herniated lower lumbar discs in the spine. Chymopapain injections are normally given under local, rather than general, anaesthesia. The dose for a single intervertebral disc is 2 to 4 nanokatals, with a maximum dose per patient of 8 nanokatals. The procedure is referred to as chemonucleolysis. The sale and distribution of chymopapain was discontinued in the United States on January 27, 2003 after the company producing it decided to stop selling worldwide. # Side effects Serious side effects from the use of chymopapain include anaphylaxis, paralysis of the legs, or death.	Chymopapain Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Chymopapain (EC 3.4.22.6, chymopapain A, chymopapain B, chymopapain S, brand name Chymodiactin) is a proteolytic enzyme isolated from the latex of papaya (Carica papaya). It is a medication used to treat herniated lower lumbar discs in the spine.[1] Chymopapain injections are normally given under local, rather than general, anaesthesia. The dose for a single intervertebral disc is 2 to 4 nanokatals, with a maximum dose per patient of 8 nanokatals. The procedure is referred to as chemonucleolysis. The sale and distribution of chymopapain was discontinued in the United States on January 27, 2003 after the company producing it decided to stop selling worldwide.[2][3] # Side effects Serious side effects from the use of chymopapain include anaphylaxis, paralysis of the legs, or death.[4]	https://www.wikidoc.org/index.php/Chymopapain
8e2f2532f770b49e823fb24133501e63aa67ce4e	wikidoc	Cilansetron	Cilansetron # Overview Cilansetron is a drug that is a 5HT-3 antagonist currently under trial phase in the EU and US it is manufactured by Solvay Pharmaceuticals INC. 5HT-3 receptors are responsible for causing many things from nausea to excess bowel movements. It is thought in conditions like irritable bowel syndrome (IBS) the receptors have become faulty or oversensitive. 5HT-3 antagonists work by blocking the nervous and chemical signals from reaching these receptors. Studies have shown that the drug can greatly improve quality of life in men and women with diahorrea predominant IBS (1) Cilansetron is the first 5HT antagonist specifically designed for IBS that is effective in men as well as women.(1) Solvay has had considerable difficulty with the medicines regulators in the UK, EU and USA with regards to licensing the drug. This could possibly be due to the problems discovered after licensing with the drug Lotronex. At time of writing; Solvay had recently withdrawn its application to the U.S. Food and Drug Administration (FDA) but was continuing its talks with the MHRA in the UK and EU regulators. (2) It is not currently known what sort of timeframe the public are looking at to be able to obtain the drug. This matter is not helped by the lack of information about cilansetron and its trials in the public domain. The regulators have also stated this in their responses. There is no information about future trials currently available. Some people have tried the Anti-emetic ondansetron HCl (Zofran) as a substitute for the time being, results are mixed but noted effect has been shown in some males and females (3) However; due to its license in the UK it is usually only prescribable at consultant level. Since the licensing of a generic version it is more likely an NHS prescription will be accepted as the branded version is very expensive (Official NHS pricing.) In the USA and Canada: availability often depends on insurance and the doctors personal opinion on off-label prescribing.	Cilansetron Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cilansetron is a drug that is a 5HT-3 antagonist currently under trial phase in the EU and US it is manufactured by Solvay Pharmaceuticals INC. 5HT-3 receptors are responsible for causing many things from nausea to excess bowel movements. It is thought in conditions like irritable bowel syndrome (IBS) the receptors have become faulty or oversensitive. 5HT-3 antagonists work by blocking the nervous and chemical signals from reaching these receptors. Studies have shown that the drug can greatly improve quality of life in men and women with diahorrea predominant IBS (1) Cilansetron is the first 5HT antagonist specifically designed for IBS that is effective in men as well as women.(1) Solvay has had considerable difficulty with the medicines regulators in the UK, EU and USA with regards to licensing the drug. This could possibly be due to the problems discovered after licensing with the drug Lotronex. At time of writing; Solvay had recently withdrawn its application to the U.S. Food and Drug Administration (FDA) but was continuing its talks with the MHRA in the UK and EU regulators. (2) It is not currently known what sort of timeframe the public are looking at to be able to obtain the drug. This matter is not helped by the lack of information about cilansetron and its trials in the public domain. The regulators have also stated this in their responses.[citation needed] There is no information about future trials currently available. Some people have tried the Anti-emetic ondansetron HCl (Zofran) as a substitute for the time being, results are mixed but noted effect has been shown in some males and females (3) However; due to its license in the UK it is usually only prescribable at consultant level. Since the licensing of a generic version it is more likely an NHS prescription will be accepted as the branded version is very expensive (Official NHS pricing.) In the USA and Canada: availability often depends on insurance and the doctors personal opinion on off-label prescribing.	https://www.wikidoc.org/index.php/Cilansetron
310944b0cf221026670e48dc9713d633ffa2b02e	wikidoc	Cilnidipine	Cilnidipine # Overview Cilnidipine (INN) is a calcium channel blocker. Clinidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved to come into market for the first time and used for high blood pressure treatment in 1995. Compared with other calcium antagonists, clinidipine can act on the N-type calcium-channel that existing sympathetic nerve end besides acting on L-type calcium-channel that similar to most of the calcium antagonists. # Medical Uses CILNIDIPINE due to its blocking action at N-type calcium channel dilates both arteriole & venules as a result the pressure in the capillary bed is reduces. It is used for hypertension management. # Lack of Supporting Data - Cilnidipine is not approved by US FDA. - Cilnidipine is backed by only 51 studies, compared to 1000s on other CCBs - Cilnidipine has only 197 studies ever done on it. - Patient count is very low for Cilnidipine. - Most of Cilnidipine data is based on Animal Testing. # Clinical Benifits Cilnidipine controls hypertension for 24 hours with once daily dose. Cilnidipine has enhanced lipophilicity leading to prolonged antihypertensive effect correlated with occupancy of the binding site. In 24 hour clinical assessment, once-daily administration of cilnidipine (5–20 mg) produced BP reduction for 24 hour period. This indicates that once-daily cilnidipine exerts a sufficient and prolonged reduction of BP. Cilnidipine has 50 times higher selectivity for N-type of calcium channels than amlodipine. The inhibitory effect on the N-type Ca2+channel may bestow an additional clinical advantage for the treatment of hypertension, such as suppression of reflex tachycardia. As catecholamines induce platelet activation via alpha 2-receptors on platelet membrane, decrease in norepinephrine level by cilnidipine causes attenuation of platelet activation.	Cilnidipine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cilnidipine (INN) is a calcium channel blocker. Clinidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved to come into market for the first time and used for high blood pressure treatment in 1995. Compared with other calcium antagonists, clinidipine can act on the N-type calcium-channel that existing sympathetic nerve end besides acting on L-type calcium-channel that similar to most of the calcium antagonists. # Medical Uses CILNIDIPINE due to its blocking action at N-type calcium channel dilates both arteriole & venules as a result the pressure in the capillary bed is reduces. It is used for hypertension management. # Lack of Supporting Data - Cilnidipine is not approved by US FDA. - Cilnidipine is backed by only 51 studies, compared to 1000s on other CCBs - Cilnidipine has only 197 studies ever done on it. - Patient count is very low for Cilnidipine. - Most of Cilnidipine data is based on Animal Testing. # Clinical Benifits Cilnidipine controls hypertension for 24 hours with once daily dose. Cilnidipine has enhanced lipophilicity leading to prolonged antihypertensive effect correlated with occupancy of the binding site. In 24 hour clinical assessment, once-daily administration of cilnidipine (5–20 mg) produced BP reduction for 24 hour period. This indicates that once-daily cilnidipine exerts a sufficient and prolonged reduction of BP. Cilnidipine has 50 times higher selectivity for N-type of calcium channels than amlodipine. The inhibitory effect on the N-type Ca2+channel may bestow an additional clinical advantage for the treatment of hypertension, such as suppression of reflex tachycardia. As catecholamines induce platelet activation via alpha 2-receptors on platelet membrane, decrease in norepinephrine level by cilnidipine causes attenuation of platelet activation.	https://www.wikidoc.org/index.php/Cilnidipine
2286d3a9e08ea844e925ab14b953c21ff02aff32	wikidoc	Cinnarizine	Cinnarizine # Overview Cinnarizine (trade names Stugeron, Stunarone, R5) is a drug derivative of piperazine, and characterized as an antihistamine and a calcium channel blocker, it is also known to promote cerebral blood flow, and so is used to treat cerebral apoplexy, post-trauma cerebral symptoms, and cerebral arteriosclerosis. However, it is more commonly prescribed for nausea and vomiting due to motion sickness or other sources such as chemotherapy, vertigo, or Ménière's disease. Cinnarizine was first synthesized by Janssen Pharmaceutica in 1955. The nonproprietary name is derived from the cinnamyl substituent on one of the nitrogen atoms, combined with the generic ending "-rizine" for "antihistaminics/cerebral (or peripheral) vasodilators". It is not available in the United States or Canada. It is manufactured and marketed in Bangladesh under the trade name Suzaraon by Rephco Pharmaceuticals Limited. It has also been cited as one of the most used drugs for seasickness within the British Royal Navy. # Pharmacokinetics Cinnarizine is most commonly taken orally, in pill form, with frequency and amount of dosage varying depending on the reason for taking the medication. Once ingested, the substance is absorbed quite rapidly and reaches a peak plasma concentration in 1–3 hours post-administration. Cmax, the maximum level of the drug in the tested area (typically blood plasma), has been measured to be 275 +/- 36 ng/mL, where tmax, the amount of time that the drug is present at the max amount in the blood, was 3.0 +/-0.5 hours. AUC∞, (the area under the curve extrapolated to infinity) which can be used to estimate bioavailability, was 4437 +/- 948 (ng.h/mL). The half-life elimination varies from 3.4–60 hours, depending on age. However, the mean terminal half-life elimination for young volunteer subjects administered 75 mg cinnarizine, was found to be 23.6 +/- 3.2 hours. A study that administered 75 mg doses of cinnarizine, twice a day for twelve days, to healthy volunteers, observed that cinnarizine did build up in the body, with a steady-state accumulation factor of 2.79 +/- 0.23. However, the AUCT for this amount of time (T=12 days) was not significantly different from the AUC∞, which was estimated from the single dose administration. As a very weakly basic and also lipophilic compound with low aqueous solubility, cinnarizine is able to cross the blood brain barrier by simple diffusion. It is because of this property that it is able to exert its effects on cerebral blood flow in the brain. Bioavailability of orally administered cinnarizine is typically low and variable due to high incidence of degradation. However, it has been found than when administered intravenously in lipid emulsion, better pharmacokinetics and tissue distribution were achieved. The lipid emulsion administration had a higher AUC and lower clearance than the solution form, which meant that there was an increased bioavailability of cinnarizine, allowing for an improved therapeutic effect. Plasma pharmacokinetics of cinnarizine administered intravenously follows a three-compartment model first with a fast distribution phase, followed by a slower distribution phase, and ending with a very slow elimination. The Vss (steady state apparent volume of distribution) for lipid emulsion administration was 2x lower (6.871+/- 1.432 L/kg) than that of cinnarizine given in solution (14.018 +/- 5.598 L/kg) and it was found that significantly less cinnarizine was taken up into the lung and brain in the lipid emulsion condition. This is significant because it would reduce the likelihood of toxic side effects in the central nervous system. # Pharmacodynamics Cinnarizine is classified as a selective antagonist of T-type voltage-operated calcium ion channels, because its binding blocks the channels and keeps them inert. It has a Ki (inhibitory constant) value of 22nM. It is also known to have antihistaminic, antiserotoninergic and antidopaminergic effects, binding to H1 histamine receptors, and dopaminergic (D2) receptors. The IC50 (half-maximal inhibitory concentration) of cinnarizine for smooth muscle contraction inhibition is 60mM and it has been shown that this drug preferentially binds to its target calcium channels when they are in an open, as opposed to closed conformation. In treatment of nausea and motion sickness it was previously hypothesized that cinnarizine exerts its effects by inhibiting the calcium currents in voltage gated channels in type II vestibular hair cells within the inner ear. However, more recent evidence supports the idea that at pharmacologically relevant levels (0.3µM–0.5µM), cinnarizine is not lessening vestibular vertigo by blocking calcium channels, but rather by inhibiting potassium (K+) currents that are activated by heightened hydrostatic pressure on the hair cells. It is true that cinnarizine does abolish calcium currents in vestibular hair cells as well; it is just that this only occurs at higher concentrations of drug (3µM). The inhibition of these currents works to lessen the vertigo and motion-induced nausea by dampening the over-reactivity of the vestibular hair cells, which send information about balance and motion to the brain. # Treatment Cinnarizine is predominantly used to treat nausea and vomiting associated with motion sickness, vertigo, Ménière's disease, or Cogan's syndrome. In fact, it is one of only a select few drugs that has shown a beneficial effect in the chronic treatment of the vertigo and tinnitus, associated with Meniere's disease. However, due to increased levels of drowsiness caused by the medication, it is generally of limited use in pilots and aircrew who must be dependably alert. In a clinical study (n=181), treatment with cinnarizine reduced the occurrence of moderate vertigo experience by 65.8% and extreme vertigo by 89.8%. It acts by interfering with the signal transmission between vestibular apparatus of the inner ear and the vomiting centre of the hypothalamus by limiting the activity of the vestibular hair cells which send signals about movement. The disparity of signal processing between inner ear motion receptors and the visual senses is abolished, so that the confusion of brain whether the individual is moving or standing is reduced. Vomiting in motion sickness could be a physiological compensatory mechanism of the brain to keep the individual from moving so that it can adjust to the signal perception, but the true evolutionary reason for this malady is currently unknown. Some sources state that the body reacts to vomit because it is under the belief that it has ingested poison(as in alcohol), as what you see does not collaborate with what you feel. When prescribed for balance problems and vertigo, cinnarizine is typically taken two or three times daily depending on the amount of each dose and when used to treat motion sickness, the pill is taken at least two hours before travelling and then again every four hours during travel. However, a recent 2012 study comparing the effects of cinnarizine to transdermal scopolamine for the treatment of seasickness, concluded that scopolamine was reported as significantly more effective and as having fewer adverse side effects than cinnarizine. This led to the conclusion that transdermal scopolamine is likely a better option for the treatment of motion sickness in naval crew and other sea travelers. Beyond an anti-vertigo treatment, cinnarizine could be also viewed as a nootropic drug because of its vasorelaxating abilities (due to calcium channel blockage), which happen mostly in brain and the fact that it is also used as a labyrinthine sedative. Cinnarizine inhibits the flow of calcium into red blood cells, which increases the elasticity of the cell wall, thereby increasing their flexibility and making the blood less viscous. This allows the blood to travel more efficiently and effectively through narrowed vessels in order to bring oxygen to damaged tissue. It is also effectively combined with other nootropics, primarily Piracetam; in such combination each drug potentiates the other in boosting brain oxygen supply. An animal study comparing the effectiveness of cinnarizine and flunarizine (a derivative of cinnarizine that is 2.5-15 times stronger for treatment of transient global cerebral ischemia, it was found that cinnarizine helped to improve the functional abnormalities of ischemia, but did not help with damage to the neurons. Flunarizine, on the other hand, offered more neuronal protection, but was less effective in treating subsequent behavioral changes. Additionally, cinnarizine can be used in scuba divers without an increased risk of central nervous system oxygen toxicity which can result in seizures, and is a high risk in closed-circuit oxygen diving. This is also relevant to divers who could potentially have to undergo hypobaric decompression therapy, which uses high oxygen pressure and could also be affected by any cinnarizine-induced CNS oxygen toxicity risk. However, cinnarizine does not heighten toxicity risk, and in fact, evidence even seems to suggest that cinnarizine may be beneficial in helping delay O2 toxicity in the central nervous system. There is also evidence that cinnarizine may be used as an effective anti-asthma medication when taken regularly. Cinnarizine has also been found to be a valuable second-line treatment for idiopathic urticarial vasculitis. # Side effects Side effects experienced while taking cinnarizine range from the mild to the quite severe. Possible side effects include drowsiness, sweating, dry mouth, headache, skin problems, lethargy, gastrointestinal irritation, hypersensitivity reactions, as well as movement problems/muscle rigidity, and tremor. Because cinnarizine can cause drowsiness and blurred vision, it is important that users make sure their reactions are normal before driving, operating machinery, or doing any other jobs which could be dangerous if they are not fully alert or able to see well. Cinnarizine is also known to cause acute and chronic parkinsonism due to its affinity for D2 receptors, which strongly counter-suggests its actual usefulness for improving neurohealth. Cinnarizine's antagonistic effects of D2 dopamine receptors in the striatum leads to symptoms of depression, tremor, muscle rigidity, tardive dyskinesia, and akathisia, which are characterized as Drug-Induced Parkinson's disease and is the second leading cause of Parkinson's. Evidence suggests that it is one of the metabolites of cinnarizine, C-2, that has an active role in contributing to the development of drug-induced Parkinson's. It is also of note that an estimated 17 of 100 new Parkinson's cases are linked to administration of either cinnarizine or Flunarizine, making cinnarizine and drug-induced Parkinson's a serious issue. Those people especially at risk are elderly patients, in particular women, and patients who have been taking the drug for a longer amount of time. There is also evidence that suggests that patients with a family history of Parkinson's, or a genetic predispostion to the disease are more likely to develop the drug induced form of this disease as a result of cinnarizine treatment. In addition to antagonizing D2 receptors, treatment with cinnarizine has also been shown to lead to reduced presynaptic dopamine and serotonin, as well as alterations in vesicular transport of dopamine. Terland et al. have shown that chronic treatment with cinnarizine builds the drug concentrations high enough that they interfere with the proton electrochemical gradient necessary for packaging dopamine into vesicles. Cinnarizine, pKa = 7.4, acts as a protonophore, which prevents the MgATP-dependent production of the electrochemical gradient crucial to the transport and storage of dopamine into vesicles, and thereby lowers the levels of dopamine in the basal ganglia neurons and leads to the Parkinson's symptoms. Additionally, several cases of pediatric and adult cinnarizine overdose have been reported, with effects including a range of symptoms such as somnolence, coma, vomiting, hypotonia, stupor, and convulsions. The cognitive complications likely result from the antihistaminic effects of cinnarizine, while the motor effects are a product of the antidopaminergic properties. In cases of overdose, the patient should be brought to and observed in a hospital for potential neurological complications. # Elimination After administration, cinnarizine is completely metabolized within the body and the metabolites are eliminated by one third in the urine and two thirds in solid waste.	Cinnarizine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cinnarizine (trade names Stugeron, Stunarone, R5) is a drug derivative of piperazine, and characterized as an antihistamine and a calcium channel blocker,[1] it is also known to promote cerebral blood flow, and so is used to treat cerebral apoplexy, post-trauma cerebral symptoms, and cerebral arteriosclerosis.[2] However, it is more commonly prescribed for nausea and vomiting due to motion sickness [3] or other sources such as chemotherapy,[4] vertigo,[5] or Ménière's disease.[6] Cinnarizine was first synthesized by Janssen Pharmaceutica in 1955. The nonproprietary name is derived from the cinnamyl substituent on one of the nitrogen atoms, combined with the generic ending "-rizine" for "antihistaminics/cerebral (or peripheral) vasodilators".[7] It is not available in the United States or Canada. It is manufactured and marketed in Bangladesh under the trade name Suzaraon by Rephco Pharmaceuticals Limited. It has also been cited as one of the most used drugs for seasickness within the British Royal Navy.[8] # Pharmacokinetics Cinnarizine is most commonly taken orally, in pill form, with frequency and amount of dosage varying depending on the reason for taking the medication. Once ingested, the substance is absorbed quite rapidly and reaches a peak plasma concentration in 1–3 hours post-administration.[9][10][11] Cmax, the maximum level of the drug in the tested area (typically blood plasma), has been measured to be 275 +/- 36 ng/mL, where tmax, the amount of time that the drug is present at the max amount in the blood, was 3.0 +/-0.5 hours.[10] AUC∞, (the area under the curve extrapolated to infinity) which can be used to estimate bioavailability, was 4437 +/- 948 (ng.h/mL).[10] The half-life elimination varies from 3.4–60 hours, depending on age.[11] However, the mean terminal half-life elimination for young volunteer subjects administered 75 mg cinnarizine, was found to be 23.6 +/- 3.2 hours.[10] A study that administered 75 mg doses of cinnarizine, twice a day for twelve days, to healthy volunteers, observed that cinnarizine did build up in the body, with a steady-state accumulation factor of 2.79 +/- 0.23.[10] However, the AUCT for this amount of time (T=12 days) was not significantly different from the AUC∞, which was estimated from the single dose administration. As a very weakly basic and also lipophilic compound with low aqueous solubility, cinnarizine is able to cross the blood brain barrier by simple diffusion.[12][13] It is because of this property that it is able to exert its effects on cerebral blood flow in the brain.[14] Bioavailability of orally administered cinnarizine is typically low and variable due to high incidence of degradation.[13] However, it has been found than when administered intravenously in lipid emulsion, better pharmacokinetics and tissue distribution were achieved.[15] The lipid emulsion administration had a higher AUC and lower clearance than the solution form, which meant that there was an increased bioavailability of cinnarizine, allowing for an improved therapeutic effect.[15] Plasma pharmacokinetics of cinnarizine administered intravenously follows a three-compartment model first with a fast distribution phase, followed by a slower distribution phase, and ending with a very slow elimination.[15] The Vss (steady state apparent volume of distribution) for lipid emulsion administration was 2x lower (6.871+/- 1.432 L/kg) than that of cinnarizine given in solution (14.018 +/- 5.598 L/kg) and it was found that significantly less cinnarizine was taken up into the lung and brain in the lipid emulsion condition.[15] This is significant because it would reduce the likelihood of toxic side effects in the central nervous system. # Pharmacodynamics Cinnarizine is classified as a selective antagonist of T-type voltage-operated calcium ion channels, because its binding blocks the channels and keeps them inert.[16][17] It has a Ki (inhibitory constant) value of 22nM.[18] It is also known to have antihistaminic, antiserotoninergic and antidopaminergic effects,[16] binding to H1 histamine receptors, and dopaminergic (D2) receptors.[19] The IC50 (half-maximal inhibitory concentration) of cinnarizine for smooth muscle contraction inhibition is 60mM[20] and it has been shown that this drug preferentially binds to its target calcium channels when they are in an open, as opposed to closed conformation.[21] In treatment of nausea and motion sickness it was previously hypothesized that cinnarizine exerts its effects by inhibiting the calcium currents in voltage gated channels in type II vestibular hair cells within the inner ear.[6] However, more recent evidence supports the idea that at pharmacologically relevant levels (0.3µM–0.5µM), cinnarizine is not lessening vestibular vertigo by blocking calcium channels, but rather by inhibiting potassium (K+) currents that are activated by heightened hydrostatic pressure on the hair cells.[22] It is true that cinnarizine does abolish calcium currents in vestibular hair cells as well; it is just that this only occurs at higher concentrations of drug (3µM).[22] The inhibition of these currents works to lessen the vertigo and motion-induced nausea by dampening the over-reactivity of the vestibular hair cells, which send information about balance and motion to the brain. # Treatment Cinnarizine is predominantly used to treat nausea and vomiting associated with motion sickness,[3] vertigo,[5] Ménière's disease,[6] or Cogan's syndrome.[17] In fact, it is one of only a select few drugs that has shown a beneficial effect in the chronic treatment of the vertigo and tinnitus, associated with Meniere's disease.[24] However, due to increased levels of drowsiness caused by the medication, it is generally of limited use in pilots and aircrew who must be dependably alert.[3] In a clinical study (n=181), treatment with cinnarizine reduced the occurrence of moderate vertigo experience by 65.8% and extreme vertigo by 89.8%.[5] It acts by interfering with the signal transmission between vestibular apparatus of the inner ear and the vomiting centre of the hypothalamus by limiting the activity of the vestibular hair cells which send signals about movement.[22] The disparity of signal processing between inner ear motion receptors and the visual senses is abolished, so that the confusion of brain whether the individual is moving or standing is reduced. Vomiting in motion sickness could be a physiological compensatory mechanism of the brain to keep the individual from moving so that it can adjust to the signal perception, but the true evolutionary reason for this malady is currently unknown.[25] Some sources state that the body reacts to vomit because it is under the belief that it has ingested poison(as in alcohol), as what you see does not collaborate with what you feel. When prescribed for balance problems and vertigo, cinnarizine is typically taken two or three times daily depending on the amount of each dose and when used to treat motion sickness, the pill is taken at least two hours before travelling and then again every four hours during travel.[26] However, a recent 2012 study comparing the effects of cinnarizine to transdermal scopolamine for the treatment of seasickness, concluded that scopolamine was reported as significantly more effective and as having fewer adverse side effects than cinnarizine.[27] This led to the conclusion that transdermal scopolamine is likely a better option for the treatment of motion sickness in naval crew and other sea travelers. Beyond an anti-vertigo treatment, cinnarizine could be also viewed as a nootropic drug because of its vasorelaxating abilities (due to calcium channel blockage), which happen mostly in brain and the fact that it is also used as a labyrinthine sedative.[28][29] Cinnarizine inhibits the flow of calcium into red blood cells, which increases the elasticity of the cell wall, thereby increasing their flexibility and making the blood less viscous.[17] This allows the blood to travel more efficiently and effectively through narrowed vessels in order to bring oxygen to damaged tissue.[17] It is also effectively combined with other nootropics, primarily Piracetam; in such combination each drug potentiates the other in boosting brain oxygen supply.[30] An animal study comparing the effectiveness of cinnarizine and flunarizine (a derivative of cinnarizine that is 2.5-15 times stronger [31] for treatment of transient global cerebral ischemia, it was found that cinnarizine helped to improve the functional abnormalities of ischemia, but did not help with damage to the neurons.[32] Flunarizine, on the other hand, offered more neuronal protection, but was less effective in treating subsequent behavioral changes.[32] Additionally, cinnarizine can be used in scuba divers without an increased risk of central nervous system oxygen toxicity which can result in seizures, and is a high risk in closed-circuit oxygen diving.[33] This is also relevant to divers who could potentially have to undergo hypobaric decompression therapy, which uses high oxygen pressure and could also be affected by any cinnarizine-induced CNS oxygen toxicity risk. However, cinnarizine does not heighten toxicity risk, and in fact, evidence even seems to suggest that cinnarizine may be beneficial in helping delay O2 toxicity in the central nervous system.[33] There is also evidence that cinnarizine may be used as an effective anti-asthma medication when taken regularly.[34] Cinnarizine has also been found to be a valuable second-line treatment for idiopathic urticarial vasculitis.[35] # Side effects Side effects experienced while taking cinnarizine range from the mild to the quite severe. Possible side effects include drowsiness, sweating, dry mouth, headache, skin problems, lethargy, gastrointestinal irritation, hypersensitivity reactions, as well as movement problems/muscle rigidity, and tremor.[26] Because cinnarizine can cause drowsiness and blurred vision, it is important that users make sure their reactions are normal before driving, operating machinery, or doing any other jobs which could be dangerous if they are not fully alert or able to see well.[3] Cinnarizine is also known to cause acute and chronic parkinsonism [31] due to its affinity for D2 receptors, which strongly counter-suggests its actual usefulness for improving neurohealth. Cinnarizine's antagonistic effects of D2 dopamine receptors in the striatum leads to symptoms of depression, tremor, muscle rigidity, tardive dyskinesia, and akathisia, which are characterized as Drug-Induced Parkinson's disease and is the second leading cause of Parkinson's.[31] Evidence suggests that it is one of the metabolites of cinnarizine, C-2, that has an active role in contributing to the development of drug-induced Parkinson's.[19] It is also of note that an estimated 17 of 100 new Parkinson's cases are linked to administration of either cinnarizine or Flunarizine,[1] making cinnarizine and drug-induced Parkinson's a serious issue. Those people especially at risk are elderly patients, in particular women, and patients who have been taking the drug for a longer amount of time.[16] There is also evidence that suggests that patients with a family history of Parkinson's, or a genetic predispostion to the disease are more likely to develop the drug induced form of this disease as a result of cinnarizine treatment.[36] In addition to antagonizing D2 receptors, treatment with cinnarizine has also been shown to lead to reduced presynaptic dopamine and serotonin, as well as alterations in vesicular transport of dopamine.[1] Terland et al.[1] have shown that chronic treatment with cinnarizine builds the drug concentrations high enough that they interfere with the proton electrochemical gradient necessary for packaging dopamine into vesicles. Cinnarizine, pKa = 7.4, acts as a protonophore, which prevents the MgATP-dependent production of the electrochemical gradient crucial to the transport and storage of dopamine into vesicles, and thereby lowers the levels of dopamine in the basal ganglia neurons and leads to the Parkinson's symptoms.[1] Additionally, several cases of pediatric and adult cinnarizine overdose have been reported, with effects including a range of symptoms such as somnolence, coma, vomiting, hypotonia, stupor, and convulsions.[37] The cognitive complications likely result from the antihistaminic effects of cinnarizine, while the motor effects are a product of the antidopaminergic properties. In cases of overdose, the patient should be brought to and observed in a hospital for potential neurological complications. # Elimination After administration, cinnarizine is completely metabolized within the body and the metabolites are eliminated by one third in the urine and two thirds in solid waste.[17]	https://www.wikidoc.org/index.php/Cinnarizine
848928d60a13f059bc423f718cc50be085017395	wikidoc	Cinolazepam	Cinolazepam # Overview Cinolazepam (marketed under the brand name Gerodorm) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Due to its strong sedative properties, it is primarily used as an hypnotic. Cinolazepam is not approved for sale in the United States or Canada.	Cinolazepam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cinolazepam[1] (marketed under the brand name Gerodorm)[2] is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Due to its strong sedative properties, it is primarily used as an hypnotic. Cinolazepam is not approved for sale in the United States or Canada.	https://www.wikidoc.org/index.php/Cinolazepam
01d21f1e62cbb2a38b78b21f38d5731fc5a54364	wikidoc	Citric acid	Citric acid Citric acid is a weak organic acid found in citrus fruits. It is a natural preservative and is also used to add an acidic (sour) taste to foods and soft drinks. In biochemistry, it is important as an intermediate in the citric acid cycle and therefore occurs in the metabolism of almost all living things. It also serves as an environmentally benign cleaning agent and acts as an antioxidant. Citric acid exists in a variety of fruits and vegetables, but it is most concentrated in lemons and limes, where it can comprise as much as 8% of the dry weight of the fruit. # Properties At room temperature, citric acid is a white crystalline powder. It can exist either in an anhydrous (water-free) form, or as a monohydrate. The anhydrous form crystallizes from hot water, while the monohydrate forms when citric acid is crystallized from cold water. The monohydrate can be converted to the anhydrous form by heating it above 74 °C. Citric acid also dissolves in absolute (anhydrous) ethanol (76 parts of citric acid per 100 parts of ethanol) at 15 degrees Celsius. Chemically, citric acid shares the properties of other carboxylic acids. When heated above 175 °C, it decomposes through the loss of carbon dioxide and water. # History The discovery of citric acid has been credited to the 8th century alchemist Jabir Ibn Hayyan (Geber). Medieval scholars in Europe were aware of the acidic nature of lemon and lime juices; such knowledge is recorded in the 13th century encyclopedia Speculum Majus (The Great Mirror), compiled by Vincent of Beauvais. Citric acid was first isolated in 1784 by the Swedish chemist Carl Wilhelm Scheele, who crystallized it from lemon juice. Industrial-scale citric acid production began in 1860, based on the Italian citrus fruit industry. In 1893, C. Wehmer discovered that Penicillium mold could produce citric acid from sugar. However, microbial production of citric acid did not become industrially important until World War I disrupted Italian citrus exports. In 1917, the American food chemist James Currie discovered that certain strains of the mold Aspergillus niger could be efficient citric acid producers, and Pfizer began industrial-level production using this technique two years later. # Production In this production technique, which is still the major industrial route to citric acid used today, cultures of Aspergillus niger are fed on a sucrose or glucose-containing medium to produce citric acid. The source of sugar is corn steep liquor, molasses, hydrolyzed corn starch or other inexpensive sugary solutions. After the mold is filtered out of the resulting solution, citric acid is isolated by precipitating it with lime (calcium hydroxide) to yield calcium citrate salt, from which citric acid is regenerated by treatment with sulfuric acid. # Krebs cycle Citric acid is one of a series of compounds involved in the physiological oxidation of fats, proteins, and carbohydrates to carbon dioxide and water. This series of chemical reactions is central to nearly all metabolic reactions, and is the source of two-thirds of the food-derived energy in higher organisms. It was discovered by the Sir Hans Adolf Krebs. Krebs received the 1953 Nobel Prize in Physiology or Medicine for the discovery. The series of reactions is known by various names, including the citric acid cycle, the Krebs cycle, and the tricarboxylic acid cycle (or TCA cycle). # Uses ## Food additive As a food additive, citric acid is used as a flavouring and preservative in food and beverages, especially soft drinks. It is denoted by E number E330. Citrate salts of various metals are used to deliver those minerals in a biologically available form in many dietary supplements. The buffering properties of citrates are used to control pH in household cleaners and pharmaceuticals. In the United States the purity requirements for citric acid as a food additive is defined by the Food Chemical Codex (FCC), which is published by the United States Pharmacopoeia (USP). ## Water softening Citric acid's ability to chelate metals makes it useful in soaps and laundry detergents. By chelating the metals in hard water, it lets these cleaners produce foam and work better without need for water softening. Similarly, citric acid is used to regenerate the ion exchange materials used in water softeners by stripping off the accumulated metal ions as citrate complexes. ## Others Citric acid is used in the biotechnology and pharmaceutical industry to passivate high purity process piping (in lieu of using nitric acid). Nitric acid is considered hazardous to dispose once used for this purpose, while citric acid is not. Citric acid is the active ingredient in some bathroom and kitchen cleaning solutions. A solution with a 6% concentration of citric acid will remove hard water stains from glass without scrubbing. In industry it is used to dissolve rust from steel. Citric acid is commonly used as a buffer to increase the solubility of brown heroin. Single-use citric acid sachets have been used as an inducement to get heroin users to exchange their dirty needles for clean needles in an attempt to decrease the spread of AIDS and hepatitis. Other acidifiers used for brown heroin are ascorbic acid, acetic acid, and lactic acid; in their absence, a drug user will often substitute lemon juice or vinegar. Citric acid is one of the chemicals required for the synthesis of HMTD, a highly heat-, friction-, and shock-sensitive explosive similar to acetone peroxide. Purchases of large quantities of citric acid may rouse suspicion of potential terrorist activity. Citric acid can be added to ice cream to keep fat globules separate, and can be added to recipes in place of fresh lemon juice as well. Citric acid is used along with sodium bicarbonate in a wide range of effervescent formulae, both for ingestion (e.g., powders and tablets) and for personal care (e.g., bath salts, bath bombs, and cleaning of grease). When applied to hair, citric acid opens up the outer layer, also known as the cuticle. While the cuticle is open, it allows for a deeper penetration into the hair shaft. It can be used in shampoo to wash out wax and coloring from the hair. It is notably used in the product "Sun-in" for bleaching, but is generally not recommended due to the amount of damage it causes. Citric acid is also used as a stop bath in photography. The developer is normally alkaline, so a mild acid will neutralize it, increasing the effectiveness of the stop bath when compared to plain water. # Safety Citric acid is recognized as safe for use in food by all major national and international food regulatory agencies. It is naturally present in almost all forms of life, and excess citric acid is readily metabolized and eliminated from the body. Interestingly, despite its ubiquity in the body, intolerance to citric acid in the diet is known to exist. Little information is available as the condition appears to be rare, but like other types of food intolerance it is often described as a "pseudo-allergic" reaction. Contact with dry citric acid or with concentrated solutions can result in skin and eye irritation, so protective clothing should be worn when handling these materials. Excessive consumption is capable of eroding the tooth enamel. Close contact to the eyes can cause a slight burning sensation, and may cause loss of sight. ## Cancer claims There have been erroneous reports that E330 is a major cause of cancer. It is thought that this has been brought about by misunderstanding and confusion over the word Krebs. In this case, it refers to Sir Hans Adolf Krebs, discoverer of the Krebs cycle, and not the German word for cancer. Citric acid is not known to be harmful to the body when taken alone.	Citric acid Template:Chembox new Citric acid is a weak organic acid found in citrus fruits. It is a natural preservative and is also used to add an acidic (sour) taste to foods and soft drinks. In biochemistry, it is important as an intermediate in the citric acid cycle and therefore occurs in the metabolism of almost all living things. It also serves as an environmentally benign cleaning agent and acts as an antioxidant. Citric acid exists in a variety of fruits and vegetables, but it is most concentrated in lemons and limes, where it can comprise as much as 8% of the dry weight of the fruit. # Properties At room temperature, citric acid is a white crystalline powder. It can exist either in an anhydrous (water-free) form, or as a monohydrate. The anhydrous form crystallizes from hot water, while the monohydrate forms when citric acid is crystallized from cold water. The monohydrate can be converted to the anhydrous form by heating it above 74 °C. Citric acid also dissolves in absolute (anhydrous) ethanol (76 parts of citric acid per 100 parts of ethanol) at 15 degrees Celsius. Chemically, citric acid shares the properties of other carboxylic acids. When heated above 175 °C, it decomposes through the loss of carbon dioxide and water. # History The discovery of citric acid has been credited to the 8th century alchemist Jabir Ibn Hayyan (Geber). Medieval scholars in Europe were aware of the acidic nature of lemon and lime juices; such knowledge is recorded in the 13th century encyclopedia Speculum Majus (The Great Mirror), compiled by Vincent of Beauvais. Citric acid was first isolated in 1784 by the Swedish chemist Carl Wilhelm Scheele, who crystallized it from lemon juice. Industrial-scale citric acid production began in 1860, based on the Italian citrus fruit industry. In 1893, C. Wehmer discovered that Penicillium mold could produce citric acid from sugar. However, microbial production of citric acid did not become industrially important until World War I disrupted Italian citrus exports. In 1917, the American food chemist James Currie discovered that certain strains of the mold Aspergillus niger could be efficient citric acid producers, and Pfizer began industrial-level production using this technique two years later. # Production In this production technique, which is still the major industrial route to citric acid used today, cultures of Aspergillus niger are fed on a sucrose or glucose-containing medium to produce citric acid. The source of sugar is corn steep liquor,[1] molasses, hydrolyzed corn starch or other inexpensive sugary solutions.[2] After the mold is filtered out of the resulting solution, citric acid is isolated by precipitating it with lime (calcium hydroxide) to yield calcium citrate salt, from which citric acid is regenerated by treatment with sulfuric acid. # Krebs cycle Citric acid is one of a series of compounds involved in the physiological oxidation of fats, proteins, and carbohydrates to carbon dioxide and water. This series of chemical reactions is central to nearly all metabolic reactions, and is the source of two-thirds of the food-derived energy in higher organisms. It was discovered by the Sir Hans Adolf Krebs. Krebs received the 1953 Nobel Prize in Physiology or Medicine for the discovery. The series of reactions is known by various names, including the citric acid cycle, the Krebs cycle, and the tricarboxylic acid cycle (or TCA cycle). # Uses ## Food additive As a food additive, citric acid is used as a flavouring and preservative in food and beverages, especially soft drinks. It is denoted by E number E330. Citrate salts of various metals are used to deliver those minerals in a biologically available form in many dietary supplements. The buffering properties of citrates are used to control pH in household cleaners and pharmaceuticals. In the United States the purity requirements for citric acid as a food additive is defined by the Food Chemical Codex (FCC), which is published by the United States Pharmacopoeia (USP). ## Water softening Citric acid's ability to chelate metals makes it useful in soaps and laundry detergents. By chelating the metals in hard water, it lets these cleaners produce foam and work better without need for water softening. Similarly, citric acid is used to regenerate the ion exchange materials used in water softeners by stripping off the accumulated metal ions as citrate complexes. ## Others Citric acid is used in the biotechnology and pharmaceutical industry to passivate high purity process piping (in lieu of using nitric acid). Nitric acid is considered hazardous to dispose once used for this purpose, while citric acid is not. Citric acid is the active ingredient in some bathroom and kitchen cleaning solutions. A solution with a 6% concentration of citric acid will remove hard water stains from glass without scrubbing. In industry it is used to dissolve rust from steel.[3] Citric acid is commonly used as a buffer to increase the solubility of brown heroin. Single-use citric acid sachets have been used as an inducement to get heroin users to exchange their dirty needles for clean needles in an attempt to decrease the spread of AIDS and hepatitis[4]. Other acidifiers used for brown heroin are ascorbic acid, acetic acid, and lactic acid; in their absence, a drug user will often substitute lemon juice or vinegar. Citric acid is one of the chemicals required for the synthesis of HMTD, a highly heat-, friction-, and shock-sensitive explosive similar to acetone peroxide. Purchases of large quantities of citric acid may rouse suspicion of potential terrorist activity. Citric acid can be added to ice cream to keep fat globules separate, and can be added to recipes in place of fresh lemon juice as well. Citric acid is used along with sodium bicarbonate in a wide range of effervescent formulae, both for ingestion (e.g., powders and tablets) and for personal care (e.g., bath salts, bath bombs, and cleaning of grease). When applied to hair, citric acid opens up the outer layer, also known as the cuticle. While the cuticle is open, it allows for a deeper penetration into the hair shaft. It can be used in shampoo to wash out wax and coloring from the hair. It is notably used in the product "Sun-in" for bleaching, but is generally not recommended due to the amount of damage it causes. Citric acid is also used as a stop bath in photography. The developer is normally alkaline, so a mild acid will neutralize it, increasing the effectiveness of the stop bath when compared to plain water.[5] # Safety Citric acid is recognized as safe for use in food by all major national and international food regulatory agencies. It is naturally present in almost all forms of life, and excess citric acid is readily metabolized and eliminated from the body. Interestingly, despite its ubiquity in the body, intolerance to citric acid in the diet is known to exist.[citation needed] Little information is available as the condition appears to be rare, but like other types of food intolerance it is often described as a "pseudo-allergic" reaction. Contact with dry citric acid or with concentrated solutions can result in skin and eye irritation, so protective clothing should be worn when handling these materials. Excessive consumption is capable of eroding the tooth enamel. Close contact to the eyes can cause a slight burning sensation, and may cause loss of sight. ## Cancer claims There have been erroneous reports that E330 is a major cause of cancer. It is thought that this has been brought about by misunderstanding and confusion over the word Krebs. In this case, it refers to Sir Hans Adolf Krebs, discoverer of the Krebs cycle, and not the German word for cancer. Citric acid is not known to be harmful to the body when taken alone.	https://www.wikidoc.org/index.php/Citric_Acid
0e750fe495dcd9d46442d54896020d12511fad44	wikidoc	Citrobacter	Citrobacter # Overview Citrobacter is a genus of Gram-negative coliform bacteria in the Enterobacteriaceae family. They are rarely the source of illnesses, except for infections of the urinary tract and infant meningitis and sepsis. # Organism - Citrobacter is a genus of gram-negative Coliform bacteria in the Enterobacteriaceae family. - The species C. amalonaticus, C. koseri, and C. freundii use solely citrate as a carbon source. These bacteria can be found almost everywhere in soil, water, wastewater, etc. It can also be found in the human intestine. They are rarely the source of illnesses, except for infections of the urinary tract and infant meningitis. - Citrobacter shows the ability to accumulate uranium by building phosphate complexes. ## Citrobacter freundi - Citrobacter freundi is a species of facultative. aerobic. Gram-negative bacilli of the Enterobacteriaceae family. The bacteria are long rod-shaped with a typical length of 1–5 μm. Most C. freundii cells are surrounded by several flagella used for locomotion, but a few are not mobile. It can be found in soil, water, sewage, food, and the intestinal tracts of animals and humans. The Citrobacter genus was discovered in 1932 by Werkman and Gillen. Cultures of C. freundii were isolated and identified in the same year from soil extracts. - As an opportunistic pathogen, C. freundii is responsible for a number of significant infections. It is known to be the cause of a number of nosocomial infections of the respiratory tract, urinary tract, blood, and many other normally sterile sites in patients. C. freundii represents about 29% of all opportunistic infections. - Surprisingly, this infectious microbe in humans plays a positive role in the environment. C. freundii is responsible for reducing nitrate to nitrite in the environment. This conversion is an important and crucial stage in the nitrogen cycle. These bacteria also help in recycling nitrogen. - C. freundii has also been investigated for biodegradation of tannic acid used in tanneries. - For metabolism, C. freundii has an ability to grow on glycerol as the sole carbon and energy source. Within its cell, a bacterial microcompartment can be found, which is capable of processing propanediol. ## Antimicrobial regimen - Citrobacter freundii - Preferred regimen (1): Meropenem 1-2 g IV q8h - Preferred regimen (2): Imipenem 1 g IV q6h - Preferred regimen (3): Doripenem 500 mg IV q8h - Preferred regimen (4): Cefepime 1-2 g IV q8h - Preferred regimen (5): Ciprofloxacin 400 mg IV q12h or 500 mg PO bid for UTI - Preferred regimen (6): Gentamicin 5 mg/kg IV q24h - Alternative regimen (1): Piperacillin-tazobactam 3.375 mg IV q6h - Alternative regimen (2): Aztreonam 1-2 g IV q6h - Alternative regimen (3): TMP-SMX 5 mg/kg q6h IV or DS PO bid for UTI - Note: Usually Carbenicillin sensitive, Cephalothin resistant - Citrobacter koseri - Preferred regimen (1): Ceftriaxone 1-2 g IV q12-24h - Preferred regimen (2): Cefotaxime 1-2 g IV q6h - Preferred regimen (3): Cefepime 1-2 IV q8h - Alternative regimen (1): Ciprofloxacin 400 mg IV q12h or 500 mg PO q12h for UTI - Alternative regimen (2): Imipenem 1 g IV q6h - Alternative regimen (3): Doripenem 500 mg IV q8h - Alternative regimen (4): Meropenem 1-2 g IV q8h - Alternative regimen (5): Aztreonam 1-2 g IV q6h - Alternative regimen (6): TMP-SMX 5 mg/kg IV q6h or DS PO bid for UTI - Note: Usually Ampicillin resistant, but may be sensitive to first generation cephalosporins. # Gallery - Triple sugar iron agar (TSI) tested for Salmonella (H2S+) and (H2S-); Citrobacter sp. and S. arizonae. From Public Health Image Library (PHIL).	Citrobacter Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Citrobacter is a genus of Gram-negative coliform bacteria in the Enterobacteriaceae family. They are rarely the source of illnesses, except for infections of the urinary tract and infant meningitis and sepsis.[1][2] # Organism - Citrobacter is a genus of gram-negative Coliform bacteria in the Enterobacteriaceae family. - The species C. amalonaticus, C. koseri, and C. freundii use solely citrate as a carbon source. These bacteria can be found almost everywhere in soil, water, wastewater, etc. It can also be found in the human intestine. They are rarely the source of illnesses, except for infections of the urinary tract and infant meningitis. - Citrobacter shows the ability to accumulate uranium by building phosphate complexes.[3] ## Citrobacter freundi - Citrobacter freundi is a species of facultative. aerobic. Gram-negative bacilli of the Enterobacteriaceae family.[4] The bacteria are long rod-shaped with a typical length of 1–5 μm.[5] Most C. freundii cells are surrounded by several flagella used for locomotion, but a few are not mobile. It can be found in soil, water, sewage, food, and the intestinal tracts of animals and humans.[5] The Citrobacter genus was discovered in 1932 by Werkman and Gillen. Cultures of C. freundii were isolated and identified in the same year from soil extracts.[5] - As an opportunistic pathogen, C. freundii is responsible for a number of significant infections. It is known to be the cause of a number of nosocomial infections of the respiratory tract, urinary tract, blood, and many other normally sterile sites in patients.[6] C. freundii represents about 29% of all opportunistic infections.[6] - Surprisingly, this infectious microbe in humans plays a positive role in the environment. C. freundii is responsible for reducing nitrate to nitrite in the environment.[7] This conversion is an important and crucial stage in the nitrogen cycle. These bacteria also help in recycling nitrogen.[7] - C. freundii has also been investigated for biodegradation of tannic acid used in tanneries.[7] - For metabolism, C. freundii has an ability to grow on glycerol as the sole carbon and energy source. Within its cell, a bacterial microcompartment can be found, which is capable of processing propanediol.[8] ## Antimicrobial regimen - Citrobacter freundii[9] - Preferred regimen (1): Meropenem 1-2 g IV q8h - Preferred regimen (2): Imipenem 1 g IV q6h - Preferred regimen (3): Doripenem 500 mg IV q8h - Preferred regimen (4): Cefepime 1-2 g IV q8h - Preferred regimen (5): Ciprofloxacin 400 mg IV q12h or 500 mg PO bid for UTI - Preferred regimen (6): Gentamicin 5 mg/kg IV q24h - Alternative regimen (1): Piperacillin-tazobactam 3.375 mg IV q6h - Alternative regimen (2): Aztreonam 1-2 g IV q6h - Alternative regimen (3): TMP-SMX 5 mg/kg q6h IV or DS PO bid for UTI - Note: Usually Carbenicillin sensitive, Cephalothin resistant - Citrobacter koseri[10] - Preferred regimen (1): Ceftriaxone 1-2 g IV q12-24h - Preferred regimen (2): Cefotaxime 1-2 g IV q6h - Preferred regimen (3): Cefepime 1-2 IV q8h - Alternative regimen (1): Ciprofloxacin 400 mg IV q12h or 500 mg PO q12h for UTI - Alternative regimen (2): Imipenem 1 g IV q6h - Alternative regimen (3): Doripenem 500 mg IV q8h - Alternative regimen (4): Meropenem 1-2 g IV q8h - Alternative regimen (5): Aztreonam 1-2 g IV q6h - Alternative regimen (6): TMP-SMX 5 mg/kg IV q6h or DS PO bid for UTI - Note: Usually Ampicillin resistant, but may be sensitive to first generation cephalosporins. # Gallery - Triple sugar iron agar (TSI) tested for Salmonella (H2S+) and (H2S-); Citrobacter sp. and S. arizonae. From Public Health Image Library (PHIL). [11]	https://www.wikidoc.org/index.php/Citrobacter
0ed06a9caca4d969da98bfb17675a6953a482600	wikidoc	Citronellal	Citronellal Citronellal or rhodinal or 3,7-dimethyloct-6-en-1-al (C10H18O) is a monoterpenoid, the main component in the mixture of terpenoid chemical compounds that give citronella oil its distinctive lemon scent. Citronellal is a major isolate in distilled oils from the plants Cymbopogon, lemon-scented gum, and lemon-scented teatree. Citronellal has insect repellent properties, and research shows high repellent effectiveness against misquitoes. Research shows that citronellal has strong antifungal qualities.	Citronellal Citronellal or rhodinal or 3,7-dimethyloct-6-en-1-al (C10H18O) is a monoterpenoid, the main component in the mixture of terpenoid chemical compounds that give citronella oil its distinctive lemon scent. Citronellal is a major isolate in distilled oils from the plants Cymbopogon, lemon-scented gum, and lemon-scented teatree. Citronellal has insect repellent properties, and research shows high repellent effectiveness against misquitoes.[1] Research shows that citronellal has strong antifungal qualities.[2]	https://www.wikidoc.org/index.php/Citronellal
d7e4df4da038996628b5ff9f28100f1f85ef7724	wikidoc	Citronellol	Citronellol Citronellol, or dihydrogeraniol, is a natural acyclic monoterpenoid. Both enantiomers occur in nature. (+)-Citronellol, which is found citronella oils, including Cymbopogon nardus (50%), is the more common isomer. (−)-Citronellol is found in the oils of rose (18-55%) and geranium. Citronellol is used in perfumes and insect repellents, and as a mite attractant. # Health & Safety information The United States FDA considers citronellol as GRAS (Generally Recognized as Safe for food use). Citronellol should be avoided by people with perfume allergy.	Citronellol Citronellol, or dihydrogeraniol, is a natural acyclic monoterpenoid. Both enantiomers occur in nature. (+)-Citronellol, which is found citronella oils, including Cymbopogon nardus (50%), is the more common isomer. (−)-Citronellol is found in the oils of rose (18-55%) and geranium.[1] Citronellol is used in perfumes and insect repellents,[2] and as a mite attractant.[3] # Health & Safety information The United States FDA considers citronellol as GRAS (Generally Recognized as Safe for food use).[4] Citronellol should be avoided by people with perfume allergy.[5]	https://www.wikidoc.org/index.php/Citronellol
4faae969fa760d4f015ec164061c197d44567fb7	wikidoc	Diaphoresis	Diaphoresis Synonyms and keywords: Cold sweat, clammy # Overview Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions. It is distinguished from hyperhidrosis by the "clammy" or "cold state" state of the patient. # Classification of Sweating There are four types of sweats: - Diaphoresis: Diaphoresis is a cold sweat. Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions. It is distinguished from hyperhidrosis by the "clammy" or "cold state" state of the patient. - Primary Hyperhidrosis: Primary hyperhidrosis is a condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature. This is not a cold sweat. - Secondary Hyperhidrosis: Secondary hyperhidrosis is a condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature that is secondary to an underlying pathologic process such as infections, disorders of the thyroid or pituitary gland, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning. This is not a cold sweat. - Night sweats: Sleep hyperhidrosis, more commonly known as the night sweats, is the occurrence of excessive sweating (hyperhidrosis) during sleep. The sufferer may or may not also suffer from excessive perspiration while awake. # Physiological (normal) causes of Sweating Normal physical causes of diaphoresis include exercise, menopause, fever, spicy foods, high environmental temperature, and vigorous sports. Strong emotions (anger, fear) and remembrance of past trauma can also trigger profuse sweating. The vast majority of sweat glands in the body are innervated by sympathetic cholinergic neurons. Sympathetic cholinergic neurons are sympathetic postganglionic neurons that happen to release acetylcholine instead of norepinephrine. # Pathological causes Diaphoresis may be associated with some abnormal conditions, such as hyperthyroidism and shock. If it is accompanied by unexplained weight loss or fever or by palpitations, shortness of breath, or chest discomfort, a physician should be consulted. Diabetics relying on insulin shots or oral medications may have low blood sugar, which can also cause diaphoresis. Various drugs (including caffeine, morphine, alcohol, and certain antipsychotics) may be causes, as well as withdrawal from alcohol or narcotic painkiller dependencies. Sympathetic nervous system stimulants such as cocaine and amphetamines have also been associated with diaphoresis. Diaphoresis due to ectopic catecholamine is a classic symptom of a pheochromocytoma, a rare tumor of the adrenal gland. Diaphoresis is also seen in an acute myocardial infarction, from the increased firing of the sympathetic nervous system. # Differential Diagnosis of Diaphoresis # Causes ## Life Threatening Causes - Anaphylactic shock - Cardiogenic shock - Myocardial infarction - Pesticide poisoning - Pulmonary embolism - Shock ## Common Causes - Anxiety - Fever - Heat exhaustion - Hypoglycemia - Menopause - Thyrotoxicosis ## Causes by Organ System ## Causes in Alphabetical Order - Abscess - Acetaminophen - Acrodynia - Acromegaly - Acute hypertensive crisis - Acute monocytic leukemia - Acute pulmonary oedema - Acute rheumatic fever - Acute stress disorder - AIDS - Alcohol withdrawal - Alternating hemiplegia of childhood - Ambenonium - Amitriptyline - Amonafide - Anaphylactic shock - Anastrozole - Anoxemia - Anxiety - Anxiety disorders - Aromatic amino acid decarboxylase deficiency - Aspirin - Atypical mycobacteria - Autonomic dysreflexia - Autonomic dystonia - Autonomic hyperreflexia - Autonomic neuropathy - Aztreonam - Babesiosis - Bacteremia - Bacterial meningitis - Basal cell carcinoma - Beta blockers - Beta-agonists - Bethanechol - Bland-White-Garland syndrome - Blue rubber bleb nevus syndrome - Bromocriptine - Brucellosis - Bupropion - Calcium channel blockers - Carbamate insecticide poisoning - Carcinoid syndrome - Cardiogenic shock - Cardiomyopathy - Castration - Chronic fatigue syndrome - Chronic hepatitis C - Chronic infections - Circulatory shock - Cladribine - Clozapine - Cocaine withdrawal - Cold-induced sweating syndrome type 1 - Collagen vascular disease - Common blushing - Congenital hepatic porphyria - Cor pulmonale - Cyclosporine - Demecarium bromide - Dermatopathia pigmentosa reticularis - Desipramine - Desvenlafaxine - Diabetes insipidus - Diabetes Mellitus - Diabetic neuropathy - Dimebon - Discontinuation syndrome - Distigmine - Donepezil - Dothiepin - Duloxetine - Dumping syndrome - Eccrine angiomatous hamartoma - Eccrine nevus - Echothiophate iodide - Encephalitis - Endocardial fibroelastosis - Endocarditis - Endocarditis lenta - Exemestane - Flumazenil - Flutamide - Fluvoxamine - Food additives - Frey's syndrome - Fructose intolerance - Fucosidosis - Fungal infections - Gamstorp-Wohlfart syndrome - Gonadorelin - Goserelin - Granulosis rubra nasi - Growth hormone secreting pituitary adenoma - Growth hormone - Heart attack - Heart failure - Heat exhaustion - Hereditary sensorimotor neuropathy type 2 - Hereditary sensory and autonomic neuropathy - Hereditary sensory and autonomic neuropathy type 3 - Heroin withdrawal - Herpes zoster of the preauricular region - Histrelin - HIV - Hodgkin's disease - Hodgkin's Lymphoma - Humorsol - Hydralazine - Hyperthyroidism - Hypertryptophanemia - Hypoglycaemia - Hypogonadism - Hypovolemic shock - Idiopathic - Idiopathic syringomyelia - Imatinib - Indian tobacco (lobelia inflata) - Indole alkaloids poisoning - Infliximab - Insulin - Insulinoma - Interferon alfa-2b - Jadassohn-Lewandowsky syndrome - Left heart failure - Letrozole - Leuprolide - Liver abscess - Lobstein disease - Loewenthal syndrome - Lung abscess - Lymphoma - Malaria - Malignancy - Mastocytosis - Medullary carcinoma of the thyroid - Meleda disease - Menopause - Mercury poisoning - Methadone - Morphine - Motion sickness - Multiple endocrine neoplasia type 1 - Multiple endocrine neoplasia type 2 - Multiple endocrine neoplasia type 3 - Muscarine - Myocardial infarction - Myotonic dystrophy - Nafarelin - Neostigmine - Neurogenic shock - Neuroleptic malignant syndrome - Niacin - Nitroglycerin - Non-Hodgkin's lymphoma - Nonsteroidal anti-inflammatory drugs - Serotonin-norepinephrine reuptake inhibitor - Nortriptyline - Obesity - Omeprazole - Opioids withdrawal - Organophosphate insecticide poisoning - Orthostatic hypotension - Osteomyelitis - Pachydermoperiostosis - Pain - Palmoplantar punctate keratoderma type 3 - Panic attack - Parkinson's Disease - Pesticide poisoning - Phaeochromocytoma - Phenylephrine - Phospholine iodide - Physostigmine - Pilocarpine - Pitted keratolysis - Pneumonia - POEMS syndrome - Poison hemlock (conium maculatum) - Polycythaemia rubra vera - Postorchiectomy - Posttraumatic syringomyelia - Pourfour du petit syndrome - Prostate cancer - Protease inhibitors - Pulmonary Embolism - Pyridostigmine - Raloxifene - Rebound hypertension - Reflex sympathetic dystrophy syndrome - Reflex sympathetic osteodystrophy - Relapsing fever - Renal calculi - Renal cell carcinoma - Rheumatoid Arthritis - Rickets - Rituximab - Ropinirole - Rosacea - Ross' syndrome - Sarcoidosis - Sarcomas - Selective serotonin reuptake inhibitors - Sepsis - Septic shock - Serotonin syndrome - Shock - Sibutramine - Sildenafil - Sleep apnea - Sleep disorders - Soft tissue sarcoma - Spinal autonomic dysreflexia - Spinal muscular atrophy with respiratory distress 1 - Stroke - Sulfonylureas - Syringomyelia - Tamoxifen - Temporal arteritis - Tetanus - Theophylline - Thiazolidinediones - Thyrotoxicosis - Tobacco plant poisoning - Toxic mushrooms - Tramadol - Traumatic brain injury - Tricyclic antidepressants - Trophoblastic cancer - Tuberculosis - Tufted angioma - Urolithiasis - Vancomycin resistant enterococcal bacteremia - Venlafaxine - Ventriculo-arterial discordance, isolated - Viral infections - Volume depletion - Withdrawal in drug addicts - Xanthic urolithiasis # Treatment When diaphoresis is pathologic, the underlying cause should be treated. When the cause is menopause, estrogen replacement therapy may improve the symptoms.	Diaphoresis Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] Synonyms and keywords: Cold sweat, clammy # Overview Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions. It is distinguished from hyperhidrosis by the "clammy" or "cold state" state of the patient. # Classification of Sweating There are four types of sweats: - Diaphoresis: Diaphoresis is a cold sweat. Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions. It is distinguished from hyperhidrosis by the "clammy" or "cold state" state of the patient. - Primary Hyperhidrosis: Primary hyperhidrosis is a condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature. This is not a cold sweat. - Secondary Hyperhidrosis: Secondary hyperhidrosis is a condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature that is secondary to an underlying pathologic process such as infections, disorders of the thyroid or pituitary gland, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning. This is not a cold sweat. - Night sweats: Sleep hyperhidrosis, more commonly known as the night sweats, is the occurrence of excessive sweating (hyperhidrosis) during sleep. The sufferer may or may not also suffer from excessive perspiration while awake. # Physiological (normal) causes of Sweating Normal physical causes of diaphoresis include exercise, menopause, fever, spicy foods, high environmental temperature, and vigorous sports. Strong emotions (anger, fear) and remembrance of past trauma can also trigger profuse sweating. The vast majority of sweat glands in the body are innervated by sympathetic cholinergic neurons. Sympathetic cholinergic neurons are sympathetic postganglionic neurons that happen to release acetylcholine instead of norepinephrine. # Pathological causes Diaphoresis may be associated with some abnormal conditions, such as hyperthyroidism and shock. If it is accompanied by unexplained weight loss or fever or by palpitations, shortness of breath, or chest discomfort, a physician should be consulted. Diabetics relying on insulin shots or oral medications may have low blood sugar, which can also cause diaphoresis. Various drugs (including caffeine, morphine, alcohol, and certain antipsychotics) may be causes, as well as withdrawal from alcohol or narcotic painkiller dependencies. Sympathetic nervous system stimulants such as cocaine and amphetamines have also been associated with diaphoresis. Diaphoresis due to ectopic catecholamine is a classic symptom of a pheochromocytoma, a rare tumor of the adrenal gland. Diaphoresis is also seen in an acute myocardial infarction, from the increased firing of the sympathetic nervous system. # Differential Diagnosis of Diaphoresis # Causes ## Life Threatening Causes - Anaphylactic shock - Cardiogenic shock - Myocardial infarction - Pesticide poisoning - Pulmonary embolism - Shock ## Common Causes - Anxiety - Fever - Heat exhaustion - Hypoglycemia - Menopause - Thyrotoxicosis ## Causes by Organ System ## Causes in Alphabetical Order - Abscess - Acetaminophen - Acrodynia - Acromegaly - Acute hypertensive crisis - Acute monocytic leukemia - Acute pulmonary oedema - Acute rheumatic fever - Acute stress disorder - AIDS - Alcohol withdrawal - Alternating hemiplegia of childhood - Ambenonium - Amitriptyline - Amonafide - Anaphylactic shock - Anastrozole - Anoxemia - Anxiety - Anxiety disorders - Aromatic amino acid decarboxylase deficiency - Aspirin - Atypical mycobacteria - Autonomic dysreflexia - Autonomic dystonia - Autonomic hyperreflexia - Autonomic neuropathy - Aztreonam - Babesiosis - Bacteremia - Bacterial meningitis - Basal cell carcinoma - Beta blockers - Beta-agonists - Bethanechol - Bland-White-Garland syndrome - Blue rubber bleb nevus syndrome - Bromocriptine - Brucellosis - Bupropion - Calcium channel blockers - Carbamate insecticide poisoning - Carcinoid syndrome - Cardiogenic shock - Cardiomyopathy - Castration - Chronic fatigue syndrome - Chronic hepatitis C - Chronic infections - Circulatory shock - Cladribine - Clozapine - Cocaine withdrawal - Cold-induced sweating syndrome type 1 - Collagen vascular disease - Common blushing - Congenital hepatic porphyria - Cor pulmonale - Cyclosporine - Demecarium bromide - Dermatopathia pigmentosa reticularis - Desipramine - Desvenlafaxine - Diabetes insipidus - Diabetes Mellitus - Diabetic neuropathy - Dimebon - Discontinuation syndrome - Distigmine - Donepezil - Dothiepin - Duloxetine - Dumping syndrome - Eccrine angiomatous hamartoma - Eccrine nevus - Echothiophate iodide - Encephalitis - Endocardial fibroelastosis - Endocarditis - Endocarditis lenta - Exemestane - Flumazenil - Flutamide - Fluvoxamine - Food additives - Frey's syndrome - Fructose intolerance - Fucosidosis - Fungal infections - Gamstorp-Wohlfart syndrome - Gonadorelin - Goserelin - Granulosis rubra nasi - Growth hormone secreting pituitary adenoma - Growth hormone - Heart attack - Heart failure - Heat exhaustion - Hereditary sensorimotor neuropathy type 2 - Hereditary sensory and autonomic neuropathy - Hereditary sensory and autonomic neuropathy type 3 - Heroin withdrawal - Herpes zoster of the preauricular region - Histrelin - HIV - Hodgkin's disease - Hodgkin's Lymphoma - Humorsol - Hydralazine - Hyperthyroidism - Hypertryptophanemia - Hypoglycaemia - Hypogonadism - Hypovolemic shock - Idiopathic - Idiopathic syringomyelia - Imatinib - Indian tobacco (lobelia inflata) - Indole alkaloids poisoning - Infliximab - Insulin - Insulinoma - Interferon alfa-2b - Jadassohn-Lewandowsky syndrome - Left heart failure - Letrozole - Leuprolide - Liver abscess - Lobstein disease - Loewenthal syndrome - Lung abscess - Lymphoma - Malaria - Malignancy - Mastocytosis - Medullary carcinoma of the thyroid - Meleda disease - Menopause - Mercury poisoning - Methadone - Morphine - Motion sickness - Multiple endocrine neoplasia type 1 - Multiple endocrine neoplasia type 2 - Multiple endocrine neoplasia type 3 - Muscarine - Myocardial infarction - Myotonic dystrophy - Nafarelin - Neostigmine - Neurogenic shock - Neuroleptic malignant syndrome - Niacin - Nitroglycerin - Non-Hodgkin's lymphoma - Nonsteroidal anti-inflammatory drugs - Serotonin-norepinephrine reuptake inhibitor - Nortriptyline - Obesity - Omeprazole - Opioids withdrawal - Organophosphate insecticide poisoning - Orthostatic hypotension - Osteomyelitis - Pachydermoperiostosis - Pain - Palmoplantar punctate keratoderma type 3 - Panic attack - Parkinson's Disease - Pesticide poisoning - Phaeochromocytoma - Phenylephrine - Phospholine iodide - Physostigmine - Pilocarpine - Pitted keratolysis - Pneumonia - POEMS syndrome - Poison hemlock (conium maculatum) - Polycythaemia rubra vera - Postorchiectomy - Posttraumatic syringomyelia - Pourfour du petit syndrome - Prostate cancer - Protease inhibitors - Pulmonary Embolism - Pyridostigmine - Raloxifene - Rebound hypertension - Reflex sympathetic dystrophy syndrome - Reflex sympathetic osteodystrophy - Relapsing fever - Renal calculi - Renal cell carcinoma - Rheumatoid Arthritis - Rickets - Rituximab - Ropinirole - Rosacea - Ross' syndrome - Sarcoidosis - Sarcomas - Selective serotonin reuptake inhibitors - Sepsis - Septic shock - Serotonin syndrome - Shock - Sibutramine - Sildenafil - Sleep apnea - Sleep disorders - Soft tissue sarcoma - Spinal autonomic dysreflexia - Spinal muscular atrophy with respiratory distress 1 - Stroke - Sulfonylureas - Syringomyelia - Tamoxifen - Temporal arteritis - Tetanus - Theophylline - Thiazolidinediones - Thyrotoxicosis - Tobacco plant poisoning - Toxic mushrooms - Tramadol - Traumatic brain injury - Tricyclic antidepressants - Trophoblastic cancer - Tuberculosis - Tufted angioma - Urolithiasis - Vancomycin resistant enterococcal bacteremia - Venlafaxine - Ventriculo-arterial discordance, isolated - Viral infections - Volume depletion - Withdrawal in drug addicts - Xanthic urolithiasis # Treatment When diaphoresis is pathologic, the underlying cause should be treated. When the cause is menopause, estrogen replacement therapy may improve the symptoms.	https://www.wikidoc.org/index.php/Clammy_sweat
7cc047f49e522b8190ad59448eb9795fdf02f3b2	wikidoc	MHC class I	MHC class I # Overview There are two primary classes of major histocompatibility complex (MHC) molecules, class I and II. MHC class I molecules are found on almost every nucleated cell of the body. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway. # Structure MHC class I molecules are heterodimers, consisting of a single transmembrane polypeptide chain (the α-chain) and a β2 microglobulin (which is encoded elsewhere, not in the MHC). The α chain has three polymorphic domains, α1, α2, α3. Between α1 and α2 is the peptide-binding groove which binds peptides derived from cytosolic proteins. The groove consists of eight β-pleated sheets on the bottom and two α helices making up sides. The peptide in the groove remains bound for the life of the class I molecule, and is typically 8-9 amino acids in length. # Production The peptides are mainly generated in the cytosol by the proteasome. The proteasome is a macromolecule that consists of 28 subunits, of which half of them contain proteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. The peptides have to be translocated from the cytosol into the endoplasmic reticulum (ER) to meet the MHC class I molecule, whose peptide-binding site is in the lumen of the ER. # Translocation The peptide translocation from the cytosol into the lumen of the ER is accomplished by the transporter associated with antigen processing (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2. The two subunits form a peptide binding site and two ATP binding sites that face the lumen of the cytosol. TAP binds peptides on the cytoplasmic site and translocates them under ATP consumption into to the lumen of the ER. The MHC class I molecule is then in turn loaded with peptides in the lumen of the ER. The peptide-loading process involves several other molecules that form a large multimeric complex consisting of TAP, tapasin, calreticulin, calnexin, and ERP57. Once the peptide is loaded onto the MHC class I molecule, it leaves the ER through the secretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modifications of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to the N-glycan regions of the protein, followed by extensive changes to the N-glycans in the Golgi apparatus. The N-glycans mature fully before they reach the cell surface. # Peptide removal Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum are removed from the ER via the sec61 channel into the cytosol, where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to an MHC class I molecule. # Effect of viruses MHC class I molecules are loaded with proteins generated in the cytosol. As viruses infect a cell by entering its cytoplasm, this cytosolic, MHC class I-dependent pathway of antigen presentation is the primary way for a virus-infected cell to signal T cells. MHC class I molecules generally interact exclusively with CD8+ ("cytotoxic") T cells (CTLs). The fate of the virus-infected cell is almost always apoptosis initiated by the CTL, effectively reducing the risk of infecting neighboring cells. # Genes and isotypes - Very polymorphic HLA-A (HLA-A) HLA-B (HLA-B, including HLA-B27) HLA-C (HLA-C) - HLA-A (HLA-A) - HLA-B (HLA-B, including HLA-B27) - HLA-C (HLA-C) - Less polymorphic HLA-E HLA-F HLA-G HLA-K HLA-L - HLA-E - HLA-F - HLA-G - HLA-K - HLA-L # Additional images - TCR-MHC bindings	MHC class I Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview There are two primary classes of major histocompatibility complex (MHC) molecules, class I and II. MHC class I molecules are found on almost every nucleated cell of the body. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway. # Structure MHC class I molecules are heterodimers, consisting of a single transmembrane polypeptide chain (the α-chain) and a β2 microglobulin (which is encoded elsewhere, not in the MHC). The α chain has three polymorphic domains, α1, α2, α3. Between α1 and α2 is the peptide-binding groove which binds peptides derived from cytosolic proteins. The groove consists of eight β-pleated sheets on the bottom and two α helices making up sides. The peptide in the groove remains bound for the life of the class I molecule, and is typically 8-9 amino acids in length. # Production The peptides are mainly generated in the cytosol by the proteasome. The proteasome is a macromolecule that consists of 28 subunits, of which half of them contain proteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. The peptides have to be translocated from the cytosol into the endoplasmic reticulum (ER) to meet the MHC class I molecule, whose peptide-binding site is in the lumen of the ER. # Translocation The peptide translocation from the cytosol into the lumen of the ER is accomplished by the transporter associated with antigen processing (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2. The two subunits form a peptide binding site and two ATP binding sites that face the lumen of the cytosol. TAP binds peptides on the cytoplasmic site and translocates them under ATP consumption into to the lumen of the ER. The MHC class I molecule is then in turn loaded with peptides in the lumen of the ER. The peptide-loading process involves several other molecules that form a large multimeric complex consisting of TAP, tapasin, calreticulin, calnexin, and ERP57. Once the peptide is loaded onto the MHC class I molecule, it leaves the ER through the secretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modifications of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to the N-glycan regions of the protein, followed by extensive changes to the N-glycans in the Golgi apparatus. The N-glycans mature fully before they reach the cell surface. # Peptide removal Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum are removed from the ER via the sec61 channel into the cytosol, where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to an MHC class I molecule. # Effect of viruses MHC class I molecules are loaded with proteins generated in the cytosol. As viruses infect a cell by entering its cytoplasm, this cytosolic, MHC class I-dependent pathway of antigen presentation is the primary way for a virus-infected cell to signal T cells. MHC class I molecules generally interact exclusively with CD8+ ("cytotoxic") T cells (CTLs). The fate of the virus-infected cell is almost always apoptosis initiated by the CTL, effectively reducing the risk of infecting neighboring cells. # Genes and isotypes - Very polymorphic HLA-A (HLA-A) HLA-B (HLA-B, including HLA-B27) HLA-C (HLA-C) - HLA-A (HLA-A) - HLA-B (HLA-B, including HLA-B27) - HLA-C (HLA-C) - Less polymorphic HLA-E HLA-F HLA-G HLA-K HLA-L - HLA-E - HLA-F - HLA-G - HLA-K - HLA-L # Additional images - TCR-MHC bindings # External links - Histocompatibility+Antigens+Class+I at the US National Library of Medicine Medical Subject Headings (MeSH) - MHC+Class+I+Genes at the US National Library of Medicine Medical Subject Headings (MeSH) Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Class_I_MHC
d648e5671d24c7c746a038cbfff300f1c73dfef9	wikidoc	Clenbuterol	Clenbuterol Clenbuterol is a drug prescribed to sufferers of breathing disorders as a decongestant and bronchodilator. People with chronic breathing disorders like asthma use this as a bronchodilator to make breathing easier. It is most commonly available in salt form as Clenbuterol hydrochloride. Clenbuterol is often mistaken for a steroid because of its illicit use in athletics. # Effects and Dosage Clenbuterol is a β2 adrenergic agonist with some similarities to ephedrine, but its effects are more potent and longer-lasting as a stimulant and thermogenic drug. It causes an increase in aerobic capacity, CNS stimulation, and an increase in blood pressure and oxygen transportation. It increases the rate at which fat and protein is used up in the body at the same time as slowing down the storage of glycogen. It is commonly used for smooth muscle relaxant properties. This means that it is a bronchodilator and tocolytic. It is usually used in dosages anywhere from 20-60 micrograms a day when prescribed. A dose of about 150 μg should never be exceeded in a day. It is also prescribed for treatment of horses, however, equestrian usage is usually the liquid form of clenbuterol. # Human use Recently clenbuterol has been touted as a weight loss drug and in some countries is prescribed as a bronchodilator for asthma patients. Human use can lead to side-effects. # Veterinary use Clenbuterol is used worldwide for the treatment of allergic respiratory disease in horses as it is a bronchodilator. A common trade name is Ventipulmin. It can be used both orally and intravenously. It is also a non-steroidal anabolic and metabolism accelerator, through a mechanism not well understood. Its ability to induce weight gain and a greater proportion of muscle to fat makes its illegal use in livestock popular. # Food contamination In September 2006 over 330 people in Shanghai were reported to have been poisoned by eating pork contaminated by Clenbuterol that had been fed to the animals to keep their meat lean. # Legal status As of fall, 2006, Clenbuterol is not an ingredient of any therapeutic drug approved by the U.S. Food and Drug Administration, but is still used as an unproven slimming aid, and is now banned for IOC-tested athletes. Jason Grimsley, former Major League baseball pitcher, admitted to using this drug. The tennis player Mariano Puerta was once penalized for use of clenbuterol. Australian wrestler Mitchil Mann was also suspended for testing positive for the drug.	Clenbuterol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Clenbuterol is a drug prescribed to sufferers of breathing disorders as a decongestant and bronchodilator. People with chronic breathing disorders like asthma use this as a bronchodilator to make breathing easier. It is most commonly available in salt form as Clenbuterol hydrochloride. Clenbuterol is often mistaken for a steroid because of its illicit use in athletics. # Effects and Dosage Clenbuterol is a β2 adrenergic agonist with some similarities to ephedrine, but its effects are more potent and longer-lasting as a stimulant and thermogenic drug. It causes an increase in aerobic capacity, CNS stimulation, and an increase in blood pressure and oxygen transportation. It increases the rate at which fat and protein is used up in the body at the same time as slowing down the storage of glycogen. It is commonly used for smooth muscle relaxant properties. This means that it is a bronchodilator and tocolytic. It is usually used in dosages anywhere from 20-60 micrograms a day when prescribed. A dose of about 150 μg should never be exceeded in a day. It is also prescribed for treatment of horses, however, equestrian usage is usually the liquid form of clenbuterol. # Human use Recently clenbuterol has been touted as a weight loss drug and in some countries is prescribed as a bronchodilator for asthma patients. Human use can lead to side-effects. # Veterinary use Clenbuterol is used worldwide for the treatment of allergic respiratory disease in horses as it is a bronchodilator. A common trade name is Ventipulmin. It can be used both orally and intravenously. It is also a non-steroidal anabolic and metabolism accelerator, through a mechanism not well understood. Its ability to induce weight gain and a greater proportion of muscle to fat makes its illegal use in livestock popular. # Food contamination In September 2006 over 330 people in Shanghai were reported to have been poisoned by eating pork contaminated by Clenbuterol that had been fed to the animals to keep their meat lean.[1] # Legal status As of fall, 2006, Clenbuterol is not an ingredient of any therapeutic drug approved by the U.S. Food and Drug Administration, but is still used as an unproven slimming aid,[2] and is now banned for IOC-tested athletes.[3] Jason Grimsley, former Major League baseball pitcher, admitted to using this drug. The tennis player Mariano Puerta was once penalized for use of clenbuterol. Australian wrestler Mitchil Mann was also suspended for testing positive for the drug.[4]	https://www.wikidoc.org/index.php/Clenbuterol
d891cf8110890347225da665960d1f0822882b81	wikidoc	Clevidipine	Clevidipine # 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 Clevidipine is a calcium channel blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include nausea, vomiting, headache, acute renal failure. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information - Initial dosage: 1-2 mg/hour - Dose titration: The dose may be doubled at short (90 second) intervals initially. As the blood pressure approaches goal, the increase in doses should be less than doubling and the time between dose adjustments should be lengthened to every 5-10 minutes. An approximately 1-2 mg/hour increase will generally produce an additional 2-4 mmHg decrease in systolic pressure. - Maintenance dose: The desired therapeutic response for most patients occurs at doses of 4-6 mg/hour. Patients with severe hypertension may require doses up to 32 mg/hour, but there is limited experience at this dose rate. - Maximum dose: Most patients were treated with maximum doses of 16 mg/hour or less. There is limited short-term experience with doses up to 32 mg/hour. Because of lipid load restrictions, no more than 1000 mL or an average of 21 mg/hour of Clevidipine infusion is recommended per 24 hour period. - Transition to an oral antihypertensive agent: Discontinue Clevidipine or titrate downward while appropriate oral therapy is established. When an oral antihypertensive agent is being instituted, consider the lag time of onset of the oral agent’s effect. Continue blood pressure monitoring until desired effect is achieved. - Special populations: Special populations were not specifically studied. In clinical trials, 78 patients with abnormal hepatic function (one or more of the following: elevated serum bilirubin, AST/SGOT, ALT/SGPT) and 121 patients with moderate to severe renal impairment were treated with Clevidipine. An initial Clevidipine infusion rate of 1-2 mg/hour is appropriate in these patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clevidipine sandbox in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Clevidipine sandbox in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information about the FDA-labeled indications and dosage information for children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clevidipine sandbox in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Clevidipine sandbox in pediatric patients. # Contraindications - Clevidipine is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products. - Clevidipine is contraindicated in patients with defective lipid metabolism such as pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is accompanied by hyperlipidemia. - Clevidipine is contraindicated in patients with severe aortic stenosis because afterload reduction can be expected to reduce myocardial oxygen delivery. # Warnings ## Need for Aseptic Technique - Use aseptic technique and discard any unused product within 12 hours of stopper puncture. - Clevidipine may produce systemic hypotension and reflex tachycardia. If either occurs, decrease the dose of Clevidipine. There is limited experience with short-duration therapy with beta-blockers as a treatment for Clevidipine-induced tachycardia. Beta-blocker use for this purpose is not recommended. - Clevidipine contains approximately 0.2 g of lipid per mL (2.0 kcal). Lipid intake restrictions may be necessary for patients with significant disorders of lipid metabolism. For these patients, a reduction in the quantity of concurrently administered lipids may be necessary to compensate for the amount of lipid infused as part of the Clevidipine formulation. - Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. - Clevidipine is not a beta-blocker, does not reduce heart rate, and gives no protection against the effects of abrupt beta-blocker withdrawal. Beta-blockers should be withdrawn only after a gradual reduction in dose. - Patients who receive prolonged Clevidipine infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped. - There is no information to guide use of Clevidipine in treating hypertension associated with pheochromocytoma. # Adverse Reactions ## Clinical Trials Experience ## Clinical Trials Experience - Clevidipine clinical development included 19 studies, with 99 healthy subjects and 1307 hypertensive patients who received at least one dose of clevidipine (1406 total exposures). Clevidipine was evaluated in 15 studies in hypertensive patients: 1099 patients with perioperative hypertension, 126 with severe hypertension and 82 patients with essential hypertension. - The desired therapeutic response was achieved at doses of 4-6 mg/hour. Clevidipine was infused for <24 hours in the majority of patients (n=1199); it was infused as a continuous infusion in an additional 93 patients for durations between 24 and 72 hours. - 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 placebo-controlled experience with Clevidipine in the perioperative setting was both small and brief (about 30 minutes). Table 2 shows treatment-emergent adverse reactions and the category of “any common adverse event” in ESCAPE-1 and ESCAPE-2 where the rate on Clevidipine exceeded the rate on placebo by at least 5% (common adverse reactions). - Three randomized, parallel, open-label studies called ECLIPSE, with longer exposure in cardiac surgery patients define the adverse reactions for patients with perioperative hypertension. Each ECLIPSE study compared Cleviprex (n=752) to an active comparator: nitroglycerin (NTG, n=278), sodium nitroprusside (SNP, n=283), or nicardipine (NIC, n=193). The pooled mean maximum dose in these studies was 10 mg/hour and the mean duration of treatment was 8 hours. - There were many adverse events associated with the operative procedure in the clinical studies of Cleviprex and relatively few plausibly related to the drugs used to lower blood pressure. Thus, the ability to differentiate the adverse event profile between treatments is limited. The adverse events observed within one hour of the end of the infusion were similar in patients who received Cleviprex and in those who received comparator agents. There was no adverse reaction that was more than 2% more common on Cleviprex than on the average of all comparators. - Serious Adverse Events and Discontinuation – Perioperative hypertension Studies - The incidence of adverse events leading to study drug discontinuation in patients with perioperative hypertension receiving Cleviprex was 5.9% versus 3.2% for all active comparators. :For patients receiving Cleviprex and all active comparators the incidence of serious adverse events within one hour of drug infusion discontinuation was similar. - The adverse events for patients with severe hypertension are based on an uncontrolled study in patients with severe hypertension (VELOCITY, n=126). - The common adverse reactions for Cleviprex in severe hypertension included headache (6.3%), nausea (4.8%), and vomiting (3.2%). The incidence of adverse events leading to study drug discontinuation for Cleviprex in severe hypertension was 4.8%. - Adverse reactions that were reported in <1% of patients with severe or essential hypertension included: Myocardial infarction, cardiac arrest Syncope Dyspnea ## Postmarketing Experience - Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of Clevidipine: increased blood triglycerides, ileus, hypersensitivity, hypotension, nausea, decreased oxygen saturation (possible pulmonary shunting) and reflex tachycardia. # Drug Interactions No clinical drug interaction studies were conducted. Clevidipine and its major dihydropyridine metabolite do not have the potential for blocking or inducing any CYP enzyme. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies of Clevidipine use in pregnant women. In animal studies, clevidipine caused increases in maternal and fetal mortality and length of gestation. Clevidipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - There was decreased fetal survival when pregnant rats and rabbits were treated with clevidipine during organogenesis at doses 0.7 times (on a body surface area basis) the maximum recommended human dose (MRHD) in rats and 2 times the MRHD in rabbits. - In pregnant rats dosed with clevidipine during late gestation and lactation, there were dose-related increases in maternal mortality, length of gestation and prolonged parturition at doses greater than or equal to 1/6 of the MRHD based on body surface area. When offspring of these dams were mated, they had a conception rate lower than that of controls. Clevidipine has been shown to cross the placenta in rats. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clevidipine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Clevidipine during labor and delivery. ### Nursing Mothers - It is not known whether clevidipine is excreted in human milk. Because many drugs are excreted in human milk, consider possible infant exposure when Clevidipine is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of Clevidipine in children under 18 years of age have not been established. ### Geriatic Use - Of the 1406 subjects (1307 with hypertension) treated with Clevidipine in clinical studies, 620 were ≥65 years of age and 232 were ≥75 years of age. No overall differences in safety or effectiveness were observed between these and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, for an elderly patient doses should be titrated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Clevidipine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Clevidipine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Clevidipine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Clevidipine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Clevidipine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Clevidipine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Clevidipine is intended for intravenous use. Titrate drug to achieve the desired blood pressure reduction. Individualize dosage depending on the blood pressure to be obtained and the response of the patient. ## Instructions for Administration - Maintain aseptic technique while handling Clevidipine. Clevidipine is a single-use parenteral product. Do not use if contamination is suspected. Once the stopper is punctured, use within 12 hours and discard any unused portion. - Clevidipine is supplied in sterile, pre-mixed, ready-to-use 50 mL or 100 mL vials. Invert vial gently several times before use to ensure uniformity of the emulsion prior to administration. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. Administer Clevidipine using an infusion device allowing calibrated infusion rates. Commercially available standard plastic cannulae may be used to administer the infusion.Administer Clevidipine by a central line or a peripheral line. - Clevidipine should not be administered in the same line as other medications. - Clevidipine should not be diluted, but it can be administered with the following: - Water for Injection, USP - Sodium Chloride (0.9%) Injection, USP - Dextrose (5%) Injection, USP - Dextrose (5%) in Sodium Chloride (0.9%) Injection, USP - Dextrose (5%) in Ringers Lactate Injection, USP - Lactated Ringers Injection, USP - 10% amino acid ### Monitoring - Monitor blood pressure and heart rate continually during infusion, and then until vital signs are stable. Patients who receive prolonged Clevidipine infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped. These patients may need follow-up adjustments in blood pressure control. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - There has been no experience of overdosage in human clinical trials. In clinical trials, doses of Clevidipine up to 106 mg/hour or 1153 mg maximum total dose were administered. The expected major effects of overdose would be hypotension and reflex tachycardia. - Discontinuation of Clevidipine leads to a reduction in antihypertensive effects within 5 to 15 minutes . In case of suspected overdosage, Clevidipine should be discontinued immediately and the patient’s blood pressure should be supported. # Pharmacology ## Mechanism of Action - Clevidipine is a dihydropyridine L-type calcium channel blocker. L-type calcium channels mediate the influx of calcium during depolarization in arterial smooth muscle. Experiments in anesthetized rats and dogs show that clevidipine reduces mean arterial blood pressure by decreasing systemic vascular resistance. Clevidipine does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels. ## Structure - Clevidipine is a sterile, milky-white emulsion containing 0.5 mg/mL of clevidipine suitable for intravenous administration. Clevidipine is a dihydropyridine calcium channel blocker. Chemically, the active substance, clevidipine, is butyroxymethyl methyl 4-(2´,3´-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. It is a racemic mixture with a molecular weight of 456.3 g/mol. Each enantiomer has equipotent antihypertensive activity. The structure and formula are: - Clevidipine is practically insoluble in water and is formulated in an oil-in-water emulsion. In addition to the active ingredient, clevidipine, Clevidipine contains soybean oil (200 mg/mL), glycerin (22.5 mg/mL), purified egg yolk phospholipids (12 mg/mL), oleic acid (0.3 mg/mL), disodium edetate (0.05 mg/mL), and sodium hydroxide to adjust pH. Clevidipine has a pH of 6.0 – 8.0 and is a ready-to-use emulsion. ## Pharmacodynamics - Clevidipine is titrated to the desired reduction in blood pressure. The effect of Clevidipine appears to plateau at approximately 25% of baseline systolic pressure. The infusion rate for which half the maximal effect is observed is approximately 10 mg/hour. Onset of Effect - In the perioperative patient population, Clevidipine produces a 4-5% reduction in systolic blood pressure within 2-4 minutes after starting a 0.4 mcg/kg/min infusion (approximately 1-2 mg/hr). Maintenance of Effect - In studies up to 72 hours of continuous infusion, there was no evidence of tolerance or hysteresis. Offset of Effect - In most patients, full recovery of blood pressure is achieved in 5-15 minutes after the infusion is stopped. - In studies up to 72 hours of continuous infusion, in patients that were not transitioned to other antihypertensive therapies, there was some evidence of rebound hypertension following Clevidipine discontinuation. Hemodynamics - Clevidipine causes a dose-dependent decrease in systemic vascular resistance. Heart Rate - An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced. Electrophysiologic Effects - In healthy volunteers, clevidipine or its major carboxylic acid metabolite, at therapeutic and supratherapeutic concentrations (approximately 2.8 times steady-state), did not prolong cardiac repolarization. ## Pharmacokinetics - Clevidipine is rapidly distributed and metabolized resulting in a very short half life. The arterial blood concentration of clevidipine declines in a multi-phasic pattern following termination of the infusion. The initial phase half-life is approximately 1 minute, and accounts for 85-90% of clevidipine elimination. The terminal half-life is approximately 15 minutes. Distribution - Clevidipine is >99.5% bound to proteins in plasma at 37°C. The steady-state volume of distribution was determined to be 0.17 L/kg in arterial blood. Metabolism and Elimination - Clevidipine is rapidly metabolized by hydrolysis of the ester linkage, primarily by esterases in the blood and extravascular tissues, making its elimination unlikely to be affected by hepatic or renal dysfunction. The primary metabolites are the carboxylic acid metabolite and formaldehyde formed by hydrolysis of the ester group. The carboxylic acid metabolite is inactive as an antihypertensive. This metabolite is further metabolized by glucuronidation or oxidation to the corresponding pyridine derivative. The clearance of the primary dihydropyridine metabolite is 0.03 L/h/kg and the terminal half life is approximately 9 hours. - In vitro studies show that clevidipine and its metabolite at the concentrations achieved in clinical practice will not inhibit or induce any CYP enzyme. - In a clinical study with radiolabeled clevidipine, 83% of the drug was excreted in urine and feces. The major fraction, 63-74% is excreted in the urine, 7-22% in the feces. More than 90% of the recovered radioactivity is excreted within the first 72 hours of collection. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Clevidipine displayed positive genotoxic potential in vitro in the Ames test, mouse lymphoma thymidine kinase locus assay, and chromosomal aberration assay but not in vivo in the mouse micronucleus test. Formaldehyde, a metabolite of clevidipine, a known genotoxicant in vitro and a probable human carcinogen, appears to be at least partially responsible for the positive in vitro results. Long-term studies for evaluation of carcinogenic potential have not been performed with clevidipine due to the intended short-term duration of human use. There were no adverse effects on fertility or mating behavior of male rats at clevidipine doses of up to 55 mg/kg/day, approximately equivalent to the maximum recommended human dose (MRHD) of 504 mg/day (21 mg/hour x 24 hours) on a body surface area basis. Female rats demonstrated pseudopregnancy and changes in estrus cycle at doses as low as 13 mg/kg/day (about 1/4th the MRHD); however, doses of up to 55 mg/kg/day did not affect mating performance or fertility. ## Developmental Toxicology - When pregnant rats were dosed with clevidipine during late gestation and lactation, there were dose-related increases in mortality, length of gestation and prolonged parturition at dose levels as low as 13 mg/kg/day (about 1/4th the maximum recommended human dose of 504 mg/day (21 mg/hour x 24 hours) on a body surface area basis). When offspring of these dams were mated, they had a conception rate lower than that of controls. Clevidipine crosses the placental membrane in this species and doses of 35 or more mg/kg/day (about 0.7 times the MRHD) administered during organogenesis adversely affected fetal survival. Fetal survival was also adversely affected when pregnant rabbits were treated during organogenesis with 55 mg/kg/day (about twice the MRHD on a body surface area basis). # Clinical Studies ## Perioperative Hypertension - Clevidipine was evaluated in two double-blind, randomized, parallel, placebo-controlled, multicenter trials of cardiac surgery patients—pre-operative use in ESCAPE-1 (n=105) and post-operative use in ESCAPE-2 (n=110). Patients were undergoing coronary artery bypass grafting, with or without valve replacement. Inclusion in ESCAPE-1 required a systolic pressure ≥160 mmHg. In ESCAPE-2, the entry criterion was systolic pressure of ≥140 mmHg within 4 hours of the completed surgery. The mean baseline blood pressure was 178/77 mmHg in ESCAPE -1 and 150/71 mmHg in ESCAPE 2. The population of both studies included 27% females and 47% patients older than age 65. - Clevidipine was infused in ESCAPE-1 preoperatively for 30 minutes, until treatment failure, or until induction of anesthesia, whichever came first. Clevidipine was infused in ESCAPE-2 postoperatively for a minimum of 30 minutes unless alternative therapy was required. The maximum infusion time allowed in the ESCAPE studies was 60 minutes. - In both studies infusion of Clevidipine was started at a dose of 1- 2 mg/hour and was titrated upwards, as tolerated, in doubling increments every 90 seconds up to an infusion rate of 16 mg/hour in order to achieve the desired blood pressure-lowering effect. At doses above 16 mg/hour increments were 7 mg/hour. The average Clevidipine infusion rate in ESCAPE-1 was 15.3 mg/hour and in ESCAPE-2 it was 5.1 mg/hour. The mean duration of exposure in the same ESCAPE studies was 30 minutes for the Clevidipine treated patients. - Approximately 4% of Clevidipine-treated subjects in ESCAPE-1 and 41% in ESCAPE-2 were on concomitant vasodilators during the first 30 minutes of Clevidipine administration. - Clevidipine lowered blood pressure within 2-4 minutes. The change in systolic blood pressure over 30 minutes for ESCAPE-1 (preoperative) and ESCAPE-2 (postoperative) are shown in Figure 1 and 2. - The change in heart rate over 30 minutes for ESCAPE-1 (preoperative) and ESCAPE-2 (postoperative) are shown in Figure 3 and 4. - In three Phase 3 open-label clinical trials (ECLIPSE), 1512 patients were randomized to receive Clevidipine, nitroglycerin (perioperative hypertension), sodium nitroprusside (perioperative hypertension), or nicardipine (postoperative hypertension), for the treatment of hypertension in cardiac surgery. The mean exposure in the ECLIPSE studies was 8 hours at 4.5 mg/hour for the 752 patients who were treated with Clevidipine. Blood pressure control was assessed by measuring the magnitude and duration of SBP excursions outside the predefined pre- and post-operative SBP target range of 75-145 mmHg and the predefined intra-operative SBP range of 65-135 mmHg. In general, blood pressure control was similar with the four treatments. ## Severe Hypertension - Clevidipine was evaluated in an open-label, uncontrolled clinical trial (VELOCITY) in 126 patients with severe hypertension (SBP >180 mmHg or diastolic blood pressure >115 mmHg). Clevidipine infusion was initiated at 2 mg/hour and up-titrated every 3 minutes, doubling up to a maximum dose of 32 mg/hour as required to achieve a prespecified target blood pressure range within 30 minutes (primary endpoint). The transition to oral antihypertensive therapy was assessed for up to 6 hours following cessation of Clevidipine infusion. - The blood pressure effect in this study is shown in Figure 5. The average infusion rate was 9.5 mg/hour. The mean duration of Clevidipine exposure was 21 hours. - Figure 5. Mean percent change in SBP (%) during the first 30 minutes of infusion, VELOCITY (severe hypertension) # How Supplied - Clevidipine (clevidipine) injectable emulsion is supplied as a sterile, milky white liquid emulsion product in single-use 50 mL or 100 mL glass vials at a concentration of 0.5 mg/mL of clevidipine. - NDC 65293-005-50: 50 mL vial - NDC 65293-005-00: 100 mL vial ## Storage - Leave vials in cartons until use. Clevidipine is photosensitive and storage in cartons protects against photodegradation. Protection from light during administration is not required. - Store vials refrigerated at 2-8°C (36-46°F). Do not freeze. Vials in cartons may be transferred to 25°C (77°F, USP controlled room temperature) for a period not to exceed 2 months. Upon transfer to room temperature, mark vials in cartons “This product was removed from the refrigerator on _/_/_ date. It must be used or discarded 2 months after this date or the labeled expiration date (whichever date comes first).” Do not return to refrigerated storage after beginning room temperature storage. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients with underlying hypertension that they require continued follow up for their medical condition, and, if applicable, encourage patients to continue taking their oral antihypertensive medication(s) as directed. - Advise patients to contact a healthcare professional immediately for any of the following signs of a new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure. # Precautions with Alcohol Alcohol-Clevidipine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Cleviprex # Look-Alike Drug Names There is limited information about the look-alike drugs. # Drug Shortage Status # Price	Clevidipine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Clevidipine is a calcium channel blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include nausea, vomiting, headache, acute renal failure. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information - Initial dosage: 1-2 mg/hour - Dose titration: The dose may be doubled at short (90 second) intervals initially. As the blood pressure approaches goal, the increase in doses should be less than doubling and the time between dose adjustments should be lengthened to every 5-10 minutes. An approximately 1-2 mg/hour increase will generally produce an additional 2-4 mmHg decrease in systolic pressure. - Maintenance dose: The desired therapeutic response for most patients occurs at doses of 4-6 mg/hour. Patients with severe hypertension may require doses up to 32 mg/hour, but there is limited experience at this dose rate. - Maximum dose: Most patients were treated with maximum doses of 16 mg/hour or less. There is limited short-term experience with doses up to 32 mg/hour. Because of lipid load restrictions, no more than 1000 mL or an average of 21 mg/hour of Clevidipine infusion is recommended per 24 hour period. - Transition to an oral antihypertensive agent: Discontinue Clevidipine or titrate downward while appropriate oral therapy is established. When an oral antihypertensive agent is being instituted, consider the lag time of onset of the oral agent’s effect. Continue blood pressure monitoring until desired effect is achieved. - Special populations: Special populations were not specifically studied. In clinical trials, 78 patients with abnormal hepatic function (one or more of the following: elevated serum bilirubin, AST/SGOT, ALT/SGPT) and 121 patients with moderate to severe renal impairment were treated with Clevidipine. An initial Clevidipine infusion rate of 1-2 mg/hour is appropriate in these patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clevidipine sandbox in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Clevidipine sandbox in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information about the FDA-labeled indications and dosage information for children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clevidipine sandbox in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Clevidipine sandbox in pediatric patients. # Contraindications - Clevidipine is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products. - Clevidipine is contraindicated in patients with defective lipid metabolism such as pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is accompanied by hyperlipidemia. - Clevidipine is contraindicated in patients with severe aortic stenosis because afterload reduction can be expected to reduce myocardial oxygen delivery. # Warnings ## Need for Aseptic Technique - Use aseptic technique and discard any unused product within 12 hours of stopper puncture. - Clevidipine may produce systemic hypotension and reflex tachycardia. If either occurs, decrease the dose of Clevidipine. There is limited experience with short-duration therapy with beta-blockers as a treatment for Clevidipine-induced tachycardia. Beta-blocker use for this purpose is not recommended. - Clevidipine contains approximately 0.2 g of lipid per mL (2.0 kcal). Lipid intake restrictions may be necessary for patients with significant disorders of lipid metabolism. For these patients, a reduction in the quantity of concurrently administered lipids may be necessary to compensate for the amount of lipid infused as part of the Clevidipine formulation. - Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. - Clevidipine is not a beta-blocker, does not reduce heart rate, and gives no protection against the effects of abrupt beta-blocker withdrawal. Beta-blockers should be withdrawn only after a gradual reduction in dose. - Patients who receive prolonged Clevidipine infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped. - There is no information to guide use of Clevidipine in treating hypertension associated with pheochromocytoma. # Adverse Reactions ## Clinical Trials Experience ## Clinical Trials Experience - Clevidipine clinical development included 19 studies, with 99 healthy subjects and 1307 hypertensive patients who received at least one dose of clevidipine (1406 total exposures). Clevidipine was evaluated in 15 studies in hypertensive patients: 1099 patients with perioperative hypertension, 126 with severe hypertension and 82 patients with essential hypertension. - The desired therapeutic response was achieved at doses of 4-6 mg/hour. Clevidipine was infused for <24 hours in the majority of patients (n=1199); it was infused as a continuous infusion in an additional 93 patients for durations between 24 and 72 hours. - 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 placebo-controlled experience with Clevidipine in the perioperative setting was both small and brief (about 30 minutes). Table 2 shows treatment-emergent adverse reactions and the category of “any common adverse event” in ESCAPE-1 and ESCAPE-2 where the rate on Clevidipine exceeded the rate on placebo by at least 5% (common adverse reactions). - Three randomized, parallel, open-label studies called ECLIPSE, with longer exposure in cardiac surgery patients define the adverse reactions for patients with perioperative hypertension. Each ECLIPSE study compared Cleviprex (n=752) to an active comparator: nitroglycerin (NTG, n=278), sodium nitroprusside (SNP, n=283), or nicardipine (NIC, n=193). The pooled mean maximum dose in these studies was 10 mg/hour and the mean duration of treatment was 8 hours. - There were many adverse events associated with the operative procedure in the clinical studies of Cleviprex and relatively few plausibly related to the drugs used to lower blood pressure. Thus, the ability to differentiate the adverse event profile between treatments is limited. The adverse events observed within one hour of the end of the infusion were similar in patients who received Cleviprex and in those who received comparator agents. There was no adverse reaction that was more than 2% more common on Cleviprex than on the average of all comparators. - Serious Adverse Events and Discontinuation – Perioperative hypertension Studies - The incidence of adverse events leading to study drug discontinuation in patients with perioperative hypertension receiving Cleviprex was 5.9% versus 3.2% for all active comparators. :For patients receiving Cleviprex and all active comparators the incidence of serious adverse events within one hour of drug infusion discontinuation was similar. - The adverse events for patients with severe hypertension are based on an uncontrolled study in patients with severe hypertension (VELOCITY, n=126). - The common adverse reactions for Cleviprex in severe hypertension included headache (6.3%), nausea (4.8%), and vomiting (3.2%). The incidence of adverse events leading to study drug discontinuation for Cleviprex in severe hypertension was 4.8%. - Adverse reactions that were reported in <1% of patients with severe or essential hypertension included: Myocardial infarction, cardiac arrest Syncope Dyspnea ## Postmarketing Experience - Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of Clevidipine: increased blood triglycerides, ileus, hypersensitivity, hypotension, nausea, decreased oxygen saturation (possible pulmonary shunting) and reflex tachycardia. # Drug Interactions No clinical drug interaction studies were conducted. Clevidipine and its major dihydropyridine metabolite do not have the potential for blocking or inducing any CYP enzyme. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies of Clevidipine use in pregnant women. In animal studies, clevidipine caused increases in maternal and fetal mortality and length of gestation. Clevidipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - There was decreased fetal survival when pregnant rats and rabbits were treated with clevidipine during organogenesis at doses 0.7 times (on a body surface area basis) the maximum recommended human dose (MRHD) in rats and 2 times the MRHD in rabbits. - In pregnant rats dosed with clevidipine during late gestation and lactation, there were dose-related increases in maternal mortality, length of gestation and prolonged parturition at doses greater than or equal to 1/6 of the MRHD based on body surface area. When offspring of these dams were mated, they had a conception rate lower than that of controls. Clevidipine has been shown to cross the placenta in rats. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clevidipine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Clevidipine during labor and delivery. ### Nursing Mothers - It is not known whether clevidipine is excreted in human milk. Because many drugs are excreted in human milk, consider possible infant exposure when Clevidipine is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of Clevidipine in children under 18 years of age have not been established. ### Geriatic Use - Of the 1406 subjects (1307 with hypertension) treated with Clevidipine in clinical studies, 620 were ≥65 years of age and 232 were ≥75 years of age. No overall differences in safety or effectiveness were observed between these and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, for an elderly patient doses should be titrated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Clevidipine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Clevidipine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Clevidipine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Clevidipine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Clevidipine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Clevidipine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Clevidipine is intended for intravenous use. Titrate drug to achieve the desired blood pressure reduction. Individualize dosage depending on the blood pressure to be obtained and the response of the patient. ## Instructions for Administration - Maintain aseptic technique while handling Clevidipine. Clevidipine is a single-use parenteral product. Do not use if contamination is suspected. Once the stopper is punctured, use within 12 hours and discard any unused portion. - Clevidipine is supplied in sterile, pre-mixed, ready-to-use 50 mL or 100 mL vials. Invert vial gently several times before use to ensure uniformity of the emulsion prior to administration. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. Administer Clevidipine using an infusion device allowing calibrated infusion rates. Commercially available standard plastic cannulae may be used to administer the infusion.Administer Clevidipine by a central line or a peripheral line. - Clevidipine should not be administered in the same line as other medications. - Clevidipine should not be diluted, but it can be administered with the following: - Water for Injection, USP - Sodium Chloride (0.9%) Injection, USP - Dextrose (5%) Injection, USP - Dextrose (5%) in Sodium Chloride (0.9%) Injection, USP - Dextrose (5%) in Ringers Lactate Injection, USP - Lactated Ringers Injection, USP - 10% amino acid ### Monitoring - Monitor blood pressure and heart rate continually during infusion, and then until vital signs are stable. Patients who receive prolonged Clevidipine infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped. These patients may need follow-up adjustments in blood pressure control. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - There has been no experience of overdosage in human clinical trials. In clinical trials, doses of Clevidipine up to 106 mg/hour or 1153 mg maximum total dose were administered. The expected major effects of overdose would be hypotension and reflex tachycardia. - Discontinuation of Clevidipine leads to a reduction in antihypertensive effects within 5 to 15 minutes [see Clinical Pharmacology (12.2)]. In case of suspected overdosage, Clevidipine should be discontinued immediately and the patient’s blood pressure should be supported. # Pharmacology ## Mechanism of Action - Clevidipine is a dihydropyridine L-type calcium channel blocker. L-type calcium channels mediate the influx of calcium during depolarization in arterial smooth muscle. Experiments in anesthetized rats and dogs show that clevidipine reduces mean arterial blood pressure by decreasing systemic vascular resistance. Clevidipine does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels. ## Structure - Clevidipine is a sterile, milky-white emulsion containing 0.5 mg/mL of clevidipine suitable for intravenous administration. Clevidipine is a dihydropyridine calcium channel blocker. Chemically, the active substance, clevidipine, is butyroxymethyl methyl 4-(2´,3´-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. It is a racemic mixture with a molecular weight of 456.3 g/mol. Each enantiomer has equipotent antihypertensive activity. The structure and formula are: - Clevidipine is practically insoluble in water and is formulated in an oil-in-water emulsion. In addition to the active ingredient, clevidipine, Clevidipine contains soybean oil (200 mg/mL), glycerin (22.5 mg/mL), purified egg yolk phospholipids (12 mg/mL), oleic acid (0.3 mg/mL), disodium edetate (0.05 mg/mL), and sodium hydroxide to adjust pH. Clevidipine has a pH of 6.0 – 8.0 and is a ready-to-use emulsion. ## Pharmacodynamics - Clevidipine is titrated to the desired reduction in blood pressure. The effect of Clevidipine appears to plateau at approximately 25% of baseline systolic pressure. The infusion rate for which half the maximal effect is observed is approximately 10 mg/hour. Onset of Effect - In the perioperative patient population, Clevidipine produces a 4-5% reduction in systolic blood pressure within 2-4 minutes after starting a 0.4 mcg/kg/min infusion (approximately 1-2 mg/hr). Maintenance of Effect - In studies up to 72 hours of continuous infusion, there was no evidence of tolerance or hysteresis. Offset of Effect - In most patients, full recovery of blood pressure is achieved in 5-15 minutes after the infusion is stopped. - In studies up to 72 hours of continuous infusion, in patients that were not transitioned to other antihypertensive therapies, there was some evidence of rebound hypertension following Clevidipine discontinuation. Hemodynamics - Clevidipine causes a dose-dependent decrease in systemic vascular resistance. Heart Rate - An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced. Electrophysiologic Effects - In healthy volunteers, clevidipine or its major carboxylic acid metabolite, at therapeutic and supratherapeutic concentrations (approximately 2.8 times steady-state), did not prolong cardiac repolarization. ## Pharmacokinetics - Clevidipine is rapidly distributed and metabolized resulting in a very short half life. The arterial blood concentration of clevidipine declines in a multi-phasic pattern following termination of the infusion. The initial phase half-life is approximately 1 minute, and accounts for 85-90% of clevidipine elimination. The terminal half-life is approximately 15 minutes. Distribution - Clevidipine is >99.5% bound to proteins in plasma at 37°C. The steady-state volume of distribution was determined to be 0.17 L/kg in arterial blood. Metabolism and Elimination - Clevidipine is rapidly metabolized by hydrolysis of the ester linkage, primarily by esterases in the blood and extravascular tissues, making its elimination unlikely to be affected by hepatic or renal dysfunction. The primary metabolites are the carboxylic acid metabolite and formaldehyde formed by hydrolysis of the ester group. The carboxylic acid metabolite is inactive as an antihypertensive. This metabolite is further metabolized by glucuronidation or oxidation to the corresponding pyridine derivative. The clearance of the primary dihydropyridine metabolite is 0.03 L/h/kg and the terminal half life is approximately 9 hours. - In vitro studies show that clevidipine and its metabolite at the concentrations achieved in clinical practice will not inhibit or induce any CYP enzyme. - In a clinical study with radiolabeled clevidipine, 83% of the drug was excreted in urine and feces. The major fraction, 63-74% is excreted in the urine, 7-22% in the feces. More than 90% of the recovered radioactivity is excreted within the first 72 hours of collection. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Clevidipine displayed positive genotoxic potential in vitro in the Ames test, mouse lymphoma thymidine kinase locus assay, and chromosomal aberration assay but not in vivo in the mouse micronucleus test. Formaldehyde, a metabolite of clevidipine, a known genotoxicant in vitro and a probable human carcinogen, appears to be at least partially responsible for the positive in vitro results. Long-term studies for evaluation of carcinogenic potential have not been performed with clevidipine due to the intended short-term duration of human use. There were no adverse effects on fertility or mating behavior of male rats at clevidipine doses of up to 55 mg/kg/day, approximately equivalent to the maximum recommended human dose (MRHD) of 504 mg/day (21 mg/hour x 24 hours) on a body surface area basis. Female rats demonstrated pseudopregnancy and changes in estrus cycle at doses as low as 13 mg/kg/day (about 1/4th the MRHD); however, doses of up to 55 mg/kg/day did not affect mating performance or fertility. ## Developmental Toxicology - When pregnant rats were dosed with clevidipine during late gestation and lactation, there were dose-related increases in mortality, length of gestation and prolonged parturition at dose levels as low as 13 mg/kg/day (about 1/4th the maximum recommended human dose of 504 mg/day (21 mg/hour x 24 hours) on a body surface area basis). When offspring of these dams were mated, they had a conception rate lower than that of controls. Clevidipine crosses the placental membrane in this species and doses of 35 or more mg/kg/day (about 0.7 times the MRHD) administered during organogenesis adversely affected fetal survival. Fetal survival was also adversely affected when pregnant rabbits were treated during organogenesis with 55 mg/kg/day (about twice the MRHD on a body surface area basis). # Clinical Studies ## Perioperative Hypertension - Clevidipine was evaluated in two double-blind, randomized, parallel, placebo-controlled, multicenter trials of cardiac surgery patients—pre-operative use in ESCAPE-1 (n=105) and post-operative use in ESCAPE-2 (n=110). Patients were undergoing coronary artery bypass grafting, with or without valve replacement. Inclusion in ESCAPE-1 required a systolic pressure ≥160 mmHg. In ESCAPE-2, the entry criterion was systolic pressure of ≥140 mmHg within 4 hours of the completed surgery. The mean baseline blood pressure was 178/77 mmHg in ESCAPE -1 and 150/71 mmHg in ESCAPE 2. The population of both studies included 27% females and 47% patients older than age 65. - Clevidipine was infused in ESCAPE-1 preoperatively for 30 minutes, until treatment failure, or until induction of anesthesia, whichever came first. Clevidipine was infused in ESCAPE-2 postoperatively for a minimum of 30 minutes unless alternative therapy was required. The maximum infusion time allowed in the ESCAPE studies was 60 minutes. - In both studies infusion of Clevidipine was started at a dose of 1- 2 mg/hour and was titrated upwards, as tolerated, in doubling increments every 90 seconds up to an infusion rate of 16 mg/hour in order to achieve the desired blood pressure-lowering effect. At doses above 16 mg/hour increments were 7 mg/hour. The average Clevidipine infusion rate in ESCAPE-1 was 15.3 mg/hour and in ESCAPE-2 it was 5.1 mg/hour. The mean duration of exposure in the same ESCAPE studies was 30 minutes for the Clevidipine treated patients. - Approximately 4% of Clevidipine-treated subjects in ESCAPE-1 and 41% in ESCAPE-2 were on concomitant vasodilators during the first 30 minutes of Clevidipine administration. - Clevidipine lowered blood pressure within 2-4 minutes. The change in systolic blood pressure over 30 minutes for ESCAPE-1 (preoperative) and ESCAPE-2 (postoperative) are shown in Figure 1 and 2. - The change in heart rate over 30 minutes for ESCAPE-1 (preoperative) and ESCAPE-2 (postoperative) are shown in Figure 3 and 4. - In three Phase 3 open-label clinical trials (ECLIPSE), 1512 patients were randomized to receive Clevidipine, nitroglycerin (perioperative hypertension), sodium nitroprusside (perioperative hypertension), or nicardipine (postoperative hypertension), for the treatment of hypertension in cardiac surgery. The mean exposure in the ECLIPSE studies was 8 hours at 4.5 mg/hour for the 752 patients who were treated with Clevidipine. Blood pressure control was assessed by measuring the magnitude and duration of SBP excursions outside the predefined pre- and post-operative SBP target range of 75-145 mmHg and the predefined intra-operative SBP range of 65-135 mmHg. In general, blood pressure control was similar with the four treatments. ## Severe Hypertension - Clevidipine was evaluated in an open-label, uncontrolled clinical trial (VELOCITY) in 126 patients with severe hypertension (SBP >180 mmHg or diastolic blood pressure [DBP] >115 mmHg). Clevidipine infusion was initiated at 2 mg/hour and up-titrated every 3 minutes, doubling up to a maximum dose of 32 mg/hour as required to achieve a prespecified target blood pressure range within 30 minutes (primary endpoint). The transition to oral antihypertensive therapy was assessed for up to 6 hours following cessation of Clevidipine infusion. - The blood pressure effect in this study is shown in Figure 5. The average infusion rate was 9.5 mg/hour. The mean duration of Clevidipine exposure was 21 hours. - Figure 5. Mean percent change in SBP (%) during the first 30 minutes of infusion, VELOCITY (severe hypertension) # How Supplied - Clevidipine (clevidipine) injectable emulsion is supplied as a sterile, milky white liquid emulsion product in single-use 50 mL or 100 mL glass vials at a concentration of 0.5 mg/mL of clevidipine. - NDC 65293-005-50: 50 mL vial - NDC 65293-005-00: 100 mL vial ## Storage - Leave vials in cartons until use. Clevidipine is photosensitive and storage in cartons protects against photodegradation. Protection from light during administration is not required. - Store vials refrigerated at 2-8°C (36-46°F). Do not freeze. Vials in cartons may be transferred to 25°C (77°F, USP controlled room temperature) for a period not to exceed 2 months. Upon transfer to room temperature, mark vials in cartons “This product was removed from the refrigerator on _/_/_ date. It must be used or discarded 2 months after this date or the labeled expiration date (whichever date comes first).” Do not return to refrigerated storage after beginning room temperature storage. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients with underlying hypertension that they require continued follow up for their medical condition, and, if applicable, encourage patients to continue taking their oral antihypertensive medication(s) as directed. - Advise patients to contact a healthcare professional immediately for any of the following signs of a new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure. # Precautions with Alcohol Alcohol-Clevidipine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Cleviprex # Look-Alike Drug Names There is limited information about the look-alike drugs. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Clevidipine
f489d6f6842345777371950abfee9636465dd41b	wikidoc	Clobenzorex	Clobenzorex # Overview Clobenzorex (also known under the brand names Asenlix, Finedal, or Rexigen; or the US slang "greenies") is a stimulant drug used as an anorectic (that is, a medication that suppresses appetite). The drug is legally distributed in Mexico under the trade name Asenlix by the Aventis pharmaceutical corporation. Chemically, clobenzorex is an N-substituted amphetamine analog that is converted to (d) amphetamine soon after ingestion. In commercial production, clobenzorex is supplied in 30mg doses as the hydrochloride salt in green-tinted capsules. The drug gained use as a prescription anorectic in the 1970s; however, adverse reactions were eventually observed, which led to the prohibition of clobenzorex in the US and certain other countries. In the United States of America, clobenzorex tablets (among other varieties of stimulants, such as amphetamine) have been used by athletes who ingest the drug to reduce fatigue, increase attention, and improve reaction times during athletic activities. The green-tinted Asenlix capsules (generic forms can be seen as half light green, half dark green capsules marked "IFA") are known as "greenies" among US baseball players, a slang term that in current use has expanded to generically refer to any amphetamine-class stimulant.	Clobenzorex Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Clobenzorex (also known under the brand names Asenlix, Finedal, or Rexigen; or the US slang "greenies") is a stimulant drug used as an anorectic (that is, a medication that suppresses appetite). The drug is legally distributed in Mexico under the trade name Asenlix by the Aventis pharmaceutical corporation. Chemically, clobenzorex is an N-substituted amphetamine analog that is converted to (d) amphetamine soon after ingestion. In commercial production, clobenzorex is supplied in 30mg doses as the hydrochloride salt in green-tinted capsules. The drug gained use as a prescription anorectic in the 1970s; however, adverse reactions were eventually observed, which led to the prohibition of clobenzorex in the US and certain other countries.[1] In the United States of America, clobenzorex tablets (among other varieties of stimulants, such as amphetamine) have been used by athletes who ingest the drug to reduce fatigue, increase attention, and improve reaction times during athletic activities. The green-tinted Asenlix capsules (generic forms can be seen as half light green, half dark green capsules marked "IFA") are known as "greenies" among US baseball players, a slang term that in current use has expanded to generically refer to any amphetamine-class stimulant.	https://www.wikidoc.org/index.php/Clobenzorex
063c873df5b676c8074a8ca99db2f42fc7ac6e79	wikidoc	Clobetasone	Clobetasone # Overview Clobetasone (INN) is a corticosteroid used in dermatology, for treating such skin inflammation as seen in eczema, psoriasis and other forms of dermatitis, and ophthalmology. Topical clobetasone butyrate has shown minimal suppression of the Hypothalamic-pituitary-adrenal axis. It is available as clobetasone butyrate under the brand names Eumosone or Eumovate both manufactured by GlaxoSmithKline. Trimovate also contains Oxytetracycline, an antibiotic, and nystatin, an antifungal. # Uses In dermatology, topical clobestasone butyrate helps to reduce the itchiness and erythema associated with eczema and dermatitis. In ophthalmology, clobetasone butyrate 0.1% eye drops have been shown to be safe and effective in the treatment of dry eyes in Sjögren's Syndrome. Sjögren's Syndrome is an autoimmune disorder that affects the moisture producing glands of the body causing many symptoms including dry eyes. When compared to other corticosteroid eye drops; clobetasone butyrate showed only minimal rises in intraocular pressure. Increased pressure within the eye can lead to glaucoma. # Adverse effects Side effects associated with clobetasone cream and ointment include: burning, irritation, itching, thinning of the skin, and changes in skin color.	Clobetasone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Clobetasone (INN) is a corticosteroid used in dermatology, for treating such skin inflammation as seen in eczema, psoriasis and other forms of dermatitis, and ophthalmology. Topical clobetasone butyrate has shown minimal suppression of the Hypothalamic-pituitary-adrenal axis. It is available as clobetasone butyrate under the brand names Eumosone or Eumovate both manufactured by GlaxoSmithKline. Trimovate also contains Oxytetracycline, an antibiotic, and nystatin, an antifungal. # Uses In dermatology, topical clobestasone butyrate helps to reduce the itchiness and erythema associated with eczema and dermatitis. In ophthalmology, clobetasone butyrate 0.1% eye drops have been shown to be safe and effective in the treatment of dry eyes in Sjögren's Syndrome. Sjögren's Syndrome is an autoimmune disorder that affects the moisture producing glands of the body causing many symptoms including dry eyes. When compared to other corticosteroid eye drops; clobetasone butyrate showed only minimal rises in intraocular pressure. Increased pressure within the eye can lead to glaucoma. # Adverse effects Side effects associated with clobetasone cream and ointment include: burning, irritation, itching, thinning of the skin, and changes in skin color.	https://www.wikidoc.org/index.php/Clobetasone
338e88c6d2189e707337e5dd99d66385da95ebff	wikidoc	Clofarabine	Clofarabine # 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 Clofarabine is an antineoplastic agent that is FDA approved for the treatment of relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Common adverse reactions include hypotension, tachycardia, abdominal pain,diarrhea, anemia, lymphocytopenia, thrombocytopenia, headache, anxiety, epistaxis, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Guideline-Supported Use of Clofarabine in adult patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clofarabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Clofarabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Clofarabine Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Clofarabine. # Dosage - Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days. - Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. The dosage is based on the patient's body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, no other medications should be administered through the same intravenous line. - Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of Clofarabine administration to reduce the effects of tumor lysis and other adverse events. - Discontinue Clofarabine if hypotension develops during the 5 days of administration. - Reduce the dose by 50% in patients with creatinine clearance (CrCL) between 30 and 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min. # Dose Modifications and Reinitiation of Therapy Hematologic Toxicity - Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patient's ANC is ≥ 0.75 × 109/L. - If a patient experiences a Grade 4 neutropenia (ANC <0.5 × 109/L) lasting ≥4 weeks, reduce dose by 25% for the next cycle. Non-hematologic Toxicity - Withhold Clofarabine if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose. - Withhold Clofarabine for a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). Re-institute Clofarabine administration at a 25% dose reduction when resolution or return to baseline. - Discontinue Clofarabine administration for a Grade 4 non-infectious non-hematologic toxicity. - Discontinue Clofarabine administration if a patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures. - Discontinue Clofarabine administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute Clofarabine with a 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid. # DOSAGE FORMS AND STRENGTHS - 20 mg/20 mL (1 mg/mL) single-use vial ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clofarabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Clofarabine in pediatric patients. # Contraindications - None # Warnings Myelosuppression - Clofarabine causes myelosuppression which may be severe and prolonged. Febrile neutropenia occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical trials. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Myelosuppression is usually reversible with interruption of Clofarabine treatment and appears to be dose-dependent. Monitor complete blood counts. Hemorrhage - Serious and fatal hemorrhage, including cerebral, gastrointestinal and pulmonary hemorrhage, has occurred. The majority of the cases were associated with thrombocytopenia. Monitor platelets and coagulation parameters and treat accordingly. Infections - Clofarabine increases the risk of infection, including severe and fatal sepsis, and opportunistic infections. At baseline, 48% of the pediatric patients had one or more concurrent infections. A total of 83% of patients experienced at least one infection after Clofarabine treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue Clofarabine, and treat promptly. Hyperuricemia (Tumor Lysis) - Administration of Clofarabine may result in tumor lysis syndrome associated with the break-down metabolic products from peripheral leukemia cell death. Monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome and initiate preventive measures including adequate intravenous fluids and measures to control uric acid. Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome - Clofarabine may cause a cytokine release syndrome (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that may progress to the systemic inflammatory response syndrome (SIRS) with capillary leak syndrome and organ impairment which may be fatal. Monitor patients frequently for these conditions. In clinical trials, SIRS was reported in two patients (2%); capillary leak syndrome was reported in four patients (4%). Symptoms included rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multi-organ failure. Close monitoring for this syndrome and early intervention may reduce the risk. Immediately discontinue Clofarabine and provide appropriate supportive measures. The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak. Consider use of diuretics and/or albumin. After the patient is stabilized and organ function has returned to baseline, re-treatment with Clofarabine can be considered with a 25% dose reduction. Venous Occlusive Disease of the Liver - Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for veno-occlusive disease (VOD) of the liver following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in a combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia. Two cases (2%) of VOD in the mono-therapy studies were considered related to study drug. Monitor for and discontinue Clofarabine if VOD is suspected. Hepatotoxicity - Severe and fatal hepatotoxicity has occurred with the use of Clofarabine. In clinical studies, Grade 3–4 liver enzyme elevations were observed in pediatric patients during treatment with Clofarabine at the following rates: elevated aspartate aminotransferase (AST) occurred in 36% of patients; elevated alanine aminotransferase (ALT) occurred in 44% of patients. AST and ALT elevations typically occurred within 10 days of Clofarabine administration and returned to Grade 2 or less within 15 days. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as Grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation and one patient had multi-organ failure and died. Eight patients (7%) had Grade 3 or 4 elevations in serum bilirubin at the last time point measured; these patients died due to sepsis and/or multi-organ failure. Monitor hepatic function and discontinue Clofarabine for Grade 3 or greater liver enzyme elevations. Renal Toxicity - In clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of patients; acute renal failure was reported as Grade 3 in three patients (3%) and Grade 4 in two patients (2%). Hematuria was observed in 13% of patients overall. Monitor patients for renal toxicity and interrupt or discontinue Clofarabine as necessary. Enterocolitis - Fatal and serious cases of enterocolitis, including neutropenic colitis, cecitis, and C. difficile colitis, have occurred during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation, hemorrhage or sepsis complications . Monitor patients for signs and symptoms of enterocolitis and treat promptly. Skin Reactions - Serious and fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported. Discontinue Clofarabine for exfoliative or bullous rash, or if SJS or TEN is suspected. Embryo-fetal Toxicity - Clofarabine can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the label: - Myelosuppression - Hemorrhage - Serious Infections - Hyperuricemia (Tumor Lysis) - Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome - Venous Occlusive Disease of the Liver - Hepatotoxicity - Renal Toxicity - Enterocolitis - Skin Reactions Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data described below reflect exposure to Clofarabine in 115 pediatric patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) (70 patients) or Acute Myelogenous Leukemia (AML) (45 patients). - In total, 115 pediatric patients treated in clinical trials received the recommended dose of Clofarabine 52 mg/m2 daily × 5. The median number of cycles was 2. The median cumulative amount of Clofarabine received by pediatric patients during all cycles was 540 mg. - The most common adverse reactions occurring in 10% or more of patients treated with Clofarabine are: nausea, vomiting, diarrhea, febrile neutropenia, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar erythrodysesthesia syndrome, anxiety, flushing, and mucosal inflammation. - Table 1 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTC Grade 3 or Grade 4), reported in ≥ 5% of the 115 patients in the 52 mg/m2/day dose group (pooled analysis of pediatric patients with ALL and AML). More detailed information and follow-up of certain events is given below. - The following less common adverse reactions have been reported in 1–4% of the 115 pediatric patients with ALL or AML: - Gastrointestinal Disorders: cecitis, pancreatitis - Hepatobiliary Disorders: hyperbilirubinemia - Immune System Disorders: hypersensitivity - Infections and Infestations: bacterial infection, Enterococcal bacteremia, Escherichia bacteremia, Escherichia sepsis, fungal infection, fungal sepsis, gastroenteritis adenovirus, infection, influenza, parainfluenza virus infection, fungal pneumonia, pneumonia primary atypical, Respiratory syncytial virus infection, sinusitis, staphylococcal infection - Investigations: blood creatinine increased - Psychiatric Disorders: mental status change - Respiratory, Thoracic and Mediastinal Disorder: pulmonary edema - Table 2 lists the incidence of treatment-emergent laboratory abnormalities after Clofarabine administration at 52 mg/m2 among pediatric patients with ALL and AML (N=115). ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Clofarabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to Clofarabine. - Gastrointestinal disorders: Gastrointestinal hemorrhage including fatalities. - Metabolism and nutrition disorders: hyponatremia - Skin and subcutaneous tissue disorders: Occurrences of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported in patients who were receiving or had recently been treated with Clofarabine and other medications (e.g., allopurinol or antibiotics) known to cause these syndromes. Other exfoliative conditions have also been reported. # Drug Interactions - No in-vivo drug interaction studies have been conducted # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category D - Clofarabine (clofarabine) may cause fetal harm when administered to a pregnant woman. - Clofarabine was teratogenic in rats and rabbits. Developmental toxicity (reduced fetal body weight and increased post-implantation loss) and increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 54 mg/m2/day (approximately equivalent to the recommended clinical dose on a mg/m2 basis), and in rabbits receiving 12 mg/m2/day (approximately 23% of the recommended clinical dose on a mg/m2 basis). - There are no adequate and well-controlled studies in pregnant women using clofarabine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with clofarabine. All patients should be advised to use effective contraceptive measures to prevent pregnancy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clofarabine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Clofarabine during labor and delivery. ### Nursing Mothers - It is not known whether clofarabine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse reactions, women treated with clofarabine should not nurse. Female patients should be advised to avoid breast-feeding during treatment with Clofarabine. ### Pediatric Use - Safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia. ### Geriatic Use - Safety and effectiveness of Clofarabine has not been established in geriatric patients aged 65 and older. ### Gender There is no FDA guidance on the use of Clofarabine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Clofarabine with respect to specific racial populations. ### Renal Impairment - Reduce the Clofarabine starting dose by 50% in patients with CrCL of 30 to 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min or in patients on dialysis. - The pharmacokinetics of clofarabine in patients with renal impairment and normal renal function were obtained from a population pharmacokinetic analysis of three pediatric and two adult studies. In patients with CrCL 60 to less than 90 mL/min (N = 47) and CrCL 30 to less than 60 mL/min (N = 30), the average AUC of clofarabine increased by 60% and 140%, respectively, compared to patients with normal (N = 66) renal function (CrCL greater than 90 mL/min). ### Hepatic Impairment - Clofarabine has not been studied in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Clofarabine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Clofarabine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous Incompatibilities - Do not administer any other medications through the same intravenous line. ### Monitoring - Monitor renal and hepatic function during the 5 days of Clofarabine administration. - Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clofarabine. # IV Compatibility Reconstitution/Preparation - Clofarabine should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous (IV) infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Store diluted Clofarabine at room temperature (15–30ºC). # Overdosage - There were no known overdoses of Clofarabine. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included Grade 4 hyperbilirubinemia, Grade 2 and 3 vomiting, and Grade 3 maculopapular rash. - In a Phase 1 study of adults with refractory and/or relapsed hematologic malignancies, the recommended pediatric dose of 52 mg/m2/day was not tolerated. # Pharmacology ## Mechanism of Action - Clofarabine is sequentially metabolized intracellularly to the 5'-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5'-triphosphate metabolite. Clofarabine has affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. - Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro. ## Structure - Clofarabine (clofarabine) Injection contains clofarabine, a purine nucleoside metabolic inhibitor. Clofarabine (1 mg/mL) is supplied in a 20 mL, single-use vial. The 20 mL vial contains 20 mg clofarabine formulated in 20 mL unbuffered normal saline (comprised of Water for Injection, USP, and Sodium Chloride, USP). The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, and is preservative-free. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Clofarabine in the drug label. ## Pharmacokinetics - The population pharmacokinetics of Clofarabine were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m2 dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on non-compartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females. - No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population. - Based on 24-hour urine collections in the pediatric studies, 49–60% of the dose is excreted in the urine unchanged. In vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%). The pathways of non-hepatic elimination remain unknown. Drug-Drug Interactions - In vitro studies suggested that clofarabine undergoes limited metabolism and does not inhibit or induce major CYP enzymes. CYP inhibitors and inducers are unlikely to affect the metabolism of clofarabine. Clofarabine is unlikely to affect the metabolism of CYP substrates. However, no in vivo drug interaction studies have been conducted. - An in vitro transporter study suggested that clofarabine is a substrate of human transporters OAT1, OAT3, and OCT1. A preclinical study using perfused rat kidney demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an inhibitor of the hOCT2. Although the clinical implications of this finding have not been determined, signs of Clofarabine toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Clofarabine has not been tested for carcinogenic potential. - Clofarabine showed clastogenic activity in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. It did not show evidence of mutagenic activity in the bacterial mutation assay (Ames test). - Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal (IP) doses of 3 mg/kg/day (9 mg/m2/day, approximately 17% of clinical recommended dose on a mg/m2 basis). The testes of rats receiving 25 mg/kg/day (150 mg/m2/day, approximately 3 times the recommended clinical dose on a mg/m2 basis) in a 6-month IV study had bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month IV dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (7.5 mg/m2/day, approximately 14% of the clinical recommended dose on a mg/m2 basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m2/day, approximately 4-fold of recommended human dose on a mg/m2 basis), the only dose administered to female mice. The effect on human fertility is unknown. # Clinical Studies - Seventy-eight (78) pediatric patients with ALL were exposed to Clofarabine. Seventy (70) of the patients received the recommended pediatric dose of Clofarabine 52 mg/m2 daily for 5 days as an intravenous (IV) infusion. Dose Escalation Study in Pediatric Patients with Hematologic Malignancies - The safety and efficacy of Clofarabine were evaluated in pediatric patients with refractory or relapsed hematologic malignancies in an open-label, dose-escalation, noncomparative study. The starting dose of Clofarabine was 11.25 mg/m2/day IV infusion daily × 5 and escalated to 70 mg/m2/day IV infusion daily × 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with Clofarabine 52 mg/m2 daily for 5 days. In the 17 ALL patients there were 2 complete remissions (12%) and 2 partial remissions (12%) at varying doses. Dose-limiting toxicities (DLTs) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m2. As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m2/day for 5 days. Single-Arm Study in Pediatric ALL - Clofarabine was evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m2 over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles. There was no dose escalation in this study. - All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 38/61 (62%), had received > 2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years, 61% were male, 39% were female, 44% were Caucasian, 38% were Hispanic, 12% were African-American, 2% were Asian and 5% were Other race. - The overall remission (OR) rate (Complete Remission + CR in the absence of total platelet recovery ) was evaluated. CR was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (≤ 5% blasts), and recovery of peripheral counts . CRp was defined as meeting all criteria for CR except for recovery of platelet counts to ≥ 100 × 109/L. Partial Response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow (≥ 5% and ≤ 25% blasts), and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. Duration of remission was also evaluated. Transplantation rate was not a study endpoint. - Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP). - Table 3 summarizes results for the pediatric ALL study. Responses were seen in both pre-B and T-cell immunophenotypes of ALL. The median cumulative dose was 530 mg (range 29–2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. The median number of cycles was 2 (range 1–12). The median time between cycles was 28 days with a range of 12 to 55 days. - Six (9.8%) patients achieved a PR; the clinical relevance of a PR in this setting is unknown. - Of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17%) achieved a CR or CRp. Of 18 patients who had at least 1 prior hematopoietic stem cell transplant (HSCT), 5 (28%) achieved a CR or CRp. - Among the 12 patients who achieved at least a CRp, 6 patients achieved the best response after 1 cycle of clofarabine, 5 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy. # How Supplied - Clofarabine (clofarabine) Injection is supplied in single-use flint vials containing 20 mg of clofarabine in 20 mL of solution. Each box contains one Clofarabine vial (NDC 0024-5860-01). The 20mL flint vials contain 20 mL (20 mg) of solution. The pH range of the solution is 4.5 to 7.5. ## Storage - Vials containing undiluted Clofarabine should be stored at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F). - Diluted admixtures may be stored at room temperature, but must be used within 24 hours of preparation. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hematologic Toxicity: Advise patients to return for regular blood counts and to report any symptoms associated with hematologic toxicity (such as weakness, fatigue, pallor, shortness of breath, easy bruising, petechiae, purpura, fever) to their physician. - Infection: Advise patients of the signs or symptoms of infection (e.g., fever) and report to the physician immediately if any occur. - Hepatic and Renal Toxicity: Advise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the 5 days of Clofarabine administration. Also, advise patients of the possibility of developing liver function abnormalities and to immediately report signs or symptoms of jaundice . - Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome: Advise patients of the signs or symptoms of SIRS, such as fever, tachycardia, tachypnea, dyspnea and symptoms suggestive of hypotension . - Pregnancy and Breast-feeding: Advise male and female patients with reproductive potential to use effective contraceptive measures to prevent pregnancy. Advise female patients to avoid breast- feeding during Clofarabine treatment. - Gastrointestinal Disorders: Advise patients that they may experience nausea,vomiting, and/or diarrhea with Clofarabine. If these symptoms are significant, they should seek medical attention. - Rash: Advise patients that they may experience skin rash with Clofarabine. If this symptom is significant, they should seek medical attention. # Precautions with Alcohol - Alcohol-Clofarabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Clofarabine # Look-Alike Drug Names There is limited information regarding Clofarabine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Clofarabine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]; Sree Teja Yelamanchili, MBBS [3] # 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 Clofarabine is an antineoplastic agent that is FDA approved for the treatment of relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Common adverse reactions include hypotension, tachycardia, abdominal pain,diarrhea, anemia, lymphocytopenia, thrombocytopenia, headache, anxiety, epistaxis, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Guideline-Supported Use of Clofarabine in adult patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clofarabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Clofarabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Clofarabine Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Clofarabine. # Dosage - Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days. - Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. The dosage is based on the patient's body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, no other medications should be administered through the same intravenous line. - Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of Clofarabine administration to reduce the effects of tumor lysis and other adverse events. - Discontinue Clofarabine if hypotension develops during the 5 days of administration. - Reduce the dose by 50% in patients with creatinine clearance (CrCL) between 30 and 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min. # Dose Modifications and Reinitiation of Therapy Hematologic Toxicity - Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patient's ANC is ≥ 0.75 × 109/L. - If a patient experiences a Grade 4 neutropenia (ANC <0.5 × 109/L) lasting ≥4 weeks, reduce dose by 25% for the next cycle. Non-hematologic Toxicity - Withhold Clofarabine if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose. - Withhold Clofarabine for a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). Re-institute Clofarabine administration at a 25% dose reduction when resolution or return to baseline. - Discontinue Clofarabine administration for a Grade 4 non-infectious non-hematologic toxicity. - Discontinue Clofarabine administration if a patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures. - Discontinue Clofarabine administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute Clofarabine with a 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid. # DOSAGE FORMS AND STRENGTHS - 20 mg/20 mL (1 mg/mL) single-use vial ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clofarabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Clofarabine in pediatric patients. # Contraindications - None # Warnings Myelosuppression - Clofarabine causes myelosuppression which may be severe and prolonged. Febrile neutropenia occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical trials. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Myelosuppression is usually reversible with interruption of Clofarabine treatment and appears to be dose-dependent. Monitor complete blood counts. Hemorrhage - Serious and fatal hemorrhage, including cerebral, gastrointestinal and pulmonary hemorrhage, has occurred. The majority of the cases were associated with thrombocytopenia. Monitor platelets and coagulation parameters and treat accordingly. Infections - Clofarabine increases the risk of infection, including severe and fatal sepsis, and opportunistic infections. At baseline, 48% of the pediatric patients had one or more concurrent infections. A total of 83% of patients experienced at least one infection after Clofarabine treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue Clofarabine, and treat promptly. Hyperuricemia (Tumor Lysis) - Administration of Clofarabine may result in tumor lysis syndrome associated with the break-down metabolic products from peripheral leukemia cell death. Monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome and initiate preventive measures including adequate intravenous fluids and measures to control uric acid. Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome - Clofarabine may cause a cytokine release syndrome (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that may progress to the systemic inflammatory response syndrome (SIRS) with capillary leak syndrome and organ impairment which may be fatal. Monitor patients frequently for these conditions. In clinical trials, SIRS was reported in two patients (2%); capillary leak syndrome was reported in four patients (4%). Symptoms included rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multi-organ failure. Close monitoring for this syndrome and early intervention may reduce the risk. Immediately discontinue Clofarabine and provide appropriate supportive measures. The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak. Consider use of diuretics and/or albumin. After the patient is stabilized and organ function has returned to baseline, re-treatment with Clofarabine can be considered with a 25% dose reduction. Venous Occlusive Disease of the Liver - Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for veno-occlusive disease (VOD) of the liver following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in a combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia. Two cases (2%) of VOD in the mono-therapy studies were considered related to study drug. Monitor for and discontinue Clofarabine if VOD is suspected. Hepatotoxicity - Severe and fatal hepatotoxicity has occurred with the use of Clofarabine. In clinical studies, Grade 3–4 liver enzyme elevations were observed in pediatric patients during treatment with Clofarabine at the following rates: elevated aspartate aminotransferase (AST) occurred in 36% of patients; elevated alanine aminotransferase (ALT) occurred in 44% of patients. AST and ALT elevations typically occurred within 10 days of Clofarabine administration and returned to Grade 2 or less within 15 days. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as Grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation and one patient had multi-organ failure and died. Eight patients (7%) had Grade 3 or 4 elevations in serum bilirubin at the last time point measured; these patients died due to sepsis and/or multi-organ failure. Monitor hepatic function and discontinue Clofarabine for Grade 3 or greater liver enzyme elevations. Renal Toxicity - In clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of patients; acute renal failure was reported as Grade 3 in three patients (3%) and Grade 4 in two patients (2%). Hematuria was observed in 13% of patients overall. Monitor patients for renal toxicity and interrupt or discontinue Clofarabine as necessary. Enterocolitis - Fatal and serious cases of enterocolitis, including neutropenic colitis, cecitis, and C. difficile colitis, have occurred during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation, hemorrhage or sepsis complications . Monitor patients for signs and symptoms of enterocolitis and treat promptly. Skin Reactions - Serious and fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported. Discontinue Clofarabine for exfoliative or bullous rash, or if SJS or TEN is suspected. Embryo-fetal Toxicity - Clofarabine can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the label: - Myelosuppression - Hemorrhage - Serious Infections - Hyperuricemia (Tumor Lysis) - Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome - Venous Occlusive Disease of the Liver - Hepatotoxicity - Renal Toxicity - Enterocolitis - Skin Reactions Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data described below reflect exposure to Clofarabine in 115 pediatric patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) (70 patients) or Acute Myelogenous Leukemia (AML) (45 patients). - In total, 115 pediatric patients treated in clinical trials received the recommended dose of Clofarabine 52 mg/m2 daily × 5. The median number of cycles was 2. The median cumulative amount of Clofarabine received by pediatric patients during all cycles was 540 mg. - The most common adverse reactions occurring in 10% or more of patients treated with Clofarabine are: nausea, vomiting, diarrhea, febrile neutropenia, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar erythrodysesthesia syndrome, anxiety, flushing, and mucosal inflammation. - Table 1 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTC Grade 3 or Grade 4), reported in ≥ 5% of the 115 patients in the 52 mg/m2/day dose group (pooled analysis of pediatric patients with ALL and AML). More detailed information and follow-up of certain events is given below. - The following less common adverse reactions have been reported in 1–4% of the 115 pediatric patients with ALL or AML: - Gastrointestinal Disorders: cecitis, pancreatitis - Hepatobiliary Disorders: hyperbilirubinemia - Immune System Disorders: hypersensitivity - Infections and Infestations: bacterial infection, Enterococcal bacteremia, Escherichia bacteremia, Escherichia sepsis, fungal infection, fungal sepsis, gastroenteritis adenovirus, infection, influenza, parainfluenza virus infection, fungal pneumonia, pneumonia primary atypical, Respiratory syncytial virus infection, sinusitis, staphylococcal infection - Investigations: blood creatinine increased - Psychiatric Disorders: mental status change - Respiratory, Thoracic and Mediastinal Disorder: pulmonary edema - Table 2 lists the incidence of treatment-emergent laboratory abnormalities after Clofarabine administration at 52 mg/m2 among pediatric patients with ALL and AML (N=115). ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Clofarabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to Clofarabine. - Gastrointestinal disorders: Gastrointestinal hemorrhage including fatalities. - Metabolism and nutrition disorders: hyponatremia - Skin and subcutaneous tissue disorders: Occurrences of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported in patients who were receiving or had recently been treated with Clofarabine and other medications (e.g., allopurinol or antibiotics) known to cause these syndromes. Other exfoliative conditions have also been reported. # Drug Interactions - No in-vivo drug interaction studies have been conducted # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category D - Clofarabine (clofarabine) may cause fetal harm when administered to a pregnant woman. - Clofarabine was teratogenic in rats and rabbits. Developmental toxicity (reduced fetal body weight and increased post-implantation loss) and increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 54 mg/m2/day (approximately equivalent to the recommended clinical dose on a mg/m2 basis), and in rabbits receiving 12 mg/m2/day (approximately 23% of the recommended clinical dose on a mg/m2 basis). - There are no adequate and well-controlled studies in pregnant women using clofarabine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with clofarabine. All patients should be advised to use effective contraceptive measures to prevent pregnancy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clofarabine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Clofarabine during labor and delivery. ### Nursing Mothers - It is not known whether clofarabine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse reactions, women treated with clofarabine should not nurse. Female patients should be advised to avoid breast-feeding during treatment with Clofarabine. ### Pediatric Use - Safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia. ### Geriatic Use - Safety and effectiveness of Clofarabine has not been established in geriatric patients aged 65 and older. ### Gender There is no FDA guidance on the use of Clofarabine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Clofarabine with respect to specific racial populations. ### Renal Impairment - Reduce the Clofarabine starting dose by 50% in patients with CrCL of 30 to 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min or in patients on dialysis. - The pharmacokinetics of clofarabine in patients with renal impairment and normal renal function were obtained from a population pharmacokinetic analysis of three pediatric and two adult studies. In patients with CrCL 60 to less than 90 mL/min (N = 47) and CrCL 30 to less than 60 mL/min (N = 30), the average AUC of clofarabine increased by 60% and 140%, respectively, compared to patients with normal (N = 66) renal function (CrCL greater than 90 mL/min). ### Hepatic Impairment - Clofarabine has not been studied in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Clofarabine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Clofarabine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous Incompatibilities - Do not administer any other medications through the same intravenous line. ### Monitoring - Monitor renal and hepatic function during the 5 days of Clofarabine administration. - Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clofarabine. # IV Compatibility Reconstitution/Preparation - Clofarabine should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous (IV) infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Store diluted Clofarabine at room temperature (15–30ºC). # Overdosage - There were no known overdoses of Clofarabine. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included Grade 4 hyperbilirubinemia, Grade 2 and 3 vomiting, and Grade 3 maculopapular rash. - In a Phase 1 study of adults with refractory and/or relapsed hematologic malignancies, the recommended pediatric dose of 52 mg/m2/day was not tolerated. # Pharmacology ## Mechanism of Action - Clofarabine is sequentially metabolized intracellularly to the 5'-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5'-triphosphate metabolite. Clofarabine has affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. - Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro. ## Structure - Clofarabine (clofarabine) Injection contains clofarabine, a purine nucleoside metabolic inhibitor. Clofarabine (1 mg/mL) is supplied in a 20 mL, single-use vial. The 20 mL vial contains 20 mg clofarabine formulated in 20 mL unbuffered normal saline (comprised of Water for Injection, USP, and Sodium Chloride, USP). The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, and is preservative-free. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Clofarabine in the drug label. ## Pharmacokinetics - The population pharmacokinetics of Clofarabine were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m2 dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on non-compartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females. - No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population. - Based on 24-hour urine collections in the pediatric studies, 49–60% of the dose is excreted in the urine unchanged. In vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%). The pathways of non-hepatic elimination remain unknown. Drug-Drug Interactions - In vitro studies suggested that clofarabine undergoes limited metabolism and does not inhibit or induce major CYP enzymes. CYP inhibitors and inducers are unlikely to affect the metabolism of clofarabine. Clofarabine is unlikely to affect the metabolism of CYP substrates. However, no in vivo drug interaction studies have been conducted. - An in vitro transporter study suggested that clofarabine is a substrate of human transporters OAT1, OAT3, and OCT1. A preclinical study using perfused rat kidney demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an inhibitor of the hOCT2. Although the clinical implications of this finding have not been determined, signs of Clofarabine toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Clofarabine has not been tested for carcinogenic potential. - Clofarabine showed clastogenic activity in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. It did not show evidence of mutagenic activity in the bacterial mutation assay (Ames test). - Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal (IP) doses of 3 mg/kg/day (9 mg/m2/day, approximately 17% of clinical recommended dose on a mg/m2 basis). The testes of rats receiving 25 mg/kg/day (150 mg/m2/day, approximately 3 times the recommended clinical dose on a mg/m2 basis) in a 6-month IV study had bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month IV dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (7.5 mg/m2/day, approximately 14% of the clinical recommended dose on a mg/m2 basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m2/day, approximately 4-fold of recommended human dose on a mg/m2 basis), the only dose administered to female mice. The effect on human fertility is unknown. # Clinical Studies - Seventy-eight (78) pediatric patients with ALL were exposed to Clofarabine. Seventy (70) of the patients received the recommended pediatric dose of Clofarabine 52 mg/m2 daily for 5 days as an intravenous (IV) infusion. Dose Escalation Study in Pediatric Patients with Hematologic Malignancies - The safety and efficacy of Clofarabine were evaluated in pediatric patients with refractory or relapsed hematologic malignancies in an open-label, dose-escalation, noncomparative study. The starting dose of Clofarabine was 11.25 mg/m2/day IV infusion daily × 5 and escalated to 70 mg/m2/day IV infusion daily × 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with Clofarabine 52 mg/m2 daily for 5 days. In the 17 ALL patients there were 2 complete remissions (12%) and 2 partial remissions (12%) at varying doses. Dose-limiting toxicities (DLTs) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m2. As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m2/day for 5 days. Single-Arm Study in Pediatric ALL - Clofarabine was evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m2 over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles. There was no dose escalation in this study. - All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 38/61 (62%), had received > 2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years, 61% were male, 39% were female, 44% were Caucasian, 38% were Hispanic, 12% were African-American, 2% were Asian and 5% were Other race. - The overall remission (OR) rate (Complete Remission [CR] + CR in the absence of total platelet recovery [CRp]) was evaluated. CR was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (≤ 5% blasts), and recovery of peripheral counts [platelets ≥ 100 × 109/L and absolute neutrophil count (ANC) ≥ 1.0 × 109/L]. CRp was defined as meeting all criteria for CR except for recovery of platelet counts to ≥ 100 × 109/L. Partial Response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow (≥ 5% and ≤ 25% blasts), and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. Duration of remission was also evaluated. Transplantation rate was not a study endpoint. - Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP). - Table 3 summarizes results for the pediatric ALL study. Responses were seen in both pre-B and T-cell immunophenotypes of ALL. The median cumulative dose was 530 mg (range 29–2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. The median number of cycles was 2 (range 1–12). The median time between cycles was 28 days with a range of 12 to 55 days. - Six (9.8%) patients achieved a PR; the clinical relevance of a PR in this setting is unknown. - Of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17%) achieved a CR or CRp. Of 18 patients who had at least 1 prior hematopoietic stem cell transplant (HSCT), 5 (28%) achieved a CR or CRp. - Among the 12 patients who achieved at least a CRp, 6 patients achieved the best response after 1 cycle of clofarabine, 5 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy. # How Supplied - Clofarabine (clofarabine) Injection is supplied in single-use flint vials containing 20 mg of clofarabine in 20 mL of solution. Each box contains one Clofarabine vial (NDC 0024-5860-01). The 20mL flint vials contain 20 mL (20 mg) of solution. The pH range of the solution is 4.5 to 7.5. ## Storage - Vials containing undiluted Clofarabine should be stored at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F). - Diluted admixtures may be stored at room temperature, but must be used within 24 hours of preparation. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hematologic Toxicity: Advise patients to return for regular blood counts and to report any symptoms associated with hematologic toxicity (such as weakness, fatigue, pallor, shortness of breath, easy bruising, petechiae, purpura, fever) to their physician. - Infection: Advise patients of the signs or symptoms of infection (e.g., fever) and report to the physician immediately if any occur. - Hepatic and Renal Toxicity: Advise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the 5 days of Clofarabine administration. Also, advise patients of the possibility of developing liver function abnormalities and to immediately report signs or symptoms of jaundice . - Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome: Advise patients of the signs or symptoms of SIRS, such as fever, tachycardia, tachypnea, dyspnea and symptoms suggestive of hypotension . - Pregnancy and Breast-feeding: Advise male and female patients with reproductive potential to use effective contraceptive measures to prevent pregnancy. Advise female patients to avoid breast- feeding during Clofarabine treatment. - Gastrointestinal Disorders: Advise patients that they may experience nausea,vomiting, and/or diarrhea with Clofarabine. If these symptoms are significant, they should seek medical attention. - Rash: Advise patients that they may experience skin rash with Clofarabine. If this symptom is significant, they should seek medical attention. # Precautions with Alcohol - Alcohol-Clofarabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Clofarabine # Look-Alike Drug Names There is limited information regarding Clofarabine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Clofarabine
0bcc32d007913809e1281b8ee10ffddbbfd2883d	wikidoc	Clofazimine	Clofazimine # Overview Clofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy (MDT) for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients. Clofazimine also has a marked anti-inflammatory effect and is given to control the leprosy reaction, erythema nodosum leprosum (ENL). # Category Antimycobacterial # US Brand Names LAMPRENE® (DISCONTINUED) # Historical Perspective Clofazimine, initially known as B663, was first synthesised in 1954 by a team led by Dr Vincent Barry at Trinity College, Dublin as an anti-tuberculosis drug. The drug proved ineffective against tuberculosis but in 1959 a researcher named Chang identified its effectiveness against leprosy. After clinical trials in Nigeria and elsewhere during the 1960s, some sponsored by the Swiss pharmaceutical company Geigy (today member of the Novartis group of drug producers), the product was launched in 1969 as Lamprene. The U.S. government named Clofazimine an orphan drug in June 1986. Geigy gained FDA approval for the drug in December 1986. # Supply Clofazimine is marketed under the trade name Lamprene® by Novartis. One of the only suppliers of Clofazimine Active Pharmaceutical Ingredient in the world is Sangrose Laboratories, located at Mavelikara in the southern Indian state of Kerala. # Metabolism Clofazimine has a very long half life of about 70 days. Clofazimine produces pink to brownish skin pigmentation in 75-100% of patients within a few weeks. # Mechanism of Action Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae. It inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. It also exerts anti-inflammatory properties in controlling erythema nodosum leprosum reactions. However, its precise mechanisms of action are unknown.	Clofazimine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Clofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy (MDT) for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients. Clofazimine also has a marked anti-inflammatory effect and is given to control the leprosy reaction, erythema nodosum leprosum (ENL).[1] # Category Antimycobacterial # US Brand Names LAMPRENE® (DISCONTINUED) # Historical Perspective Clofazimine, initially known as B663, was first synthesised in 1954 by a team led by Dr Vincent Barry at Trinity College, Dublin as an anti-tuberculosis drug. The drug proved ineffective against tuberculosis but in 1959 a researcher named Chang identified its effectiveness against leprosy. After clinical trials in Nigeria and elsewhere during the 1960s, some sponsored by the Swiss pharmaceutical company Geigy (today member of the Novartis group of drug producers), the product was launched in 1969 as Lamprene. The U.S. government named Clofazimine an orphan drug in June 1986. Geigy gained FDA approval for the drug in December 1986. # Supply Clofazimine is marketed under the trade name Lamprene® by Novartis. One of the only suppliers of Clofazimine Active Pharmaceutical Ingredient in the world is Sangrose Laboratories, located at Mavelikara in the southern Indian state of Kerala. # Metabolism Clofazimine has a very long half life of about 70 days. Clofazimine produces pink to brownish skin pigmentation in 75-100% of patients within a few weeks. # Mechanism of Action Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae. It inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. It also exerts anti-inflammatory properties in controlling erythema nodosum leprosum reactions. However, its precise mechanisms of action are unknown. # External links - Official FDA Drug Label - RxList Clofazimine (most information taken from FDA) - ↑ LastName, FirstName (1992). Drug evaluations annual 1993. Chicago, Ill: American Medical Association. 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d32b78454b393a2d29f6d06bc2be9422f82ce513	wikidoc	Clofenotane	Clofenotane # Overview DDT (dichlorodiphenyltrichloroethane) is a colorless, crystalline, tasteless and almost odorless organochloride known for its insecticidal properties. DDT has been formulated in almost every conceivable form, including solutions in xylene or petroleum distillates, emulsifiable concentrates, water-wettable powders, granules, aerosols, smoke candles and charges for vaporizers and lotions. First synthesized in 1874, DDT's insecticidal action was discovered by the Swiss chemist Paul Hermann Müller in 1939. It was then used in the second half of World War II to control malaria and typhus among civilians and troops. After the war, DDT was made available for use as an agricultural insecticide and its production and use duly increased. Müller was awarded the Nobel Prize in Physiology or Medicine "for his discovery of the high efficiency of DDT as a contact poison against several arthropods" in 1948. In 1962, the book Silent Spring by American biologist Rachel Carson was published. It cataloged the environmental impacts of indiscriminate DDT spraying in the United States and questioned the logic of releasing large amounts of potentially dangerous chemicals into the environment without a sufficient understanding of their effects on ecology or human health. The book claimed that DDT and other pesticides had been shown to cause cancer and that their agricultural use was a threat to wildlife, particularly birds. Its publication was a seminal event for the environmental movement and resulted in a large public outcry that eventually led, in 1972, to a ban on the agricultural use of DDT in the United States. A worldwide ban on its agricultural use was later formalized under the Stockholm Convention, but its limited use in disease vector control continues to this day and remains controversial, because of its effectiveness in reducing deaths due to malaria, countered by environmental and health concerns. Along with the passage of the Endangered Species Act, the US ban on DDT is cited by scientists as a major factor in the comeback of the bald eagle (the national bird of the United States) and the peregrine falcon from near-extirpation in the contiguous United States. # Properties and chemistry DDT is similar in structure to the insecticide methoxychlor and the acaricide dicofol. Being highly hydrophobic, it is nearly insoluble in water but has good solubility in most organic solvents, fats and oils. DDT does not occur naturally, but is produced by the reaction of chloral (CCl3CHO) with chlorobenzene (C6H5Cl) in the presence of sulfuric acid as a catalyst. Trade names that DDT has been marketed under include Anofex, Cezarex, Chlorophenothane, Clofenotane, Dicophane, Dinocide, Gesarol, Guesapon, Guesarol, Gyron, Ixodex, Neocid, Neocidol and Zerdane. ## Isomers and related compounds Commercial DDT is a mixture of several closely–related compounds. The major component (77%) is the p,p' isomer which is pictured at the top of this article. The o,p' isomer (pictured to the right) is also present in significant amounts (15%). Dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) make up the balance. DDE and DDD are also the major metabolites and breakdown products in the environment. The term "total DDT" is often used to refer to the sum of all DDT related compounds (p,p'-DDT, o,p'-DDT, DDE, and DDD) in a sample. ## Production and use statistics From 1950 to 1980, DDT was extensively used in agriculture – more than 40,000 tonnes were used each year worldwide – and it has been estimated that a total of 1.8 million tonnes have been produced globally since the 1940s. In the U.S., where it was manufactured by some 15 companies including Monsanto, Ciba, Montrose Chemical Company, Pennwalt and Velsicol Chemical Corporation, production peaked in 1963 at 82,000 tonnes per year. More than 600,000 tonnes (1.35 billion lbs) were applied in the U.S. before the 1972 ban. Usage peaked in 1959 at about 36,000 tonnes. In 2009, 3314 tonnes were produced for the control of malaria and visceral leishmaniasis. India is the only country still manufacturing DDT, with China having ceased production in 2007. India is the largest consumer. ## Mechanism of insecticide action In insects it opens sodium ion channels in neurons, causing them to fire spontaneously, which leads to spasms and eventual death. Insects with certain mutations in their sodium channel gene are resistant to DDT and other similar insecticides. DDT resistance is also conferred by up-regulation of genes expressing cytochrome P450 in some insect species, as greater quantities of some enzymes of this group accelerate metabolism of the toxin into inactive metabolites. # History DDT was first synthesized in 1874 by Othmar Zeidler under the supervision of Adolf von Baeyer. It was further described in 1929 in a dissertation by W. Bausch and in two subsequent publications in 1930. The insecticide properties of "multiple chlorinated aliphatic or fat-aromatic alcohols with at least one trichloromethane group" were described in a patent in 1934 by Wolfgang von Leuthold. DDT's insecticidal properties were not, however, discovered until 1939 by the Swiss scientist Paul Hermann Müller, who was awarded the 1948 Nobel Prize in Physiology and Medicine for his efforts. ## Use in the 1940s and 1950s DDT is the best-known of several chlorine-containing pesticides used in the 1940s and 1950s. With pyrethrum in short supply, DDT was used extensively during World War II by the Allies to control the insect vectors of typhus – nearly eliminating the disease in many parts of Europe. In the South Pacific, it was sprayed aerially for malaria and dengue fever control with spectacular effects. While DDT's chemical and insecticidal properties were important factors in these victories, advances in application equipment coupled with a high degree of organization and sufficient manpower were also crucial to the success of these programs. In 1945, DDT was made available to farmers as an agricultural insecticide, and it played a role in the final elimination of malaria in Europe and North America. In 1955, the World Health Organization commenced a program to eradicate malaria in countries with low to moderate transmission rates worldwide, relying largely on DDT for mosquito control and rapid diagnosis and treatment to reduce transmission. The program was initially highly successful, eliminating the disease in "Taiwan, much of the Caribbean, the Balkans, parts of northern Africa, the northern region of Australia, and a large swath of the South Pacific" and dramatically reducing mortality in Sri Lanka and India. However, failure to sustain the program, increasing resistance of mosquito to DDT, and increasing parasite resistance led to a resurgence. In many areas early victories partially or completely reversed, and in some cases rates of transmission even increased. The program was successful in eliminating malaria only in areas with "high socio-economic status, well-organized healthcare systems, and relatively less intensive or seasonal malaria transmission". DDT was less effective in tropical regions due to the continuous life cycle of mosquitoes and poor infrastructure. It was not applied at all in sub-Saharan Africa due to these perceived difficulties. Mortality rates in that area never declined to the same dramatic extent, and now constitute the bulk of malarial deaths worldwide, especially following the disease's resurgence as a result of resistance to drug treatments and the spread of the deadly malarial variant caused by Plasmodium falciparum. The goal of eradication was abandoned in 1969 and attention was instead focused on controlling and treating the disease. Spraying programs (especially using DDT) were curtailed due to concerns over safety and environmental effects, as well as problems in administrative, managerial and financial implementation. Efforts shifted from spraying to the use of bednets impregnated with insecticides and other interventions. ## U.S. ban As early as the 1940s, scientists in the U.S. had begun expressing concern over possible hazards associated with DDT, and in the 1950s the government began tightening some of the regulations governing its use. However, these early events received little attention, and it was not until 1957, when the New York Times reported an unsuccessful struggle to restrict DDT use in Nassau County, New York, that the issue came to the attention of the popular naturalist-author, Rachel Carson. William Shawn, editor of The New Yorker, urged her to write a piece on the subject, which developed into her famous book Silent Spring, published in 1962. The book argued that pesticides, including DDT, were poisoning both wildlife and the environment and were also endangering human health. Silent Spring was a best seller, and public reaction to it launched the modern environmental movement in the United States. The year after it appeared, President Kennedy ordered his Science Advisory Committee to investigate Carson's claims. The report the committee issued "add up to a fairly thorough-going vindication of Rachel Carson’s Silent Spring thesis," in the words of the journal Science, and recommended a phaseout of "persistent toxic pesticides". DDT became a prime target of the growing anti-chemical and anti-pesticide movements, and in 1967 a group of scientists and lawyers founded the Environmental Defense Fund (EDF) with the specific goal of winning a ban on DDT. Victor Yannacone, Charles Wurster, Art Cooley and others associated with inception of EDF had all witnessed bird kills or declines in bird populations and suspected that DDT was the cause. In their campaign against the chemical, EDF petitioned the government for a ban and filed a series of lawsuits. Around this time, toxicologist David Peakall was measuring DDE levels in the eggs of peregrine falcons and California condors and finding that increased levels corresponded with thinner shells. In response to an EDF suit, the U.S. District Court of Appeals in 1971 ordered the EPA to begin the de-registration procedure for DDT. After an initial six-month review process, William Ruckelshaus, the Agency's first Administrator rejected an immediate suspension of DDT's registration, citing studies from the EPA's internal staff stating that DDT was not an imminent danger to human health and wildlife. However, the findings of these staff members were criticized, as they were performed mostly by economic entomologists inherited from the United States Department of Agriculture, who many environmentalists felt were biased towards agribusiness and tended to minimize concerns about human health and wildlife. The decision not to ban thus created public controversy. The EPA then held seven months of hearings in 1971–1972, with scientists giving evidence both for and against the use of DDT. The hearings produced a 113-page decision, in which Hearing Examiner Edmund Sweeney wrote: “DDT is not a carcinogenic, mutagenic, or teratogenic hazard to man. The uses under regulations involved here do not have a deleterious effect on fresh water fish, estuarine organisms, wild birds, or other wildlife. The evidence in this proceeding supports the conclusion that there is a present need for essential uses of DDT.” In the summer of 1972, Ruckelshaus announced the cancellation of most uses of DDT – an exemption allowed for public health uses under some conditions. He later wrote, in a letter to American Farm Bureau President Allan Grant, that “in such decisions the ultimate judgement remains political.” Immediately after the cancellation was announced, both EDF and the DDT manufacturers filed suit against the EPA, with the industry seeking to overturn the ban, and EDF seeking a comprehensive ban. The cases were consolidated, and in 1973 the U.S. Court of Appeals for the District of Columbia ruled that the EPA had acted properly in banning DDT. Some uses of DDT continued under the public health exemption. For example, in June 1979, the California Department of Health Services was permitted to use DDT to suppress flea vectors of bubonic plague. DDT also continued to be produced in the US for foreign markets until as late as 1985, when over 300 tons were exported. ## Restrictions on usage In the 1970s and 1980s, agricultural use was banned in most developed countries, beginning with Hungary in 1968 then in Norway and Sweden in 1970, Germany and the United States in 1972, but not in the United Kingdom until 1984. By 1991 total bans on the use of DDT, including in disease control, were in place in at least 26 countries; for example Cuba in 1970, Singapore in 1984, Chile in 1985 and the Republic of Korea in 1986. The Stockholm Convention, which took effect in 2004, outlawed several persistent organic pollutants, and restricted DDT use to vector control. The Convention has been ratified by more than 170 countries and is endorsed by most environmental groups. Recognizing that total elimination in many malaria-prone countries is currently unfeasible because there are few affordable or effective alternatives, the convention exempts public health use within World Health Organization (WHO) guidelines from the ban. Resolution 60.18 of the World Health Assembly commits the World Health Organization to the Stockholm Convention's aim of reducing and ultimately eliminating the use of DDT. Malaria Foundation International states, "The outcome of the treaty is arguably better than the status quo going into the negotiations. For the first time, there is now an insecticide which is restricted to vector control only, meaning that the selection of resistant mosquitoes will be slower than before." Despite the worldwide ban, agricultural use continued in India, North Korea, and possibly elsewhere as of 2008. Today, about 3,000 to 4,000 tonnes of DDT are produced each year for disease vector control. DDT is applied to the inside walls of homes to kill or repel mosquitoes. This intervention, called indoor residual spraying (IRS), greatly reduces environmental damage. It also reduces the incidence of DDT resistance. For comparison, treating 40 hectares (98.8421524 acres) of cotton during a typical U.S. growing season requires the same amount of chemical as roughly 1,700 homes. # Environmental impact DDT is a persistent organic pollutant that is readily adsorbed to soils and sediments, which can act both as sinks and as long-term sources of exposure contributing to terrestrial organisms. Depending on conditions, its soil half life can range from 22 days to 30 years. Routes of loss and degradation include runoff, volatilization, photolysis and aerobic and anaerobic biodegradation. Due to hydrophobic properties, in aquatic ecosystems DDT and its metabolites are absorbed by aquatic organisms and adsorbed on suspended particles, leaving little DDT dissolved in the water itself. Its breakdown products and metabolites, DDE and DDD, are also highly persistent and have similar chemical and physical properties. DDT and its breakdown products are transported from warmer regions of the world to the Arctic by the phenomenon of global distillation, where they then accumulate in the region's food web. Because of its lipophilic properties, DDT has a high potential to bioaccumulate, especially in predatory birds. DDT, DDE, and DDD magnify through the food chain, with apex predators such as raptor birds concentrating more chemicals than other animals in the same environment. They are very lipophilic and are stored mainly in body fat. DDT and DDE are very resistant to metabolism; in humans, their half-lives are 6 and up to 10 years, respectively. In the United States, these chemicals were detected in almost all human blood samples tested by the Centers for Disease Control in 2005, though their levels have sharply declined since most uses were banned in the US. Estimated dietary intake has also declined, although FDA food tests commonly detect it. Marine macroalgae (seaweed) help reduce soil toxicity by up to 80% within six weeks. ## Effects on wildlife and eggshell thinning DDT is toxic to a wide range of living organisms, including marine animals such as crayfish, daphnids, sea shrimp and many species of fish. DDT, through its metabolite DDE (dichlorodiphenyldichloroethylene), caused eggshell thinning and resulted in severe population declines in multiple North American and European bird of prey species. Eggshell thinning lowers the reproductive rate of certain bird species by causing egg breakage and embryo deaths. DDE related eggshell thinning is considered a major reason for the decline of the bald eagle, brown pelican, peregrine falcon, and osprey. However, different groups of birds vary greatly in their sensitivity to these chemicals. Birds of prey, waterfowl, and song birds are more susceptible to eggshell thinning than chickens and related species, and DDE appears to be more potent than DDT. Even in 2010, more than forty years after the U.S. ban, California condors which feed on sea lions at Big Sur which in turn feed in the Palos Verdes Shelf area of the Montrose Chemical Superfund site seemed to be having continued thin-shell problems. Scientists with the Ventana Wildlife Society and others are intensifying studies and remediations of the condors' problems. The biological thinning mechanism is not entirely known, but there is strong evidence that p,p'-DDE inhibits calcium ATPase in the membrane of the shell gland and reduces the transport of calcium carbonate from blood into the eggshell gland. This results in a dose-dependent thickness reduction. There is also evidence that o,p'-DDT disrupts female reproductive tract development, impairing eggshell quality later. Multiple mechanisms may be at work, or different mechanisms may operate in different species. Some studies show that although DDE levels have fallen dramatically, eggshell thickness remains 10–12 percent thinner than before DDT was first used. # Effects on human health DDT is an endocrine disruptor. It is considered likely to be a human carcinogen although the majority of studies suggest it is not directly genotoxic. The DDT metabolite DDE acts as an antiandrogen, but not as an estrogen. p,p'-DDT, DDT's main component, has little or no androgenic or estrogenic activity. The minor component o,p'-DDT has weak estrogenic activity. ## Acute toxicity DDT is classified as "moderately toxic" by the United States National Toxicology Program (NTP) and "moderately hazardous" by the World Health Organization (WHO), based on the rat oral Template:LD50 of 113 mg/kg. DDT has on rare occasions been administered orally as a treatment for barbiturate poisoning. ## Chronic toxicity ### Developmental toxicity DDT and DDE, like other organochlorines, have been shown to have xenoestrogenic activity, meaning they are chemically similar enough to estrogens to trigger hormonal responses in animals. This endocrine disrupting activity has been observed in mice and rat toxicological studies, and available epidemiological evidence indicates that these effects may be occurring in humans as a result of DDT exposure. The US Environmental Protection Agency states that DDT exposure damages the reproductive system and reduces reproductive success. These effects may cause developmental and reproductive toxicity: - A review article in The Lancet states, "research has shown that exposure to DDT at amounts that would be needed in malaria control might cause preterm birth and early weaning ... toxicological evidence shows endocrine-disrupting properties; human data also indicate possible disruption in semen quality, menstruation, gestational length, and duration of lactation." - Other studies document decreases in semen quality among men with high exposures (generally from IRS). - Studies generally find that high blood DDT or DDE levels do not increase time to pregnancy (TTP.)Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) There is some evidence that the daughters of highly exposed women may have more difficulty getting pregnant (i.e. increased TTP).Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) - DDT is associated with early pregnancy loss, a type of miscarriage. A prospective cohort study of Chinese textile workers found "a positive, monotonic, exposure-response association between preconception serum total DDT and the risk of subsequent early pregnancy losses."Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) The median serum DDE level of study group was lower than that typically observed in women living in homes sprayed with DDT.Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) - A Japanese study of congenital hypothyroidism concluded that in utero DDT exposure may affect thyroid hormone levels and "play an important role in the incidence and/or causation of cretinism."Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) Other studies have also found that DDT or DDE interfere with proper thyroid function.Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) ## Carcinogenicity In 2002, the Centers for Disease Control reported that "Overall, in spite of some positive associations for some cancers within certain subgroups of people, there is no clear evidence that exposure to DDT/DDE causes cancer in humans." The NTP classifies it as "reasonably anticipated to be a carcinogen," the International Agency for Research on Cancer classifies it as a "possible" human carcinogen, and the EPA classifies DDT, DDE, and DDD as class B2 "probable" carcinogens. These evaluations are based mainly on the results of animal studies. A Lancet review of epidemiological studies concluded that that DDT causes cancers of the liver, and pancreas, that there is mixed evidence that it causes cancers of the testes, and that it probably does not contribute to cancers of the rectum, prostate, endometrium, lung, or stomach. A second review, whose co-authors included persons engaged in DDT-related litigation, reached broadly similar conclusions, but also found possible associations with breast cancer, leukemia, lymphoma, and testicular cancer. ### Breast cancer The question of whether DDT or DDE are risk factors in breast cancer has not been conclusively answered. Several meta analyses of observational studies have concluded that there is no overall relationship between DDT exposure and breast cancer risk. The United States Institute of Medicine reviewed data on the association of breast cancer with DDT exposure in 2012 and concluded that a causative relationship could neither be proven nor disproven. A 2007 case control study using archived blood samples found that breast cancer risk was increased 5-fold among women who were born prior to 1931 and who had high serum DDT levels in 1963. Reasoning that DDT use became widespread in 1945 and peaked around 1950, they concluded that the ages of 14-20 were a critical period in which DDT exposure leads to increased risk. This study, which suggests a connection between DDT exposure and breast cancer that would not be picked up by most studies, has received variable commentary in third party reviews. One review suggested that "previous studies that measured exposure in older women may have missed the critical period." A second review suggested a cautious approach to the interpretation of these results given methodological weaknesses in the study design. The National Toxicology Program notes that while the majority of studies have not found a relationship between DDT exposure and breast cancer that positive associations have been seen in a "few studies among women with higher levels of exposure and among certain subgroups of women" # Use against malaria Malaria remains a major public health challenge in many countries. 2008 WHO estimates were 243 million cases, and 863,000 deaths. About 89% of these deaths occur in Africa, and mostly to children under the age of 5. DDT is one of many tools that public health officials use to fight the disease. Its use in this context has been called everything from a "miracle weapon like Kryptonite to the mosquitoes," to "toxic colonialism." Before DDT, eliminating mosquito breeding grounds by drainage or poisoning with Paris green or pyrethrum was sometimes successful in fighting malaria. In parts of the world with rising living standards, the elimination of malaria was often a collateral benefit of the introduction of window screens and improved sanitation. Today, a variety of usually simultaneous interventions is the norm. These include antimalarial drugs to prevent or treat infection; improvements in public health infrastructure to quickly diagnose, sequester, and treat infected individuals; bednets and other methods intended to keep mosquitoes from biting humans; and vector control strategies such as larvaciding with insecticides, ecological controls such as draining mosquito breeding grounds or introducing fish to eat larvae, and indoor residual spraying (IRS) with insecticides, possibly including DDT. IRS involves the treatment of all interior walls and ceilings with insecticides, and is particularly effective against mosquitoes, since many species rest on an indoor wall before or after feeding. DDT is one of 12 WHO–approved IRS insecticides. WHO's anti-malaria campaign of the 1950s and 1960s relied heavily on DDT and the results were promising, though temporary. Experts tie the resurgence of malaria to multiple factors, including poor leadership, management and funding of malaria control programs; poverty; civil unrest; and increased irrigation. The evolution of resistance to first-generation drugs (e.g. chloroquine) and to insecticides exacerbated the situation. Resistance was largely fueled by often unrestricted agricultural use. Resistance and the harm both to humans and the environment led many governments to restrict or curtail the use of DDT in vector control as well as agriculture. In 2006 the WHO reversed a longstanding policy against DDT by recommending that it be used as an indoor pesticide in regions where malaria is a major problem. Once the mainstay of anti-malaria campaigns, as of 2008 only 12 countries used DDT, including India and some southern African states, though the number is expected to rise. ## Initial effectiveness of DDT against malaria When it was first introduced in World War II, DDT was very effective in reducing malaria morbidity and mortality. The WHO's anti-malaria campaign, which consisted mostly of spraying DDT and rapid treatment and diagnosis to break the transmission cycle, was initially very successful as well. For example, in Sri Lanka, the program reduced cases from about one million per year before spraying to just 18 in 1963 and 29 in 1964. Thereafter the program was halted to save money and malaria rebounded to 600,000 cases in 1968 and the first quarter of 1969. The country resumed DDT vector control but the mosquitoes had evolved resistance in the interim, presumably because of continued agricultural use. The program switched to malathion, but despite initial successes, malaria continued its resurgence into the 1980s. Today, DDT remains on the WHO's list of insecticides recommended for IRS. Since the appointment of Arata Kochi as head of its anti-malaria division, WHO's policy has shifted from recommending IRS only in areas of seasonal or episodic transmission of malaria, to also advocating it in areas of continuous, intense transmission. The WHO has reaffirmed its commitment to eventually phasing out DDT, aiming "to achieve a 30% cut in the application of DDT world-wide by 2014 and its total phase-out by the early 2020s if not sooner" while simultaneously combating malaria. The WHO plans to implement alternatives to DDT to achieve this goal. South Africa is one country that continues to use DDT under WHO guidelines. In 1996, the country switched to alternative insecticides and malaria incidence increased dramatically. Returning to DDT and introducing new drugs brought malaria back under control. Malaria cases increased in South America after countries in that continent stopped using DDT. Research data shows a significantly strong negative relationship between DDT residual house sprayings and malaria rates. In a research from 1993 to 1995, Ecuador increased its use of DDT and resulted in a 61% reduction in malaria rates, while each of the other countries that gradually decreased its DDT use had large increase in malaria rates. ## Mosquito resistance In some areas resistance has greatly reduced DDT's effectiveness. WHO guidelines require that absence of resistance must be confirmed before using the chemical. Resistance is largely due to agricultural use, in much greater quantities than required for disease prevention. Resistance was noted early in spray campaigns. Paul Russell, a former head of the Allied Anti-Malaria campaign, observed in 1956 that "resistance has appeared after six or seven years." Resistance has been detected in Sri Lanka, Pakistan, Turkey and Central America, and it has largely been replaced by organophosphate or carbamate insecticides, e.g. malathion or bendiocarb. In many parts of India, DDT has also largely lost its effectiveness. Agricultural uses were banned in 1989 and its anti-malarial use has been declining. Urban use has halted completely. Nevertheless, DDT is still manufactured and used, and one study had concluded that "DDT is still a viable insecticide in indoor residual spraying owing to its effectivity in well supervised spray operation and high excito-repellency factor." Studies of malaria-vector mosquitoes in KwaZulu-Natal Province, South Africa found susceptibility to 4% DDT (the WHO susceptibility standard), in 63% of the samples, compared to the average of 86.5% in the same species caught in the open. The authors concluded that "Finding DDT resistance in the vector An. arabiensis, close to the area where we previously reported pyrethroid-resistance in the vector An. funestus Giles, indicates an urgent need to develop a strategy of insecticide resistance management for the malaria control programmes of southern Africa." DDT can still be effective against resistant mosquitoes, and the avoidance of DDT-sprayed walls by mosquitoes is an additional benefit of the chemical. For example, a 2007 study reported that resistant mosquitoes avoided treated huts. The researchers argued that DDT was the best pesticide for use in IRS (even though it did not afford the most protection from mosquitoes out of the three test chemicals) because the others pesticides worked primarily by killing or irritating mosquitoes – encouraging the development of resistance to these agents. Others argue that the avoidance behavior slows the eradication of the disease. Unlike other insecticides such as pyrethroids, DDT requires long exposure to accumulate a lethal dose; however its irritant property shortens contact periods. "For these reasons, when comparisons have been made, better malaria control has generally been achieved with pyrethroids than with DDT." In India, with its outdoor sleeping habits and frequent night duties, "the excito-repellent effect of DDT, often reported useful in other countries, actually promotes outdoor transmission." Genomic studies in the model genetic organism Drosophila melanogaster have revealed that high level DDT resistance is polygenic, involving multiple resistance mechanisms. ## Residents' concerns IRS is effective if at least 80% of homes and barns in a residential area are sprayed. Lower coverage rates can jeopardize program effectiveness. Many residents resist DDT spraying, objecting to the lingering smell, stains on walls, and the potential exacerbation of problems with other insect pests. Pyrethroid insecticides (e.g. deltamethrin and lambda-cyhalothrin) can overcome some of these issues, increasing participation. ## Human exposure A 1994 study found that compared to contemporaries living where DDT is not used, South Africans living in sprayed homes have levels that are several orders of magnitude greater. Breast milk from South African mothers contains high levels of DDT and DDE. It is unclear to what extent these levels arise from home spraying vs. residues in food. There is some evidence that these levels are associated with neurological abnormalities in babies. Most studies of DDT's human health effects have been conducted in developed countries where DDT is not used and exposure is relatively low. Many experts urge that alternatives be used instead of IRS. Illegal diversion to agriculture is also a concern as it is almost impossible to prevent and its subsequent use on crops is uncontrolled. For example, DDT use is widespread in Indian agriculture, particularly mango production, and is reportedly used by librarians to protect books. Other examples include Ethiopia, where DDT intended for malaria control is reportedly being used in coffee production, and Ghana where it is used for fishing." The residues in crops at levels unacceptable for export have been an important factor in recent bans in several tropical countries. Adding to this problem is a lack of skilled personnel and supervision. ## Criticism of restrictions on DDT use Critics argue that limitations on DDT use for public heath purposes have caused unnecessary morbidity and mortality from vector borne diseases, with some claims of malaria deaths ranging as high as the hundreds of thousands, and millions. Robert Gwadz of the US National Institutes of Health said in 2007, "The ban on DDT may have killed 20 million children." In his novel State of Fear, author Michael Crichton wrote "Banning DDT killed more people than Hitler." These arguments have been dismissed as "outrageous" by former WHO scientist Socrates Litsios. May Berenbaum, University of Illinois entomologist, says, "to blame environmentalists who oppose DDT for more deaths than Hitler is worse than irresponsible." Investigative journalist Adam Sarvana and others characterize this notion as a "myth" promoted principally by Roger Bate of the pro-DDT advocacy group Africa Fighting Malaria (AFM). Criticisms of a DDT "ban" often specifically reference the 1972 US ban (with the erroneous implication that this constituted a worldwide ban and prohibited use of DDT in vector control). Reference is often made to Rachel Carson's Silent Spring, even though she never pushed for a ban on DDT specifically. John Quiggin and Tim Lambert wrote, "the most striking feature of the claim against Carson is the ease with which it can be refuted." It has also been alleged that donor governments and agencies have refused to fund DDT spraying, or made aid contingent upon not using DDT. According to a report in the British Medical Journal, use of DDT in Mozambique "was stopped several decades ago, because 80% of the country's health budget came from donor funds, and donors refused to allow the use of DDT." Roger Bate asserts, "many countries have been coming under pressure from international health and environment agencies to give up DDT or face losing aid grants: Belize and Bolivia are on record admitting they gave in to pressure on this issue from ." The United States Agency for International Development (USAID) has been the focus of much criticism. While the agency is currently funding the use of DDT in some African countries, in the past it did not. When John Stossel accused USAID of not funding DDT because it wasn't "politically correct," Anne Peterson, the agency's assistant administrator for global health, replied that "I believe that the strategies we are using are as effective as spraying with DDT ... So, politically correct or not, I am very confident that what we are doing is the right strategy." USAID's Kent R. Hill states that the agency has been misrepresented: "USAID strongly supports spraying as a preventative measure for malaria and will support the use of DDT when it is scientifically sound and warranted." The Agency's website states that "USAID has never had a 'policy' as such either 'for' or 'against' DDT for IRS. The real change in the past two years has been a new interest and emphasis on the use of IRS in general – with DDT or any other insecticide – as an effective malaria prevention strategy in tropical Africa." The website further explains that in many cases alternative malaria control measures were judged to be more cost-effective that DDT spraying, and so were funded instead. ## Alternatives ### Other insecticides Organophosphate and carbamate insecticides, e.g. malathion and bendiocarb, respectively, are more expensive than DDT per kilogram and are applied at roughly the same dosage. Pyrethroids such as deltamethrin are also more expensive than DDT, but are applied more sparingly (0.02–0.3 g/m2 vs 1–2 g/m2), so the net cost per house is about the same over 6 months. ### Non-chemical vector control Before DDT, malaria was successfully eliminated or curtailed in several tropical areas by removing or poisoning mosquito breeding grounds and larva habitats, for example by filling or applying oil to standing water. These methods have seen little application in Africa for more than half a century. According to the United States CDC, such methods are not practical in Africa because "Anopheles gambiae, one of the primary vectors of malaria in Africa, breeds in numerous small pools of water that form due to rainfall.... It is difficult, if not impossible, to predict when and where the breeding sites will form, and to find and treat them before the adults emerge." The relative effectiveness of IRS (with DDT or alternative insecticides) versus other malaria control techniques (e.g. bednets or prompt access to anti-malarial drugs) varies greatly and is highly dependent on local conditions. A WHO study released in January 2008 found that mass distribution of insecticide-treated mosquito nets and artemisinin–based drugs cut malaria deaths in half in Rwanda and Ethiopia, countries with high malaria burdens. IRS with DDT did not play an important role in mortality reduction in these countries. Vietnam has enjoyed declining malaria cases and a 97% mortality reduction after switching in 1991 from a poorly funded DDT-based campaign to a program based on prompt treatment, bednets, and pyrethroid group insecticides. In Mexico, effective and affordable chemical and non-chemical strategies against malaria have been so successful that the Mexican DDT manufacturing plant ceased production due to lack of demand. A review of fourteen studies on the subject in sub-Saharan Africa, covering insecticide-treated nets, residual spraying, chemoprophylaxis for children, chemoprophylaxis or intermittent treatment for pregnant women, a hypothetical vaccine, and changing front–line drug treatment, found decision making limited by the gross lack of information on the costs and effects of many interventions, the very small number of cost-effectiveness analyses available, the lack of evidence on the costs and effects of packages of measures, and the problems in generalizing or comparing studies that relate to specific settings and use different methodologies and outcome measures. The two cost-effectiveness estimates of DDT residual spraying examined were not found to provide an accurate estimate of the cost-effectiveness of DDT spraying; furthermore, the resulting estimates may not be good predictors of cost-effectiveness in current programs. However, a study in Thailand found the cost per malaria case prevented of DDT spraying ($1.87 US) to be 21% greater than the cost per case prevented of lambda-cyhalothrin–treated nets ($1.54 US), at very least casting some doubt on the unexamined assumption that DDT was the most cost-effective measure to use in all cases. The director of Mexico's malaria control program finds similar results, declaring that it is 25% cheaper for Mexico to spray a house with synthetic pyrethroids than with DDT. However, another study in South Africa found generally lower costs for DDT spraying than for impregnated nets. A more comprehensive approach to measuring cost-effectiveness or efficacy of malarial control would not only measure the cost in dollars of the project, as well as the number of people saved, but would also consider ecological damage and negative aspects of insecticide use on human health. One preliminary study regarding the effect of DDT found that it is likely the detriment to human health approaches or exceeds the beneficial reductions in malarial cases, except perhaps in malarial epidemic situations. It is similar to the earlier mentioned study regarding estimated theoretical infant mortality caused by DDT and subject to the criticism also mentioned earlier. A study in the Solomon Islands found that "although impregnated bed nets cannot entirely replace DDT spraying without substantial increase in incidence, their use permits reduced DDT spraying." A comparison of four successful programs against malaria in Brazil, India, Eritrea, and Vietnam does not endorse any single strategy but instead states, "Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing." DDT resistant mosquitoes have generally proved susceptible to pyrethroids. Thus far, pyrethroid resistance in Anopheles has not been a major problem.	Clofenotane Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview DDT (dichlorodiphenyltrichloroethane) is a colorless, crystalline, tasteless and almost odorless organochloride known for its insecticidal properties. DDT has been formulated in almost every conceivable form, including solutions in xylene or petroleum distillates, emulsifiable concentrates, water-wettable powders, granules, aerosols, smoke candles and charges for vaporizers and lotions.[1] First synthesized in 1874, DDT's insecticidal action was discovered by the Swiss chemist Paul Hermann Müller in 1939. It was then used in the second half of World War II to control malaria and typhus among civilians and troops. After the war, DDT was made available for use as an agricultural insecticide and its production and use duly increased.[2] Müller was awarded the Nobel Prize in Physiology or Medicine "for his discovery of the high efficiency of DDT as a contact poison against several arthropods" in 1948.[3] In 1962, the book Silent Spring by American biologist Rachel Carson was published. It cataloged the environmental impacts of indiscriminate DDT spraying in the United States and questioned the logic of releasing large amounts of potentially dangerous chemicals into the environment without a sufficient understanding of their effects on ecology or human health. The book claimed that DDT and other pesticides had been shown to cause cancer and that their agricultural use was a threat to wildlife, particularly birds. Its publication was a seminal event for the environmental movement and resulted in a large public outcry that eventually led, in 1972, to a ban on the agricultural use of DDT in the United States.[4] A worldwide ban on its agricultural use was later formalized under the Stockholm Convention, but its limited use in disease vector control continues to this day and remains controversial,[5][6] because of its effectiveness in reducing deaths due to malaria, countered by environmental and health concerns. Along with the passage of the Endangered Species Act, the US ban on DDT is cited by scientists as a major factor in the comeback of the bald eagle (the national bird of the United States) and the peregrine falcon from near-extirpation in the contiguous United States.[7][8] # Properties and chemistry DDT is similar in structure to the insecticide methoxychlor and the acaricide dicofol. Being highly hydrophobic, it is nearly insoluble in water but has good solubility in most organic solvents, fats and oils. DDT does not occur naturally, but is produced by the reaction of chloral (CCl3CHO) with chlorobenzene (C6H5Cl) in the presence of sulfuric acid as a catalyst. Trade names that DDT has been marketed under include Anofex, Cezarex, Chlorophenothane, Clofenotane, Dicophane, Dinocide, Gesarol, Guesapon, Guesarol, Gyron, Ixodex, Neocid, Neocidol and Zerdane.[2] ## Isomers and related compounds Commercial DDT is a mixture of several closely–related compounds. The major component (77%) is the p,p' isomer which is pictured at the top of this article. The o,p' isomer (pictured to the right) is also present in significant amounts (15%). Dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) make up the balance. DDE and DDD are also the major metabolites and breakdown products in the environment.[2] The term "total DDT" is often used to refer to the sum of all DDT related compounds (p,p'-DDT, o,p'-DDT, DDE, and DDD) in a sample. ## Production and use statistics From 1950 to 1980, DDT was extensively used in agriculture – more than 40,000 tonnes were used each year worldwide[9] – and it has been estimated that a total of 1.8 million tonnes have been produced globally since the 1940s.[10] In the U.S., where it was manufactured by some 15 companies including Monsanto,[11] Ciba,[12] Montrose Chemical Company, Pennwalt[13] and Velsicol Chemical Corporation,[14] production peaked in 1963 at 82,000 tonnes per year.[2] More than 600,000 tonnes (1.35 billion lbs) were applied in the U.S. before the 1972 ban. Usage peaked in 1959 at about 36,000 tonnes.[15] In 2009, 3314 tonnes were produced for the control of malaria and visceral leishmaniasis. India is the only country still manufacturing DDT, with China having ceased production in 2007.[16] India is the largest consumer.[17] ## Mechanism of insecticide action In insects it opens sodium ion channels in neurons, causing them to fire spontaneously, which leads to spasms and eventual death. Insects with certain mutations in their sodium channel gene are resistant to DDT and other similar insecticides. DDT resistance is also conferred by up-regulation of genes expressing cytochrome P450 in some insect species,[18] as greater quantities of some enzymes of this group accelerate metabolism of the toxin into inactive metabolites. # History DDT was first synthesized in 1874 by Othmar Zeidler under the supervision of Adolf von Baeyer.[2][19] It was further described in 1929 in a dissertation by W. Bausch and in two subsequent publications in 1930.[20][21] The insecticide properties of "multiple chlorinated aliphatic or fat-aromatic alcohols with at least one trichloromethane group" were described in a patent in 1934 by Wolfgang von Leuthold.[22] DDT's insecticidal properties were not, however, discovered until 1939 by the Swiss scientist Paul Hermann Müller, who was awarded the 1948 Nobel Prize in Physiology and Medicine for his efforts.[3] ## Use in the 1940s and 1950s DDT is the best-known of several chlorine-containing pesticides used in the 1940s and 1950s. With pyrethrum in short supply, DDT was used extensively during World War II by the Allies to control the insect vectors of typhus – nearly eliminating the disease in many parts of Europe. In the South Pacific, it was sprayed aerially for malaria and dengue fever control with spectacular effects. While DDT's chemical and insecticidal properties were important factors in these victories, advances in application equipment coupled with a high degree of organization and sufficient manpower were also crucial to the success of these programs.[23] In 1945, DDT was made available to farmers as an agricultural insecticide,[2] and it played a role in the final elimination of malaria in Europe and North America.[5][24][25] In 1955, the World Health Organization commenced a program to eradicate malaria in countries with low to moderate transmission rates worldwide, relying largely on DDT for mosquito control and rapid diagnosis and treatment to reduce transmission.[26] The program was initially highly successful, eliminating the disease in "Taiwan, much of the Caribbean, the Balkans, parts of northern Africa, the northern region of Australia, and a large swath of the South Pacific"[27] and dramatically reducing mortality in Sri Lanka and India.[28] However, failure to sustain the program, increasing resistance of mosquito to DDT, and increasing parasite resistance led to a resurgence. In many areas early victories partially or completely reversed, and in some cases rates of transmission even increased.[29] The program was successful in eliminating malaria only in areas with "high socio-economic status, well-organized healthcare systems, and relatively less intensive or seasonal malaria transmission".[30] DDT was less effective in tropical regions due to the continuous life cycle of mosquitoes and poor infrastructure. It was not applied at all in sub-Saharan Africa due to these perceived difficulties. Mortality rates in that area never declined to the same dramatic extent, and now constitute the bulk of malarial deaths worldwide, especially following the disease's resurgence as a result of resistance to drug treatments and the spread of the deadly malarial variant caused by Plasmodium falciparum.[citation needed] The goal of eradication was abandoned in 1969 and attention was instead focused on controlling and treating the disease. Spraying programs (especially using DDT) were curtailed due to concerns over safety and environmental effects, as well as problems in administrative, managerial and financial implementation.[29] Efforts shifted from spraying to the use of bednets impregnated with insecticides and other interventions.[30][31] ## U.S. ban As early as the 1940s, scientists in the U.S. had begun expressing concern over possible hazards associated with DDT, and in the 1950s the government began tightening some of the regulations governing its use.[15] However, these early events received little attention, and it was not until 1957, when the New York Times reported an unsuccessful struggle to restrict DDT use in Nassau County, New York, that the issue came to the attention of the popular naturalist-author, Rachel Carson. William Shawn, editor of The New Yorker, urged her to write a piece on the subject, which developed into her famous book Silent Spring, published in 1962. The book argued that pesticides, including DDT, were poisoning both wildlife and the environment and were also endangering human health.[4] Silent Spring was a best seller, and public reaction to it launched the modern environmental movement in the United States. The year after it appeared, President Kennedy ordered his Science Advisory Committee to investigate Carson's claims. The report the committee issued "add[ed] up to a fairly thorough-going vindication of Rachel Carson’s Silent Spring thesis," in the words of the journal Science,[32] and recommended a phaseout of "persistent toxic pesticides".[33] DDT became a prime target of the growing anti-chemical and anti-pesticide movements, and in 1967 a group of scientists and lawyers founded the Environmental Defense Fund (EDF) with the specific goal of winning a ban on DDT. Victor Yannacone, Charles Wurster, Art Cooley and others associated with inception of EDF had all witnessed bird kills or declines in bird populations and suspected that DDT was the cause. In their campaign against the chemical, EDF petitioned the government for a ban and filed a series of lawsuits.[34] Around this time, toxicologist David Peakall was measuring DDE levels in the eggs of peregrine falcons and California condors and finding that increased levels corresponded with thinner shells. In response to an EDF suit, the U.S. District Court of Appeals in 1971 ordered the EPA to begin the de-registration procedure for DDT. After an initial six-month review process, William Ruckelshaus, the Agency's first Administrator rejected an immediate suspension of DDT's registration, citing studies from the EPA's internal staff stating that DDT was not an imminent danger to human health and wildlife.[15] However, the findings of these staff members were criticized, as they were performed mostly by economic entomologists inherited from the United States Department of Agriculture, who many environmentalists felt were biased towards agribusiness and tended to minimize concerns about human health and wildlife. The decision not to ban thus created public controversy.[23] The EPA then held seven months of hearings in 1971–1972, with scientists giving evidence both for and against the use of DDT. The hearings produced a 113-page decision, in which Hearing Examiner Edmund Sweeney wrote: “DDT is not a carcinogenic, mutagenic, or teratogenic hazard to man. The uses under regulations involved here do not have a deleterious effect on fresh water fish, estuarine organisms, wild birds, or other wildlife. The evidence in this proceeding supports the conclusion that there is a present need for essential uses of DDT.” [35] In the summer of 1972, Ruckelshaus announced the cancellation of most uses of DDT – an exemption allowed for public health uses under some conditions.[15] He later wrote, in a letter to American Farm Bureau President Allan Grant, that “in such decisions the ultimate judgement remains political.”[36] Immediately after the cancellation was announced, both EDF and the DDT manufacturers filed suit against the EPA, with the industry seeking to overturn the ban, and EDF seeking a comprehensive ban. The cases were consolidated, and in 1973 the U.S. Court of Appeals for the District of Columbia ruled that the EPA had acted properly in banning DDT.[15] Some uses of DDT continued under the public health exemption. For example, in June 1979, the California Department of Health Services was permitted to use DDT to suppress flea vectors of bubonic plague.[37] DDT also continued to be produced in the US for foreign markets until as late as 1985, when over 300 tons were exported.[10] ## Restrictions on usage In the 1970s and 1980s, agricultural use was banned in most developed countries, beginning with Hungary in 1968[38] then in Norway and Sweden in 1970, Germany and the United States in 1972, but not in the United Kingdom until 1984. By 1991 total bans on the use of DDT, including in disease control, were in place in at least 26 countries; for example Cuba in 1970, Singapore in 1984, Chile in 1985 and the Republic of Korea in 1986.[39] The Stockholm Convention, which took effect in 2004, outlawed several persistent organic pollutants, and restricted DDT use to vector control. The Convention has been ratified by more than 170 countries and is endorsed by most environmental groups. Recognizing that total elimination in many malaria-prone countries is currently unfeasible because there are few affordable or effective alternatives, the convention exempts public health use within World Health Organization (WHO) guidelines from the ban.[40] Resolution 60.18 of the World Health Assembly commits the World Health Organization to the Stockholm Convention's aim of reducing and ultimately eliminating the use of DDT.[41] Malaria Foundation International states, "The outcome of the treaty is arguably better than the status quo going into the negotiations. For the first time, there is now an insecticide which is restricted to vector control only, meaning that the selection of resistant mosquitoes will be slower than before."[42] Despite the worldwide ban, agricultural use continued in India,[43] North Korea, and possibly elsewhere as of 2008.[17] Today, about 3,000 to 4,000 tonnes of DDT are produced each year for disease vector control.[16] DDT is applied to the inside walls of homes to kill or repel mosquitoes. This intervention, called indoor residual spraying (IRS), greatly reduces environmental damage. It also reduces the incidence of DDT resistance.[44] For comparison, treating 40 hectares (98.8421524 acres) of cotton during a typical U.S. growing season requires the same amount of chemical as roughly 1,700 homes.[45] # Environmental impact DDT is a persistent organic pollutant that is readily adsorbed to soils and sediments, which can act both as sinks and as long-term sources of exposure contributing to terrestrial organisms.[1] Depending on conditions, its soil half life can range from 22 days to 30 years. Routes of loss and degradation include runoff, volatilization, photolysis and aerobic and anaerobic biodegradation. Due to hydrophobic properties, in aquatic ecosystems DDT and its metabolites are absorbed by aquatic organisms and adsorbed on suspended particles, leaving little DDT dissolved in the water itself. Its breakdown products and metabolites, DDE and DDD, are also highly persistent and have similar chemical and physical properties.[10] DDT and its breakdown products are transported from warmer regions of the world to the Arctic by the phenomenon of global distillation, where they then accumulate in the region's food web.[46] Because of its lipophilic properties, DDT has a high potential to bioaccumulate, especially in predatory birds.[47] DDT, DDE, and DDD magnify through the food chain, with apex predators such as raptor birds concentrating more chemicals than other animals in the same environment. They are very lipophilic and are stored mainly in body fat. DDT and DDE are very resistant to metabolism; in humans, their half-lives are 6 and up to 10 years, respectively. In the United States, these chemicals were detected in almost all human blood samples tested by the Centers for Disease Control in 2005, though their levels have sharply declined since most uses were banned in the US.[48] Estimated dietary intake has also declined,[48] although FDA food tests commonly detect it.[49] Marine macroalgae (seaweed) help reduce soil toxicity by up to 80% within six weeks.[50] ## Effects on wildlife and eggshell thinning DDT is toxic to a wide range of living organisms, including marine animals such as crayfish, daphnids, sea shrimp and many species of fish. DDT, through its metabolite DDE (dichlorodiphenyldichloroethylene), caused eggshell thinning and resulted in severe population declines in multiple North American and European bird of prey species.[51] Eggshell thinning lowers the reproductive rate of certain bird species by causing egg breakage and embryo deaths. DDE related eggshell thinning is considered a major reason for the decline of the bald eagle,[7] brown pelican,[52] peregrine falcon, and osprey.[10] However, different groups of birds vary greatly in their sensitivity to these chemicals.[1] Birds of prey, waterfowl, and song birds are more susceptible to eggshell thinning than chickens and related species, and DDE appears to be more potent than DDT.[10] Even in 2010, more than forty years after the U.S. ban, California condors which feed on sea lions at Big Sur which in turn feed in the Palos Verdes Shelf area of the Montrose Chemical Superfund site seemed to be having continued thin-shell problems. Scientists with the Ventana Wildlife Society and others are intensifying studies and remediations of the condors' problems.[53] The biological thinning mechanism is not entirely known, but there is strong evidence that p,p'-DDE inhibits calcium ATPase in the membrane of the shell gland and reduces the transport of calcium carbonate from blood into the eggshell gland. This results in a dose-dependent thickness reduction.[10][54][55][56] There is also evidence that o,p'-DDT disrupts female reproductive tract development, impairing eggshell quality later.[57] Multiple mechanisms may be at work, or different mechanisms may operate in different species.[10] Some studies show that although DDE levels have fallen dramatically, eggshell thickness remains 10–12 percent thinner than before DDT was first used.[58] # Effects on human health DDT is an endocrine disruptor.[59][60] It is considered likely to be a human carcinogen although the majority of studies suggest it is not directly genotoxic.[61][62][63] The DDT metabolite DDE acts as an antiandrogen, but not as an estrogen. p,p'-DDT, DDT's main component, has little or no androgenic or estrogenic activity.[64] The minor component o,p'-DDT has weak estrogenic activity. ## Acute toxicity DDT is classified as "moderately toxic" by the United States National Toxicology Program (NTP)[65] and "moderately hazardous" by the World Health Organization (WHO), based on the rat oral Template:LD50 of 113 mg/kg.[66] DDT has on rare occasions been administered orally as a treatment for barbiturate poisoning.[67] ## Chronic toxicity ### Developmental toxicity DDT and DDE, like other organochlorines, have been shown to have xenoestrogenic activity, meaning they are chemically similar enough to estrogens to trigger hormonal responses in animals. This endocrine disrupting activity has been observed in mice and rat toxicological studies, and available epidemiological evidence indicates that these effects may be occurring in humans as a result of DDT exposure. The US Environmental Protection Agency states that DDT exposure damages the reproductive system and reduces reproductive success. These effects may cause developmental and reproductive toxicity: - A review article in The Lancet states, "research has shown that exposure to DDT at amounts that would be needed in malaria control might cause preterm birth and early weaning ... toxicological evidence shows endocrine-disrupting properties; human data also indicate possible disruption in semen quality, menstruation, gestational length, and duration of lactation."[31] - Other studies document decreases in semen quality among men with high exposures (generally from IRS).[68] - Studies generally find that high blood DDT or DDE levels do not increase time to pregnancy (TTP.)Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) There is some evidence that the daughters of highly exposed women may have more difficulty getting pregnant (i.e. increased TTP).Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) - DDT is associated with early pregnancy loss, a type of miscarriage. A prospective cohort study of Chinese textile workers found "a positive, monotonic, exposure-response association between preconception serum total DDT and the risk of subsequent early pregnancy losses."Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) The median serum DDE level of study group was lower than that typically observed in women living in homes sprayed with DDT.Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) - A Japanese study of congenital hypothyroidism concluded that in utero DDT exposure may affect thyroid hormone levels and "play an important role in the incidence and/or causation of cretinism."Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) Other studies have also found that DDT or DDE interfere with proper thyroid function.Error creating thumbnail: File missingThis article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) ## Carcinogenicity In 2002, the Centers for Disease Control reported that "Overall, in spite of some positive associations for some cancers within certain subgroups of people, there is no clear evidence that exposure to DDT/DDE causes cancer in humans."[10] The NTP classifies it as "reasonably anticipated to be a carcinogen," the International Agency for Research on Cancer classifies it as a "possible" human carcinogen, and the EPA classifies DDT, DDE, and DDD as class B2 "probable" carcinogens. These evaluations are based mainly on the results of animal studies.[10][31] A Lancet review of epidemiological studies concluded that that DDT causes cancers of the liver, and pancreas, that there is mixed evidence that it causes cancers of the testes, and that it probably does not contribute to cancers of the rectum, prostate, endometrium, lung, or stomach.[31] A second review, whose co-authors included persons engaged in DDT-related litigation, reached broadly similar conclusions, but also found possible associations with breast cancer, leukemia, lymphoma, and testicular cancer.[48] ### Breast cancer The question of whether DDT or DDE are risk factors in breast cancer has not been conclusively answered. Several meta analyses of observational studies have concluded that there is no overall relationship between DDT exposure and breast cancer risk.[69][70] The United States Institute of Medicine reviewed data on the association of breast cancer with DDT exposure in 2012 and concluded that a causative relationship could neither be proven nor disproven.[71] A 2007 case control study using archived blood samples found that breast cancer risk was increased 5-fold among women who were born prior to 1931 and who had high serum DDT levels in 1963. Reasoning that DDT use became widespread in 1945 and peaked around 1950, they concluded that the ages of 14-20 were a critical period in which DDT exposure leads to increased risk. This study, which suggests a connection between DDT exposure and breast cancer that would not be picked up by most studies, has received variable commentary in third party reviews. One review suggested that "previous studies that measured exposure in older women may have missed the critical period."[48][72] A second review suggested a cautious approach to the interpretation of these results given methodological weaknesses in the study design.[73] The National Toxicology Program notes that while the majority of studies have not found a relationship between DDT exposure and breast cancer that positive associations have been seen in a "few studies among women with higher levels of exposure and among certain subgroups of women"[74] # Use against malaria Malaria remains a major public health challenge in many countries. 2008 WHO estimates were 243 million cases, and 863,000 deaths. About 89% of these deaths occur in Africa, and mostly to children under the age of 5.[75] DDT is one of many tools that public health officials use to fight the disease. Its use in this context has been called everything from a "miracle weapon [that is] like Kryptonite to the mosquitoes,"[76] to "toxic colonialism."[77] Before DDT, eliminating mosquito breeding grounds by drainage or poisoning with Paris green or pyrethrum was sometimes successful in fighting malaria. In parts of the world with rising living standards, the elimination of malaria was often a collateral benefit of the introduction of window screens and improved sanitation.[27] Today, a variety of usually simultaneous interventions is the norm. These include antimalarial drugs to prevent or treat infection; improvements in public health infrastructure to quickly diagnose, sequester, and treat infected individuals; bednets and other methods intended to keep mosquitoes from biting humans; and vector control strategies[75] such as larvaciding with insecticides, ecological controls such as draining mosquito breeding grounds or introducing fish to eat larvae, and indoor residual spraying (IRS) with insecticides, possibly including DDT. IRS involves the treatment of all interior walls and ceilings with insecticides, and is particularly effective against mosquitoes, since many species rest on an indoor wall before or after feeding. DDT is one of 12 WHO–approved IRS insecticides. WHO's anti-malaria campaign of the 1950s and 1960s relied heavily on DDT and the results were promising, though temporary. Experts tie the resurgence of malaria to multiple factors, including poor leadership, management and funding of malaria control programs; poverty; civil unrest; and increased irrigation. The evolution of resistance to first-generation drugs (e.g. chloroquine) and to insecticides exacerbated the situation.[17][78] Resistance was largely fueled by often unrestricted agricultural use. Resistance and the harm both to humans and the environment led many governments to restrict or curtail the use of DDT in vector control as well as agriculture.[29] In 2006 the WHO reversed a longstanding policy against DDT by recommending that it be used as an indoor pesticide in regions where malaria is a major problem.[79] Once the mainstay of anti-malaria campaigns, as of 2008 only 12 countries used DDT, including India and some southern African states,[75] though the number is expected to rise.[17] ## Initial effectiveness of DDT against malaria When it was first introduced in World War II, DDT was very effective in reducing malaria morbidity and mortality.[23] The WHO's anti-malaria campaign, which consisted mostly of spraying DDT and rapid treatment and diagnosis to break the transmission cycle, was initially very successful as well. For example, in Sri Lanka, the program reduced cases from about one million per year before spraying to just 18 in 1963[80][81] and 29 in 1964. Thereafter the program was halted to save money and malaria rebounded to 600,000 cases in 1968 and the first quarter of 1969. The country resumed DDT vector control but the mosquitoes had evolved resistance in the interim, presumably because of continued agricultural use. The program switched to malathion, but despite initial successes, malaria continued its resurgence into the 1980s.[28][82] Today, DDT remains on the WHO's list of insecticides recommended for IRS. Since the appointment of Arata Kochi as head of its anti-malaria division, WHO's policy has shifted from recommending IRS only in areas of seasonal or episodic transmission of malaria, to also advocating it in areas of continuous, intense transmission.[83] The WHO has reaffirmed its commitment to eventually phasing out DDT, aiming "to achieve a 30% cut in the application of DDT world-wide by 2014 and its total phase-out by the early 2020s if not sooner" while simultaneously combating malaria. The WHO plans to implement alternatives to DDT to achieve this goal.[84] South Africa is one country that continues to use DDT under WHO guidelines. In 1996, the country switched to alternative insecticides and malaria incidence increased dramatically. Returning to DDT and introducing new drugs brought malaria back under control.[85] Malaria cases increased in South America after countries in that continent stopped using DDT. Research data shows a significantly strong negative relationship between DDT residual house sprayings and malaria rates. In a research from 1993 to 1995, Ecuador increased its use of DDT and resulted in a 61% reduction in malaria rates, while each of the other countries that gradually decreased its DDT use had large increase in malaria rates.[45][86][87] ## Mosquito resistance In some areas resistance has greatly reduced DDT's effectiveness. WHO guidelines require that absence of resistance must be confirmed before using the chemical.[88] Resistance is largely due to agricultural use, in much greater quantities than required for disease prevention. Resistance was noted early in spray campaigns. Paul Russell, a former head of the Allied Anti-Malaria campaign, observed in 1956 that "resistance has appeared after six or seven years."[27] Resistance has been detected in Sri Lanka, Pakistan, Turkey and Central America, and it has largely been replaced by organophosphate or carbamate insecticides, e.g. malathion or bendiocarb.[89] In many parts of India, DDT has also largely lost its effectiveness.[90] Agricultural uses were banned in 1989 and its anti-malarial use has been declining. Urban use has halted completely.[91] Nevertheless, DDT is still manufactured and used,[92] and one study had concluded that "DDT is still a viable insecticide in indoor residual spraying owing to its effectivity in well supervised spray operation and high excito-repellency factor."[93] Studies of malaria-vector mosquitoes in KwaZulu-Natal Province, South Africa found susceptibility to 4% DDT (the WHO susceptibility standard), in 63% of the samples, compared to the average of 86.5% in the same species caught in the open. The authors concluded that "Finding DDT resistance in the vector An. arabiensis, close to the area where we previously reported pyrethroid-resistance in the vector An. funestus Giles, indicates an urgent need to develop a strategy of insecticide resistance management for the malaria control programmes of southern Africa."[94] DDT can still be effective against resistant mosquitoes,[95] and the avoidance of DDT-sprayed walls by mosquitoes is an additional benefit of the chemical.[93] For example, a 2007 study reported that resistant mosquitoes avoided treated huts. The researchers argued that DDT was the best pesticide for use in IRS (even though it did not afford the most protection from mosquitoes out of the three test chemicals) because the others pesticides worked primarily by killing or irritating mosquitoes – encouraging the development of resistance to these agents.[95] Others argue that the avoidance behavior slows the eradication of the disease.[96] Unlike other insecticides such as pyrethroids, DDT requires long exposure to accumulate a lethal dose; however its irritant property shortens contact periods. "For these reasons, when comparisons have been made, better malaria control has generally been achieved with pyrethroids than with DDT."[89] In India, with its outdoor sleeping habits and frequent night duties, "the excito-repellent effect of DDT, often reported useful in other countries, actually promotes outdoor transmission."[97] Genomic studies in the model genetic organism Drosophila melanogaster have revealed that high level DDT resistance is polygenic, involving multiple resistance mechanisms.[98] ## Residents' concerns IRS is effective if at least 80% of homes and barns in a residential area are sprayed.[88] Lower coverage rates can jeopardize program effectiveness. Many residents resist DDT spraying, objecting to the lingering smell, stains on walls, and the potential exacerbation of problems with other insect pests.[89][96][99] Pyrethroid insecticides (e.g. deltamethrin and lambda-cyhalothrin) can overcome some of these issues, increasing participation.[89] ## Human exposure A 1994 study found that compared to contemporaries living where DDT is not used, South Africans living in sprayed homes have levels that are several orders of magnitude greater.[48] Breast milk from South African mothers contains high levels of DDT and DDE.[48] It is unclear to what extent these levels arise from home spraying vs. residues in food. There is some evidence that these levels are associated with neurological abnormalities in babies.[89] Most studies of DDT's human health effects have been conducted in developed countries where DDT is not used and exposure is relatively low. Many experts urge that alternatives be used instead of IRS.[31][48][100] Illegal diversion to agriculture is also a concern as it is almost impossible to prevent and its subsequent use on crops is uncontrolled. For example, DDT use is widespread in Indian agriculture,[101] particularly mango production,[102] and is reportedly used by librarians to protect books.[103] Other examples include Ethiopia, where DDT intended for malaria control is reportedly being used in coffee production,[104] and Ghana where it is used for fishing."[105][106] The residues in crops at levels unacceptable for export have been an important factor in recent bans in several tropical countries.[89] Adding to this problem is a lack of skilled personnel and supervision.[96] ## Criticism of restrictions on DDT use Critics argue that limitations on DDT use for public heath purposes have caused unnecessary morbidity and mortality from vector borne diseases, with some claims of malaria deaths ranging as high as the hundreds of thousands,[107] and millions. Robert Gwadz of the US National Institutes of Health said in 2007, "The ban on DDT may have killed 20 million children."[108] In his novel State of Fear, author Michael Crichton wrote "Banning DDT killed more people than Hitler."[109] These arguments have been dismissed as "outrageous" by former WHO scientist Socrates Litsios. May Berenbaum, University of Illinois entomologist, says, "to blame environmentalists who oppose DDT for more deaths than Hitler is worse than irresponsible."[76] Investigative journalist Adam Sarvana and others characterize this notion as a "myth" promoted principally by Roger Bate of the pro-DDT advocacy group Africa Fighting Malaria (AFM).[110][111] Criticisms of a DDT "ban" often specifically reference the 1972 US ban (with the erroneous implication that this constituted a worldwide ban and prohibited use of DDT in vector control). Reference is often made to Rachel Carson's Silent Spring, even though she never pushed for a ban on DDT specifically. John Quiggin and Tim Lambert wrote, "the most striking feature of the claim against Carson is the ease with which it can be refuted."[112] It has also been alleged that donor governments and agencies have refused to fund DDT spraying, or made aid contingent upon not using DDT. According to a report in the British Medical Journal, use of DDT in Mozambique "was stopped several decades ago, because 80% of the country's health budget came from donor funds, and donors refused to allow the use of DDT."[113] Roger Bate asserts, "many countries have been coming under pressure from international health and environment agencies to give up DDT or face losing aid grants: Belize and Bolivia are on record admitting they gave in to pressure on this issue from [USAID]."[114] The United States Agency for International Development (USAID) has been the focus of much criticism. While the agency is currently funding the use of DDT in some African countries,[115] in the past it did not. When John Stossel accused USAID of not funding DDT because it wasn't "politically correct," Anne Peterson, the agency's assistant administrator for global health, replied that "I believe that the strategies we are using are as effective as spraying with DDT ... So, politically correct or not, I am very confident that what we are doing is the right strategy."[116] USAID's Kent R. Hill states that the agency has been misrepresented: "USAID strongly supports spraying as a preventative measure for malaria and will support the use of DDT when it is scientifically sound and warranted."[117] The Agency's website states that "USAID has never had a 'policy' as such either 'for' or 'against' DDT for IRS. The real change in the past two years [2006/07] has been a new interest and emphasis on the use of IRS in general – with DDT or any other insecticide – as an effective malaria prevention strategy in tropical Africa."[115] The website further explains that in many cases alternative malaria control measures were judged to be more cost-effective that DDT spraying, and so were funded instead.[118] ## Alternatives ### Other insecticides Organophosphate and carbamate insecticides, e.g. malathion and bendiocarb, respectively, are more expensive than DDT per kilogram and are applied at roughly the same dosage. Pyrethroids such as deltamethrin are also more expensive than DDT, but are applied more sparingly (0.02–0.3 g/m2 vs 1–2 g/m2), so the net cost per house is about the same over 6 months.[30] ### Non-chemical vector control Before DDT, malaria was successfully eliminated or curtailed in several tropical areas by removing or poisoning mosquito breeding grounds and larva habitats, for example by filling or applying oil to standing water. These methods have seen little application in Africa for more than half a century.[119] According to the United States CDC, such methods are not practical in Africa because "Anopheles gambiae, one of the primary vectors of malaria in Africa, breeds in numerous small pools of water that form due to rainfall.... It is difficult, if not impossible, to predict when and where the breeding sites will form, and to find and treat them before the adults emerge."[120] The relative effectiveness of IRS (with DDT or alternative insecticides) versus other malaria control techniques (e.g. bednets or prompt access to anti-malarial drugs) varies greatly and is highly dependent on local conditions.[30] A WHO study released in January 2008 found that mass distribution of insecticide-treated mosquito nets and artemisinin–based drugs cut malaria deaths in half in Rwanda and Ethiopia, countries with high malaria burdens. IRS with DDT did not play an important role in mortality reduction in these countries.[121][122] Vietnam has enjoyed declining malaria cases and a 97% mortality reduction after switching in 1991 from a poorly funded DDT-based campaign to a program based on prompt treatment, bednets, and pyrethroid group insecticides.[123] In Mexico, effective and affordable chemical and non-chemical strategies against malaria have been so successful that the Mexican DDT manufacturing plant ceased production due to lack of demand.[124] A review of fourteen studies on the subject in sub-Saharan Africa, covering insecticide-treated nets, residual spraying, chemoprophylaxis for children, chemoprophylaxis or intermittent treatment for pregnant women, a hypothetical vaccine, and changing front–line drug treatment, found decision making limited by the gross lack of information on the costs and effects of many interventions, the very small number of cost-effectiveness analyses available, the lack of evidence on the costs and effects of packages of measures, and the problems in generalizing or comparing studies that relate to specific settings and use different methodologies and outcome measures. The two cost-effectiveness estimates of DDT residual spraying examined were not found to provide an accurate estimate of the cost-effectiveness of DDT spraying; furthermore, the resulting estimates may not be good predictors of cost-effectiveness in current programs.[125] However, a study in Thailand found the cost per malaria case prevented of DDT spraying ($1.87 US) to be 21% greater than the cost per case prevented of lambda-cyhalothrin–treated nets ($1.54 US),[126] at very least casting some doubt on the unexamined assumption that DDT was the most cost-effective measure to use in all cases. The director of Mexico's malaria control program finds similar results, declaring that it is 25% cheaper for Mexico to spray a house with synthetic pyrethroids than with DDT.[124] However, another study in South Africa found generally lower costs for DDT spraying than for impregnated nets.[127] A more comprehensive approach to measuring cost-effectiveness or efficacy of malarial control would not only measure the cost in dollars of the project, as well as the number of people saved, but would also consider ecological damage and negative aspects of insecticide use on human health. One preliminary study regarding the effect of DDT found that it is likely the detriment to human health approaches or exceeds the beneficial reductions in malarial cases, except perhaps in malarial epidemic situations. It is similar to the earlier mentioned study regarding estimated theoretical infant mortality caused by DDT and subject to the criticism also mentioned earlier.[128] A study in the Solomon Islands found that "although impregnated bed nets cannot entirely replace DDT spraying without substantial increase in incidence, their use permits reduced DDT spraying."[129] A comparison of four successful programs against malaria in Brazil, India, Eritrea, and Vietnam does not endorse any single strategy but instead states, "Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing."[130] DDT resistant mosquitoes have generally proved susceptible to pyrethroids. Thus far, pyrethroid resistance in Anopheles has not been a major problem.[89]	https://www.wikidoc.org/index.php/Clofenotane
6101c138e3d326cbf6b68c4ffde078d7110b851f	wikidoc	Clopidogrel	Clopidogrel # 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 Clopidogrel is a P2Y12 platelet inhibitor, platelet aggregation inhibitor that is FDA approved for the treatment of acute coronary syndrome (ACS), recent MI, recent stroke, or established peripheral arterial disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include non-major bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Acute Coronary Syndrome - For patients with non-ST-elevation ACS - Initial loading dosage: 300 mg PO - Maitaining dosage: 75 mg PO qd - In combination with: Aspirin 75-300 mg PO qd - For patients with STEMI - Recommended dosage: 75 mg PO qd (With or without the loading dosage) - In combination with: Aspirin 75-300 mg PO qd ### Recent MI, Recent Stroke, or Established Peripheral Arterial Disease - Dosing information - 75 mg PO qd ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about the guideline-supported use. ### Non–Guideline-Supported Use Prophylaxis of Thrombosis in Patient with Atrial Fibrillation - Dosing Information - 75 mg/day incombination with aspirin 75-100 mg Prophylaxis of Thrombosis in Patient with Congestive Heart Failure - Dosing information - 75 mg/day Stasis Ulcer - Dosing information - Recommended dosage: 75 mg/day for 2-4 weeks # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Clopidogrel FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about the guideline-supported use. ### Non–Guideline-Supported Use Prophylaxis of Arterial thrombosis - Dosing Information - Recommended dosage: 0.2 mg/kg/day # Contraindications - Active Bleeding - Clopidogrel is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. - Hypersensitivity - Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product. # Warnings - Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function - Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19. - Proton Pump Inhibitors - Avoid concomitant use of clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel. - General Risk of Bleeding - Thienopyridines, including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel five days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% clopidogrel + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo + aspirin. - Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective. - Discontinuation of Clopidogrel - Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events. - Patients With Recent Transient Ischemic Attack (TIA) or Stroke - In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding. - Thrombotic Thrombocytopenic Purpura (TTP) - TTP, sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes seen on peripheral smear), neurological findings, renal dysfunction, and fever. - Cross-Reactivity Among Thienopyridines - Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. - The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below. Bleeding - CURE - In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal bleeding and at puncture sites) compared to placebo with aspirin. The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise. The overall incidence of bleeding is described in Table 1. - Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results. - COMMIT - In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin. - Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results. COMMIT - In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin. - CAPRIE (Clopidogrel bisulfate vs. Aspirin) - In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin. - Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma. - Other Adverse Events - In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo. - In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of clopidogrel. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A - Eye disorders: Eye (conjunctival, ocular, retinal) bleeding - Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea - General disorders and administration site condition: Fever, hemorrhage of operative wound - Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test - Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness - Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis - Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache - Psychiatric disorders: Confusion, hallucinations - Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, eosinophilic pneumonia - Renal and urinary disorders: Increased creatinine levels - Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus - Vascular disorders: Vasculitis, hypotension # Drug Interactions - Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. - Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole. - Coadministration of clopidogrel and NSAIDs increases the risk of gastrointestinal bleeding. - Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. - However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. - Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clopidogrel in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Clopidogrel during labor and delivery. ### Nursing Mothers Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and effectiveness in pediatric populations have not been established. Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. ### Geriatic Use Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients. ### Gender There is no FDA guidance on the use of Clopidogrel with respect to specific gender populations. ### Race There is no FDA guidance on the use of Clopidogrel with respect to specific racial populations. ### Renal Impairment Experience is limited in patients with severe and moderate renal impairment. ### Hepatic Impairment No dosage adjustment is necessary in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Clopidogrel in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Clopidogrel in patients who are immunocompromised. # Administration and Monitoring ### Administration Clopidogrel tablets USP can be administered with or without food. For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel tablets USP with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75 to 325 mg once daily) and continue in combination with clopidogrel tablets USP. For patients with STEMI, the recommended dose of clopidogrel tablets USP is 75 mg once daily orally, administered in combination with aspirin (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets USP may be initiated with or without a loading dose. The recommended daily dose of clopidogrel tablets USP is 75 mg once daily orally, with or without food. CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established. Avoid using omeprazole or esomeprazole with clopidogrel tablets USP. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel tablets USP. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. ### Monitoring There is limited information regarding Clopidogrel Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Clopidogrel and IV administrations. # Overdosage Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals. Based on biological plausibility, platelet transfusion may restore clotting ability. # Pharmacology ## Mechanism of Action Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. ## Structure Clopidogrel bisulfate, USP is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothienopyridine-5(4H)-acetate sulfate (1:1). The structural formula is as follows: C16H16ClNO2SH2SO4 M.W. 419.9 Clopidogrel bisulfate, USP is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°. Clopidogrel bisulfate, USP for oral administration is provided as light-pink to pink, debossed, film-coated, capsule shaped tablets containing 97.875 mg of clopidogrel bisulfate, USP which is the molar equivalent of 75 mg of clopidogrel base. Each tablet contains the following inactive ingredients: crospovidone, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, indigo carmine aluminum lake FD&C blue #2, iron oxide red, iron oxide yellow, lactose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide. ## Pharmacodynamics Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days. Geriatric Patients Elderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation. Renally-Impaired Patients After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation. Hepatically-Impaired Patients After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. Gender In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women. ## Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites. Absorption - After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Effect of Food - Clopidogrel can be administered with or without food. In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast. Metabolism - Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet. - The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0 and 2.7 fold increases in Cmax and AUC, respectively. Elimination - Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes. Drug Interactions - Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Proton Pump Inhibitors (PPI) - The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1. ## Nonclinical Toxicology There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures > 25 times that in humans at the recommended daily dose of 75 mg. Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice). Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis). # Clinical Studies CURE The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥ 65 years of age. Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization. The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel-treated group. Most of the benefit of clopidogrel occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months). In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with clopidogrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE. The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients in the clopidogrel group, 126 patients in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients in the clopidogrel group, 454 patients in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients in the clopidogrel group, 2324 patients in the placebo group; relative risk reduction of 4.0%). COMMIT In patients with STEMI, the safety and efficacy of clopidogrel were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first. The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI. As shown in Table 5 and Figures 4 and 5 below, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002). - All treated patients received aspirin. The effect of clopidogrel did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously. - Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model. CAPRIE The CAPRIE trial was a 19,185 patient, 304 center, international, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years). The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular. As shown in Table 6, clopidogrel was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel group. The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3 year follow-up period. The statistical significance favoring clopidogrel over aspirin was marginal (p = 0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel is substantial. The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel relative to aspirin was heterogeneous across these randomized subgroups (p = 0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was not numerically superior to aspirin. CHARISMA The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p = 0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel. # How Supplied Clopidogrel tablets USP are available as follows: 75 mg – light-pink to pink, film-coated, capsule shaped tablets debossed with “TV” on one side and “7314” on the other side, in bottles of 30, 90, and 500. ## Storage Store at 20° to 25°C (68° to 77°F) . Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information For patient information about clopidogrel, click here. # Precautions with Alcohol Alcohol-Clopidogrel 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 Clopidogrel Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Clopidogrel Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Clopidogrel Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Sree Teja Yelamanchili, MBBS [3] # 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 Clopidogrel is a P2Y12 platelet inhibitor, platelet aggregation inhibitor that is FDA approved for the treatment of acute coronary syndrome (ACS), recent MI, recent stroke, or established peripheral arterial disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include non-major bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Acute Coronary Syndrome - For patients with non-ST-elevation ACS - Initial loading dosage: 300 mg PO - Maitaining dosage: 75 mg PO qd - In combination with: Aspirin 75-300 mg PO qd - For patients with STEMI - Recommended dosage: 75 mg PO qd (With or without the loading dosage) - In combination with: Aspirin 75-300 mg PO qd ### Recent MI, Recent Stroke, or Established Peripheral Arterial Disease - Dosing information - 75 mg PO qd ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about the guideline-supported use. ### Non–Guideline-Supported Use Prophylaxis of Thrombosis in Patient with Atrial Fibrillation - Dosing Information - 75 mg/day incombination with aspirin 75-100 mg[1] Prophylaxis of Thrombosis in Patient with Congestive Heart Failure - Dosing information - 75 mg/day[2] Stasis Ulcer - Dosing information - Recommended dosage: 75 mg/day for 2-4 weeks[3] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Clopidogrel FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about the guideline-supported use. ### Non–Guideline-Supported Use Prophylaxis of Arterial thrombosis - Dosing Information - Recommended dosage: 0.2 mg/kg/day[4] # Contraindications - Active Bleeding - Clopidogrel is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. - Hypersensitivity - Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product. # Warnings - Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function - Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19. - Proton Pump Inhibitors - Avoid concomitant use of clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel. - General Risk of Bleeding - Thienopyridines, including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel five days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% clopidogrel + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo + aspirin. - Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective. - Discontinuation of Clopidogrel - Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events. - Patients With Recent Transient Ischemic Attack (TIA) or Stroke - In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding. - Thrombotic Thrombocytopenic Purpura (TTP) - TTP, sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. - Cross-Reactivity Among Thienopyridines - Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. - The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below. Bleeding - CURE - In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal bleeding and at puncture sites) compared to placebo with aspirin. The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise. The overall incidence of bleeding is described in Table 1. - Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results. - COMMIT - In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin. - Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results. COMMIT - In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin. - CAPRIE (Clopidogrel bisulfate vs. Aspirin) - In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin. - Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma. - Other Adverse Events - In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo. - In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of clopidogrel. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A - Eye disorders: Eye (conjunctival, ocular, retinal) bleeding - Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea - General disorders and administration site condition: Fever, hemorrhage of operative wound - Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test - Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness - Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis - Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache - Psychiatric disorders: Confusion, hallucinations - Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, eosinophilic pneumonia - Renal and urinary disorders: Increased creatinine levels - Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus - Vascular disorders: Vasculitis, hypotension # Drug Interactions - Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. - Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole. - Coadministration of clopidogrel and NSAIDs increases the risk of gastrointestinal bleeding. - Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. - However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. - Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clopidogrel in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Clopidogrel during labor and delivery. ### Nursing Mothers Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and effectiveness in pediatric populations have not been established. Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. ### Geriatic Use Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients. ### Gender There is no FDA guidance on the use of Clopidogrel with respect to specific gender populations. ### Race There is no FDA guidance on the use of Clopidogrel with respect to specific racial populations. ### Renal Impairment Experience is limited in patients with severe and moderate renal impairment. ### Hepatic Impairment No dosage adjustment is necessary in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Clopidogrel in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Clopidogrel in patients who are immunocompromised. # Administration and Monitoring ### Administration Clopidogrel tablets USP can be administered with or without food. For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel tablets USP with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75 to 325 mg once daily) and continue in combination with clopidogrel tablets USP. For patients with STEMI, the recommended dose of clopidogrel tablets USP is 75 mg once daily orally, administered in combination with aspirin (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets USP may be initiated with or without a loading dose. The recommended daily dose of clopidogrel tablets USP is 75 mg once daily orally, with or without food. CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established. Avoid using omeprazole or esomeprazole with clopidogrel tablets USP. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel tablets USP. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. ### Monitoring There is limited information regarding Clopidogrel Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Clopidogrel and IV administrations. # Overdosage Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals. Based on biological plausibility, platelet transfusion may restore clotting ability. # Pharmacology ## Mechanism of Action Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. ## Structure Clopidogrel bisulfate, USP is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). The structural formula is as follows: C16H16ClNO2S•H2SO4 M.W. 419.9 Clopidogrel bisulfate, USP is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°. Clopidogrel bisulfate, USP for oral administration is provided as light-pink to pink, debossed, film-coated, capsule shaped tablets containing 97.875 mg of clopidogrel bisulfate, USP which is the molar equivalent of 75 mg of clopidogrel base. Each tablet contains the following inactive ingredients: crospovidone, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, indigo carmine aluminum lake FD&C blue #2, iron oxide red, iron oxide yellow, lactose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide. ## Pharmacodynamics Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days. Geriatric Patients Elderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation. Renally-Impaired Patients After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation. Hepatically-Impaired Patients After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. Gender In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women. ## Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites. Absorption - After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Effect of Food - Clopidogrel can be administered with or without food. In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast. Metabolism - Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet. - The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0 and 2.7 fold increases in Cmax and AUC, respectively. Elimination - Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes. Drug Interactions - Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Proton Pump Inhibitors (PPI) - The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1. ## Nonclinical Toxicology There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures > 25 times that in humans at the recommended daily dose of 75 mg. Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice). Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis). # Clinical Studies CURE The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥ 65 years of age. Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization. The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel-treated group. Most of the benefit of clopidogrel occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months). In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with clopidogrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE. The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the clopidogrel group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%). COMMIT In patients with STEMI, the safety and efficacy of clopidogrel were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first. The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI. As shown in Table 5 and Figures 4 and 5 below, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002). - All treated patients received aspirin. The effect of clopidogrel did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously. - Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model. CAPRIE The CAPRIE trial was a 19,185 patient, 304 center, international, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years). The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular. As shown in Table 6, clopidogrel was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel group. The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3 year follow-up period. The statistical significance favoring clopidogrel over aspirin was marginal (p = 0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel is substantial. The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel relative to aspirin was heterogeneous across these randomized subgroups (p = 0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was not numerically superior to aspirin. CHARISMA The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p = 0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel. # How Supplied Clopidogrel tablets USP are available as follows: 75 mg – light-pink to pink, film-coated, capsule shaped tablets debossed with “TV” on one side and “7314” on the other side, in bottles of 30, 90, and 500. ## Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information For patient information about clopidogrel, click here. # Precautions with Alcohol Alcohol-Clopidogrel 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 Clopidogrel Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Clopidogrel Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Clopidogrel
6ce0eefeebd43bd50e4572179dccfea926c9d831	wikidoc	Clostridium	Clostridium # Overview Clostridium is a large genus of Gram-positive bacteria, belonging to the Firmicutes. They are obligate anaerobes capable of producing endospores. Individual cells are rod-shaped, which gives them their name, from the Greek kloster or spindle. These characteristics traditionally defined the genus, but they are not phylogenetically significant; many species originally classified as Clostridium have been reclassified in other genera. # Pathology Clostridium includes common free-living bacteria as well as important pathogens. There are four main species responsible for disease in humans: - C. botulinum, an organism producing a toxin in food that causes botulism. - C. difficile, which can overgrow other bacteria in the gut during antibiotic therapy, can cause pseudomembranous colitis. - C. perfringens, causes a wide range of symptoms, from food poisoning to gas gangrene. Also responsible for enterotoxemia (also known as "overeating disease" or "pulpy kidney disease") in sheep and goats. - C. tetani, the causative organism of tetanus (lockjaw). Honey sometimes contains Clostridium bacteria which may cause infant botulism in humans one year old and under. Infant botulism causes the infant to produce botulinium toxin, which eventually paralyzes the breathing muscles. C. sordellii has been linked to the deaths of more than a dozen women after childbirth. # Commercial uses C. thermocellum can utilize lignocellulosic waste and generate ethanol, thus making it a possible candidate for use in ethanol production. It also has no oxygen requirement and is thermophilic, reducing cooling cost. C. acetobutylicum, also known as the Weizmann organism, which was first used by Chaim Weizmann to produce acetone and biobutanol from starch in 1916 for the production of gunpowder and TNT. The anaerobic bacterium C. ljungdahlii, recently discovered in commercial chicken wastes, can produce ethanol from single-carbon sources including synthesis gas, a mixture of carbon monoxide and hydrogen that can be generated from the partial combustion of either fossil fuels or biomass. Use of these bacteria to produce ethanol from synthesis gas has progressed to the pilot plant stage at the BRI Energy facility in Fayetteville, Arkansas.	Clostridium For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Clostridium is a large genus of Gram-positive bacteria, belonging to the Firmicutes. They are obligate anaerobes capable of producing endospores.[1] Individual cells are rod-shaped, which gives them their name, from the Greek kloster or spindle. These characteristics traditionally defined the genus, but they are not phylogenetically significant; many species originally classified as Clostridium have been reclassified in other genera. # Pathology Clostridium includes common free-living bacteria as well as important pathogens.[2] There are four main species responsible for disease in humans: - C. botulinum, an organism producing a toxin in food that causes botulism.[3] - C. difficile, which can overgrow other bacteria in the gut during antibiotic therapy, can cause pseudomembranous colitis.[4] - C. perfringens, causes a wide range of symptoms, from food poisoning to gas gangrene. Also responsible for enterotoxemia (also known as "overeating disease" or "pulpy kidney disease") in sheep and goats.[5] - C. tetani, the causative organism of tetanus (lockjaw).[6] Honey sometimes contains Clostridium bacteria which may cause infant botulism in humans one year old and under. Infant botulism causes the infant to produce botulinium toxin, which eventually paralyzes the breathing muscles.[7] C. sordellii has been linked to the deaths of more than a dozen women after childbirth. # Commercial uses C. thermocellum can utilize lignocellulosic waste and generate ethanol, thus making it a possible candidate for use in ethanol production. It also has no oxygen requirement and is thermophilic, reducing cooling cost. C. acetobutylicum, also known as the Weizmann organism, which was first used by Chaim Weizmann to produce acetone and biobutanol from starch in 1916 for the production of gunpowder and TNT. The anaerobic bacterium C. ljungdahlii, recently discovered in commercial chicken wastes, can produce ethanol from single-carbon sources including synthesis gas, a mixture of carbon monoxide and hydrogen that can be generated from the partial combustion of either fossil fuels or biomass. Use of these bacteria to produce ethanol from synthesis gas has progressed to the pilot plant stage at the BRI Energy facility in Fayetteville, Arkansas.[8]	https://www.wikidoc.org/index.php/Clostridium
36ad7021cad2c456ba6a28ab771ee8964c634c2d	wikidoc	Clotiazepam	Clotiazepam # Overview Clotiazepam (marketed under brand name Clozan, Distensan, Trecalmo, Rize, Rizen and Veratran) is a thienodiazepine drug which is a benzodiazepine analog. The clotiazepam molecule differs from most other benzodiazepines in that the benzene ring has been replaced by a thiophene ring. It possesses anxiolytic, skeletal muscle relaxant, anticonvulsant, sedative properties. Stage 2 NREM sleep is significantly increased by clotiazepam. # Indications Clotiazepam has been trialed and found to be effective in the short-term management of anxiety. Clotiazepam is also used as a premedicant in minor surgery in France and Japan, where the drug is commercially available under the brand names Veratran and Rize, respectively. # Pharmacokinetics A cross-over study in six healthy volunteers (median age 28 years) was conducted using single-dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets. The formulations had similar systemic availability. Compared with oral tablets, the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly. # Pharmacology Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties. Clotiazepam binds to the benzodiazepine site of the GABAA receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABAA receptor which results in the pharmacological effects of clotiazepam. Clotiazepam has a relatively short elimination half-life and is less prone to accumulation after repeated dosing compared to longer-acting benzodiazepine agents. It is metabolised via oxidation. Clotiazepam is metabolised to hydroxy-clotiazepam and desmethyl-clotiazepam. After oral ingestion of a single 5 mg dose of clotiazepam by three healthy volunteers the drug was rapidly absorbed. The elimination half-life of the drug and its metabolites range from 6.5 hours to 18 hours. Clotiazepam is 99 percent bound to plasma protein. In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased. Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not affect the kinetics of clotiazepam. # Side effects Drowsiness and asthenia are common side effects. There has been a report of hepatitis caused by clotiazepam. # Abuse Clotiazepam is a recognised drug of abuse.	Clotiazepam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Clotiazepam[1] (marketed under brand name Clozan, Distensan, Trecalmo, Rize, Rizen and Veratran) is a thienodiazepine drug which is a benzodiazepine analog. The clotiazepam molecule differs from most other benzodiazepines in that the benzene ring has been replaced by a thiophene ring.[2] It possesses anxiolytic,[3] skeletal muscle relaxant,[4] anticonvulsant, sedative properties.[5] Stage 2 NREM sleep is significantly increased by clotiazepam.[6] # Indications Clotiazepam has been trialed and found to be effective in the short-term management of anxiety.[7] Clotiazepam is also used as a premedicant in minor surgery in France and Japan, where the drug is commercially available under the brand names Veratran and Rize, respectively.[8][9] # Pharmacokinetics A cross-over study in six healthy volunteers (median age 28 years) was conducted using single-dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets. The formulations had similar systemic availability. Compared with oral tablets, the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly.[10] # Pharmacology Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties.[5] Clotiazepam binds to the benzodiazepine site of the GABAA receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABAA receptor which results in the pharmacological effects of clotiazepam.[11] Clotiazepam has a relatively short elimination half-life and is less prone to accumulation after repeated dosing compared to longer-acting benzodiazepine agents. It is metabolised via oxidation.[12] Clotiazepam is metabolised to hydroxy-clotiazepam and desmethyl-clotiazepam. After oral ingestion of a single 5 mg dose of clotiazepam by three healthy volunteers the drug was rapidly absorbed.[13] The elimination half-life of the drug and its metabolites range from 6.5 hours to 18 hours. Clotiazepam is 99 percent bound to plasma protein.[13] In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.[14] Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not affect the kinetics of clotiazepam.[15] # Side effects Drowsiness and asthenia are common side effects.[16] There has been a report of hepatitis caused by clotiazepam.[17] # Abuse Clotiazepam is a recognised drug of abuse.[18]	https://www.wikidoc.org/index.php/Clotiazepam
932c9f7e59fae280305ff8c0e96f2b2345144fe7	wikidoc	Cloxacillin	Cloxacillin Cloxacillin is an antibiotic useful for the treatment of a number of bacterial infections. It is semisynthetic and in the same class as penicillin. Cloxacillin is used against staphylococci that produce beta-lactamase, due to its large R chain, which does not allow the beta-lactamases to bind. This drug has a weaker antibacterial activity than benzylpenicillin, and is devoid of serious toxicity except for allergic reactions. Cloxacillin was discovered and developed by Beecham. It is sold under a number of trade names, including Cloxapen, Cloxacap, Tegopen and Orbenin. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.	Cloxacillin Cloxacillin is an antibiotic useful for the treatment of a number of bacterial infections. It is semisynthetic and in the same class as penicillin. Cloxacillin is used against staphylococci that produce beta-lactamase, due to its large R chain, which does not allow the beta-lactamases to bind. This drug has a weaker antibacterial activity than benzylpenicillin, and is devoid of serious toxicity except for allergic reactions. Cloxacillin was discovered and developed by Beecham.[1] It is sold under a number of trade names, including Cloxapen, Cloxacap, Tegopen and Orbenin. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]	https://www.wikidoc.org/index.php/Cloxacillin
cbc887cd51c3b00e2759fcded2009e3db097e35f	wikidoc	Co-dydramol	Co-dydramol Co-dydramol (BAN) is a non-proprietary name used to denote a combination of dihydrocodeine tartrate and paracetamol. Co-dydramol tablets are used for the relief of moderate pain. Co-dydramol is in fact part of a series of combination drugs available in the UK and other countries including Co-codaprin (aspirin and codeine), Co-codamol (dihydrocodeine and paracetamol) and Co-proxamol (dextropropoxyphene and paracetamol). # Formulation All formulations contain 500 mg of paracetamol per tablet and may only be sold at a pharmacy as an over-the-counter item without prescription if containing less than 7.5 mg of dihydrocodeine per tablet. Higher strengths are prescription only medicines. Four strengths of dihydrocodeine tartrate in each tablet are available: - 7.46 mg dihydrocodeine in the brand Paramol. - 10 mg dihydrocodeine, BAN of Co-dydramol 10/500, this is also the preparation to be dispensed if no strength is specified on a prescription. - 20 mg dihydrocodeine, BAN of Co-dydramol 20/500 (branded product Remedeine). - 30 mg dihydrocodeine, BAN of Co-dydramol 30/500 (branded product Remedeine forte). Co-dydramol is one of a number of drugs using its particular method of deriving a proprietary and/or common name beginning with "co" and a hyphen. In fact, the "co" is for "combination", and in the British National Formulary there are many combination drugs with names using this naming convention, including antibiotics, gastrointestinal perparations, drugs to lower blood pressure, diuretics, anti-Parkinsonism agents and others. This list includes other agents for combating migrane headaches, such as Co-dergocrine, Co-careldopa, and others. The other commonly-encountered opioid combination is the anti-diarrhoeal, non-analgesic mixture of diphenoxylate and atropine, Co-phenotrope (a.k.a. Lomotil)	Co-dydramol Co-dydramol (BAN) is a non-proprietary name used to denote a combination of dihydrocodeine tartrate and paracetamol. Co-dydramol tablets are used for the relief of moderate pain. Co-dydramol is in fact part of a series of combination drugs available in the UK and other countries including Co-codaprin (aspirin and codeine), Co-codamol (dihydrocodeine and paracetamol) and Co-proxamol (dextropropoxyphene and paracetamol). # Formulation All formulations contain 500 mg of paracetamol per tablet and may only be sold at a pharmacy as an over-the-counter item without prescription if containing less than 7.5 mg of dihydrocodeine per tablet. Higher strengths are prescription only medicines. Four strengths of dihydrocodeine tartrate in each tablet are available: - 7.46 mg dihydrocodeine in the brand Paramol. - 10 mg dihydrocodeine, BAN of Co-dydramol 10/500, this is also the preparation to be dispensed if no strength is specified on a prescription. - 20 mg dihydrocodeine, BAN of Co-dydramol 20/500 (branded product Remedeine). - 30 mg dihydrocodeine, BAN of Co-dydramol 30/500 (branded product Remedeine forte). Co-dydramol is one of a number of drugs using its particular method of deriving a proprietary and/or common name beginning with "co" and a hyphen. In fact, the "co" is for "combination", and in the British National Formulary there are many combination drugs with names using this naming convention, including antibiotics, gastrointestinal perparations, drugs to lower blood pressure, diuretics, anti-Parkinsonism agents and others. This list includes other agents for combating migrane headaches, such as Co-dergocrine, Co-careldopa, and others. The other commonly-encountered opioid combination is the anti-diarrhoeal, non-analgesic mixture of diphenoxylate and atropine, Co-phenotrope (a.k.a. Lomotil)	https://www.wikidoc.org/index.php/Co-dydramol
230628f38ada28b3b8398d355bd43461510dd347	wikidoc	Co-sleeping	Co-sleeping Co-sleeping, also called the family bed, is a practice in which babies and young children sleep with one or both parents. It is standard practice in many parts of the world outside of North America, Europe and Australia, although sometimes children may crawl into bed with their parents. One 2006 study of children age 3-10 in India reported 93% of children co-sleeping. Co-sleeping was widely practiced in all areas up until the 19th century, until the advent of giving the child his or her own room and the crib. In many parts of the world, co-sleeping simply has the practical benefit of keeping the child warm at night. Co-sleeping has been relatively recently re-introduced into Western culture by practitioners of attachment parenting. A 2006 study of children in Kentucky in the United States reported 15% of infants and toddlers 2 weeks to 2 years co-sleeping. Proponents variously believe that co-sleeping saves babies' lives (especially in conjunction with nursing), promotes bonding, lets the parents get more sleep, facilitates breastfeeding, and protects against sudden infant death syndrome ("SIDS"). Older babies can breastfeed during the night without waking their mother. Opponents argue that co-sleeping is both stressful and dangerous for the baby, and argue that modern-day bedding is not safe for co-sleeping. They point to evidence that co-sleeping may increase the risk of SIDS, and argue that the parent may smother the child or promote an unhealthy dependence of the child on the parent. On the other side, they note that this practice may interfere with the parents' own relationship in terms of reducing both communication and sexual intercourse at bedtime. According to some advice, co-sleeping is likely to end after a year or two if the child is not forced to co-sleep. The child may choose a place of their own, possibly on a surface that would appear to be uncomfortable by adult standards. Hot weather and weaning can encourage this natural separation. # Safety and health Co-sleeping triggers conflicting advice among health care professionals. The U.S. Consumer Product Safety Commission warns against it. However, many pediatricians, breast-feeding advocates, and others have harshly criticized the CPSC recommendation. ## Advantages There may be health advantages to co-sleeping. One study reported mothers getting more sleep by co-sleeping and breastfeeding than by other arrangements. It has been argued that co-sleeping evolved over five million years, that it alters the infant's sleep experience and the number of maternal inspections of the infant, and that it provides a beginning point for considering possibly unconventional ways of helping reduce the risk of SIDS. Stress hormones are lower in mothers and babies who co-sleep, specifically the balance of the stress hormone cortisol, the control of which is essential for a baby's healthy growth. In studies with animals, infants who stayed close to their mothers had higher levels of growth hormones and enzymes necessary for brain and heart growth. The physiology of co-sleeping babies is more stable, including more stable temperatures, more regular heart rhythms, and fewer long pauses in breathing than babies who sleep alone. Co-sleeping promotes long-term emotional health. In long-term follow-up studies of infants who slept with their parents and those who slept alone, the children who co-slept were happier, less anxious, had higher self-esteem, were less likely to be afraid of sleep, had fewer behavioral problems, tended to be more comfortable with intimacy, and were generally more independent as adults. ## Dangers Co-sleeping is known to be dangerous when a parent smokes, but there are other risk factors as well. Web sites give advice on reducing the risks. Safebedsharing.org . Some common advice given is to keep a baby on its back, not its stomach, that a child should never sleep with a parent who smokes, is taking drugs (including alcohol) that impede alertness, or is extremely obese. It is also recommended that the bed should be firm, and should not be a waterbed or couch; and that heavy quilts, comforters, and pillows should not be used. Young children should never sleep next to babies under nine months of age. It is often recommended that a baby should never be left unattended in an adult bed even if the bed surface itself is no more dangerous than a crib surface. There is also the risk of the baby falling to a hard floor. ## Products There are several products which can be used to facilitate safe co-sleeping with an infant. - bassinets that attach to the side of an adult bed, and which have barriers on three sides, but are open to the parent's bed. - bed top co-sleeping products (Family Sleeper) designed to prevent baby from rolling off the adult bed and absorbing breastfeeding and other night time leaks. - side rails to prevent the child from rolling off the adult bed. - co-sleeping infant enclosures which are placed directly in the adult bed. # Prevalence A study of a small population in Northeast England showed a variety of nighttime parenting strategies and that 65% of the sample had bedshared, 95% of them having done so with both parents. The study reported that some of the parents found bedsharing effective, yet were covert in their practices, fearing disapproval of health professionals and relatives. Additionally, a National Center for Health Statistics survey from 1991 to 1999 found that 25% of American families always, or almost always, slept with their baby in bed, 42% slept with their baby "sometimes", and 32% never co-slept with their baby. # Further reading - Jackson, Deborah. Three in a Bed: The Benefits of Sharing Your Bed with Your Baby, New York: Bloomsbury, 1999. - Thevenin, Tine. The Family Bed, New Jersey: Avery Publishing Group, 1987.	Co-sleeping Co-sleeping, also called the family bed, is a practice in which babies and young children sleep with one or both parents. It is standard practice in many parts of the world outside of North America, Europe and Australia, although sometimes children may crawl into bed with their parents. One 2006 study of children age 3-10 in India reported 93% of children co-sleeping.[1] Co-sleeping was widely practiced in all areas up until the 19th century, until the advent of giving the child his or her own room and the crib. In many parts of the world, co-sleeping simply has the practical benefit of keeping the child warm at night. Co-sleeping has been relatively recently re-introduced into Western culture by practitioners of attachment parenting. A 2006 study of children in Kentucky in the United States reported 15% of infants and toddlers 2 weeks to 2 years co-sleeping.[2] Proponents variously believe that co-sleeping saves babies' lives (especially in conjunction with nursing),[3] promotes bonding, lets the parents get more sleep, facilitates breastfeeding, and protects against sudden infant death syndrome ("SIDS"). Older babies can breastfeed during the night without waking their mother. Opponents argue that co-sleeping is both stressful and dangerous for the baby,[4] and argue that modern-day bedding is not safe for co-sleeping. They point to evidence that co-sleeping may increase the risk of SIDS,[4] and argue that the parent may smother the child or promote an unhealthy dependence of the child on the parent. On the other side, they note that this practice may interfere with the parents' own relationship in terms of reducing both communication and sexual intercourse at bedtime. According to some advice, co-sleeping is likely to end after a year or two if the child is not forced to co-sleep. The child may choose a place of their own, possibly on a surface that would appear to be uncomfortable by adult standards. Hot weather and weaning can encourage this natural separation.[citation needed] # Safety and health Co-sleeping triggers conflicting advice among health care professionals.[5] The U.S. Consumer Product Safety Commission warns against it. [1] However, many pediatricians, breast-feeding advocates, and others have harshly criticized the CPSC recommendation. [2] ## Advantages There may be health advantages to co-sleeping. One study reported mothers getting more sleep by co-sleeping and breastfeeding than by other arrangements.[6] It has been argued that co-sleeping evolved over five million years, that it alters the infant's sleep experience and the number of maternal inspections of the infant, and that it provides a beginning point for considering possibly unconventional ways of helping reduce the risk of SIDS.[7][8] Stress hormones are lower in mothers and babies who co-sleep, specifically the balance of the stress hormone cortisol, the control of which is essential for a baby's healthy growth.[9][10][11][12] In studies with animals, infants who stayed close to their mothers had higher levels of growth hormones and enzymes necessary for brain and heart growth.[13][14] The physiology of co-sleeping babies is more stable, including more stable temperatures, more regular heart rhythms, and fewer long pauses in breathing than babies who sleep alone.[15][16] Co-sleeping promotes long-term emotional health. In long-term follow-up studies of infants who slept with their parents and those who slept alone, the children who co-slept were happier, less anxious, had higher self-esteem, were less likely to be afraid of sleep, had fewer behavioral problems, tended to be more comfortable with intimacy, and were generally more independent as adults.[17][18][19][20] ## Dangers Co-sleeping is known to be dangerous when a parent smokes, but there are other risk factors as well.[5] Web sites give advice on reducing the risks. Safebedsharing.org[3] [4]. Some common advice given is to keep a baby on its back, not its stomach, that a child should never sleep with a parent who smokes, is taking drugs (including alcohol) that impede alertness, or is extremely obese. It is also recommended that the bed should be firm, and should not be a waterbed or couch; and that heavy quilts, comforters, and pillows should not be used. Young children should never sleep next to babies under nine months of age.[21] It is often recommended that a baby should never be left unattended in an adult bed even if the bed surface itself is no more dangerous than a crib surface. There is also the risk of the baby falling to a hard floor. ## Products There are several products which can be used to facilitate safe co-sleeping with an infant. - bassinets that attach to the side of an adult bed, and which have barriers on three sides, but are open to the parent's bed. - bed top co-sleeping products (Family Sleeper) designed to prevent baby from rolling off the adult bed and absorbing breastfeeding and other night time leaks. - side rails to prevent the child from rolling off the adult bed. - co-sleeping infant enclosures which are placed directly in the adult bed. # Prevalence A study of a small population in Northeast England showed a variety of nighttime parenting strategies and that 65% of the sample had bedshared, 95% of them having done so with both parents. The study reported that some of the parents found bedsharing effective, yet were covert in their practices, fearing disapproval of health professionals and relatives.[22] Additionally, a National Center for Health Statistics survey from 1991 to 1999 found that 25% of American families always, or almost always, slept with their baby in bed, 42% slept with their baby "sometimes", and 32% never co-slept with their baby.[23] # Further reading - Jackson, Deborah. Three in a Bed: The Benefits of Sharing Your Bed with Your Baby, New York: Bloomsbury, 1999. - Thevenin, Tine. The Family Bed, New Jersey: Avery Publishing Group, 1987.	https://www.wikidoc.org/index.php/Co-sleeping
a0e764a6ce450d6095c20e8ce099797437c5a9fd	wikidoc	Co-tenidone	Co-tenidone Co-tenidone (BAN) is a non-proprietary name used to denote a combination of atenolol and chlortalidone. Co-tenidone is used in the treatment of hypertension. The use of β-blockers in hypertension was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, and that atenolol, the most frequently used β-blocker, at usual doses carries an unacceptable risk of provoking type 2 diabetes. # Formulation Two strengths of co-amilozide is currently available in the UK: - 50 mg atenolol and 12.5 mg chlortalidone , BAN of Co-tenidone 50/12.5 - 100 mg atenolol and 25 mg chlortalidone , BAN of Co-tenidone 100/25	Co-tenidone Co-tenidone (BAN) is a non-proprietary name used to denote a combination of atenolol and chlortalidone. Co-tenidone is used in the treatment of hypertension. The use of β-blockers in hypertension was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, and that atenolol, the most frequently used β-blocker, at usual doses carries an unacceptable risk of provoking type 2 diabetes.[1] # Formulation Two strengths of co-amilozide is currently available in the UK: - 50 mg atenolol and 12.5 mg chlortalidone , BAN of Co-tenidone 50/12.5 - 100 mg atenolol and 25 mg chlortalidone , BAN of Co-tenidone 100/25	https://www.wikidoc.org/index.php/Co-tenidone
e00f784466833b4a0eff7e0b5acb83f62613a79d	wikidoc	Factor XIII	Factor XIII Factor XIII or fibrin stabilizing factor is an enzyme (EC 2.3.2.13) of the blood coagulation system that crosslinks fibrin. Deficiency of this factor (FXIIID) affects clot stability. FXIIID, while generally rare, does occur, with Iran having the highest global incidence of the disorder with 473 cases. The city of Khash, located in Sistan and Balochistan provinces, has the highest incidence in Iran, with a high rate of consanguineous marriage. # Function Factor XIII is a transglutaminase that circulates in the plasma as a heterotetramer of two catalytic A subunits and two carrier B subunits. When thrombin has converted fibrinogen to fibrin, the latter forms a proteinaceous network in which every E-unit is crosslinked to only one D-unit. Factor XIII is activated by thrombin into factor XIIIa; its activation into Factor XIIIa requires calcium as a cofactor. A cleavage by thrombin between residue Arg37 and Gly38 on the N-terminus of the A subunit, leads to the release of the activation peptide (MW 4000 da). In the presence of calcium the carrier subunits dissociate from the catalytic subunits, leading to a 3D change in conformation of factor XIII and hence the exposure of catalytic cysteine residue. Upon activation by thrombin, factor XIIIa acts on fibrin to form γ-glutamyl-Є-lysyl amide cross links between fibrin molecules to form an insoluble clot. # Discovery FXIII is also known as Laki–Lorand factor, after Kalman Laki and Laszlo Lorand, the scientists who first proposed its existence in 1948. A 2005 conference recommended standardization of nomenclature. # Genetics Zymogen factor XIII is a 320kDa glycoprotein tetramer consisting of two twin subunits (2 A and 2 B), the genes for which are on different chromosomes: - A subunit (6p25-p24). The transglutaminase part; this adds an alkyl group to the nitrogen on a glutamine residue, which binds in turn with a lysine on the other chain. The molecular weight of the A chain is approximately 83kDa. - B subunit (1q31-q32.1). This has no clear enzymatic activity, and may serve as a carrier for the A subunit. The molecular weight of the B chain is approximately 76.5kDa. # Structure Factor XIII has two forms: a plasmatic form that flows freely in the blood plasma, and a cellular form carried inside platelet alpha-granules. The cellular form is a dimer of two identical subunits, FXIII-A, each consisting of an activation peptide that is cleaved upon activation, a β-sandwich domain, a catalytic transglutaminase domain and two β-barrel domains. The plasmatic form includes two additional identical subunits, FXIII-B, that is released in a calcium-dependent manner upon activation peptide cleavage. Each FXIII-B is both inhibitory and serves as a plasma carrier, and consists of ten repetitive sushi domains held together by two internal disulfide bond each. During circulation, this subunit binds fibrinogen. # Physiology Typical concentrations of FXIII in plasma is 10 μg/ml (2A2B heterodimer), while the concentration of free B chain is 22 μg/ml. FXIII has a long half-life, ranging from 5 to 9 days. It is present in plasma, platelets, and monocytes, as well as macrophages and bone marrow precursors of these cell types. A clot that has not been stabilized by FXIIIa is soluble in 5 mol/L urea, while a stabilized clot is resistant to this phenomenon. # Diagnostic use Factor XIII levels are not measured routinely, but may be considered in patients with an unexplained bleeding tendency. As the enzyme is quite specific for monocytes and macrophages, determination of the presence of factor XIII may be used to identify and classify malignant diseases involving these cells.	Factor XIII Factor XIII or fibrin stabilizing factor is an enzyme (EC 2.3.2.13) of the blood coagulation system that crosslinks fibrin. Deficiency of this factor (FXIIID) affects clot stability. FXIIID, while generally rare, does occur, with Iran having the highest global incidence of the disorder with 473 cases. The city of Khash, located in Sistan and Balochistan provinces, has the highest incidence in Iran, with a high rate of consanguineous marriage.[1] # Function Factor XIII is a transglutaminase that circulates in the plasma as a heterotetramer of two catalytic A subunits and two carrier B subunits. When thrombin has converted fibrinogen to fibrin, the latter forms a proteinaceous network in which every E-unit is crosslinked to only one D-unit. Factor XIII is activated by thrombin into factor XIIIa; its activation into Factor XIIIa requires calcium as a cofactor. A cleavage by thrombin between residue Arg37 and Gly38 on the N-terminus of the A subunit, leads to the release of the activation peptide (MW 4000 da). In the presence of calcium the carrier subunits dissociate from the catalytic subunits, leading to a 3D change in conformation of factor XIII and hence the exposure of catalytic cysteine residue. Upon activation by thrombin, factor XIIIa acts on fibrin to form γ-glutamyl-Є-lysyl amide cross links between fibrin molecules to form an insoluble clot.[citation needed] # Discovery FXIII is also known as Laki–Lorand factor, after Kalman Laki and Laszlo Lorand, the scientists who first proposed its existence in 1948.[2] A 2005 conference recommended standardization of nomenclature.[3] # Genetics Zymogen factor XIII is a 320kDa glycoprotein tetramer consisting of two twin subunits (2 A and 2 B),[3] the genes for which are on different chromosomes: - A subunit (6p25-p24). The transglutaminase part; this adds an alkyl group to the nitrogen on a glutamine residue, which binds in turn with a lysine on the other chain. The molecular weight of the A chain is approximately 83kDa. - B subunit (1q31-q32.1). This has no clear enzymatic activity, and may serve as a carrier for the A subunit. The molecular weight of the B chain is approximately 76.5kDa. # Structure Factor XIII has two forms: a plasmatic form that flows freely in the blood plasma, and a cellular form carried inside platelet alpha-granules. The cellular form is a dimer of two identical subunits, FXIII-A, each consisting of an activation peptide that is cleaved upon activation, a β-sandwich domain, a catalytic transglutaminase domain and two β-barrel domains. The plasmatic form includes two additional identical subunits, FXIII-B, that is released in a calcium-dependent manner upon activation peptide cleavage. Each FXIII-B is both inhibitory and serves as a plasma carrier, and consists of ten repetitive sushi domains held together by two internal disulfide bond each. During circulation, this subunit binds fibrinogen. [4] # Physiology Typical concentrations of FXIII in plasma is 10 μg/ml (2A2B heterodimer), while the concentration of free B chain is 22 μg/ml. FXIII has a long half-life, ranging from 5 to 9 days. It is present in plasma, platelets, and monocytes, as well as macrophages and bone marrow precursors of these cell types.[3] A clot that has not been stabilized by FXIIIa is soluble in 5 mol/L urea, while a stabilized clot is resistant to this phenomenon.[2] # Diagnostic use Factor XIII levels are not measured routinely, but may be considered in patients with an unexplained bleeding tendency. As the enzyme is quite specific for monocytes and macrophages, determination of the presence of factor XIII may be used to identify and classify malignant diseases involving these cells.[3]	https://www.wikidoc.org/index.php/Coagulation_factor_XIII
1c7b5896df242f2e8ba458fef4541895831d4f20	wikidoc	Cobaltocene	Cobaltocene # Overview Cobaltocene, Co(C5H5)2, is known as bis(cyclopentadienyl)cobalt(II) or even "bis Cp cobalt." This dark purple compound is solid at room temperature that sublimes at 40 °C in a good vacuum, ca. 0.1 mm. Cobaltocene was discovered shortly after ferrocene, the first "metallocene." The compound must be handled and stored in the absence of air due to the ease with which it reacts with O2. Cobaltocene is prepared by the reaction of sodium cyclopentadienide, NaC5H5, with anhydrous CoCl2 in THF solution. Sodium chloride is generated, and the organometallic product is usually purified by vacuum sublimation. # Structure and bonding Co(C5H5)2 belongs to a group of organometallic compounds called metallocenes that consist of a metal atom sandwiched between two cyclopentadienyl (Cp) rings. Thus, metallocenes are sometimes referred as sandwich compounds. Cobaltocene has 19 valence electrons, one more than usually found in organotransition metal complexes, such as its very stable relative ferrocene. This additional electron occupies an orbital that is antibonding with respect to the Co-C bonds. Consequently, the Co-C distances are slightly longer than the Fe-C bonds in ferrocene. Many chemical reactions of Co(C5H5)2 are characterized by its tendency lose this "extra" electron, yielding 18-electron cation known as cobaltocenium: # Redox properties Co(C5H5)2 is a common one-electron reducing agent in the laboratory. In fact, the reversibility of the Co(C5H5)2 redox couple is so well behaved that Co(C5H5)2 may be used in cyclic voltammetry as an internal standard. One of its analogues called decamethylcobaltocene Co(C5Me5)2 is an especially powerful reducing agent, due to inductive donation of electron density from the 10 methyl groups, prompting the cobalt to give up its "extra" electron even more so. These two compounds are rare examples of reductants that dissolve in non-polar organic solvents. The reduction potentials of these compounds follow, using the ferrocene-ferrocenium couple as the reference: We can see from this data that the decamethyl compounds are ca. 600 mV more reducing than the parent metallocenes. This substituent effect is, however, overshadowed by the influence of the metal: changing from Fe to Co renders the reduction more favorable by over 1.3 volts. # Other reactions Treatment of Co(C5H5)2 with carbon monoxide gives the cobalt(I) derivative Co(C5H5)(CO)2, concomitant with loss of one Cp ligand. This air-stable, distillable liquid has "two-legged piano-stool" structure.	Cobaltocene Template:Chembox new # Overview Cobaltocene, Co(C5H5)2, is known as bis(cyclopentadienyl)cobalt(II) or even "bis Cp cobalt." This dark purple compound is solid at room temperature that sublimes at 40 °C in a good vacuum, ca. 0.1 mm. Cobaltocene was discovered shortly after ferrocene, the first "metallocene." The compound must be handled and stored in the absence of air due to the ease with which it reacts with O2. Cobaltocene is prepared by the reaction of sodium cyclopentadienide, NaC5H5, with anhydrous CoCl2 in THF solution. Sodium chloride is generated, and the organometallic product is usually purified by vacuum sublimation.[1] # Structure and bonding Co(C5H5)2 belongs to a group of organometallic compounds called metallocenes that consist of a metal atom sandwiched between two cyclopentadienyl (Cp) rings.[2] Thus, metallocenes are sometimes referred as sandwich compounds. Cobaltocene has 19 valence electrons, one more than usually found in organotransition metal complexes, such as its very stable relative ferrocene. This additional electron occupies an orbital that is antibonding with respect to the Co-C bonds. Consequently, the Co-C distances are slightly longer than the Fe-C bonds in ferrocene. Many chemical reactions of Co(C5H5)2 are characterized by its tendency lose this "extra" electron, yielding 18-electron cation known as cobaltocenium: # Redox properties Co(C5H5)2 is a common one-electron reducing agent in the laboratory.[3] In fact, the reversibility of the Co(C5H5)2 redox couple is so well behaved that Co(C5H5)2 may be used in cyclic voltammetry as an internal standard. One of its analogues called decamethylcobaltocene Co(C5Me5)2 is an especially powerful reducing agent, due to inductive donation of electron density from the 10 methyl groups, prompting the cobalt to give up its "extra" electron even more so. These two compounds are rare examples of reductants that dissolve in non-polar organic solvents. The reduction potentials of these compounds follow, using the ferrocene-ferrocenium couple as the reference: We can see from this data that the decamethyl compounds are ca. 600 mV more reducing than the parent metallocenes. This substituent effect is, however, overshadowed by the influence of the metal: changing from Fe to Co renders the reduction more favorable by over 1.3 volts. # Other reactions Treatment of Co(C5H5)2 with carbon monoxide gives the cobalt(I) derivative Co(C5H5)(CO)2, concomitant with loss of one Cp ligand. This air-stable, distillable liquid has "two-legged piano-stool" structure.	https://www.wikidoc.org/index.php/Cobaltocene
677d743b2ce44477d34d2a66db1acbc8076654f7	wikidoc	Cobimetinib	Cobimetinib # 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 Cobimetinib is a kinase inhibitor that is FDA approved for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. Common adverse reactions include diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting (≥20%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cobimetinib is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib - Patient Selection Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with Cobimetinib with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: . - Recommended Dose The recommended dosage regimen of Cobimetinib is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take Cobimetinib with or without food. If a dose of Cobimetinib is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose. - Dose Modifications - Concurrent CYP3A Inhibitors Do not take strong or moderate CYP3A inhibitors while taking Cobimetinib. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking Cobimetinib 60 mg, reduce Cobimetinib dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume previous dose of Cobimetinib 60 mg. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of Cobimetinib (40 or 20 mg daily). - Adverse Reactions Review the Full Prescribing Information for vemurafenib for recommended dose modifications. - Table 1. Recommended Dose Reductions for Cobimetinib COTELLIC: Cobimetinib's Brand name - Table 2. Recommended Dose Modifications for Cobimetinib for Adverse Reactions COTELLIC: Cobimetinib's Brand name ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cobimetinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cobimetinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Cobimetinib have not been established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cobimetinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cobimetinib in pediatric patients. # Contraindications None # Warnings Review the Full Prescribing Information for vemurafenib for information on the serious risks of vemurafenib. - New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur with Cobimetinib. - Cutaneous Malignancies: In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the Cobimetinib with vemurafenib arm and the vemurafenib arm, respectively: cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6% and 20%), basal cell carcinoma (4.5% and 2.4%), and second primary melanoma (0.8% and 2.4%). Among patients receiving Cobimetinib with vemurafenib, the median time to detection of first cuSCC/KA was 4 months (range: 2 to 11 months), and the median time to detection of basal cell carcinoma was 4 months (range: 27 days to 13 months). The time to onset in the two patients with second primary melanoma was 9 months and 12 months. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. No dose modifications are recommended for Cobimetinib. Conduct dermatologic monitoring for 6 months following discontinuation of Cobimetinib when administered with vemurafenib. - Non-Cutaneous Malignancies: Based on its mechanism of action, vemurafenib may promote growth and development of malignancies . In Trial 1, 0.8% of patients in the Cobimetinib with vemurafenib arm and 1.2% of patients in the vemurafenib arm developed non-cutaneous malignancies. Monitor patients receiving Cobimetinib, when administered with vemurafenib, for signs or symptoms of non-cutaneous malignancies. - Hemorrhage Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with Cobimetinib. In Trial 1, the incidence of Grade 3–4 hemorrhages was 1.2% in patients receiving Cobimetinib with vemurafenib and 0.8% in patients receiving vemurafenib. Hemorrhage (all grades) was 13% in patients receiving Cobimetinib with vemurafenib and 7% in patients receiving vemurafenib. Cerebral hemorrhage occurred in 0.8% of patients receiving Cobimetinib with vemurafenib and in none of the patients receiving vemurafenib. Gastrointestinal tract hemorrhage (3.6% vs 1.2%), reproductive system hemorrhage (2.0% vs 0.4%), and hematuria (2.4% vs 0.8%) also occurred at a higher incidence in patients receiving Cobimetinib with vemurafenib compared with patients receiving vemurafenib. Withhold Cobimetinib for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume Cobimetinib at a lower dose level. Discontinue Cobimetinib for Grade 4 hemorrhagic events and any Grade 3 hemorrhagic events that do not improve. - Cardiomyopathy Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with Cobimetinib . The safety of Cobimetinib has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%. In Trial 1, patients were assessed for decreases in LVEF by echocardiograms or MUGA at baseline, Week 5, Week 17, Week 29, Week 43, and then every 4 to 6 months thereafter while receiving treatment. Grade 2 or 3 decrease in LVEF occurred in 26% of patients receiving Cobimetinib with vemurafenib and 19% of patients receiving vemurafenib. The median time to first onset of LVEF decrease was 4 months (range 23 days to 13 months). Of the patients with decreased LVEF, 22% had dose interruption and/or reduction and 14% required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 62% of patients receiving Cobimetinib with a median time to resolution of 3 months (range: 4 days to 12 months). Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of Cobimetinib. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation. In patients restarting Cobimetinib after a dose reduction or interruption, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated. - Severe Dermatologic Reactions Severe rash and other skin reactions can occur with Cobimetinib. In Trial 1, Grade 3 to 4 rash, occurred in 16% of patients receiving Cobimetinib with vemurafenib and in 17% of patients receiving vemurafenib, including Grade 4 rash in 1.6% of patients receiving Cobimetinib with vemurafenib and 0.8% of the patients receiving vemurafenib. The incidence of rash resulting in hospitalization was 3.2% in patients receiving Cobimetinib with vemurafenib and 2.0% in patients receiving vemurafenib. In patients receiving Cobimetinib, the median time to onset of Grade 3 or 4 rash events was 11 days (range: 3 days to 2.8 months). Among patients with Grade 3 or 4 rash events, 95% experienced complete resolution with the median time to resolution of 21 days (range 4 days to 17 months). Interrupt, reduce the dose, or discontinue Cobimetinib. - Serous Retinopathy and Retinal Vein Occlusion Ocular toxicities can occur with Cobimetinib, including serous retinopathy (fluid accumulation under layers of the retina). In Trial 1, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving Cobimetinib with vemurafenib. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged between 2 days to 9 months. The reported duration of serous retinopathy ranged between 1 day to 15 months. One patient in each arm developed retinal vein occlusion. Perform an ophthalmological evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt Cobimetinib until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation. - Hepatotoxicity Hepatotoxicity can occur with Cobimetinib. The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving Cobimetinib with vemurafenib compared to patients receiving vemurafenib were: 11% vs. 5% for alanine aminotransferase, 8% vs. 2.1% for aspartate aminotransferase, 1.6% vs. 1.2% for total bilirubin, and 7% vs. 3.3% for alkaline phosphatase. Concurrent elevation in ALT >3 times the upper limit of normal (ULN) and bilirubin >2 × ULN in the absence of significant alkaline phosphatase >2 × ULN occurred in one patient (0.4%) receiving Cobimetinib with vemurafenib and no patients receiving single-agent vemurafenib. Monitor liver laboratory tests before initiation of Cobimetinib and monthly during treatment, or more frequently as clinically indicated. Manage Grade 3 and 4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of Cobimetinib. - Rhabdomyolysis Rhabdomyolysis can occur with Cobimetinib. In Trial 1, Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, occurred in 14% of patients receiving Cobimetinib with vemurafenib and 0.5% of patients receiving vemurafenib. The median time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months) in patients receiving Cobimetinib with vemurafenib; the median time to complete resolution was 15 days (range: 9 days to 11 months). Elevation of serum CPK increase of more than 10 times the baseline value with a concurrent increase in serum creatinine of 1.5 times or greater compared to baseline occurred in 3.6% of patients receiving Cobimetinib with vemurafenib and in 0.4% of patients receiving vemurafenib. Obtain baseline serum CPK and creatinine levels prior to initiating Cobimetinib, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of Cobimetinib may be required. - Severe Photosensitivity Photosensitivity, including severe cases, can occur with Cobimetinib. In Trial 1, photosensitivity was reported in 47% of patients receiving Cobimetinib with vemurafenib: 43% of patients with Grades 1 or 2 photosensitivity and the remaining 4% with Grade 3 photosensitivity. Median time to first onset of photosensitivity of any grade was 2 months (range: 1 day to 14 months) in patients receiving Cobimetinib with vemurafenib, and the median duration of photosensitivity was 3 months (range: 2 days to 14 months). Among the 47% of patients with photosensitivity reactions on Cobimetinib with vemurafenib, 63% experienced resolution of photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Manage intolerable Grade 2 or greater photosensitivity with dose modifications. - Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal reproduction studies, Cobimetinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of Cobimetinib in pregnant rats during the period of organogenesis was teratogenic and embryotoxic at doses resulting in exposures that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Cobimetinib, and for 2 weeks following the final dose of Cobimetinib. # 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 safety of Cobimetinib was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma. All patients received vemurafenib 960 mg twice daily on Days 1–28 and received either Cobimetinib 60 mg once daily (n=247) or placebo (n=246) on Days 1–21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the Cobimetinib plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year. Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies. In Trial 1, 15% of patients receiving Cobimetinib experienced an adverse reaction that resulted in permanent discontinuation of Cobimetinib. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving Cobimetinib, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of Cobimetinib were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). The most common (≥20%) adverse reactions with Cobimetinib were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. - Table 3. Incidence of Adverse Drug Reactions Occurring in ≥10% (All Grades) of Patients Receiving Cobimetinib with Vemurafenib and at a Higher Incidence- than Patients Receiving Vemurafenib in Trial 1 COTELLIC: Cobimetinib's Brand name Adverse reactions of vemurafenib which occurred at a lower rate in patients receiving Cobimetinib plus vemurafenib were alopecia (15%), hyperkeratosis (11%), and erythema (10%). The following adverse reactions (all grades) of Cobimetinib were reported with <10% incidence in Trial 1: Respiratory, thoracic and mediastinal disorders: Pneumonitis - Table 4. Incidence of Laboratory Abnormalities Occurring in ≥10% (All Grades) or ≥2% (Grades 3–4) of Patients in Trial 1* COTELLIC: Cobimetinib's Brand name ## Postmarketing Experience There is limited information regarding Cobimetinib Postmarketing Experience in the drug label. # Drug Interactions - Effect of Strong or Moderate CYP3A Inhibitors on Cobimetinib Coadministration of Cobimetinib with itraconazole (a strong CYP3A4 inhibitor) increased Cobimetinib systemic exposure by 6.7-fold. Avoid concurrent use of Cobimetinib and strong or moderate CYP3A inhibitors. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable for patients who are taking Cobimetinib 60 mg, reduce Cobimetinib dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume Cobimetinib at the previous dose. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of Cobimetinib (40 or 20 mg daily). - Effect of Strong or Moderate CYP3A Inducers on Cobimetinib Coadministration of Cobimetinib with a strong CYP3A inducer may decrease Cobimetinib systemic exposure by more than 80% and reduce its efficacy. Avoid concurrent use of Cobimetinib and strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. John's Wort. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary Based on findings from animal reproduction studies and its mechanism of action, Cobimetinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Cobimetinib during pregnancy. In animal reproduction studies, oral administration of Cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. Advise pregnant women 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 2–4% and 15–20%, respectively. - Data - Animal Data Administration of Cobimetinib to pregnant rats during the period of organogenesis resulted in increased post-implantation loss, including total litter loss, at exposures (AUC) of 0.9–1.4 times those in humans at the recommended dose of 60 mg. Post-implantation loss was primarily due to early resorptions. Fetal malformations of the great vessels and skull (eye sockets) occurred at the same exposures. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cobimetinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cobimetinib during labor and delivery. ### Nursing Mothers There is no information regarding the presence of Cobimetinib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman not to breastfeed during treatment with Cobimetinib and for 2 weeks after the final dose. ### Pediatric Use The safety and effectiveness of Cobimetinib have not been established in pediatric patients. - Juvenile Animal Data In a 4-week juvenile rat toxicology study, daily oral doses of 3 mg/kg (approximately 0.13–0.5 times the adult human AUC at the recommended dose of 60 mg) between postnatal Days 10–17 (approximately equivalent to ages 1–2 years in humans) were associated with mortality, the cause of which was not defined. ### Geriatic Use Clinical studies of Cobimetinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Cobimetinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cobimetinib with respect to specific racial populations. ### Renal Impairment No dedicated pharmacokinetic trial in patients with renal impairment has been conducted. Dose adjustment is not recommended for mild to moderate renal impairment (CLcr 30 to 89 mL/min) based on the results of the population pharmacokinetic analysis. A recommended dose has not been established for patients with severe renal impairment. ### Hepatic Impairment Adjustment in the starting dose of Cobimetinib is not required in patients with mild (Child-Pugh score A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. ### Females of Reproductive Potential and Males - Contraception - Females Cobimetinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Cobimetinib and for 2 weeks after the final dose of Cobimetinib. - Infertility - Females and Males Based on findings in animals, Cobimetinib may reduce fertility in females and males of reproductive potential. ### Immunocompromised Patients There is no FDA guidance one the use of Cobimetinib in patients who are immunocompromised. # Administration and Monitoring ### Administration The recommended dosage regimen of Cobimetinib is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. - Take Cobimetinib with or without food. - If a dose of Cobimetinib is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose. ### Monitoring There is limited information regarding Cobimetinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Cobimetinib and IV administrations. # Overdosage There is no information on overdosage of Cobimetinib. # Pharmacology ## Mechanism of Action Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines expressing BRAF V600E, Cobimetinib inhibited tumor cell growth. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of Cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model. ## Structure Cobimetinib is a fumarate salt appearing as white to off-white solid and exhibits a pH dependent solubility. Cobimetinib tablets are supplied as white, round, film-coated 20 mg tablets for oral administration, debossed on one side with "COB". Each 20 mg tablet contains 22 mg of cobimetinib fumarate, which corresponds to 20 mg of the cobimetinib free base. The inactive ingredients of Cobimetinib are: Tablet Core: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate. Coating: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc. ## Pharmacodynamics - Cardiac Electrophysiology Clinically relevant QT prolongation has been reported with vemurafenib, further QTc prolongation was not observed when Cobimetinib 60 mg daily was co-administered with vemurafenib. Monitor ECG and electrolytes before initiating treatment and routinely during treatment with Cobimetinib, when administered with vemurafenib. Review the Full Prescribing Information for vemurafenib for details. ## Pharmacokinetics The pharmacokinetics of Cobimetinib was studied in healthy subjects and cancer patients. Cobimetinib exhibits linear pharmacokinetics in the dose range of 3.5 to 100 mg (i.e., 0.06 to 1.7 times the recommended dosage). Following oral administration of Cobimetinib 60 mg once daily, steady-state was reached by 9 days with a mean accumulation ratio of 2.4-fold (44% CV). - Absorption Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels (Tmax) was 2.4 (range:1–24) hours, geometric mean steady-state AUC(0-24h) was 4340 ng∙h/mL (61% CV) and Cmax was 273 ng/mL (60% CV). The absolute bioavailability of Cobimetinib was 46% (90% CI: 40%, 53%) in healthy subjects. A high-fat meal (comprised of approximately 150 calories from protein, 250 calories from carbohydrate, and 500–600 calories from fat) had no effect on Cobimetinib AUC and Cmax after a single 20 mg Cobimetinib was administered to healthy subjects. - Distribution Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. No preferential binding to human red blood cells was observed (blood to plasma ratio of 0.93). The estimated apparent volume of distribution was 806 L in cancer patients based on a population PK analysis. - Elimination Following oral administration of Cobimetinib 60 mg once daily in cancer patients, the mean elimination half-life (t1/2) was 44 (range: 23–70) hours and the mean apparent clearance (CL/F) was 13.8 L/h (61% CV). - Metabolism CYP3A oxidation and UGT2B7 glucuronidation were the major pathways of Cobimetinib metabolism in vitro. Following oral administration of a single 20 mg radiolabeled Cobimetinib dose, no oxidative metabolites >10% of total circulating radioactivity were observed. - Excretion Following oral administration of a single 20 mg radiolabeled Cobimetinib dose, 76% of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was recovered in the urine (with 1.6% as unchanged drug). - Specific Populations - Age, Sex, and Race/Ethnicity Based on the population pharmacokinetic analysis, age (19–88 years), sex, or race/ethnicity does not have a clinically important effect on the systemic exposure of Cobimetinib. - Hepatic Impairment Following a single 10 mg Cobimetinib dose, the geometric mean total Cobimetinib exposure (AUC(inf)) values were similar in subjects with mild or moderate hepatic impairment and was decreased by 31% in subjects with severe hepatic impairment compared to subjects with normal hepatic function. - Renal Impairment Cobimetinib undergoes minimal renal elimination. Cobimetinib exposures were similar in 151 patients with mild renal impairment (CLcr 60 to 89 mL/min), 48 patients with moderate renal impairment (CLcr 30 to 59 mL/min) and 286 patients with normal renal function (CLcr ≥90 mL/min). - Drug Interaction Studies - Vemurafenib: Coadministration of Cobimetinib 60 mg once daily and vemurafenib 960 mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions. - Effect of Strong and Moderate CYP3A Inhibitors on Cobimetinib: In vitro studies show that Cobimetinib is a substrate of CYP3A. Coadministration of itraconazole (a strong CYP3A inhibitor) 200 mg once daily for 14 days with a single 10 mg Cobimetinib dose increased mean Cobimetinib AUC (90% CI) by 6.7-fold (5.6, 8.0) and mean Cmax (90% CI) by 3.2-fold (2.7, 3.7) in 15 healthy subjects. Simulations showed that predicted steady-state concentrations of Cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of Cobimetinib at the 60 mg dose alone. - Effect of Strong and Moderate CYP3A Inducers on Cobimetinib: Based on simulations, Cobimetinib exposures would decrease by 83% when coadministered with a strong CYP3A inducer and by 73% when coadministered with a moderate CYP3A inducer. - Effect of Cobimetinib on CYP Substrates: Coadministration of Cobimetinib 60 mg once daily for 15 days with a single 30 mg dose of dextromethorphan (sensitive CYP2D6 substrate) or a single 2 mg dose of midazolam (sensitive CYP3A substrate) to 20 patients with solid tumors did not change dextromethorphan or midazolam systemic exposure. In vitro data indicated that Cobimetinib may inhibit CYP3A and CYP2D6. Cobimetinib at clinically relevant concentrations is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9 and 2C19 or inducer of CYP1A2, 2B6 and 3A4. - Effect of Transporters on Cobimetinib: Cobimetinib is a substrate of efflux transporter P-glycoprotein (P-gp), but is not a substrate of Breast Cancer Resistance Protein (BCRP), Organic Anion Transporting Polypeptide (OATP1B1 or OATP1B3) or Organic Cation Transporter (OCT1) in vitro. Drugs that inhibit P-gp may increase Cobimetinib concentrations. - Effect of Cobimetinib on Transporters: In vitro data suggest that Cobimetinib at clinically relevant concentrations does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2. - Effect of Gastric Acid Reducing Drugs on Cobimetinib: Coadministration of a proton pump inhibitor, rabeprazole 20 mg once daily for 5 days, with a single dose of 20 mg Cobimetinib under fed and fasted conditions did not result in a clinically important change in Cobimetinib exposure. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with Cobimetinib have not been conducted. Cobimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in bone marrow of rats. No dedicated fertility studies have been performed with Cobimetinib in animals; however, effects on reproductive tissues observed in general toxicology studies conducted in animals suggest that there is potential for Cobimetinib to impair fertility. In female rats, degenerative changes included increased apoptosis/necrosis of corpora lutea and vaginal epithelial cells at Cobimetinib doses approximately twice those in humans at the clinically recommended dose of 60 mg based on body surface area. In male dogs, testicular degeneration occurred at exposures as low as approximately 0.1 times the exposure in humans at the clinically recommended dose of 60 mg. # Clinical Studies The safety and efficacy of Cobimetinib was established in a multicenter, randomized (1:1), double-blinded, placebo-controlled trial conducted in 495 patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic, melanoma. The presence of BRAF V600 mutation was detected using the cobas® 4800 BRAF V600 mutation test. All patients received vemurafenib 960 mg orally twice daily on days 1–28 and were randomized to receive Cobimetinib 60 mg or matching placebo orally once daily on days 1–21 of an every 28-day cycle. Randomization was stratified by geographic region (North America vs. Europe vs. Australia/New Zealand/others) and disease stage (unresectable Stage IIIc, M1a, or M1b vs. Stage M1c). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive placebo were not offered Cobimetinib at the time of disease progression. The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Additional efficacy outcomes were investigator-assessed confirmed objective response rate, overall survival, PFS as assessed by blinded independent central review, and duration of response. The median age of the study population was 55 years (range 23 to 88 years), 58% of patients were male, 93% were White and 5% had no race reported, 60% had stage M1c disease, 72% had a baseline ECOG performance status of 0, 45% had an elevated baseline serum lactate dehydrogenase (LDH), 10% had received prior adjuvant therapy, and <1% had previously treated brain metastases. Patients with available tumor samples were retrospectively tested using next generation sequencing to further classify mutations as V600E or V600K; test results were obtained on 81% of randomized patients. Of these, 86% were identified as having a V600E mutation and 14% as having a V600K mutation. Efficacy results are summarized in TABLE 5 and FIGURE 1. - Table 5 Efficacy Results from Trial 1 COTELLIC: Cobimetinib's Brand name - Figure 1 Kaplan-Meier Curves of Overall Survival The effect on PFS was also supported by analysis of PFS based on the assessment by blinded independent review. A trend favoring the Cobimetinib with vemurafenib arm was observed in exploratory subgroup analyses of PFS, OS, and ORR in both BRAF V600 mutation subtypes (V600E or V600K) in the 81% of patients in this trial where BRAF V600 mutation type was determined. # How Supplied Cobimetinib is supplied as 20 mg film-coated tablets debossed on one side with "COB". Cobimetinib tablets are available in bottles of 63 tablets. (NDC 50242-717-01) ## Storage Store at room temperature below 30°C (86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Inform patients of the following: - New primary cutaneous malignancies: Advise patients to contact their health care provider immediately for change in or development of new skin lesions. - Hemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage. - Cardiomyopathy: Advise patients to report any history of cardiac disease and of the requirement for cardiac monitoring prior to and during Cobimetinib administration. Instruct patients to immediately report any signs or symptoms of left ventricular dysfunction to their healthcare provider. - Serious dermatologic reactions: Instruct patients to contact their healthcare provider to immediately report severe skin changes. - Serous retinopathy and retinal vein occlusion: Instruct patients to immediately contact their healthcare provider if they experience any changes in their vision. - Hepatotoxicity: Advise patients that treatment with Cobimetinib requires monitoring of their liver function. Instruct patients to report any signs or symptoms of liver dysfunction. - Rhabdomyolysis: Instruct patients to report any signs and symptoms of muscle pain or weakness to their healthcare provider. - Severe photosensitivity: Advise patients to avoid sun exposure, wear protective clothing, and use broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. - Embryo-fetal toxicity: Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Cobimetinib. - Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with Cobimetinib and for at least 2 weeks after the final dose of Cobimetinib. - Lactation: Advise females not to breastfeed during treatment with Cobimetinib and for 2 weeks after the final dose. # Precautions with Alcohol Alcohol-Cobimetinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names COTELLIC® # Look-Alike Drug Names There is limited information regarding Cobimetinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cobimetinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Cobimetinib is a kinase inhibitor that is FDA approved for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. Common adverse reactions include diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting (≥20%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cobimetinib is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib - Patient Selection Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with Cobimetinib with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. - Recommended Dose The recommended dosage regimen of Cobimetinib is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take Cobimetinib with or without food. If a dose of Cobimetinib is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose. - Dose Modifications - Concurrent CYP3A Inhibitors Do not take strong or moderate CYP3A inhibitors while taking Cobimetinib. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking Cobimetinib 60 mg, reduce Cobimetinib dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume previous dose of Cobimetinib 60 mg. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of Cobimetinib (40 or 20 mg daily). - Adverse Reactions Review the Full Prescribing Information for vemurafenib for recommended dose modifications. - Table 1. Recommended Dose Reductions for Cobimetinib COTELLIC: Cobimetinib's Brand name - Table 2. Recommended Dose Modifications for Cobimetinib for Adverse Reactions COTELLIC: Cobimetinib's Brand name ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cobimetinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cobimetinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Cobimetinib have not been established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cobimetinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cobimetinib in pediatric patients. # Contraindications None # Warnings Review the Full Prescribing Information for vemurafenib for information on the serious risks of vemurafenib. - New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur with Cobimetinib. - Cutaneous Malignancies: In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the Cobimetinib with vemurafenib arm and the vemurafenib arm, respectively: cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6% and 20%), basal cell carcinoma (4.5% and 2.4%), and second primary melanoma (0.8% and 2.4%). Among patients receiving Cobimetinib with vemurafenib, the median time to detection of first cuSCC/KA was 4 months (range: 2 to 11 months), and the median time to detection of basal cell carcinoma was 4 months (range: 27 days to 13 months). The time to onset in the two patients with second primary melanoma was 9 months and 12 months. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. No dose modifications are recommended for Cobimetinib. Conduct dermatologic monitoring for 6 months following discontinuation of Cobimetinib when administered with vemurafenib. - Non-Cutaneous Malignancies: Based on its mechanism of action, vemurafenib may promote growth and development of malignancies [refer to the Full Prescribing Information for vemurafenib]. In Trial 1, 0.8% of patients in the Cobimetinib with vemurafenib arm and 1.2% of patients in the vemurafenib arm developed non-cutaneous malignancies. Monitor patients receiving Cobimetinib, when administered with vemurafenib, for signs or symptoms of non-cutaneous malignancies. - Hemorrhage Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with Cobimetinib. In Trial 1, the incidence of Grade 3–4 hemorrhages was 1.2% in patients receiving Cobimetinib with vemurafenib and 0.8% in patients receiving vemurafenib. Hemorrhage (all grades) was 13% in patients receiving Cobimetinib with vemurafenib and 7% in patients receiving vemurafenib. Cerebral hemorrhage occurred in 0.8% of patients receiving Cobimetinib with vemurafenib and in none of the patients receiving vemurafenib. Gastrointestinal tract hemorrhage (3.6% vs 1.2%), reproductive system hemorrhage (2.0% vs 0.4%), and hematuria (2.4% vs 0.8%) also occurred at a higher incidence in patients receiving Cobimetinib with vemurafenib compared with patients receiving vemurafenib. Withhold Cobimetinib for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume Cobimetinib at a lower dose level. Discontinue Cobimetinib for Grade 4 hemorrhagic events and any Grade 3 hemorrhagic events that do not improve. - Cardiomyopathy Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with Cobimetinib . The safety of Cobimetinib has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%. In Trial 1, patients were assessed for decreases in LVEF by echocardiograms or MUGA at baseline, Week 5, Week 17, Week 29, Week 43, and then every 4 to 6 months thereafter while receiving treatment. Grade 2 or 3 decrease in LVEF occurred in 26% of patients receiving Cobimetinib with vemurafenib and 19% of patients receiving vemurafenib. The median time to first onset of LVEF decrease was 4 months (range 23 days to 13 months). Of the patients with decreased LVEF, 22% had dose interruption and/or reduction and 14% required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 62% of patients receiving Cobimetinib with a median time to resolution of 3 months (range: 4 days to 12 months). Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of Cobimetinib. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation. In patients restarting Cobimetinib after a dose reduction or interruption, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated. - Severe Dermatologic Reactions Severe rash and other skin reactions can occur with Cobimetinib. In Trial 1, Grade 3 to 4 rash, occurred in 16% of patients receiving Cobimetinib with vemurafenib and in 17% of patients receiving vemurafenib, including Grade 4 rash in 1.6% of patients receiving Cobimetinib with vemurafenib and 0.8% of the patients receiving vemurafenib. The incidence of rash resulting in hospitalization was 3.2% in patients receiving Cobimetinib with vemurafenib and 2.0% in patients receiving vemurafenib. In patients receiving Cobimetinib, the median time to onset of Grade 3 or 4 rash events was 11 days (range: 3 days to 2.8 months). Among patients with Grade 3 or 4 rash events, 95% experienced complete resolution with the median time to resolution of 21 days (range 4 days to 17 months). Interrupt, reduce the dose, or discontinue Cobimetinib. - Serous Retinopathy and Retinal Vein Occlusion Ocular toxicities can occur with Cobimetinib, including serous retinopathy (fluid accumulation under layers of the retina). In Trial 1, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving Cobimetinib with vemurafenib. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged between 2 days to 9 months. The reported duration of serous retinopathy ranged between 1 day to 15 months. One patient in each arm developed retinal vein occlusion. Perform an ophthalmological evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt Cobimetinib until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation. - Hepatotoxicity Hepatotoxicity can occur with Cobimetinib. The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving Cobimetinib with vemurafenib compared to patients receiving vemurafenib were: 11% vs. 5% for alanine aminotransferase, 8% vs. 2.1% for aspartate aminotransferase, 1.6% vs. 1.2% for total bilirubin, and 7% vs. 3.3% for alkaline phosphatase. Concurrent elevation in ALT >3 times the upper limit of normal (ULN) and bilirubin >2 × ULN in the absence of significant alkaline phosphatase >2 × ULN occurred in one patient (0.4%) receiving Cobimetinib with vemurafenib and no patients receiving single-agent vemurafenib. Monitor liver laboratory tests before initiation of Cobimetinib and monthly during treatment, or more frequently as clinically indicated. Manage Grade 3 and 4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of Cobimetinib. - Rhabdomyolysis Rhabdomyolysis can occur with Cobimetinib. In Trial 1, Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, occurred in 14% of patients receiving Cobimetinib with vemurafenib and 0.5% of patients receiving vemurafenib. The median time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months) in patients receiving Cobimetinib with vemurafenib; the median time to complete resolution was 15 days (range: 9 days to 11 months). Elevation of serum CPK increase of more than 10 times the baseline value with a concurrent increase in serum creatinine of 1.5 times or greater compared to baseline occurred in 3.6% of patients receiving Cobimetinib with vemurafenib and in 0.4% of patients receiving vemurafenib. Obtain baseline serum CPK and creatinine levels prior to initiating Cobimetinib, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of Cobimetinib may be required. - Severe Photosensitivity Photosensitivity, including severe cases, can occur with Cobimetinib. In Trial 1, photosensitivity was reported in 47% of patients receiving Cobimetinib with vemurafenib: 43% of patients with Grades 1 or 2 photosensitivity and the remaining 4% with Grade 3 photosensitivity. Median time to first onset of photosensitivity of any grade was 2 months (range: 1 day to 14 months) in patients receiving Cobimetinib with vemurafenib, and the median duration of photosensitivity was 3 months (range: 2 days to 14 months). Among the 47% of patients with photosensitivity reactions on Cobimetinib with vemurafenib, 63% experienced resolution of photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Manage intolerable Grade 2 or greater photosensitivity with dose modifications. - Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal reproduction studies, Cobimetinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of Cobimetinib in pregnant rats during the period of organogenesis was teratogenic and embryotoxic at doses resulting in exposures [area under the curves (AUCs)] that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Cobimetinib, and for 2 weeks following the final dose of Cobimetinib. # 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 safety of Cobimetinib was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma. All patients received vemurafenib 960 mg twice daily on Days 1–28 and received either Cobimetinib 60 mg once daily (n=247) or placebo (n=246) on Days 1–21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the Cobimetinib plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year. Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies. In Trial 1, 15% of patients receiving Cobimetinib experienced an adverse reaction that resulted in permanent discontinuation of Cobimetinib. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving Cobimetinib, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of Cobimetinib were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). The most common (≥20%) adverse reactions with Cobimetinib were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. - Table 3. Incidence of Adverse Drug Reactions Occurring in ≥10% (All Grades) of Patients Receiving Cobimetinib with Vemurafenib and at a Higher Incidence* than Patients Receiving Vemurafenib in Trial 1 COTELLIC: Cobimetinib's Brand name Adverse reactions of vemurafenib which occurred at a lower rate in patients receiving Cobimetinib plus vemurafenib were alopecia (15%), hyperkeratosis (11%), and erythema (10%). The following adverse reactions (all grades) of Cobimetinib were reported with <10% incidence in Trial 1: Respiratory, thoracic and mediastinal disorders: Pneumonitis - Table 4. Incidence of Laboratory Abnormalities Occurring in ≥10% (All Grades) or ≥2% (Grades 3–4) of Patients in Trial 1* COTELLIC: Cobimetinib's Brand name ## Postmarketing Experience There is limited information regarding Cobimetinib Postmarketing Experience in the drug label. # Drug Interactions - Effect of Strong or Moderate CYP3A Inhibitors on Cobimetinib Coadministration of Cobimetinib with itraconazole (a strong CYP3A4 inhibitor) increased Cobimetinib systemic exposure by 6.7-fold. Avoid concurrent use of Cobimetinib and strong or moderate CYP3A inhibitors. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable for patients who are taking Cobimetinib 60 mg, reduce Cobimetinib dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume Cobimetinib at the previous dose. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of Cobimetinib (40 or 20 mg daily). - Effect of Strong or Moderate CYP3A Inducers on Cobimetinib Coadministration of Cobimetinib with a strong CYP3A inducer may decrease Cobimetinib systemic exposure by more than 80% and reduce its efficacy. Avoid concurrent use of Cobimetinib and strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. John's Wort. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary Based on findings from animal reproduction studies and its mechanism of action, Cobimetinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Cobimetinib during pregnancy. In animal reproduction studies, oral administration of Cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. Advise pregnant women 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 2–4% and 15–20%, respectively. - Data - Animal Data Administration of Cobimetinib to pregnant rats during the period of organogenesis resulted in increased post-implantation loss, including total litter loss, at exposures (AUC) of 0.9–1.4 times those in humans at the recommended dose of 60 mg. Post-implantation loss was primarily due to early resorptions. Fetal malformations of the great vessels and skull (eye sockets) occurred at the same exposures. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cobimetinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cobimetinib during labor and delivery. ### Nursing Mothers There is no information regarding the presence of Cobimetinib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman not to breastfeed during treatment with Cobimetinib and for 2 weeks after the final dose. ### Pediatric Use The safety and effectiveness of Cobimetinib have not been established in pediatric patients. - Juvenile Animal Data In a 4-week juvenile rat toxicology study, daily oral doses of 3 mg/kg (approximately 0.13–0.5 times the adult human AUC at the recommended dose of 60 mg) between postnatal Days 10–17 (approximately equivalent to ages 1–2 years in humans) were associated with mortality, the cause of which was not defined. ### Geriatic Use Clinical studies of Cobimetinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Cobimetinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cobimetinib with respect to specific racial populations. ### Renal Impairment No dedicated pharmacokinetic trial in patients with renal impairment has been conducted. Dose adjustment is not recommended for mild to moderate renal impairment (CLcr 30 to 89 mL/min) based on the results of the population pharmacokinetic analysis. A recommended dose has not been established for patients with severe renal impairment. ### Hepatic Impairment Adjustment in the starting dose of Cobimetinib is not required in patients with mild (Child-Pugh score A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. ### Females of Reproductive Potential and Males - Contraception - Females Cobimetinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Cobimetinib and for 2 weeks after the final dose of Cobimetinib. - Infertility - Females and Males Based on findings in animals, Cobimetinib may reduce fertility in females and males of reproductive potential. ### Immunocompromised Patients There is no FDA guidance one the use of Cobimetinib in patients who are immunocompromised. # Administration and Monitoring ### Administration The recommended dosage regimen of Cobimetinib is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. - Take Cobimetinib with or without food. - If a dose of Cobimetinib is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose. ### Monitoring There is limited information regarding Cobimetinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Cobimetinib and IV administrations. # Overdosage There is no information on overdosage of Cobimetinib. # Pharmacology ## Mechanism of Action Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines expressing BRAF V600E, Cobimetinib inhibited tumor cell growth. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of Cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model. ## Structure Cobimetinib is a fumarate salt appearing as white to off-white solid and exhibits a pH dependent solubility. Cobimetinib tablets are supplied as white, round, film-coated 20 mg tablets for oral administration, debossed on one side with "COB". Each 20 mg tablet contains 22 mg of cobimetinib fumarate, which corresponds to 20 mg of the cobimetinib free base. The inactive ingredients of Cobimetinib are: Tablet Core: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate. Coating: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc. ## Pharmacodynamics - Cardiac Electrophysiology Clinically relevant QT prolongation has been reported with vemurafenib, further QTc prolongation was not observed when Cobimetinib 60 mg daily was co-administered with vemurafenib. Monitor ECG and electrolytes before initiating treatment and routinely during treatment with Cobimetinib, when administered with vemurafenib. Review the Full Prescribing Information for vemurafenib for details. ## Pharmacokinetics The pharmacokinetics of Cobimetinib was studied in healthy subjects and cancer patients. Cobimetinib exhibits linear pharmacokinetics in the dose range of 3.5 to 100 mg (i.e., 0.06 to 1.7 times the recommended dosage). Following oral administration of Cobimetinib 60 mg once daily, steady-state was reached by 9 days with a mean accumulation ratio of 2.4-fold (44% CV). - Absorption Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels (Tmax) was 2.4 (range:1–24) hours, geometric mean steady-state AUC(0-24h) was 4340 ng∙h/mL (61% CV) and Cmax was 273 ng/mL (60% CV). The absolute bioavailability of Cobimetinib was 46% (90% CI: 40%, 53%) in healthy subjects. A high-fat meal (comprised of approximately 150 calories from protein, 250 calories from carbohydrate, and 500–600 calories from fat) had no effect on Cobimetinib AUC and Cmax after a single 20 mg Cobimetinib was administered to healthy subjects. - Distribution Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. No preferential binding to human red blood cells was observed (blood to plasma ratio of 0.93). The estimated apparent volume of distribution was 806 L in cancer patients based on a population PK analysis. - Elimination Following oral administration of Cobimetinib 60 mg once daily in cancer patients, the mean elimination half-life (t1/2) was 44 (range: 23–70) hours and the mean apparent clearance (CL/F) was 13.8 L/h (61% CV). - Metabolism CYP3A oxidation and UGT2B7 glucuronidation were the major pathways of Cobimetinib metabolism in vitro. Following oral administration of a single 20 mg radiolabeled Cobimetinib dose, no oxidative metabolites >10% of total circulating radioactivity were observed. - Excretion Following oral administration of a single 20 mg radiolabeled Cobimetinib dose, 76% of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was recovered in the urine (with 1.6% as unchanged drug). - Specific Populations - Age, Sex, and Race/Ethnicity Based on the population pharmacokinetic analysis, age (19–88 years), sex, or race/ethnicity does not have a clinically important effect on the systemic exposure of Cobimetinib. - Hepatic Impairment Following a single 10 mg Cobimetinib dose, the geometric mean total Cobimetinib exposure (AUC(inf)) values were similar in subjects with mild or moderate hepatic impairment and was decreased by 31% in subjects with severe hepatic impairment compared to subjects with normal hepatic function. - Renal Impairment Cobimetinib undergoes minimal renal elimination. Cobimetinib exposures were similar in 151 patients with mild renal impairment (CLcr 60 to 89 mL/min), 48 patients with moderate renal impairment (CLcr 30 to 59 mL/min) and 286 patients with normal renal function (CLcr ≥90 mL/min). - Drug Interaction Studies - Vemurafenib: Coadministration of Cobimetinib 60 mg once daily and vemurafenib 960 mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions. - Effect of Strong and Moderate CYP3A Inhibitors on Cobimetinib: In vitro studies show that Cobimetinib is a substrate of CYP3A. Coadministration of itraconazole (a strong CYP3A inhibitor) 200 mg once daily for 14 days with a single 10 mg Cobimetinib dose increased mean Cobimetinib AUC (90% CI) by 6.7-fold (5.6, 8.0) and mean Cmax (90% CI) by 3.2-fold (2.7, 3.7) in 15 healthy subjects. Simulations showed that predicted steady-state concentrations of Cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of Cobimetinib at the 60 mg dose alone. - Effect of Strong and Moderate CYP3A Inducers on Cobimetinib: Based on simulations, Cobimetinib exposures would decrease by 83% when coadministered with a strong CYP3A inducer and by 73% when coadministered with a moderate CYP3A inducer. - Effect of Cobimetinib on CYP Substrates: Coadministration of Cobimetinib 60 mg once daily for 15 days with a single 30 mg dose of dextromethorphan (sensitive CYP2D6 substrate) or a single 2 mg dose of midazolam (sensitive CYP3A substrate) to 20 patients with solid tumors did not change dextromethorphan or midazolam systemic exposure. In vitro data indicated that Cobimetinib may inhibit CYP3A and CYP2D6. Cobimetinib at clinically relevant concentrations is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9 and 2C19 or inducer of CYP1A2, 2B6 and 3A4. - Effect of Transporters on Cobimetinib: Cobimetinib is a substrate of efflux transporter P-glycoprotein (P-gp), but is not a substrate of Breast Cancer Resistance Protein (BCRP), Organic Anion Transporting Polypeptide (OATP1B1 or OATP1B3) or Organic Cation Transporter (OCT1) in vitro. Drugs that inhibit P-gp may increase Cobimetinib concentrations. - Effect of Cobimetinib on Transporters: In vitro data suggest that Cobimetinib at clinically relevant concentrations does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2. - Effect of Gastric Acid Reducing Drugs on Cobimetinib: Coadministration of a proton pump inhibitor, rabeprazole 20 mg once daily for 5 days, with a single dose of 20 mg Cobimetinib under fed and fasted conditions did not result in a clinically important change in Cobimetinib exposure. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with Cobimetinib have not been conducted. Cobimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in bone marrow of rats. No dedicated fertility studies have been performed with Cobimetinib in animals; however, effects on reproductive tissues observed in general toxicology studies conducted in animals suggest that there is potential for Cobimetinib to impair fertility. In female rats, degenerative changes included increased apoptosis/necrosis of corpora lutea and vaginal epithelial cells at Cobimetinib doses approximately twice those in humans at the clinically recommended dose of 60 mg based on body surface area. In male dogs, testicular degeneration occurred at exposures as low as approximately 0.1 times the exposure in humans at the clinically recommended dose of 60 mg. # Clinical Studies The safety and efficacy of Cobimetinib was established in a multicenter, randomized (1:1), double-blinded, placebo-controlled trial conducted in 495 patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic, melanoma. The presence of BRAF V600 mutation was detected using the cobas® 4800 BRAF V600 mutation test. All patients received vemurafenib 960 mg orally twice daily on days 1–28 and were randomized to receive Cobimetinib 60 mg or matching placebo orally once daily on days 1–21 of an every 28-day cycle. Randomization was stratified by geographic region (North America vs. Europe vs. Australia/New Zealand/others) and disease stage (unresectable Stage IIIc, M1a, or M1b vs. Stage M1c). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive placebo were not offered Cobimetinib at the time of disease progression. The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Additional efficacy outcomes were investigator-assessed confirmed objective response rate, overall survival, PFS as assessed by blinded independent central review, and duration of response. The median age of the study population was 55 years (range 23 to 88 years), 58% of patients were male, 93% were White and 5% had no race reported, 60% had stage M1c disease, 72% had a baseline ECOG performance status of 0, 45% had an elevated baseline serum lactate dehydrogenase (LDH), 10% had received prior adjuvant therapy, and <1% had previously treated brain metastases. Patients with available tumor samples were retrospectively tested using next generation sequencing to further classify mutations as V600E or V600K; test results were obtained on 81% of randomized patients. Of these, 86% were identified as having a V600E mutation and 14% as having a V600K mutation. Efficacy results are summarized in TABLE 5 and FIGURE 1. - Table 5 Efficacy Results from Trial 1 COTELLIC: Cobimetinib's Brand name - Figure 1 Kaplan-Meier Curves of Overall Survival The effect on PFS was also supported by analysis of PFS based on the assessment by blinded independent review. A trend favoring the Cobimetinib with vemurafenib arm was observed in exploratory subgroup analyses of PFS, OS, and ORR in both BRAF V600 mutation subtypes (V600E or V600K) in the 81% of patients in this trial where BRAF V600 mutation type was determined. # How Supplied Cobimetinib is supplied as 20 mg film-coated tablets debossed on one side with "COB". Cobimetinib tablets are available in bottles of 63 tablets. (NDC 50242-717-01) ## Storage Store at room temperature below 30°C (86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Inform patients of the following: - New primary cutaneous malignancies: Advise patients to contact their health care provider immediately for change in or development of new skin lesions. - Hemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage. - Cardiomyopathy: Advise patients to report any history of cardiac disease and of the requirement for cardiac monitoring prior to and during Cobimetinib administration. Instruct patients to immediately report any signs or symptoms of left ventricular dysfunction to their healthcare provider. - Serious dermatologic reactions: Instruct patients to contact their healthcare provider to immediately report severe skin changes. - Serous retinopathy and retinal vein occlusion: Instruct patients to immediately contact their healthcare provider if they experience any changes in their vision. - Hepatotoxicity: Advise patients that treatment with Cobimetinib requires monitoring of their liver function. Instruct patients to report any signs or symptoms of liver dysfunction. - Rhabdomyolysis: Instruct patients to report any signs and symptoms of muscle pain or weakness to their healthcare provider. - Severe photosensitivity: Advise patients to avoid sun exposure, wear protective clothing, and use broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. - Embryo-fetal toxicity: Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Cobimetinib. - Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with Cobimetinib and for at least 2 weeks after the final dose of Cobimetinib. - Lactation: Advise females not to breastfeed during treatment with Cobimetinib and for 2 weeks after the final dose. # Precautions with Alcohol Alcohol-Cobimetinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names COTELLIC® # Look-Alike Drug Names There is limited information regarding Cobimetinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cobimetinib
7065af860861f4465698e00c3b24c83ff10ce02e	wikidoc	Coconut oil	Coconut oil Coconut oil, also known as coconut butter, is a tropical oil with many applications. It is extracted from copra (derived from Malayalam word "kopra" which means dried coconut). Coconut oil constitutes seven percent of the total export income of the Philippines, the world's largest exporter of the product. Coconut oil was developed as a commercial product by merchants in the South Seas and South Asia in the 1860s. # Physical properties Coconut oil is a fat consisting of about 90% saturated fat. The oil contains predominantly medium chain triglycerides, with roughly 92% saturated fatty acids, 6% monounsaturated fatty acids, and 2% polyunsaturated fatty acids. Of the saturated fatty acids, coconut oil is primarily 44.6% lauric acid, 16.8% myristic acid a 8.2% palmitic acid and 8% caprylic acid, although it contains seven different saturated fatty acids in total. Its only monounsaturated fatty acid is oleic acid while its only polyunsaturated fatty acid is linoleic acid. Unrefined coconut oil melts at 24-25°C (76°F) and smokes at 170°C (350°F), while refined coconut oil has a higher smoke point of 232°C (450°F). Among the most stable of all oils, coconut oil is slow to oxidize and thus resistant to rancidity, lasting up to two years due to its high saturated fat content. In order to extend shelf life, it is best stored in solid form (i.e. below 24.5°C ). # Health effects ## Heart Disease Medical science has determined that consumption of saturated fats can increase the risk of developing cardiovascular disease. Since coconut oil contains a high proportion of saturated fats, regular consumption of coconut oil may elevate this risk. However, a 2004 study published in the journal Clinical Biochemistry found that coconut oil, especially virgin coconut oil, reduced the LDL cholesterol associated with cardiovascular disease, while raising beneficial HDL levels. An epidemiological study in the American Journal of Clinical Nutrition examined two indigenous populations whose food energy intake was 63% and 34% derived from coconuts respectively, and found no elevated risk of cardiovascular disease. A 2004 article in the American Journal of Clinical Nutrition raises the possibility that the supposed causal relationship between saturated fats and heart disease may actually be a statistical mistake. Other studies have found that coconut oil can help in weight loss and poison recovery. ## Antimicrobial effects A study conducted at University College Hospital in Ibadan, Nigeria published in the Journal of Medicinal Food found that coconut oil was effective in killing some strains of Candida, which cause the condition candidiasis in humans. The authors recommended that coconut oil be used in the treatment of fungal infections. # Types of oil available ## Virgin coconut oil Virgin coconut oil is derived from fresh coconuts (rather than dried, as in copra). Most oils marketed as "virgin" are produced one of three ways: - Quick drying of fresh coconut meat which is then used to press out the oil. - Wet-milling (coconut milk). With this method the oil is extracted from fresh coconut meat without drying first. "Coconut milk" is expressed first by pressing. The oil is then further separated from the water. Methods which can be used to separate the oil from the water include boiling, fermentation, refrigeration, enzymes and mechanical centrifuge. - Wet-milling (direct micro expelling). In this process, the oil is extracted from fresh coconut meat after the adjustment of the water content, then the pressing of the coconut flesh results in the direct extraction of free-flowing oil. Unlike olive oil, there is no world or governing body that sets a standard definition or set of guidelines to classify coconut oil as "virgin". The Philippines has established a Department of Science and Technology (DOST) governmental standard. ## Refined oil Refined coconut oil is referred to in the coconut industry as RBD (refined, bleached, and deodorized) coconut oil. The starting point is "copra", the dried coconut meat. Copra can be made by smoke drying, sun drying, or kiln drying. The unrefined coconut oil extracted from copra (called "crude coconut oil") is not suitable for consumption and must be refined. ### Hydrogenated oil Coconut oil is often partially or fully hydrogenated to increase their melting point in warmer temperatures. This increases the amount of saturated fat present in the oil, and may produce trans fats. ### Fractionated oil "Fractionated coconut oil" is a fraction of the whole oil, in which most of the long-chain triglycerides are removed so that only saturated fats remain. It may also referred to as "caprylic/capric triglyceride" or medium-chain triglyceride (MCT) oil because mostly the medium-chain triglycerides caprylic and capric acid are left in the oil. Because it is completely saturated, fractionated oil is even more heat stable than other forms of coconut oil and has a nearly indefinite shelf life. # Applications ## Cooking Coconut oil is commonly used in cooking, especially when frying. In communities where coconut oil is widely used in cooking, the refined oil is the one most commonly used. Coconut oil is commonly used to flavor many South Asian curries. ## Manufacturing Coconut oil is used in volume quantities for making margarine, soap and cosmetics. Hydrogenated or partially-hydrogenated coconut oil is often used in non-dairy creamers, and snack foods. Fractionated coconut oil is also used in the manufacture of essences, massage oils and cosmetics Coconut oil is an important component of many industrial lubricants, for example in the cold rolling of steel strip. ## Cosmetics and skin treatments Coconut oil is excellent as a skin moisturizer and softener. A study shows that extra virgin coconut oil is as effective and safe as mineral oil when used as a moisturizer, with absence of adverse reactions. Although not suitable for use with condoms, coconut oil is an excellent, inexpensive lubricant for sexual intercourse, though it may cause an allergic reaction. In India and Sri Lanka, coconut oil is commonly used for styling hair, and cooling or soothing the head. People of Tamil Nadu and other coastal areas such as Kerala, Karnataka, Maharashtra and Goa bathe in warm water after applying coconut oil all over the body and leaving it as is for an hour to keep body, skin, and hair healthy. ## As a fuel ### Traditional use Coconut oil is used in oil lamps. ### In diesel engines Coconut oil has been tested for use as a feedstock for biodiesel to be used as a diesel engine fuel. In this manner it can be applied to power generators and transport using diesel engines. Coconut oil is blended to make biodiesel but can also be used straight, without blending. B100 biodiesel blends are only possible in temperate climates as the gel point is approximately 10C (50 degrees Fahrenheit). The oil needs to meet the Weihenstephan standard for pure vegetable oil used as a fuel since otherwise moderate to severe damage from coking and clogging will occur in an unmodified engine . Stationary engines that are continuously loaded (>70%) may possibly be used without engine modifications but there is divergent opinion about this. The physical constraints of using raw coconut oil in a diesel engine are formed by: - higher viscosity of coconut oil (up to 10 times as high as diesel), leading to altered spray pattern of injected fuel, additional stress on injection pump - minimum combustion chamber temperature of 500 °C (Expression error: Missing operand for *. ) to avoid polymerization of the fuel, leading to clogged injectors, sticking piston rings and lubrication oil deterioration - solidification point between 22-25 °C requires an additional fuel tank heater in temperate climates. Raw coconut oil can be used as a fuel for generating electricity by remote communities that have an abundant supply of coconuts and milling capacity, provided diesel engines are adapted. Coconut oil is currently used as a fuel for transport in the Philippines. Further research into the oil's potential as a source of electricity is being carried out in the islands of the Pacific. In the 1990s Bougainville conflict, islanders cut off from supplies due to a blockade used it to fuel their vehicles. ### Aircraft Fuel During February 2008, a mixture of coconut oil and babassu oil was used to partially power one engine of a Boeing 747, in a biofuel trial sponsored by Virgin Atlantic. ### Philippines On January 16, 2008, a company converted coconut oil into engine oil using Korean biotechnology. Rey Mangio, managing director of the Chun Hae Food Processor in Matina Pangi, Davao City, Philippines unveiled the S-9 lubricating motor oil for gasoline and diesel engine: "Since 2005, more than 400 vehicles, both diesel and gasoline fueled, have tested the product at a blended rate of 20 percent of crankcase capacity; chemical analyses show that the product reduces fuel consumption up to 45 percent, it also reduces smoke emission up to 95 percent, it has more power and it has cooler engine operating temperatures." The company produces 5,000 liters of motor oil per month.	Coconut oil Template:World Coconut oil, also known as coconut butter, is a tropical oil with many applications. It is extracted from copra (derived from Malayalam word "kopra" which means dried coconut). Coconut oil constitutes seven percent of the total export income of the Philippines, the world's largest exporter of the product. Coconut oil was developed as a commercial product by merchants in the South Seas and South Asia in the 1860s. # Physical properties Coconut oil is a fat consisting of about 90% saturated fat. The oil contains predominantly medium chain triglycerides,[1] with roughly 92% saturated fatty acids, 6% monounsaturated fatty acids, and 2% polyunsaturated fatty acids. Of the saturated fatty acids, coconut oil is primarily 44.6% lauric acid, 16.8% myristic acid a 8.2% palmitic acid and 8% caprylic acid, although it contains seven different saturated fatty acids in total. Its only monounsaturated fatty acid is oleic acid while its only polyunsaturated fatty acid is linoleic acid.[2] Unrefined coconut oil melts at 24-25°C (76°F) and smokes at 170°C (350°F),[3] while refined coconut oil has a higher smoke point of 232°C (450°F). Among the most stable of all oils, coconut oil is slow to oxidize and thus resistant to rancidity, lasting up to two years due to its high saturated fat content.[citation needed] In order to extend shelf life, it is best stored in solid form (i.e. below 24.5°C [76°F]). # Health effects ## Heart Disease Medical science has determined that consumption of saturated fats can increase the risk of developing cardiovascular disease.[4][5][6] Since coconut oil contains a high proportion of saturated fats, regular consumption of coconut oil may elevate this risk.[citation needed] However, a 2004 study published in the journal Clinical Biochemistry found that coconut oil, especially virgin coconut oil, reduced the LDL cholesterol associated with cardiovascular disease, while raising beneficial HDL levels.[7] An epidemiological study in the American Journal of Clinical Nutrition examined two indigenous populations whose food energy intake was 63% and 34% derived from coconuts respectively, and found no elevated risk of cardiovascular disease.[8][9] A 2004 article in the American Journal of Clinical Nutrition raises the possibility that the supposed causal relationship between saturated fats and heart disease may actually be a statistical mistake.[10] Other studies have found that coconut oil can help in weight loss and poison recovery.[11][12] ## Antimicrobial effects A study conducted at University College Hospital in Ibadan, Nigeria published in the Journal of Medicinal Food found that coconut oil was effective in killing some strains of Candida, which cause the condition candidiasis in humans. The authors recommended that coconut oil be used in the treatment of fungal infections.[13] # Types of oil available ## Virgin coconut oil Virgin coconut oil is derived from fresh coconuts (rather than dried, as in copra). Most oils marketed as "virgin" are produced one of three ways: - Quick drying of fresh coconut meat which is then used to press out the oil. - Wet-milling (coconut milk). With this method the oil is extracted from fresh coconut meat without drying first. "Coconut milk" is expressed first by pressing. The oil is then further separated from the water. Methods which can be used to separate the oil from the water include boiling, fermentation, refrigeration, enzymes and mechanical centrifuge. - Wet-milling (direct micro expelling). In this process, the oil is extracted from fresh coconut meat after the adjustment of the water content, then the pressing of the coconut flesh results in the direct extraction of free-flowing oil. Unlike olive oil, there is no world or governing body that sets a standard definition or set of guidelines to classify coconut oil as "virgin". The Philippines has established a Department of Science and Technology (DOST) governmental standard.[14] ## Refined oil Refined coconut oil is referred to in the coconut industry as RBD (refined, bleached, and deodorized) coconut oil. The starting point is "copra", the dried coconut meat. Copra can be made by smoke drying, sun drying, or kiln drying. The unrefined coconut oil extracted from copra (called "crude coconut oil") is not suitable for consumption and must be refined. ### Hydrogenated oil Coconut oil is often partially or fully hydrogenated to increase their melting point in warmer temperatures. This increases the amount of saturated fat present in the oil, and may produce trans fats. ### Fractionated oil "Fractionated coconut oil" is a fraction of the whole oil, in which most of the long-chain triglycerides are removed so that only saturated fats remain. It may also referred to as "caprylic/capric triglyceride" or medium-chain triglyceride (MCT) oil because mostly the medium-chain triglycerides caprylic and capric acid are left in the oil. Because it is completely saturated, fractionated oil is even more heat stable than other forms of coconut oil and has a nearly indefinite shelf life.[citation needed] # Applications ## Cooking Coconut oil is commonly used in cooking, especially when frying. In communities where coconut oil is widely used in cooking, the refined oil is the one most commonly used. Coconut oil is commonly used to flavor many South Asian curries. ## Manufacturing Coconut oil is used in volume quantities for making margarine, soap and cosmetics. Hydrogenated or partially-hydrogenated coconut oil is often used in non-dairy creamers, and snack foods. Fractionated coconut oil is also used in the manufacture of essences, massage oils and cosmetics Coconut oil is an important component of many industrial lubricants, for example in the cold rolling of steel strip. ## Cosmetics and skin treatments Coconut oil is excellent as a skin moisturizer and softener. A study shows that extra virgin coconut oil is as effective and safe as mineral oil when used as a moisturizer, with absence of adverse reactions.[15] Although not suitable for use with condoms, coconut oil is an excellent, inexpensive lubricant for sexual intercourse,[16] though it may cause an allergic reaction. In India and Sri Lanka, coconut oil is commonly used for styling hair, and cooling or soothing the head. People of Tamil Nadu and other coastal areas such as Kerala, Karnataka, Maharashtra and Goa bathe in warm water after applying coconut oil all over the body and leaving it as is for an hour to keep body, skin, and hair healthy. ## As a fuel ### Traditional use Coconut oil is used in oil lamps. ### In diesel engines Template:Seealso Coconut oil has been tested for use as a feedstock for biodiesel to be used as a diesel engine fuel. In this manner it can be applied to power generators and transport using diesel engines. Coconut oil is blended to make biodiesel but can also be used straight, without blending. B100 biodiesel blends are only possible in temperate climates as the gel point is approximately 10C (50 degrees Fahrenheit). The oil needs to meet the Weihenstephan standard[17] for pure vegetable oil used as a fuel since otherwise moderate to severe damage from coking and clogging will occur in an unmodified engine . Stationary engines that are continuously loaded (>70%) may possibly be used without engine modifications but there is divergent opinion about this. The physical constraints of using raw coconut oil in a diesel engine are formed by: - higher viscosity of coconut oil (up to 10 times as high as diesel), leading to altered spray pattern of injected fuel, additional stress on injection pump - minimum combustion chamber temperature of 500 °C (Expression error: Missing operand for *. ) to avoid polymerization of the fuel, leading to clogged injectors, sticking piston rings and lubrication oil deterioration - solidification point between 22-25 °C requires an additional fuel tank heater in temperate climates. Raw coconut oil can be used as a fuel for generating electricity by remote communities that have an abundant supply of coconuts and milling capacity, provided diesel engines are adapted. Coconut oil is currently used as a fuel for transport in the Philippines.[18] Further research into the oil's potential as a source of electricity is being carried out in the islands of the Pacific.[19][20] In the 1990s Bougainville conflict, islanders cut off from supplies due to a blockade used it to fuel their vehicles.[21] ### Aircraft Fuel During February 2008, a mixture of coconut oil and babassu oil was used to partially power one engine of a Boeing 747, in a biofuel trial sponsored by Virgin Atlantic.[22] ### Philippines On January 16, 2008, a company converted coconut oil into engine oil using Korean biotechnology. Rey Mangio, managing director of the Chun Hae Food Processor in Matina Pangi, Davao City, Philippines unveiled the S-9 lubricating motor oil for gasoline and diesel engine: "Since 2005, more than 400 vehicles, both diesel and gasoline fueled, have tested the product at a blended rate of 20 percent of crankcase capacity; chemical analyses show that the product reduces fuel consumption up to 45 percent, it also reduces smoke emission up to 95 percent, it has more power and it has cooler engine operating temperatures." The company produces 5,000 liters of motor oil per month.[23]	https://www.wikidoc.org/index.php/Coconut_oil
aef4f59a7ab6536f85e61b659ab724e8a54da68a	wikidoc	Omphalocele	Omphalocele # Overview An omphalocele is a type of abdominal wall defect in which the intestines, liver, and occasionally other organs remain outside of the abdomen in a sac because of a defect in the development of the muscles of the abdominal wall. # Causes Some cases of omphalocele are believed to be due to an underlying genetic disorder. ## Congenital conditions - Pentalogy of Cantrell ## Chromosomal abnormalities - Wiedemann-Beckwith syndrome ## Mendelian inherited conditions - Opitz-Frias syndrome - Osteodysplasty (Melnick-Needles) ## Autosomal recessive conditions - Donnai-Barrow syndrome - Manitoba oculotrichoanal syndrome # Presentation The sac protrudes in the midline, through the umbilicus (navel). It is normal for the intestines to protrude from the abdomen, into the umbilical cord, until about the tenth week of pregnancy, after which they return to inside the fetal abdomen. The omphalocele can be mild, with only a small loop of intestines present outside the abdomen, or severe, containing most of the abdominal organs. In severe cases surgical treatment is made more difficult because the infant's abdomen is abnormally small because it had no need to expand to accommodate the developing organs. # Screening An omphalocele is often detected through AFP screening or a detailed fetal ultrasound. Genetic counseling and genetic testing such as amniocentesis is usually offered during the pregnancy. Some cases of omphalocele are due to an underlying genetic disorder. # Related conditions Gastroschisis is a similar birth defect, but the umbilical cord is not involved, and parts of organs may be in the amniotic fluid, and not enclosed in a membranous sac. # Examples - Omphalocele	Omphalocele Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An omphalocele is a type of abdominal wall defect in which the intestines, liver, and occasionally other organs remain outside of the abdomen in a sac because of a defect in the development of the muscles of the abdominal wall. # Causes Some cases of omphalocele are believed to be due to an underlying genetic disorder.[1][2] ## Congenital conditions - Pentalogy of Cantrell ## Chromosomal abnormalities - Wiedemann-Beckwith syndrome ## Mendelian inherited conditions - Opitz-Frias syndrome - Osteodysplasty (Melnick-Needles) ## Autosomal recessive conditions - Donnai-Barrow syndrome - Manitoba oculotrichoanal syndrome # Presentation The sac protrudes in the midline, through the umbilicus (navel). It is normal for the intestines to protrude from the abdomen, into the umbilical cord, until about the tenth week of pregnancy, after which they return to inside the fetal abdomen. The omphalocele can be mild, with only a small loop of intestines present outside the abdomen, or severe, containing most of the abdominal organs. In severe cases surgical treatment is made more difficult because the infant's abdomen is abnormally small because it had no need to expand to accommodate the developing organs. # Screening An omphalocele is often detected through AFP screening or a detailed fetal ultrasound. Genetic counseling and genetic testing such as amniocentesis is usually offered during the pregnancy. Some cases of omphalocele are due to an underlying genetic disorder. # Related conditions Gastroschisis is a similar birth defect, but the umbilical cord is not involved, and parts of organs may be in the amniotic fluid, and not enclosed in a membranous sac. # Examples - Omphalocele	https://www.wikidoc.org/index.php/Coelosomia
983dcd9bd01288d846224261a5e90f9b3f8d0856	wikidoc	Coiled coil	Coiled coil # Overview A coiled coil is a structural motif in proteins, in which 2-7 alpha-helices are coiled together like the strands of a rope (Dimers and trimers are the most common types). Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors. Notable examples are the proteins the oncoproteins c-fos and jun, and the muscle protein tropomyosin. # Molecular structure of coiled coils Coiled coils usually contain a repeated seven amino acid residue pattern called heptad repeats. The interacting surface between the helices often contain hydrophobic residues, such as leucine arranged in a so called leucine zipper. The most favorable way for such two helices to arrange them selves in the water-filled environment of the cytoplasm is to wrap the hydrophobic strands against each other sandwiched between the hydrophilic amino acids. It is thus the burial of hydrophobic surfaces, that provides the thermodynamic driving force for the dimerization. The α-helices may be parallel or antiparallel, and usually adopt a left-handed super-coil (Figure 1). Although disfavored, a few right-handed coiled coils have also been observed in nature and in designed proteins. # Biological roles of coiled coils ## Role of coiled coils in HIV infection A key step in the entry of HIV into human cells is the exposure of a trimeric, parallel coiled coil known as gp41. The gp41 trimer is normally covered by another surface glycoprotein known as gp120, which protects it from antibodies. Upon binding to the target cell, gp120 undergoes a conformational change that exposes the gp41 trimer, whose hydrophobic N-terminal tails enter the target cell membrane. Three other helices of gp41 fold down into the grooves of the gp41 coiled coil trimer, forming a hexamer, and drawing the viral membrane and target-cell membrane close enough to fuse. The virus then enters the cell and begins its replication. Recently, inhibitors that bind in the gp41 grooves have been developed, such as Fuzeon. ## Coiled coils as dimerization tags Because of their specific interaction coiled coils can be used as a dimerization "tag". # History of coiled coils The possibility of coiled coils for α-keratin was proposed by Francis Crick in 1952 as well as mathematical methods for determining their structure. Remarkably this was soon after the structure of the alpha helix was suggested in 1951 by Linus Pauling and coworkers	Coiled coil # Overview A coiled coil is a structural motif in proteins, in which 2-7[1] alpha-helices are coiled together like the strands of a rope (Dimers and trimers are the most common types). Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors. Notable examples are the proteins the oncoproteins c-fos and jun, and the muscle protein tropomyosin. # Molecular structure of coiled coils Coiled coils usually contain a repeated seven amino acid residue pattern called heptad repeats. The interacting surface between the helices often contain hydrophobic residues, such as leucine arranged in a so called leucine zipper. The most favorable way for such two helices to arrange them selves in the water-filled environment of the cytoplasm is to wrap the hydrophobic strands against each other sandwiched between the hydrophilic amino acids. It is thus the burial of hydrophobic surfaces, that provides the thermodynamic driving force for the dimerization. The α-helices may be parallel or antiparallel, and usually adopt a left-handed super-coil (Figure 1). Although disfavored, a few right-handed coiled coils have also been observed in nature and in designed proteins.[2] # Biological roles of coiled coils ## Role of coiled coils in HIV infection A key step in the entry of HIV into human cells is the exposure of a trimeric, parallel coiled coil known as gp41. The gp41 trimer is normally covered by another surface glycoprotein known as gp120, which protects it from antibodies. Upon binding to the target cell, gp120 undergoes a conformational change that exposes the gp41 trimer, whose hydrophobic N-terminal tails enter the target cell membrane. Three other helices of gp41 fold down into the grooves of the gp41 coiled coil trimer, forming a hexamer, and drawing the viral membrane and target-cell membrane close enough to fuse. The virus then enters the cell and begins its replication. Recently, inhibitors that bind in the gp41 grooves have been developed, such as Fuzeon. ## Coiled coils as dimerization tags Because of their specific interaction coiled coils can be used as a dimerization "tag". # History of coiled coils The possibility of coiled coils for α-keratin was proposed by Francis Crick in 1952 as well as mathematical methods for determining their structure. [3] Remarkably this was soon after the structure of the alpha helix was suggested in 1951 by Linus Pauling and coworkers [4]	https://www.wikidoc.org/index.php/Coiled-coil
5d985d54d3d64b1357f3fdc6c622c2eb869b3107	wikidoc	Colesevelam	Colesevelam # Disclaimer WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here. # Black Box Warning FDA Package Insert for Colesevelam contains no information regarding Black Box Warning. # Overview Colesevelam is a non-absorbed, polymeric, lipid-lowering and glucose-lowering drug that is FDA approved for the treatment of primary hyperlipidemia and type 2 diabetes mellitus. Common adverse reactions include constipation, indigestion, nausea, and nasopharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Dosing Information - one 3.75 gram packet once daily or one 1.875 gram packet twice daily - Welchol is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin). - Welchol is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: - LDL-C remains ≥ 190 mg/dL or - LDL-C remains ≥ 160 mg/dL and - There is a positive family history of premature cardiovascular disease or - Two or more other CVD risk factors are present in the pediatric patient. - Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate. - In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDL-C treatment goals are 200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol minus high density lipoprotein cholesterol ) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serum TG is set at 30 mg/dL higher than that for LDL-C. Dosing Information - 6 tablets once daily or 3 tablets twice daily - Welchol is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted. ## Important Limitations of Use - Welchol should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. - Welchol has not been studied in type 2 diabetes in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones. - Welchol has not been studied in pediatric patients with type 2 diabetes. - Welchol has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. - Welchol has not been studied in children younger than 10 years of age or in pre-menarchal girls ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Colesevelam in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Colesevelam in adult patients. # Pediatric Indications and Dosage - Dose adjustments are not required when WELCHOL is administered to children 10 to 17 years of age. - WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls. # Contraindications Welchol is contraindicated in patients with - A history of bowel obstruction - Serum TG concentrations >500 mg/dL - A history of hypertriglyceridemia-induced pancreatitis # Warnings - The effect of Welchol on cardiovascular morbidity and mortality has not been determined. - Welchol, like other bile acid sequestrants, can increase serum TG concentrations. - Welchol had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia. - In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when Welchol was used in combination with sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas) and when Welchol was used as monotherapy (median increase 9.7% compared to placebo) and in combination with insulin (median increase 22% compared to placebo in combination with insulin). Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting Welchol and periodically thereafter. Welchol should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis. Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. In patients with type 2 diabetes, the effect of Welchol on LDL-C levels may be attenuated by Welchol’s effects on TG levels and a smaller reduction in non-HDL-C compared to the reduction in LDL-C. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the Welchol clinical trials had baseline TG 500 mg/dL - Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of Welchol on the absorption of co-administered dietary or supplemental vitamin therapy. In non-clinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to Welchol. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins. - Because of its constipating effects, Welchol is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction. Because of the tablet size, Welchol Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Always mix Welchol for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting. - Welchol for Oral Suspension contains 13.5 mg phenylalanine per 1.875 gram packet and 27 mg phenylalanine per 3.75 gram packet. - There have been no clinical studies establishing conclusive evidence of macrovascular disease risk reduction with Welchol or any other antidiabetic drugs. # Adverse Reactions ## Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. - In the lipid-lowering trials, 807 adult patients received at least one dose of Welchol (total exposure 199 patient-years). In the add-on combination type 2 diabetes trials, 566 patients received at least one dose of Welchol (total exposure 209 patient-years). In the monotherapy type 2 diabetes trial, 175 patients received at least one dose of Welchol and had a post baseline follow up (total exposure 69 patient-years). - In clinical trials for the reduction of LDL-C, 68% of patients receiving Welchol vs. 64% of patients receiving placebo reported an adverse reaction. In add-on combination clinical trials of type 2 diabetes, 60% of patients receiving Welchol vs. 56% of patients receiving placebo reported an adverse reaction. In monotherapy clinical trial for type 2 diabetes, 52% of patients receiving Welchol vs. 45% of patients receiving placebo reported an adverse reaction. - Primary hyperlipidemia: In 7 double-blind, placebo-controlled, clinical trials, 807 patients with primary hyperlipidemia (age range 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with Welchol 1.5 g/day to 4.5 g/day from 4 to 24 weeks. - Pediatric Patients 10 to 17 Years of Age: In an 8-week double-blind, placebo-controlled study boys and post menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with Welchol tablets (1.9-3.8 g, daily) or placebo tablets. - The reported adverse reactions during the additional 18-week open-label treatment period with Welchol 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%). Type 2 Diabetes Mellitus: - The safety of Welchol in patients with type 2 diabetes mellitus was evaluated in 4 add-on combination and 1 monotherapy double-blind, 12-26 week, placebo-controlled clinical trials. The add-on combination trials involved 1128 patients (566 patients on Welchol; 562 patients on placebo) with inadequate glycemic control on metformin, sulfonylurea, or insulin when these agents were used alone or in combination with other anti-diabetic agents. Upon completion of the add-on combination trials, 492 patients entered a 52-week open-label uncontrolled extension study during which all patients received Welchol 3.8 g/day while continuing background treatment with metformin, sulfonylurea, or insulin alone or in combination with other anti-diabetic agents. The monotherapy trial involved 357 patients (176 Welchol and 181 placebo) who were on no prior anti-diabetes medication within 3 months of the study. - A total of 6.7% of Welchol-treated patients and 3.2% of placebo-treated patients were discontinued from the add-on combination diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation. In the monotherapy diabetes trial, a total of 4.6% of Welchol-treated patients and 4.7% of placebo-treated patients were discontinued from the trial due to adverse reactions. - One patient in the pivotal trials discontinued due to body rash and mouth blistering that occurred after the first dose of Welchol, which may represent a hypersensitivity reaction to Welchol. Hypertriglyceridemia: - Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the phase 3 diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the Welchol group and 177 mg/dL in the placebo group. Welchol therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively. In comparison, Welchol resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial. - Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 4.1% of Welchol-treated patients compared to 2.0% of placebo-treated patients. Among these patients, the TG concentrations with Welchol (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on Welchol and 2 (0.4%) patients on placebo developed TG elevations ≥1000 mg/dL. In all Welchol clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol. Cardiovascular adverse events: - During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the Welchol group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown. Hypoglycemia: - Adverse events of hypoglycemia were reported based on the clinical judgment of the blinded investigators and did not require confirmation with fingerstick glucose testing. The overall reported incidence of hypoglycemia was 3.0% in patients treated with Welchol and 2.3% in patients treated with placebo. No Welchol treated patients developed severe hypoglycemia. Hypertriglyceridemia: - Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the add-on combination diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the Welchol group and 177 mg/dL in the placebo group. Welchol therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively. In the monotherapy diabetes trial, the distribution of baseline fasting serum TG levels was similar to that from the add-on combination trials. The median baseline fasting TG for the monotherapy study population was 167 mg/dL; the median post- treatment fasting TG concentration was 182mg/dL in the Welchol group and 173mg/dL in the placebo group. Welchol treatment resulted in a median placebo-corrected increase in serum TG of 9.7% (p=0.03). In comparison, Welchol resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial. - Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 4.1% of Welchol-treated patients compared to 2.0% of placebo-treated patients in the add-on combination diabetes trials. Among these patients, the TG concentrations with Welchol (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on Welchol and 2 (0.4%) patients on placebo developed TG elevations ≥1000 mg/dL. In the monotherapy diabetes trial, a total of 8 (4.4%) patients in the placebo group and 9 (5.1%) patients in the Welchol group had a TG level <500 mg/dL at baseline and a treatment-emergent TG ≥500 mg/dL. Among these patients, the TG concentrations with Welchol (median 594 mg/dL) were similar to that observed with placebo (median 589 mg/dL). Four (2.4%) patients on Welchol and 1 (0.6%) patient on placebo developed TG elevation ≥1000 mg/dL. In all Welchol clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol. Cardiovascular adverse events: - During the add-on combination diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the Welchol group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown. In the monotherapy diabetes trial, one myocardial infarction and one case of unstable angina occurred in the Welchol group, and one case of hypotension in the placebo group. ## Postmarketing Experience - The following additional adverse reactions have been identified during post-approval use of Welchol. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions - Welchol reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively, the physician should monitor drug levels of the co-administered drug. - Table 5 lists the drugs that have been tested in in vitro binding, in vivo drug interaction studies with colesevelam and/or drugs with postmarketing reports consistent with potential drug-drug interactions. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to WELCHOL. Alternatively, the physician should monitor drug levels of the co-administered drug. a Should be administered at least 4 hours prior to WELCHOL b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. - In an in vivo drug interaction study, WELCHOL and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of WELCHOL and warfarin coadministration on INR. In postmarketing reports, concomitant use of WELCHOL and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating WELCHOL and frequently enough during early WELCHOL therapy to ensure that no significant alteration in INR occurs. Once the INR is stable, continue to monitor the INR at intervals usually recommended for patients on warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Pregnancy Category (AUS): Colesevelam is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories. - There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. Requirements for vitamins and other nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed. - In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. ### Labor and Delivery - There is no FDA guidance on use of Colesevelam during labor and delivery. ### Nursing Mothers - Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract. ### Pediatric Use - The safety and effectiveness of Welchol as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH . The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo. - Due to tablet size, Welchol for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when Welchol is administered to children 10 to 17 years of age. - Welchol has not been studied in children younger than 10 years of age or in pre-menarchal girls. ### Geriatric Use - Primary hyperlipidemia: Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ≥65 years old, and 58 (4%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender - There is no FDA guidance on the use of Colesevelam with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Colesevelam with respect to specific racial populations. ### Renal Impairment - Type 2 Diabetes Mellitus: Of the 1128 patients enrolled in the four add-on combination diabetes studies, 696 (62%) had mild renal insufficiency (creatinine clearance 50-<80 mL/min), 53 (5%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl≥50 mL/min (n=1075). Of the 357 patients enrolled in the monotherapy diabetes trial, only 3 patients had CrCl <50 mL/min. ### Hepatic Impairment - There is no FDA guidance on the use of Colesevelam in patients with hepatic impairment ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg). - Mutagenesis: Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S.typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation. - Impairment of Fertility: Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg). ### Immunocompromised Patients - There is no FDA guidance one the use of Colesevelam in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - There is limited information regarding Monitoring of Colesevelam in the drug label. ### Primary Hyperlipidemia - To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Due to tablet size, it is recommended that any patient who has difficulty swallowing tablets use Welchol for Oral Suspension. - Welchol can be dosed at the same time as a statin or the two drugs can be dosed apart. - After initiation of Welchol, lipid levels should be analyzed within 4 to 6 weeks. ### Type 2 Diabetes Mellitus - To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. # IV Compatibility - There is limited information regarding IV Compatibility of Colesevelam in the drug label. # Overdosage - Doses of Welchol in excess of 4.5 g/day have not been tested. Because Welchol is not absorbed, the risk of systemic toxicity is low. However, excessive doses of Welchol may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses. # Pharmacology ## Mechanism of Action - Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient in Welchol, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged. - Type 2 Diabetes Mellitus: The mechanism by which Welchol improves glycemic control is unknown. ## Structure - WELCHOL (colesevelam hydrochloride) is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule. - Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula: - wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone crosslinking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ≥ 100 to indicate an extended polymer network. A small amount of the amines are dialkylated, and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water. - WELCHOL Tablets are an off-white, oval, film-coated, solid tablet containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using a water-soluble black ink. - WELCHOL for Oral Suspension is a citrus-flavored, white to pale yellow powder containing yellow granules packaged in single-dose packets containing either 1.875 gram or 3.75 gram colesevelam hydrochloride. In addition, each packet contains the following inactive ingredients: lemon flavor, orange flavor, propylene glycol alginate, simethicone, aspartame, citric acid, medium chain triglycerides, and magnesium trisilicate. - PHENYLKETONURICS: WELCHOL for Oral Suspension contains 24 mg phenylalanine per 1.875 gram dose and 48 mg phenylalanine per 3.75 gram dose. ## Pharmacodynamics - A maximum therapeutic response to the lipid-lowering effects of Welchol was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to Welchol, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment. ## Pharmacokinetics Absorption: Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed. Distribution: Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract. Metabolism: Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450. Excretion: In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14C-labeled colesevelam hydrochloride dose was excreted in the urine. Drug Interactions: Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies.In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride. Therefore, an in vivo pharmacokinetic interaction of Welchol with these drugs is unlikely. Welchol was found to have no significant effect on the bioavailability of aspirin, atenolol, digoxin, enalapril, fenofibrate, lovastatin, metoprolol,phenytoin,pioglitazone,quinidine,rosiglitazone, sitagliptin,valproic acid, and warfarin. The results of additional in vivo drug interactions of Welchol are presented in Table 6. a With verapamil, the dose of Welchol was 4.5 g b Should be administered at least 4 hours prior to Welchol. c Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. d Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to Welchol. - Oral contraceptive containing norethindrone and ethinyl estradiol. N/A — Not Available ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg). - Mutagenesis: Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S.typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation. - Impairment of Fertility: Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg). ## Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies - Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride. # Clinical Studies ## Primary hyperlipidemia - Welchol reduces TC, LDL-C, apolipoprotein B (Apo B), and non-HDL-C when administered alone or in combination with a statin in patients with primary hyperlipidemia. - Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to Welchol was achieved within 2 weeks and was maintained during long-term therapy. - Monotherapy: In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), Welchol was given for 24 weeks in divided doses with the morning and evening meals. - As shown in Table 7, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. Welchol at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both Welchol doses but the changes were not statistically different from placebo. - In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), Welchol 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another. - Combination Therapy: Co-administration of Welchol and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 8, Welchol doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone. - In all 3 studies, the LDL-C reduction achieved with the combination of Welchol and any given dose of statin therapy was statistically superior to that achieved with Welchol or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of Welchol 3.8 g and atorvastatin 10 mg. - The effect of Welchol when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C ≥115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label run-in period and then randomly assigned to receive fenofibrate 160 mg plus either Welchol 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 9. - Pediatric Therapy: The safety and efficacy of Welchol in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel group study followed by an open-label phase, in 194 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (heFH), taking a stable dose of an FDA-approved statin (with LDL-C >130 mg/dL) or naïve to lipid lowering therapy (with LDL-C >160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL. - During the double-blind treatment period, patients were assigned randomly to treatment: Welchol 3.8 g/day (n=64), Welchol 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, Welchol 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non statistically significant increase in TG was observed versus placebo (Table 10). - During the open-label treatment period patients were treated with Welchol 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8. ## Type 2 Diabetes Mellitus - Welchol has been studied as monotherapy and in combination with metformin, sulfonylureas, and insulin. In these studies, Welchol and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone. - Monotherapy: The efficacy of Welchol 3.8 g/day as anti-diabetes monotherapy was evaluated in a randomized double-blind, placebo-controlled trial involving 357 patients (176 Welchol and 181 placebo) with T2DM who were treatment-naïve or had not received antihyperglycemic medication within 3 months prior to the start of the study. - In this trial, the mean age was 52.2 years (range 24-81 years), 48.7% of patients were women, 70.9% were Caucasian, 15.7% were Black, 5.6% were Asian, 6.4% were American Indian or Alaskan Native, and 1.1% were other racial groups. Hispanic/Latino accounted for 46.5% of the enrolled patients. statin use at baseline was reported in 13% of the Welchol-treated patients and 16% of the placebo-treated patients. - Welchol resulted in a statistically significant reduction in A1C of 0.27% compared to placebo. - The mean baseline LDL-C was 121 mg/dL in the monotherapy trial. Welchol treatment resulted in a placebo-corrected 11% reduction in LDL-C. Welchol treatment also reduced serum TC, ApoB, and non-HDL-C (Table 12). The mean change in body weight was -0.6 kg for Welchol and -0.7 kg for placebo treatment groups. - Add-on combination Therapy: The efficacy of Welchol 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 3 double-blind, placebo-controlled add-on therapy trials involving a total of 1018 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. - In these studies, the overall mean age was 57 years (range 24-81 years), 47% were women, and 59% of the patients were Caucasian, 23% were Hispanic, 14% were Black, 3% were Asian, and 1% were of other racial groups. statin use at baseline was reported in 42% of the Welchol-treated patients and 50% of the placebo-treated patients. - In all 3 pivotal add-on therapy trials, treatment with Welchol resulted in a statistically significant reduction in A1C of 0.5% compared to placebo. Similar placebo-corrected reductions in A1C occurred in patients who received Welchol in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other anti-diabetic agents. In the metformin and sulfonylurea trials, treatment with Welchol also resulted in statistically significant reductions in fasting plasma glucose (FPG) of 14 mg/dL compared to placebo. - Welchol had consistent effects on A1C across subgroups of age, gender, race, body mass index, and baseline A1C. Welchol’s effects on A1C were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone). - The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), and 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, Welchol treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. Welchol treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin and patients on a sulfonylurea, but not in the study of patients on metformin. The clinical significance of these increases is unknown. Welchol is contraindicated in patients with TG levels > 500 mg/dL and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended. - Body weight did not significantly increase from baseline with Welchol therapy, compared with placebo, in any of the 3 pivotal clinical studies. - Add-on Combination Therapy with Metformin: Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). A total of 60% of these patients were receiving ≥1,500 mg/day of metformin. In combination with metformin, Welchol resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 13). Welchol also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 14). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with Welchol compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for Welchol and -0.3 kg for placebo. - Add-on Combination Therapy with sulfonylurea: Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). A total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with a sulfonylurea, Welchol resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 15). Welchol also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 16). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with Welchol compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for Welchol and -0.4 kg for placebo. - Add-on Combination Therapy with Insulin: Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the Welchol group and 65 units in the placebo group. In combination with insulin, Welchol resulted in a statistically significant placebo-corrected reduction in A1C (Table 17). Welchol also reduced LDL-C and Apo B, but increased serum TG (Table 18). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with Welchol compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for Welchol and 0.2 kg for placebo. # How Supplied - National Drug Code (NDC): 65597-701-18 - Storage: For tablet: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Brief exposure to 40°C (104°F) does not adversely affect the product. Protect from moisture.For oral suspension:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. - Manufactured by: DAIICHI SANKYO ## Drug Images ## Package and Label Display Panel # Patient Information ## Patient Information from FDA - Dosing: Patients should be advised to take Welchol Tablets with a meal and liquid. Welchol can be taken as 6 tablets once daily or 3 tablets twice daily. Patients should be advised to take Welchol for Oral Suspension as one 3.75 gram packet once daily or one 1.875 gram packet twice daily. To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Always mix Welchol for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting. - Drug interactions: Drugs with a known interaction with colesevelam (e.g., cyclosporine,glimepiride,glipizide, glyburide, levothyroxine, olmesartan medoxomil, oral contraceptives) should be administered at least 4 hours prior to Welchol. In an in vivo drug interaction study, there was no significant effect on the bioavailability of phenytoin; however, due to its narrow therapeutic index and post-marketing reports consistent with potential drug-drug interactions, phenytoin should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively the physician should monitor blood levels of the coadministered drug. Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. - Gastrointestinal: Welchol can cause constipation. Welchol is contraindicated in patients with a history of bowel obstruction. Welchol is not recommended in patients who may be at risk of bowel obstruction, including patients with gastroparesis, other gastrointestinal motility disorders, or a history of major gastrointestinal surgery. Patients should be instructed to consume a diet that promotes bowel regularity. Patients should be instructed to promptly discontinue Welchol and seek medical attention if severe abdominal pain or severe constipation occurs. Because of the tablet size, Welchol Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Always mix Welchol for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting. Hypertriglyceridemia and pancreatitis: Patients should be instructed to discontinue Welchol and seek prompt medical attention if the hallmark symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting). ## Patient Information from NLM ## Why this medication is prescribed - Colesevelam is used with exercise and diet changes (restriction of cholesterol and fat intake) to reduce the amount of cholesterol and certain fatty substances in your blood. It works by binding bile acids in your intestines. Bile acids are made when cholesterol is broken down in your body. Removing these bile acids helps to lower your blood cholesterol. Accumulation of cholesterol and fats along the walls of your arteries (a process known as atherosclerosis) decreases blood flow and, therefore, the oxygen supply to your heart, brain, and other parts of your body. Lowering your blood level of cholesterol and fats may help to prevent heart disease, angina (chest pain), strokes, and heart attacks. Colesevelam may be used alone or in combination with other lipid-lowering medications known as statins (atorvastatin , cerivastatin , lovastatin , pravastatin , or simvastatin ). - This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. ## How this medication should be used - Colesevelam comes as a tablet to take by mouth. It is usually taken once or twice a day with meals and liquid. Your doctor will tell you how many tablets to take at each dose. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take colesevelam exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. - Your lipid levels should lower within 2 weeks. Colesevelam lowers your lipid levels but does not cure high cholesterol. Continue to take colesevelam even if you feel well. Do not stop taking colesevelam without talking to your doctor. ## Special Precautions Before taking colesevelam: - Tell your doctor and pharmacist if you are allergic to colesevelam or any other drugs. - Tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially sustained-release formulations of verapamil (Calan SR) and vitamins and herbal products. - Tell your doctor if you have or have ever had gastrointestinal problems, especially bowel obstruction or difficulty swallowing foods, triglyceride levels greater than 300 mg/dl, bleeding problems, and low levels of fat-soluble vitamins (vitamins A, E, and K). - Tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking colesevelam, call your doctor. ## Special dietary instructions - Eat a low-cholesterol, low-fat diet. This kind of diet includes cottage cheese, fat-free milk, fish (not canned in oil), vegetables, poultry, egg whites, and polyunsaturated oils and margarines (corn, safflower, canola, and soybean oils). Avoid foods with excess fat in them such as meat (especially liver and fatty meat), egg yolks, whole milk, cream, butter, shortening, lard, pastries, cakes, cookies, gravy, peanut butter, chocolate, olives, potato chips, coconut, cheese (other than cottage cheese), coconut oil, palm oil, and fried foods. ## What to do if you forget a dose - Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed dose. ## Side Effects ### Minor Side Effects - Side effects from colesevelam can occur. Tell your doctor if any of these symptoms are severe or do not go away: - Gas - Constipation - Upset stomach - Headache - Weakness - Muscle pain - Throat infection ## Storage conditions needed for this medication - Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. ## Other information - Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to colesevelam. - Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription. ## Brand names - Welchol® # Precaution with Alcohol Alcohol-Colesevelam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.	Colesevelam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2] # Disclaimer WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here. # Black Box Warning FDA Package Insert for Colesevelam contains no information regarding Black Box Warning. # Overview Colesevelam is a non-absorbed, polymeric, lipid-lowering and glucose-lowering drug that is FDA approved for the treatment of primary hyperlipidemia and type 2 diabetes mellitus. Common adverse reactions include constipation, indigestion, nausea, and nasopharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Dosing Information - one 3.75 gram packet once daily or one 1.875 gram packet twice daily - Welchol is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin). - Welchol is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: - LDL-C remains ≥ 190 mg/dL or - LDL-C remains ≥ 160 mg/dL and - There is a positive family history of premature cardiovascular disease or - Two or more other CVD risk factors are present in the pediatric patient. - Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate. - In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDL-C treatment goals are < 100 mg/dL. An LDL-C goal of < 70 mg/dL is a therapeutic option on the basis of recent trial evidence. If LDL-C is at goal but the serum triglyceride (TG) value is > 200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol [TC] minus high density lipoprotein cholesterol [HDL-C]) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serum TG is set at 30 mg/dL higher than that for LDL-C. Dosing Information - 6 tablets once daily or 3 tablets twice daily - Welchol is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted. ## Important Limitations of Use - Welchol should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. - Welchol has not been studied in type 2 diabetes in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones. - Welchol has not been studied in pediatric patients with type 2 diabetes. - Welchol has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. - Welchol has not been studied in children younger than 10 years of age or in pre-menarchal girls ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Colesevelam in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Colesevelam in adult patients. # Pediatric Indications and Dosage - Dose adjustments are not required when WELCHOL is administered to children 10 to 17 years of age. - WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls. # Contraindications Welchol is contraindicated in patients with - A history of bowel obstruction - Serum TG concentrations >500 mg/dL - A history of hypertriglyceridemia-induced pancreatitis # Warnings - The effect of Welchol on cardiovascular morbidity and mortality has not been determined. - Welchol, like other bile acid sequestrants, can increase serum TG concentrations. - Welchol had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia. - In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when Welchol was used in combination with sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas) and when Welchol was used as monotherapy (median increase 9.7% compared to placebo) and in combination with insulin (median increase 22% compared to placebo in combination with insulin). Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting Welchol and periodically thereafter. Welchol should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis. Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. In patients with type 2 diabetes, the effect of Welchol on LDL-C levels may be attenuated by Welchol’s effects on TG levels and a smaller reduction in non-HDL-C compared to the reduction in LDL-C. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the Welchol clinical trials had baseline TG <300 mg/dL, it is unknown whether patients with more uncontrolled baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol. In addition, the use of Welchol is contraindicated in patients with TG levels >500 mg/dL - Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of Welchol on the absorption of co-administered dietary or supplemental vitamin therapy. In non-clinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to Welchol. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins. - Because of its constipating effects, Welchol is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction. Because of the tablet size, Welchol Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Always mix Welchol for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting. - Welchol for Oral Suspension contains 13.5 mg phenylalanine per 1.875 gram packet and 27 mg phenylalanine per 3.75 gram packet. - There have been no clinical studies establishing conclusive evidence of macrovascular disease risk reduction with Welchol or any other antidiabetic drugs. # Adverse Reactions ## Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. - In the lipid-lowering trials, 807 adult patients received at least one dose of Welchol (total exposure 199 patient-years). In the add-on combination type 2 diabetes trials, 566 patients received at least one dose of Welchol (total exposure 209 patient-years). In the monotherapy type 2 diabetes trial, 175 patients received at least one dose of Welchol and had a post baseline follow up (total exposure 69 patient-years). - In clinical trials for the reduction of LDL-C, 68% of patients receiving Welchol vs. 64% of patients receiving placebo reported an adverse reaction. In add-on combination clinical trials of type 2 diabetes, 60% of patients receiving Welchol vs. 56% of patients receiving placebo reported an adverse reaction. In monotherapy clinical trial for type 2 diabetes, 52% of patients receiving Welchol vs. 45% of patients receiving placebo reported an adverse reaction. - Primary hyperlipidemia: In 7 double-blind, placebo-controlled, clinical trials, 807 patients with primary hyperlipidemia (age range 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with Welchol 1.5 g/day to 4.5 g/day from 4 to 24 weeks. - Pediatric Patients 10 to 17 Years of Age: In an 8-week double-blind, placebo-controlled study boys and post menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with Welchol tablets (1.9-3.8 g, daily) or placebo tablets. - The reported adverse reactions during the additional 18-week open-label treatment period with Welchol 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%). Type 2 Diabetes Mellitus: - The safety of Welchol in patients with type 2 diabetes mellitus was evaluated in 4 add-on combination and 1 monotherapy double-blind, 12-26 week, placebo-controlled clinical trials. The add-on combination trials involved 1128 patients (566 patients on Welchol; 562 patients on placebo) with inadequate glycemic control on metformin, sulfonylurea, or insulin when these agents were used alone or in combination with other anti-diabetic agents. Upon completion of the add-on combination trials, 492 patients entered a 52-week open-label uncontrolled extension study during which all patients received Welchol 3.8 g/day while continuing background treatment with metformin, sulfonylurea, or insulin alone or in combination with other anti-diabetic agents. The monotherapy trial involved 357 patients (176 Welchol and 181 placebo) who were on no prior anti-diabetes medication within 3 months of the study. - A total of 6.7% of Welchol-treated patients and 3.2% of placebo-treated patients were discontinued from the add-on combination diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation. In the monotherapy diabetes trial, a total of 4.6% of Welchol-treated patients and 4.7% of placebo-treated patients were discontinued from the trial due to adverse reactions. - One patient in the pivotal trials discontinued due to body rash and mouth blistering that occurred after the first dose of Welchol, which may represent a hypersensitivity reaction to Welchol. Hypertriglyceridemia: - Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the phase 3 diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the Welchol group and 177 mg/dL in the placebo group. Welchol therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively. In comparison, Welchol resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial. - Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 4.1% of Welchol-treated patients compared to 2.0% of placebo-treated patients. Among these patients, the TG concentrations with Welchol (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on Welchol and 2 (0.4%) patients on placebo developed TG elevations ≥1000 mg/dL. In all Welchol clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol. Cardiovascular adverse events: - During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the Welchol group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown. Hypoglycemia: - Adverse events of hypoglycemia were reported based on the clinical judgment of the blinded investigators and did not require confirmation with fingerstick glucose testing. The overall reported incidence of hypoglycemia was 3.0% in patients treated with Welchol and 2.3% in patients treated with placebo. No Welchol treated patients developed severe hypoglycemia. Hypertriglyceridemia: - Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the add-on combination diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the Welchol group and 177 mg/dL in the placebo group. Welchol therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively. In the monotherapy diabetes trial, the distribution of baseline fasting serum TG levels was similar to that from the add-on combination trials. The median baseline fasting TG for the monotherapy study population was 167 mg/dL; the median post- treatment fasting TG concentration was 182mg/dL in the Welchol group and 173mg/dL in the placebo group. Welchol treatment resulted in a median placebo-corrected increase in serum TG of 9.7% (p=0.03). In comparison, Welchol resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial. - Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 4.1% of Welchol-treated patients compared to 2.0% of placebo-treated patients in the add-on combination diabetes trials. Among these patients, the TG concentrations with Welchol (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on Welchol and 2 (0.4%) patients on placebo developed TG elevations ≥1000 mg/dL. In the monotherapy diabetes trial, a total of 8 (4.4%) patients in the placebo group and 9 (5.1%) patients in the Welchol group had a TG level <500 mg/dL at baseline and a treatment-emergent TG ≥500 mg/dL. Among these patients, the TG concentrations with Welchol (median 594 mg/dL) were similar to that observed with placebo (median 589 mg/dL). Four (2.4%) patients on Welchol and 1 (0.6%) patient on placebo developed TG elevation ≥1000 mg/dL. In all Welchol clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol. Cardiovascular adverse events: - During the add-on combination diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the Welchol group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown. In the monotherapy diabetes trial, one myocardial infarction and one case of unstable angina occurred in the Welchol group, and one case of hypotension in the placebo group. ## Postmarketing Experience - The following additional adverse reactions have been identified during post-approval use of Welchol. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions - Welchol reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively, the physician should monitor drug levels of the co-administered drug. - Table 5 lists the drugs that have been tested in in vitro binding, in vivo drug interaction studies with colesevelam and/or drugs with postmarketing reports consistent with potential drug-drug interactions. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to WELCHOL. Alternatively, the physician should monitor drug levels of the co-administered drug. a Should be administered at least 4 hours prior to WELCHOL b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. - In an in vivo drug interaction study, WELCHOL and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of WELCHOL and warfarin coadministration on INR. In postmarketing reports, concomitant use of WELCHOL and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating WELCHOL and frequently enough during early WELCHOL therapy to ensure that no significant alteration in INR occurs. Once the INR is stable, continue to monitor the INR at intervals usually recommended for patients on warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Pregnancy Category (AUS): Colesevelam is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories. - There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. Requirements for vitamins and other nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed. - In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. ### Labor and Delivery - There is no FDA guidance on use of Colesevelam during labor and delivery. ### Nursing Mothers - Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract. ### Pediatric Use - The safety and effectiveness of Welchol as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH . The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo. - Due to tablet size, Welchol for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when Welchol is administered to children 10 to 17 years of age. - Welchol has not been studied in children younger than 10 years of age or in pre-menarchal girls. ### Geriatric Use - Primary hyperlipidemia: Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ≥65 years old, and 58 (4%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender - There is no FDA guidance on the use of Colesevelam with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Colesevelam with respect to specific racial populations. ### Renal Impairment - Type 2 Diabetes Mellitus: Of the 1128 patients enrolled in the four add-on combination diabetes studies, 696 (62%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 53 (5%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl≥50 mL/min (n=1075). Of the 357 patients enrolled in the monotherapy diabetes trial, only 3 patients had CrCl <50 mL/min. ### Hepatic Impairment - There is no FDA guidance on the use of Colesevelam in patients with hepatic impairment ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg). - Mutagenesis: Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S.typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation. - Impairment of Fertility: Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg). ### Immunocompromised Patients - There is no FDA guidance one the use of Colesevelam in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - There is limited information regarding Monitoring of Colesevelam in the drug label. ### Primary Hyperlipidemia - To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Due to tablet size, it is recommended that any patient who has difficulty swallowing tablets use Welchol for Oral Suspension. - Welchol can be dosed at the same time as a statin or the two drugs can be dosed apart. - After initiation of Welchol, lipid levels should be analyzed within 4 to 6 weeks. ### Type 2 Diabetes Mellitus - To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. # IV Compatibility - There is limited information regarding IV Compatibility of Colesevelam in the drug label. # Overdosage - Doses of Welchol in excess of 4.5 g/day have not been tested. Because Welchol is not absorbed, the risk of systemic toxicity is low. However, excessive doses of Welchol may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses. # Pharmacology ## Mechanism of Action - Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient in Welchol, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged. - Type 2 Diabetes Mellitus: The mechanism by which Welchol improves glycemic control is unknown. ## Structure - WELCHOL (colesevelam hydrochloride) is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule. - Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula: - wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone crosslinking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ≥ 100 to indicate an extended polymer network. A small amount of the amines are dialkylated, and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water. - WELCHOL Tablets are an off-white, oval, film-coated, solid tablet containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using a water-soluble black ink. - WELCHOL for Oral Suspension is a citrus-flavored, white to pale yellow powder containing yellow granules packaged in single-dose packets containing either 1.875 gram or 3.75 gram colesevelam hydrochloride. In addition, each packet contains the following inactive ingredients: lemon flavor, orange flavor, propylene glycol alginate, simethicone, aspartame, citric acid, medium chain triglycerides, and magnesium trisilicate. - PHENYLKETONURICS: WELCHOL for Oral Suspension contains 24 mg phenylalanine per 1.875 gram dose and 48 mg phenylalanine per 3.75 gram dose. ## Pharmacodynamics - A maximum therapeutic response to the lipid-lowering effects of Welchol was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to Welchol, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment. ## Pharmacokinetics Absorption: Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed. Distribution: Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract. Metabolism: Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450. Excretion: In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14C-labeled colesevelam hydrochloride dose was excreted in the urine. Drug Interactions: Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies.In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride. Therefore, an in vivo pharmacokinetic interaction of Welchol with these drugs is unlikely. Welchol was found to have no significant effect on the bioavailability of aspirin, atenolol, digoxin, enalapril, fenofibrate, lovastatin, metoprolol,phenytoin,pioglitazone,quinidine,rosiglitazone, sitagliptin,valproic acid, and warfarin. The results of additional in vivo drug interactions of Welchol are presented in Table 6. a With verapamil, the dose of Welchol was 4.5 g b Should be administered at least 4 hours prior to Welchol. c Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. d Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to Welchol. * Oral contraceptive containing norethindrone and ethinyl estradiol. N/A — Not Available ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg). - Mutagenesis: Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S.typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation. - Impairment of Fertility: Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg). ## Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies - Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride. # Clinical Studies ## Primary hyperlipidemia - Welchol reduces TC, LDL-C, apolipoprotein B (Apo B), and non-HDL-C when administered alone or in combination with a statin in patients with primary hyperlipidemia. - Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to Welchol was achieved within 2 weeks and was maintained during long-term therapy. - Monotherapy: In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), Welchol was given for 24 weeks in divided doses with the morning and evening meals. - As shown in Table 7, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. Welchol at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both Welchol doses but the changes were not statistically different from placebo. - In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), Welchol 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another. - Combination Therapy: Co-administration of Welchol and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 8, Welchol doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone. - In all 3 studies, the LDL-C reduction achieved with the combination of Welchol and any given dose of statin therapy was statistically superior to that achieved with Welchol or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of Welchol 3.8 g and atorvastatin 10 mg. - The effect of Welchol when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C ≥115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label run-in period and then randomly assigned to receive fenofibrate 160 mg plus either Welchol 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 9. - Pediatric Therapy: The safety and efficacy of Welchol in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel group study followed by an open-label phase, in 194 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (heFH), taking a stable dose of an FDA-approved statin (with LDL-C >130 mg/dL) or naïve to lipid lowering therapy (with LDL-C >160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL. - During the double-blind treatment period, patients were assigned randomly to treatment: Welchol 3.8 g/day (n=64), Welchol 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, Welchol 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non statistically significant increase in TG was observed versus placebo (Table 10). - During the open-label treatment period patients were treated with Welchol 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8. ## Type 2 Diabetes Mellitus - Welchol has been studied as monotherapy and in combination with metformin, sulfonylureas, and insulin. In these studies, Welchol and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone. - Monotherapy: The efficacy of Welchol 3.8 g/day as anti-diabetes monotherapy was evaluated in a randomized double-blind, placebo-controlled trial involving 357 patients (176 Welchol and 181 placebo) with T2DM who were treatment-naïve or had not received antihyperglycemic medication within 3 months prior to the start of the study. - In this trial, the mean age was 52.2 years (range 24-81 years), 48.7% of patients were women, 70.9% were Caucasian, 15.7% were Black, 5.6% were Asian, 6.4% were American Indian or Alaskan Native, and 1.1% were other racial groups. Hispanic/Latino accounted for 46.5% of the enrolled patients. statin use at baseline was reported in 13% of the Welchol-treated patients and 16% of the placebo-treated patients. - Welchol resulted in a statistically significant reduction in A1C of 0.27% compared to placebo. - The mean baseline LDL-C was 121 mg/dL in the monotherapy trial. Welchol treatment resulted in a placebo-corrected 11% reduction in LDL-C. Welchol treatment also reduced serum TC, ApoB, and non-HDL-C (Table 12). The mean change in body weight was -0.6 kg for Welchol and -0.7 kg for placebo treatment groups. - Add-on combination Therapy: The efficacy of Welchol 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 3 double-blind, placebo-controlled add-on therapy trials involving a total of 1018 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. - In these studies, the overall mean age was 57 years (range 24-81 years), 47% were women, and 59% of the patients were Caucasian, 23% were Hispanic, 14% were Black, 3% were Asian, and 1% were of other racial groups. statin use at baseline was reported in 42% of the Welchol-treated patients and 50% of the placebo-treated patients. - In all 3 pivotal add-on therapy trials, treatment with Welchol resulted in a statistically significant reduction in A1C of 0.5% compared to placebo. Similar placebo-corrected reductions in A1C occurred in patients who received Welchol in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other anti-diabetic agents. In the metformin and sulfonylurea trials, treatment with Welchol also resulted in statistically significant reductions in fasting plasma glucose (FPG) of 14 mg/dL compared to placebo. - Welchol had consistent effects on A1C across subgroups of age, gender, race, body mass index, and baseline A1C. Welchol’s effects on A1C were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone). - The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), and 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, Welchol treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. Welchol treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin and patients on a sulfonylurea, but not in the study of patients on metformin. The clinical significance of these increases is unknown. Welchol is contraindicated in patients with TG levels > 500 mg/dL and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended. - Body weight did not significantly increase from baseline with Welchol therapy, compared with placebo, in any of the 3 pivotal clinical studies. - Add-on Combination Therapy with Metformin: Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). A total of 60% of these patients were receiving ≥1,500 mg/day of metformin. In combination with metformin, Welchol resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 13). Welchol also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 14). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with Welchol compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for Welchol and -0.3 kg for placebo. - Add-on Combination Therapy with sulfonylurea: Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). A total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with a sulfonylurea, Welchol resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 15). Welchol also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 16). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with Welchol compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for Welchol and -0.4 kg for placebo. - Add-on Combination Therapy with Insulin: Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the Welchol group and 65 units in the placebo group. In combination with insulin, Welchol resulted in a statistically significant placebo-corrected reduction in A1C (Table 17). Welchol also reduced LDL-C and Apo B, but increased serum TG (Table 18). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with Welchol compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for Welchol and 0.2 kg for placebo. # How Supplied - National Drug Code (NDC): 65597-701-18 - Storage: For tablet: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Brief exposure to 40°C (104°F) does not adversely affect the product. Protect from moisture.For oral suspension:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. - Manufactured by: DAIICHI SANKYO ## Drug Images ## Package and Label Display Panel # Patient Information ## Patient Information from FDA - Dosing: Patients should be advised to take Welchol Tablets with a meal and liquid. Welchol can be taken as 6 tablets once daily or 3 tablets twice daily. Patients should be advised to take Welchol for Oral Suspension as one 3.75 gram packet once daily or one 1.875 gram packet twice daily. To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Always mix Welchol for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting. - Drug interactions: Drugs with a known interaction with colesevelam (e.g., cyclosporine,glimepiride,glipizide, glyburide, levothyroxine, olmesartan medoxomil, oral contraceptives) should be administered at least 4 hours prior to Welchol. In an in vivo drug interaction study, there was no significant effect on the bioavailability of phenytoin; however, due to its narrow therapeutic index and post-marketing reports consistent with potential drug-drug interactions, phenytoin should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively the physician should monitor blood levels of the coadministered drug. Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. - Gastrointestinal: Welchol can cause constipation. Welchol is contraindicated in patients with a history of bowel obstruction. Welchol is not recommended in patients who may be at risk of bowel obstruction, including patients with gastroparesis, other gastrointestinal motility disorders, or a history of major gastrointestinal surgery. Patients should be instructed to consume a diet that promotes bowel regularity. Patients should be instructed to promptly discontinue Welchol and seek medical attention if severe abdominal pain or severe constipation occurs. Because of the tablet size, Welchol Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Always mix Welchol for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting. Hypertriglyceridemia and pancreatitis: Patients should be instructed to discontinue Welchol and seek prompt medical attention if the hallmark symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting). ## Patient Information from NLM Template:Drug header ## Why this medication is prescribed - Colesevelam is used with exercise and diet changes (restriction of cholesterol and fat intake) to reduce the amount of cholesterol and certain fatty substances in your blood. It works by binding bile acids in your intestines. Bile acids are made when cholesterol is broken down in your body. Removing these bile acids helps to lower your blood cholesterol. Accumulation of cholesterol and fats along the walls of your arteries (a process known as atherosclerosis) decreases blood flow and, therefore, the oxygen supply to your heart, brain, and other parts of your body. Lowering your blood level of cholesterol and fats may help to prevent heart disease, angina (chest pain), strokes, and heart attacks. Colesevelam may be used alone or in combination with other lipid-lowering medications known as statins (atorvastatin [Lipitor], cerivastatin [Baycol], lovastatin [Mevacor], pravastatin [Pravachol], or simvastatin [Zocor]). - This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. ## How this medication should be used - Colesevelam comes as a tablet to take by mouth. It is usually taken once or twice a day with meals and liquid. Your doctor will tell you how many tablets to take at each dose. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take colesevelam exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. - Your lipid levels should lower within 2 weeks. Colesevelam lowers your lipid levels but does not cure high cholesterol. Continue to take colesevelam even if you feel well. Do not stop taking colesevelam without talking to your doctor. ## Special Precautions Before taking colesevelam: - Tell your doctor and pharmacist if you are allergic to colesevelam or any other drugs. - Tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially sustained-release formulations of verapamil (Calan SR) and vitamins and herbal products. - Tell your doctor if you have or have ever had gastrointestinal problems, especially bowel obstruction or difficulty swallowing foods, triglyceride levels greater than 300 mg/dl, bleeding problems, and low levels of fat-soluble vitamins (vitamins A, E, and K). - Tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking colesevelam, call your doctor. ## Special dietary instructions - Eat a low-cholesterol, low-fat diet. This kind of diet includes cottage cheese, fat-free milk, fish (not canned in oil), vegetables, poultry, egg whites, and polyunsaturated oils and margarines (corn, safflower, canola, and soybean oils). Avoid foods with excess fat in them such as meat (especially liver and fatty meat), egg yolks, whole milk, cream, butter, shortening, lard, pastries, cakes, cookies, gravy, peanut butter, chocolate, olives, potato chips, coconut, cheese (other than cottage cheese), coconut oil, palm oil, and fried foods. ## What to do if you forget a dose - Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed dose. ## Side Effects ### Minor Side Effects - Side effects from colesevelam can occur. Tell your doctor if any of these symptoms are severe or do not go away: - Gas - Constipation - Upset stomach - Headache - Weakness - Muscle pain - Throat infection ## Storage conditions needed for this medication - Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. ## Other information - Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to colesevelam. - Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription. ## Brand names - Welchol® # Precaution with Alcohol Alcohol-Colesevelam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.	https://www.wikidoc.org/index.php/Colesevelam
70ef641fbe09f6bc771dd9e97ecc2b3b2cc5cd82	wikidoc	Coley Fluid	Coley Fluid # Overview Coley Fluid is a modern reformulation of a historical cancer therapy called Coley Vaccine developed by Dr. William B. Coley that was an effective treatment for many forms of cancer including advanced breast cancer. The authors of a 1982 study concluded five year survival rates of historical Coley Vaccine patients is indistinguishable from five-year survival of modern patients. In 1999, researchers found ten-year survival was higher in historical Coley Vaccine patients compared to modern sarcoma, kidney and ovarian cancer patients. Coley Fluid is manufactured by MBVax Bioscience Inc, Ancaster, Canada.	Coley Fluid Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Coley Fluid is a modern reformulation of a historical cancer therapy called Coley Vaccine developed by Dr. William B. Coley that was an effective treatment for many forms of cancer including advanced breast cancer. The authors of a 1982 study concluded five year survival rates of historical Coley Vaccine patients is indistinguishable from five-year survival of modern patients. In 1999, researchers found ten-year survival was higher in historical Coley Vaccine patients compared to modern sarcoma, kidney and ovarian cancer patients. Coley Fluid is manufactured by MBVax Bioscience Inc, Ancaster, Canada.	https://www.wikidoc.org/index.php/Coley_Fluid
5402f5db4df28377b58ca579035b278aa4a49346	wikidoc	Collagenase	Collagenase Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as Clostridium. They are considered a virulence factor, facilitating the spread of gas gangrene. They normally target the connective tissue in muscle cells and other body organs. Collagen, a key component of the animal extracellular matrix, is made through cleavage of pro-collagen by collagenase once it has been secreted from the cell. This stops large structures from forming inside the cell itself. In addition to being produced by some bacteria, collagenase can be made by the body as part of its normal immune response. This production is induced by cytokines, which stimulate cells such as fibroblasts and osteoblasts, and can cause indirect tissue damage. # Therapeutic uses Collagenases have been approved for medical uses for - treatment of Dupuytren's contracture and Peyronie's disease (Xiaflex). - wound healing (Santyl) ## The MEROPS M9 family This group of metallopeptidases constitutes the MEROPS peptidase family M9, subfamilies M9A and M9B (microbial collagenase, clan MA(E)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH. Microbial collagenases have been identified from bacteria of both the Vibrio and Clostridium genera. Collagenase is used during bacterial attack to degrade the collagen barrier of the host during invasion. Vibrio bacteria are sometimes used in hospitals to remove dead tissue from burns and ulcers. Clostridium histolyticum is a pathogen that causes gas gangrene; nevertheless, the isolated collagenase has been used to treat bed sores. Collagen cleavage occurs at an Xaa+Got in Vibrio bacteria and at Yaa+Gly bonds in Clostridium collagenases. Analysis of the primary structure of the gene product from Clostridium perfringens has revealed that the enzyme is produced with a stretch of 86 residues that contain a putative signal sequence. Within this stretch is found PLGP, an amino acid sequence typical of collagenase substrates. This sequence may thus be implicated in self-processing of the collagenase. Metalloproteases are the most diverse of the seven main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp, or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases. # Other uses Collagenases may be used for tenderizing meat in a manner similar to widely used tenderizers papain, bromelain and ficain.	Collagenase Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as Clostridium. They are considered a virulence factor, facilitating the spread of gas gangrene. They normally target the connective tissue in muscle cells and other body organs.[1] Collagen, a key component of the animal extracellular matrix, is made through cleavage of pro-collagen by collagenase once it has been secreted from the cell. This stops large structures from forming inside the cell itself. In addition to being produced by some bacteria, collagenase can be made by the body as part of its normal immune response. This production is induced by cytokines, which stimulate cells such as fibroblasts and osteoblasts, and can cause indirect tissue damage.[citation needed] # Therapeutic uses Collagenases have been approved for medical uses for - treatment of Dupuytren's contracture and Peyronie's disease (Xiaflex). - wound healing[2] (Santyl) ## The MEROPS M9 family This group of metallopeptidases constitutes the MEROPS peptidase family M9, subfamilies M9A and M9B (microbial collagenase, clan MA(E)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH.[3] Microbial collagenases have been identified from bacteria of both the Vibrio and Clostridium genera. Collagenase is used during bacterial attack to degrade the collagen barrier of the host during invasion. Vibrio bacteria are sometimes used in hospitals to remove dead tissue from burns and ulcers. Clostridium histolyticum is a pathogen that causes gas gangrene; nevertheless, the isolated collagenase has been used to treat bed sores. Collagen cleavage occurs at an Xaa+Got in Vibrio bacteria and at Yaa+Gly bonds in Clostridium collagenases. Analysis of the primary structure of the gene product from Clostridium perfringens has revealed that the enzyme is produced with a stretch of 86 residues that contain a putative signal sequence.[4] Within this stretch is found PLGP, an amino acid sequence typical of collagenase substrates. This sequence may thus be implicated in self-processing of the collagenase.[4] Metalloproteases are the most diverse of the seven main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp, or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site.[3] The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases.[3] # Other uses Collagenases may be used for tenderizing meat in a manner similar to widely used tenderizers papain, bromelain and ficain.[5]	https://www.wikidoc.org/index.php/Collagenase
452bf7f2a3db6084cb308b59b7901008a3f046d9	wikidoc	Colonoscopy	Colonoscopy # Overview Colonoscopy is the endoscopic examination of the large colon and the distal part of the small bowel with a CCD camera or a fiber optic camera on a flexible tube passed through the anus. It may provide a visual diagnosis (e.g. ulceration, polyps) and grants the opportunity for biopsy or removal of suspected lesions. Virtual colonoscopy, which uses 2D and 3D imagery reconstructed from computed tomography (CT) scans or from nuclear magnetic resonance (MR) scans, is also possible, as a totally non-invasive medical test, although it is not standard and still under investigation regarding its diagnostic abilities. Furthermore, virtual colonoscopy does not allow for therapeutic maneuvers such as polyp/tumor removal or biopsy nor visualization of lesions smaller than 5 millimeters. If a growth or polyp is detected using CT colonography, a standard colonoscopy would still need to be performed. Colonoscopy can remove polyps smaller than one millimeter. Once polyps are removed, they can be studied with the aid of a microscope to determine if they are precancerous or not. Colonoscopy is similar but not the same as sigmoidoscopy. The difference between colonoscopy and sigmoidoscopy is related to which parts of the colon each can examine. Sigmoidoscopy allows doctors to view only the final two feet of the colon, while colonoscopy allows an examination of the entire colon, which measures four to five feet in length. Often a sigmoidoscopy is used as a screening procedure for a full colonoscopy. # Uses Indications for colonoscopy include gastrointestinal hemorrhage, unexplained changes in bowel habit or suspicion of malignancy. Colonoscopies are often used to diagnose colon cancer, but are also frequently used to diagnose inflammatory bowel disease. In older patients (sometimes even younger ones) an unexplained drop in hematocrit (one sign of anemia) is an indication to do a colonoscopy, usually along with an EGD (esophagoastroduodenoscopy), even if no obvious blood has been seen in the stool (feces). Fecal occult blood is a quick test which can be done to test for microscopic traces of blood in the stool. A positive test is almost always an indication to do a colonoscopy. In most cases the positive result is just due to hemorrhoids; however, it can also be due to diverticulosis, inflammatory bowel disease (Crohn's disease, ulcerative colitis), colon cancer, or polyps. However--since its development by Dr. Hiromi Shinya in the 1960's--polypectomy has become a routine part of colonoscopy, allowing for quick and simple removal of polyps without invasive surgery. Due to the high mortality associated with colon cancer and the high effectivity and low risks associated with colonoscopy, it is now also becoming a routine screening test for people 50 years of age or older. Subsequent rescreenings are then scheduled based on the initial results found, with a five- or ten-year recall being common for colonoscopies that produce normal results. # Procedure ## Preparation The patient may be asked to skip aspirin and aspirin products such as salicylate for up to ten days before the procedure to avoid the risk of bleeding if a polypectomy is performed during the procedure. Often a blood test is performed before the procedure and upon a low platelet count, a clot time test may be done. A clotting time greater than ten minutes may contraindicate polyp removal. Many laboratories are not performing bleeding times any more, as platelet function tests are replacing it. The colon must be free of solid matter for the test to be performed properly. For one to three days, the patient is required to follow a low fibre or clear-fluid only diet. Examples of clear fluids are apple juice, bouillon, artificially flavored lemon-lime soda or sports drink, and of course water. As orange juice, prune juice, and milk contain fibre, they are banned from the list, as are liquids dyed red, orange, purple, or brown, such as cola or coffee. On the day before the colonoscopy, the patient is either given a laxative preparation (such as Bisacodyl, phospho soda, sodium picosulfate, or sodium phosphate and/or magnesium citrate) and large quantities of fluid or whole bowel irrigation is performed using a solution of polyethylene glycol and electrolytes. The most effective bowel preparation is split dose of polyethylene glycol. ## The investigation During the procedure the patient is often given sedation intravenously, employing agents such as midazolam or fentanyl. Although meperidine (Demerol) may be used as an alternative to fentanyl, the concern of seizures has relegated this agent to second choice for sedation behind the combination of midazolam and fentanyl. The average person will receive a combination of these two drugs, usually between 1-4 mg iv midazolam, and 25 to 100 µg iv fentanyl. Sedation practices vary between practitioners and nations; in some clinics in Norway, sedation is rarely administered. Some endocoscopists are experimenting with, or routinely use, alternative or additional methods such as nitrous oxide and propofol, which have advantages and disadvantages relating to recovery time (particularly the duration of amnesia after the procedure is complete), patient experience, and the degree of supervision needed for safe administration. This sedation is called "twilight anesthesia" and for some patients it doesn't take and they are indeed awake for the procedure and watch the inside of their colon on the color monitor. The first step is usually a digital rectal examination, to examine the tone of the sphincter and to determine if preparation has been adequate. The endoscope is then passed though the anus up the rectum, the colon (sigmoid, descending, transverse and ascending colon, the cecum), and ultimately the terminal ileum. The endoscope has a movable tip and multiple channels for instrumentation, air, suction and light. The bowel is occasionally insufflated with air to maximize visibility. Biopsies are frequently taken for histology. In most experienced hands, the endoscope is advanced to the junction of where the colon and small bowel join up (cecum) in under 10 minutes in 95% of cases. Due to tight turns and redundancy in areas of the colon that are not "fixed", loops may form in which advancement of the endoscope creates a "bowing" effect that causes the tip to actually retract. These loops often result in discomfort due to stretching of the colon and its associated mesentery. Maneuvers to "reduce" or remove the loop include pulling the endoscope backwards while torquing the instrument. Alternatively, body position changes and abdominal support from external hand pressure can often "straighten" the endoscope to allow the scope to move forward. In a minority of patients, looping is often cited as a cause for an incomplete examination. Usage of alternative instruments leading to completion of the examination has been investigated, including use of pediatric colonscope, push enteroscope and upper GI endoscope variants. For screening purposes, a closer visual inspection is then often performed upon withdrawal of the endoscope over the course of 20 to 25 minutes. Lawsuits over missed cancerous lesions have prompted recent institutions to better document withdrawal time as rapid withdrawal times may be a source of potential medical legal liability. This is often a real concern in private practice settings where high throughput of cases have been postulated as a financial incentive to complete colonoscopies as quickly as possible. Suspicious lesions may be cauterized, treated with laser light or cut with an electric wire for purposes of biopsy or complete removal polypectomy. Medication can be injected, e.g. to control bleeding lesions. On average, the procedure takes 20-30 minutes, depending on the indication and findings. With multiple polypectomies or biopsies, procedure times may be longer. As mentioned above, anatomic considerations may also affect procedure times. After the procedure, some recovery time is usually allowed to let the sedative wear off. Most facilities require that patients have a person with them to help them home afterwards (again, depending on the sedation method used). One very common aftereffect from the procedure is a bout of flatulence and minor wind pain caused by air insufflation into the colon during the procedure. An advantage of colonoscopy over x-ray imaging or other, less invasive tests, is the ability to perform therapeutic interventions during the test. If a polyp is found, for example, it can be removed by one of several techniques. A snare can be placed around a polyp for removal. Even if the polyp is flat on the surface it can often be removed. For example, the following show a polyp removed in stages. 1. Polyp is identified. 2. A sterile solution is injected under the polyp to lift it away from deeper tissues. 3. A portion of the polyp is now removed. 4. The polyp is fully removed. ## Risks This procedure has a low (0.2%) risk of serious complications. The most serious complication is a tear or hole in the lining of the colon called a gastrointestinal perforation, which is life-threatening and requires immediate major surgery for repair; however, the rate of perforation is less than 1 in 2000 colonoscopies. Bleeding complications may be treated immediately during the procedure by cauterization via the instrument. Delayed bleeding may also occur at the site of polyp removal up to a week after the procedure and a repeat procedure can then be performed to treat the bleeding site. Even more rarely, splenic rupture can occur after colonoscopy because of adhesions between the colon and the spleen. As with any procedure involving anaesthesia, other complications would include cardiopulmonary complications such as temporary drop in blood pressure and oxygen saturation, usually the result of overmedication and easily reversed. In rare cases, more serious cardiopulmonary events such as a heart attack, stroke, or even death may occur; these are extremely rare except in critically ill patients with multiple risk factors.	Colonoscopy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Template:Interventions infobox Colonoscopy is the endoscopic examination of the large colon and the distal part of the small bowel with a CCD camera or a fiber optic camera on a flexible tube passed through the anus. It may provide a visual diagnosis (e.g. ulceration, polyps) and grants the opportunity for biopsy or removal of suspected lesions. Virtual colonoscopy, which uses 2D and 3D imagery reconstructed from computed tomography (CT) scans or from nuclear magnetic resonance (MR) scans, is also possible, as a totally non-invasive medical test, although it is not standard and still under investigation regarding its diagnostic abilities. Furthermore, virtual colonoscopy does not allow for therapeutic maneuvers such as polyp/tumor removal or biopsy nor visualization of lesions smaller than 5 millimeters. If a growth or polyp is detected using CT colonography, a standard colonoscopy would still need to be performed. Colonoscopy can remove polyps smaller than one millimeter. Once polyps are removed, they can be studied with the aid of a microscope to determine if they are precancerous or not. Colonoscopy is similar but not the same as sigmoidoscopy. The difference between colonoscopy and sigmoidoscopy is related to which parts of the colon each can examine. Sigmoidoscopy allows doctors to view only the final two feet of the colon, while colonoscopy allows an examination of the entire colon, which measures four to five feet in length. Often a sigmoidoscopy is used as a screening procedure for a full colonoscopy. # Uses Indications for colonoscopy include gastrointestinal hemorrhage, unexplained changes in bowel habit or suspicion of malignancy. Colonoscopies are often used to diagnose colon cancer, but are also frequently used to diagnose inflammatory bowel disease. In older patients (sometimes even younger ones) an unexplained drop in hematocrit (one sign of anemia) is an indication to do a colonoscopy, usually along with an EGD (esophagoastroduodenoscopy), even if no obvious blood has been seen in the stool (feces). Fecal occult blood is a quick test which can be done to test for microscopic traces of blood in the stool. A positive test is almost always an indication to do a colonoscopy. In most cases the positive result is just due to hemorrhoids; however, it can also be due to diverticulosis, inflammatory bowel disease (Crohn's disease, ulcerative colitis), colon cancer, or polyps. However--since its development by Dr. Hiromi Shinya in the 1960's--polypectomy has become a routine part of colonoscopy, allowing for quick and simple removal of polyps without invasive surgery.[1] Due to the high mortality associated with colon cancer and the high effectivity and low risks associated with colonoscopy, it is now also becoming a routine screening test for people 50 years of age or older. Subsequent rescreenings are then scheduled based on the initial results found, with a five- or ten-year recall being common for colonoscopies that produce normal results. # Procedure ## Preparation The patient may be asked to skip aspirin and aspirin products such as salicylate for up to ten days before the procedure to avoid the risk of bleeding if a polypectomy is performed during the procedure. Often a blood test is performed before the procedure and upon a low platelet count, a clot time test may be done. A clotting time greater than ten minutes may contraindicate polyp removal. Many laboratories are not performing bleeding times any more, as platelet function tests are replacing it.[2][3] The colon must be free of solid matter for the test to be performed properly. For one to three days, the patient is required to follow a low fibre or clear-fluid only diet. Examples of clear fluids are apple juice, bouillon, artificially flavored lemon-lime soda or sports drink, and of course water. As orange juice, prune juice, and milk contain fibre, they are banned from the list, as are liquids dyed red, orange, purple, or brown, such as cola or coffee. On the day before the colonoscopy, the patient is either given a laxative preparation (such as Bisacodyl, phospho soda, sodium picosulfate, or sodium phosphate and/or magnesium citrate) and large quantities of fluid or whole bowel irrigation is performed using a solution of polyethylene glycol and electrolytes. The most effective bowel preparation is split dose of polyethylene glycol.[4][5] ## The investigation During the procedure the patient is often given sedation intravenously, employing agents such as midazolam or fentanyl. Although meperidine (Demerol) may be used as an alternative to fentanyl, the concern of seizures has relegated this agent to second choice for sedation behind the combination of midazolam and fentanyl. The average person will receive a combination of these two drugs, usually between 1-4 mg iv midazolam, and 25 to 100 µg iv fentanyl. Sedation practices vary between practitioners and nations; in some clinics in Norway, sedation is rarely administered.[6][7] Some endocoscopists are experimenting with, or routinely use, alternative or additional methods such as nitrous oxide[8][9] and propofol[10], which have advantages and disadvantages relating to recovery time (particularly the duration of amnesia after the procedure is complete), patient experience, and the degree of supervision needed for safe administration. This sedation is called "twilight anesthesia" and for some patients it doesn't take and they are indeed awake for the procedure and watch the inside of their colon on the color monitor. The first step is usually a digital rectal examination, to examine the tone of the sphincter and to determine if preparation has been adequate. The endoscope is then passed though the anus up the rectum, the colon (sigmoid, descending, transverse and ascending colon, the cecum), and ultimately the terminal ileum. The endoscope has a movable tip and multiple channels for instrumentation, air, suction and light. The bowel is occasionally insufflated with air to maximize visibility. Biopsies are frequently taken for histology. In most experienced hands, the endoscope is advanced to the junction of where the colon and small bowel join up (cecum) in under 10 minutes in 95% of cases. Due to tight turns and redundancy in areas of the colon that are not "fixed", loops may form in which advancement of the endoscope creates a "bowing" effect that causes the tip to actually retract. These loops often result in discomfort due to stretching of the colon and its associated mesentery. Maneuvers to "reduce" or remove the loop include pulling the endoscope backwards while torquing the instrument. Alternatively, body position changes and abdominal support from external hand pressure can often "straighten" the endoscope to allow the scope to move forward. In a minority of patients, looping is often cited as a cause for an incomplete examination. Usage of alternative instruments leading to completion of the examination has been investigated, including use of pediatric colonscope, push enteroscope and upper GI endoscope variants.[11] For screening purposes, a closer visual inspection is then often performed upon withdrawal of the endoscope over the course of 20 to 25 minutes. Lawsuits over missed cancerous lesions have prompted recent institutions to better document withdrawal time as rapid withdrawal times may be a source of potential medical legal liability.[12] This is often a real concern in private practice settings where high throughput of cases have been postulated as a financial incentive to complete colonoscopies as quickly as possible. Suspicious lesions may be cauterized, treated with laser light or cut with an electric wire for purposes of biopsy or complete removal polypectomy. Medication can be injected, e.g. to control bleeding lesions. On average, the procedure takes 20-30 minutes, depending on the indication and findings. With multiple polypectomies or biopsies, procedure times may be longer. As mentioned above, anatomic considerations may also affect procedure times. After the procedure, some recovery time is usually allowed to let the sedative wear off. Most facilities require that patients have a person with them to help them home afterwards (again, depending on the sedation method used). One very common aftereffect from the procedure is a bout of flatulence and minor wind pain caused by air insufflation into the colon during the procedure. An advantage of colonoscopy over x-ray imaging or other, less invasive tests, is the ability to perform therapeutic interventions during the test. If a polyp is found, for example, it can be removed by one of several techniques. A snare can be placed around a polyp for removal. Even if the polyp is flat on the surface it can often be removed. For example, the following show a polyp removed in stages. 1. Polyp is identified. 2. A sterile solution is injected under the polyp to lift it away from deeper tissues. 3. A portion of the polyp is now removed. 4. The polyp is fully removed. ## Risks This procedure has a low (0.2%) risk of serious complications. The most serious complication is a tear or hole in the lining of the colon called a gastrointestinal perforation, which is life-threatening and requires immediate major surgery for repair; however, the rate of perforation is less than 1 in 2000 colonoscopies. Bleeding complications may be treated immediately during the procedure by cauterization via the instrument. Delayed bleeding may also occur at the site of polyp removal up to a week after the procedure and a repeat procedure can then be performed to treat the bleeding site. Even more rarely, splenic rupture can occur after colonoscopy because of adhesions between the colon and the spleen. As with any procedure involving anaesthesia, other complications would include cardiopulmonary complications such as temporary drop in blood pressure and oxygen saturation, usually the result of overmedication and easily reversed. In rare cases, more serious cardiopulmonary events such as a heart attack, stroke, or even death may occur; these are extremely rare except in critically ill patients with multiple risk factors.	https://www.wikidoc.org/index.php/Colonoscope
7a77bdba43eca8a71b1b15793f5fa461e6793e92	wikidoc	Colorimetry	Colorimetry Colorimetry or Colourimetry can refer to: - the quantitative study of color perception. It is similar to spectrophotometry, but may be distinguished by its interest in reducing spectra to tristimulus values, from which the perception of color derives. - the determination of the spectral absorbance of a solution. This article is mainly about the former case, which is not an exact science due to the limitations inherent in the system (metamerism being the most troublesome), the design of the measurement devices, the values used to estimate a given light source, etc. Colors that look the same seldom have the same spectral characteristics in any colorimetric system you employ, even assuming identical viewing conditions and identical observers with normal color vision. # Instruments Colorimetric equipment is similar to that used in spectrophotometry. Some related equipment is also mentioned for completeness. - A tristimulus colorimeter measures the tristimulus values of a color. - A spectroradiometer measures the absolute spectral radiance (intensity) or irradiance of a light source. - A spectrophotometer measures the spectral reflectance, transmittance, or relative irradiance of a color sample. - A spectrocolorimeter is a spectrophotometer that can calculate tristimulus values. - A densitometer measures the degree of light passing through or reflected by a subject. - A color temperature meter measures the color temperature of an incident illuminant. ## Absorption colorimeter In physical chemistry, a colorimeter is a device used to test the concentration of a solution by measuring its absorbance of a specific wavelength of light. To use this device, different solutions must be made, and a control (usually a mixture of distilled water and another solution) is first filled into a cuvette and placed inside a colorimeter to calibrate the machine. Only after the device has been calibrated can you use it to find the densities and/or concentrations of the other solutions. You do this by repeating the calibration, except with cuvettes filled with the other solutions. The filter on a colorimeter must be set to red if the liquid is blue. The size of the filter initially chosen for the colorimeter is extremely important, as the wavelength of light that is transmitted by the colorimeter has to be same as that absorbed by the substance. ## Tristimulus colorimeter In digital imaging, colorimeters are tristimulus devices used for color calibration. Accurate color profiles ensure consistency throughout the imaging workflow, from acquisition to output. ## Spectroradiometer The absolute spectral power distribution of a light source can be measured with a spectroradiometer, which works by optically collecting the light, then passing it through a monochromator before reading it in narrow bands of wavelength. ## Spectrophotometer Reflected color can be measured using a spectrophotometer (also called spectroreflectometer or reflectometer), which takes measurements in the visible region (and a little beyond) of a given color sample. If the custom of taking readings at 10 nanometer increments is followed, the visible light range of 400-700nm will yield 31 readings. These readings are typically used to draw the sample's spectral reflectance curve (how much it reflects, as a function of wavelength); the most accurate data that can be provided regarding its characteristics. The readings by themselves are typically not as useful as their tristimulus values, which can be converted into chromaticity co-ordinates and manipulated through color space transformations. For this purpose, a spectrocolorimeter may be used, although tristimulus colorimeters offer a cheaper alternative. A spectrocolorimeter is simply a spectrophotometer that can estimate tristimulus values by numerical integration (of the color matching functions' inner product with the illuminant's spectral power distribution). The CIE recommends using measurement intervals under 5nm, even for smooth spectra. ## Color temperature meter Photographers and cinematographers use information provided by these meters to decide what color correction should be done to make different light sources appear to have the same color temperature. If the user enters the reference color temperature, the meter can calculate the mired difference between the measurement and the reference, enabling the user to choose a corrective color gel or photographic filter with the closest mired factor. Internally, the meter is typically a silicon photodiode tristimulus colorimeter.	Colorimetry Colorimetry or Colourimetry can refer to: - the quantitative study of color perception.[1] It is similar to spectrophotometry, but may be distinguished by its interest in reducing spectra to tristimulus values, from which the perception of color derives. - the determination of the spectral absorbance of a solution. This article is mainly about the former case, which is not an exact science due to the limitations inherent in the system (metamerism being the most troublesome), the design of the measurement devices, the values used to estimate a given light source, etc. Colors that look the same seldom have the same spectral characteristics in any colorimetric system you employ, even assuming identical viewing conditions and identical observers with normal color vision. # Instruments Colorimetric equipment is similar to that used in spectrophotometry. Some related equipment is also mentioned for completeness. - A tristimulus colorimeter measures the tristimulus values of a color.[2] - A spectroradiometer measures the absolute spectral radiance (intensity) or irradiance of a light source.[3] - A spectrophotometer measures the spectral reflectance, transmittance, or relative irradiance of a color sample.[3][4] - A spectrocolorimeter is a spectrophotometer that can calculate tristimulus values. - A densitometer measures the degree of light passing through or reflected by a subject.[2] - A color temperature meter measures the color temperature of an incident illuminant. ## Absorption colorimeter In physical chemistry, a colorimeter is a device used to test the concentration of a solution by measuring its absorbance of a specific wavelength of light. To use this device, different solutions must be made, and a control (usually a mixture of distilled water and another solution) is first filled into a cuvette and placed inside a colorimeter to calibrate the machine. Only after the device has been calibrated can you use it to find the densities and/or concentrations of the other solutions. You do this by repeating the calibration, except with cuvettes filled with the other solutions. The filter on a colorimeter must be set to red if the liquid is blue. The size of the filter initially chosen for the colorimeter is extremely important, as the wavelength of light that is transmitted by the colorimeter has to be same as that absorbed by the substance. ## Tristimulus colorimeter In digital imaging, colorimeters are tristimulus devices used for color calibration. Accurate color profiles ensure consistency throughout the imaging workflow, from acquisition to output. ## Spectroradiometer The absolute spectral power distribution of a light source can be measured with a spectroradiometer, which works by optically collecting the light, then passing it through a monochromator before reading it in narrow bands of wavelength. ## Spectrophotometer Reflected color can be measured using a spectrophotometer (also called spectroreflectometer or reflectometer), which takes measurements in the visible region (and a little beyond) of a given color sample. If the custom of taking readings at 10 nanometer increments is followed, the visible light range of 400-700nm will yield 31 readings. These readings are typically used to draw the sample's spectral reflectance curve (how much it reflects, as a function of wavelength); the most accurate data that can be provided regarding its characteristics. The readings by themselves are typically not as useful as their tristimulus values, which can be converted into chromaticity co-ordinates and manipulated through color space transformations. For this purpose, a spectrocolorimeter may be used, although tristimulus colorimeters offer a cheaper alternative. A spectrocolorimeter is simply a spectrophotometer that can estimate tristimulus values by numerical integration (of the color matching functions' inner product with the illuminant's spectral power distribution).[4] The CIE recommends using measurement intervals under 5nm, even for smooth spectra[3]. ## Color temperature meter Photographers and cinematographers use information provided by these meters to decide what color correction should be done to make different light sources appear to have the same color temperature. If the user enters the reference color temperature, the meter can calculate the mired difference between the measurement and the reference, enabling the user to choose a corrective color gel or photographic filter with the closest mired factor.[5] Internally, the meter is typically a silicon photodiode tristimulus colorimeter.[5]	https://www.wikidoc.org/index.php/Colorimetry
e9d39252957b1f03feac929dd194473be4561b35	wikidoc	Comminution	Comminution Comminution is one of the four main groups of mechanical processing and describes the movement of the particle size distribution (grains, drops, bubbles) into a range of finer particle sizes (The other groups are agglomeration, separation and mixing). Comminution can be found in daily life in activities such as cutting, crushing, powder metallurgy, grinding and rasping in the preparation of different foods. Industrial applications are found in biomass processing, preprocessing of cellulosic material to facilitate ethanol production, mineral processing (extraction of raw materials), chemical and ceramic industries, cement production, production of food, processing of waste. In most of the cases the word comminution is used in referral to solids. Depending on the particle size it is distinguished between crushing (coarse feed material, bigger than appr. 50 to 100 mm) and grinding. Machines used for comminution are jaw crusher, cone and gyratory crushers, roller crusher, impact crusher, tube mills (e.g. ball mills or autogenous mills), vertical roller mills, and roller presses. # Mining Comminution refers to a series of mineral processing techniques used in extractive metallurgy to reduce particle sizes of rocks and ores. Comminution processes are used to crush rocks into powder in preparation for subsequent processing methods which generally require finer particle sizes. A particle is liberated when the mineral of interest is physically free from any other minerals present (the gangue). The machinery used for comminution can be divided into classes based on the size of the fragments they produce. Devices that produce coarse chunks are called crushers and those that produce finer particles are called grinders. # Waste management Comminution is also used in the mechanical shredding or pulverizing of waste; a process found in solid and water waste treatment. # Medical The term "comminution" is also used in medicine when referring to certain types of fracture. Usually, an impact will cause one fracture, thus breaking the bone into two pieces. But when the magnitude of the impact is such that it causes a bone to break in more than one place , it will produce several (i.e. more than two) fragments of bone. This is termed a "comminuted fracture".	Comminution Comminution is one of the four main groups of mechanical processing and describes the movement of the particle size distribution (grains, drops, bubbles) into a range of finer particle sizes (The other groups are agglomeration, separation and mixing). Comminution can be found in daily life in activities such as cutting, crushing, powder metallurgy, grinding and rasping in the preparation of different foods. Industrial applications are found in biomass processing, preprocessing of cellulosic material to facilitate ethanol production, mineral processing (extraction of raw materials), chemical and ceramic industries, cement production, production of food, processing of waste. In most of the cases the word comminution is used in referral to solids. Depending on the particle size it is distinguished between crushing (coarse feed material, bigger than appr. 50 to 100 mm) and grinding. Machines used for comminution are jaw crusher, cone and gyratory crushers, roller crusher, impact crusher, tube mills (e.g. ball mills or autogenous mills), vertical roller mills, and roller presses. # Mining Comminution refers to a series of mineral processing techniques used in extractive metallurgy to reduce particle sizes of rocks and ores. Comminution processes are used to crush rocks into powder in preparation for subsequent processing methods which generally require finer particle sizes. A particle is liberated when the mineral of interest is physically free from any other minerals present (the gangue). The machinery used for comminution can be divided into classes based on the size of the fragments they produce. Devices that produce coarse chunks are called crushers and those that produce finer particles are called grinders. # Waste management Comminution is also used in the mechanical shredding or pulverizing of waste; a process found in solid and water waste treatment. # Medical The term "comminution" is also used in medicine when referring to certain types of fracture. Usually, an impact will cause one fracture, thus breaking the bone into two pieces. But when the magnitude of the impact is such that it causes a bone to break in more than one place , it will produce several (i.e. more than two) fragments of bone. This is termed a "comminuted fracture".	https://www.wikidoc.org/index.php/Comminution
5459441f8942f3eeddeb4becb4d363307730cbfe	wikidoc	Common bunt	Common bunt Common bunt, also known as stinking smut and covered smut is a disease of both spring and winter wheats. It is caused by two very closely related fungi, Tilletia tritici (syn. T. caries) and T. laevis (syn. T. foetida). # Symptoms Plants with common bunt may be moderately stunted but infected plants cannot be easily recognized until near maturity and even then it is seldom conspicuous. After initial infection, the entire kernel is converted into a sorus consisting of a dark brown to black mass of teliospores covered by a modified periderm, which is thin and papery. The sorus is light to dark brown and is called a bunt ball. The bunt balls resemble wheat kernels but tend to be more sperical. The bunted heads are slender, bluish-green and may stay greener longer than healthy heads. The bunt balls change to a dull gray-brown at maturity, at which they become conspicuous. The fragile covering of the bunt balls are ruptured at harvest, producing clouds of spores. The spores have a fishy odor. Intact sori can also be found among harvested grain. # Disease cycle Millions of spores are released at harvest and contaminate healthy kernels or land on other plant parts or the soil. The spores persist on the contaminated kernels or in the soil. The disease is initiated when soil-borne, or in particular seed-borne, teliospores germinate in response to moisture and produce hyphae that infect germinating seeds by penetrating the coleoptile before plants emerge. Cool soil temperatures (5° to 10°C) favor infection. The intercellular hyphae become established in the apical meristem and are maintained systemically within the plant. After initial infection, hyphae are sparse in plants. The fungus proliferates in the spikes when ovaries begin to form. Sporulation occurs in endosperm tissue until the entire kernel is converted into a sorus consisting of a dark brown to black mass of teliospores covered by a modified periderm, which is thin and papery. # Pathotypes Well-defined pathogenic races have been found among the bunt population, and the classic gene-for-gene relationship is present between the fungus and host. # Management Control of common bunt includes using clean seed, seed treatments chemicals and resistant cultivars. Historically, seed treatment with organomercury fungicides reduced common bunt to manageable levels. Systemic seed treatment fungicides include carboxin, difenoconazole, triadimenol and others and are highly effective. However,in Australia and Greece, strains of T. laevis have developed resistance to polychlorobenzene fungicides.	Common bunt Common bunt, also known as stinking smut and covered smut is a disease of both spring and winter wheats. It is caused by two very closely related fungi, Tilletia tritici (syn. T. caries) and T. laevis (syn. T. foetida). ## Symptoms Plants with common bunt may be moderately stunted but infected plants cannot be easily recognized until near maturity and even then it is seldom conspicuous. After initial infection, the entire kernel is converted into a sorus consisting of a dark brown to black mass of teliospores covered by a modified periderm, which is thin and papery. The sorus is light to dark brown and is called a bunt ball. The bunt balls resemble wheat kernels but tend to be more sperical. The bunted heads are slender, bluish-green and may stay greener longer than healthy heads. The bunt balls change to a dull gray-brown at maturity, at which they become conspicuous. The fragile covering of the bunt balls are ruptured at harvest, producing clouds of spores. The spores have a fishy odor. Intact sori can also be found among harvested grain. [1][2] ## Disease cycle Millions of spores are released at harvest and contaminate healthy kernels or land on other plant parts or the soil. The spores persist on the contaminated kernels or in the soil. The disease is initiated when soil-borne, or in particular seed-borne, teliospores germinate in response to moisture and produce hyphae that infect germinating seeds by penetrating the coleoptile before plants emerge. Cool soil temperatures (5° to 10°C) favor infection. The intercellular hyphae become established in the apical meristem and are maintained systemically within the plant. After initial infection, hyphae are sparse in plants. The fungus proliferates in the spikes when ovaries begin to form. Sporulation occurs in endosperm tissue until the entire kernel is converted into a sorus consisting of a dark brown to black mass of teliospores covered by a modified periderm, which is thin and papery. ## Pathotypes Well-defined pathogenic races have been found among the bunt population, and the classic gene-for-gene relationship is present between the fungus and host. ## Management Control of common bunt includes using clean seed, seed treatments chemicals and resistant cultivars. Historically, seed treatment with organomercury fungicides reduced common bunt to manageable levels. Systemic seed treatment fungicides include carboxin, difenoconazole, triadimenol and others and are highly effective. However,in Australia and Greece, strains of T. laevis have developed resistance to polychlorobenzene fungicides.	https://www.wikidoc.org/index.php/Common_bunt
e9b82bdb62538d481871142e482deb2c408c6907	wikidoc	Common sage	Common sage Common sage (Salvia officinalis) is a small evergreen subshrub, with woody stems, grayish leaves, and blue to purplish flowers native to southern Europe and the Mediterranean region. It is much cultivated as a kitchen and medicinal herb, and is also called Garden sage, Kitchen sage, and Dalmatian sage. In southern Europe related species are sometimes cultivated for the same purpose, and may be confused with the common sage. Although this plant was the one originally called by this name sage, a number of related species are now also called by it, and are described in more detail in the article on sage. The uses and benefits ascribed to it are many and varied, and are often shared with related species. Uses of common sage include: - infusions, which are considered to have a calming effect, to soothe a sore throat and as a digestive agent - preservative flavourings, for instance of cheese - as a cooking flavouring, such as in sage and onion stuffing Common sage is also grown in parts of Europe, especially the Balkans for distillation of the essential oil, though other species, such as Salvia triloba may also be harvested and distilled with it. A number of cultivars of the plant exist. The majority of these are cultivated more often for ornament than for their herbal properties. All these are valuable as small ornamental flowering shrubs, and for low ground cover, especially in sunny dry situations. They are easily raised from summer cuttings. Named cultivars include - "Purpurascens", a purple-leafed cultivar, considered by some to be strongest of the garden sages, - "Tricolor", a cultivar with white, yellow and green variegated leaves, - "Berggarten", a cultivar with huge leaves, - "Icterina", a cultivar with yellow-green variegated leaves, - "Alba", a white-flowered cultivar, - "Lavandulaefolia", a small leaved cultivar. # Culinary uses As a herb, sage is considered to have a slight peppery flavour. In Western cooking, it is used for flavouring fatty meats (especially as a marinade), cheeses (Sage Derby), and some drinks. In Britain and Flanders, sage is used with onion for poultry or pork stuffing and also in sauces. In French cuisine, sage is used for cooking white meat and in vegetable soups. Germans often use it in sausage dishes, and sage forms the dominant flavouring in the English Lincolnshire sausage. Sage is also common in Italian cooking. Sage is sauteed in olive oil and butter until crisp, then plain or stuffed pasta is added (burro e salvia). In the Balkans and the Middle East, it is used when roasting mutton. # Medicinal use Actions The Latin name for sage: salvia, means “to heal”. Although the effectiveness of Common Sage is often open to debate, it has been recommended at one time or another for virtually every ailment. Modern evidence supports its effects as an antihydrotic, antibiotic, antifungal, astringent, antispasmodic, estrogenic, hypoglycemic, and tonic.. In a double blind, randomized and placebo-controlled trial, sage was found to be effective in the management of mild to moderate Alzheimer's disease. Active Constituents The strongest active constituents of Sage are within its essential oil, which contains cineole, borneol, and thujone. Sage leaf contains tannic acid, oleic acid, ursonic acid, ursolic acid, cornsole, cornsolic acid, fumaric acid, chlorogenic acid, caffeic acid, niacin, nicotinamide, flavones, flavone glycosides, and estrogenic substances. Uses Internally for indigestion, gas, liver complaints, excessive lactation, excessive perspiration, excessive salivation, anxiety, depression, female sterility, menopausal problems. Externally for insect bites, throat, mouth, gum, skin infections, vaginal discharge. Source: The Herb Society of America New Encyclopedia of Herbs & Their Uses, Deni Bown (New York: DK, 2001) Health Precautions Toxic in excess or over long periods. Contraindicated during pregnancy and for epilepsy. Drug Interactions: from appliedhealth.com	Common sage Common sage (Salvia officinalis) is a small evergreen subshrub, with woody stems, grayish leaves, and blue to purplish flowers native to southern Europe and the Mediterranean region. It is much cultivated as a kitchen and medicinal herb, and is also called Garden sage, Kitchen sage, and Dalmatian sage. In southern Europe related species are sometimes cultivated for the same purpose, and may be confused with the common sage. Although this plant was the one originally called by this name sage, a number of related species are now also called by it, and are described in more detail in the article on sage. The uses and benefits ascribed to it are many and varied, and are often shared with related species. Uses of common sage include: - infusions, which are considered to have a calming effect, to soothe a sore throat and as a digestive agent[citation needed] - preservative flavourings, for instance of cheese - as a cooking flavouring, such as in sage and onion stuffing Common sage is also grown in parts of Europe, especially the Balkans for distillation of the essential oil, though other species, such as Salvia triloba may also be harvested and distilled with it. A number of cultivars of the plant exist. The majority of these are cultivated more often for ornament than for their herbal properties. All these are valuable as small ornamental flowering shrubs, and for low ground cover, especially in sunny dry situations. They are easily raised from summer cuttings. Named cultivars include - "Purpurascens", a purple-leafed cultivar, considered by some to be strongest of the garden sages, - "Tricolor", a cultivar with white, yellow and green variegated leaves, - "Berggarten", a cultivar with huge leaves, - "Icterina", a cultivar with yellow-green variegated leaves, - "Alba", a white-flowered cultivar, - "Lavandulaefolia", a small leaved cultivar. # Culinary uses As a herb, sage is considered to have a slight peppery flavour. In Western cooking, it is used for flavouring fatty meats (especially as a marinade), cheeses (Sage Derby), and some drinks. In Britain and Flanders, sage is used with onion for poultry or pork stuffing and also in sauces. In French cuisine, sage is used for cooking white meat and in vegetable soups. Germans often use it in sausage dishes, and sage forms the dominant flavouring in the English Lincolnshire sausage. Sage is also common in Italian cooking. Sage is sauteed in olive oil and butter until crisp, then plain or stuffed pasta is added (burro e salvia). In the Balkans and the Middle East, it is used when roasting mutton. # Medicinal use Actions The Latin name for sage: salvia, means “to heal”. Although the effectiveness of Common Sage is often open to debate, it has been recommended at one time or another for virtually every ailment. Modern evidence supports its effects as an antihydrotic, antibiotic, antifungal, astringent, antispasmodic, estrogenic, hypoglycemic, and tonic.[1]. In a double blind, randomized and placebo-controlled trial, sage was found to be effective in the management of mild to moderate Alzheimer's disease.[1] Active Constituents The strongest active constituents of Sage are within its essential oil, which contains cineole, borneol, and thujone. Sage leaf contains tannic acid, oleic acid, ursonic acid, ursolic acid, cornsole, cornsolic acid, fumaric acid, chlorogenic acid, caffeic acid, niacin, nicotinamide, flavones, flavone glycosides, and estrogenic substances.[2] Uses Internally for indigestion, gas, liver complaints, excessive lactation, excessive perspiration, excessive salivation, anxiety, depression, female sterility, menopausal problems. Externally for insect bites, throat, mouth, gum, skin infections, vaginal discharge. Source: The Herb Society of America New Encyclopedia of Herbs & Their Uses, Deni Bown (New York: DK, 2001) Health Precautions Toxic in excess or over long periods. Contraindicated during pregnancy and for epilepsy. Drug Interactions: from appliedhealth.com	https://www.wikidoc.org/index.php/Common_sage
f515261dec7376c4d63fb95f69d8fe1f1aa2ee17	wikidoc	Comorbidity	Comorbidity # Background In medicine and in psychiatry, comorbidity (literally "additional morbidity") is either - The presence of one or more disorders (or diseases) in addition to a primary disease or disorder; or - The effect of such additional disorders or diseases. # Comorbidity in medicine In medicine, comorbidity describes the effect of all other diseases an individual patient might have other than the primary disease of interest. There is currently no accepted way to quantify such comorbidity. Many tests attempt to standardize the “weight” or value of comorbid conditions, whether they are secondary or tertiary illnesses. Each test attempts to consolidate each individual comorbid condition into a single, predictive variable that measures mortality or other outcomes. Researchers have "validated" such tests because of their predictive value, but no one test is as yet recognized as a standard. The term "comorbid" currently has two definitions: 1) to indicate a medical condition existing simultaneously but independently with another condition in a patient (this is the older and more "correct" definition) 2) to indicate a medical condition in a patient that causes, is caused by, or is otherwise related to another condition in the same patient (this is a newer, nonstandard definition and less well-accepted). ## Charlson index The Charlson co-morbidity index (CCI) predicts the 1 year mortality for a patient who may have a range of co-morbid conditions such as heart disease, AIDS, or cancer (a total of 22 conditions). Each condition is assigned with a score of 1,2,3 or 6 depending on the risk of dying associated with this condition. Then the scores are summed up and given a total score which predicts mortality. For a physician, it's helpful in knowing how aggressively to treat a condition. e.g. A patient may have cancer, but also heart disease and diabetes so severe that the costs and risks of the treatment outweigh the short term benefit from treatment of the cancer. The CCI was recently rated as low. The CCI may not perform as well as the Apache (area under curve 0.67 vs 0.87). ## Diagnosis-related group Patients who are more seriously ill tend to require more hospital resources than patients who are less seriously ill, even though they are admitted to the hospital for the same reason. Recognizing this, the diagnosis-related group (DRG) manual splits certain DRGs based on the presence of secondary diagnoses for specific complications or comorbidities (CC). # Comorbidity in mental health In psychiatry, psychology and mental health counseling comorbidity refers to the presence of more than one diagnosis occurring in an individual at the same time. In psychiatry, comorbidity does not necessarily imply the presence of multiple diseases, but instead can reflect our current inability to supply a single diagnosis that accounts for all symptoms. On the DSM Axis I, Major Depressive Disorder is a very common comorbid disorder. The Axis II personality disorders are often criticized because their comorbidity rates are excessively high, approaching 60% in some cases, indicating to critics the possibility that these categories of mental illness are too imprecisely distinguished to be usefully valid for diagnostic purposes and, thus, for deciding how treatment resources should be allocated. Comorbidity is also found to be high in drug addicts, both physiologically and psychologically.	Comorbidity Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background In medicine and in psychiatry, comorbidity (literally "additional morbidity") is either - The presence of one or more disorders (or diseases) in addition to a primary disease or disorder; or - The effect of such additional disorders or diseases. # Comorbidity in medicine In medicine, comorbidity describes the effect of all other diseases an individual patient might have other than the primary disease of interest. There is currently no accepted way to quantify such comorbidity. Many tests attempt to standardize the “weight” or value of comorbid conditions, whether they are secondary or tertiary illnesses. Each test attempts to consolidate each individual comorbid condition into a single, predictive variable that measures mortality or other outcomes. Researchers have "validated" such tests because of their predictive value, but no one test is as yet recognized as a standard. The term "comorbid" currently has two definitions: 1) to indicate a medical condition existing simultaneously but independently with another condition in a patient (this is the older and more "correct" definition) 2) to indicate a medical condition in a patient that causes, is caused by, or is otherwise related to another condition in the same patient (this is a newer, nonstandard definition and less well-accepted). ## Charlson index The Charlson co-morbidity index (CCI) predicts the 1 year mortality for a patient who may have a range of co-morbid conditions such as heart disease, AIDS, or cancer (a total of 22 conditions)[1]. Each condition is assigned with a score of 1,2,3 or 6 depending on the risk of dying associated with this condition. Then the scores are summed up and given a total score which predicts mortality. For a physician, it's helpful in knowing how aggressively to treat a condition. e.g. A patient may have cancer, but also heart disease and diabetes so severe that the costs and risks of the treatment outweigh the short term benefit from treatment of the cancer. The CCI was recently rated as low[2]. The CCI may not perform as well as the Apache (area under curve 0.67 vs 0.87)[3]. ## Diagnosis-related group Patients who are more seriously ill tend to require more hospital resources than patients who are less seriously ill, even though they are admitted to the hospital for the same reason. Recognizing this, the diagnosis-related group (DRG) manual splits certain DRGs based on the presence of secondary diagnoses for specific complications or comorbidities (CC). # Comorbidity in mental health In psychiatry, psychology and mental health counseling comorbidity refers to the presence of more than one diagnosis occurring in an individual at the same time. In psychiatry, comorbidity does not necessarily imply the presence of multiple diseases, but instead can reflect our current inability to supply a single diagnosis that accounts for all symptoms.[4] On the DSM Axis I, Major Depressive Disorder is a very common comorbid disorder. The Axis II personality disorders are often criticized because their comorbidity rates are excessively high, approaching 60% in some cases, indicating to critics the possibility that these categories of mental illness are too imprecisely distinguished to be usefully valid for diagnostic purposes and, thus, for deciding how treatment resources should be allocated. Comorbidity is also found to be high in drug addicts, both physiologically and psychologically.	https://www.wikidoc.org/index.php/Comorbid
8318cb6c6e1076af1361802675d6c6ee36880fe3	wikidoc	Nephrectomy	Nephrectomy Steven C. Campbell, M.D., Ph.D. # Overview Nephrectomy is the surgical removal of a kidney. # Indications There are various indications for this procedure, such as renal cell carcinoma, a non-functioning kidney (which may cause high blood pressure) and a congenitally small kidney (in which the kidney is swelling, causing it to press on nerves which can cause pain in unrelated areas such as the back). Nephrectomy for renal cell carcinoma is rapidly being modified to allow partial removal of the kidney. When one is donating a kidney for a kidney transplant, a nephrectomy is also performed on the patient. # Procedure The surgery is performed with the patient under general anesthesia. The surgeon makes an incision in the side of the abdomen to reach the kidney. Depending on circumstances, the incision can also be made midline. The ureter and blood vessels are disconnected, and the kidney is then removed. The surgery can be done as open surgery, with one incision, or as a laparoscopic procedure, with three or four small cuts in the abdominal and flank area. Recently, this procedure is performed through a single incision in the patient's belly-button. This advanced technique is called as Single Port Access Surgery. # After Care Pain medication is often given to the patient after the surgery because of the painful location. An IV with fluids is administered. Electrolyte balace and fluids are carefully monitored, because these are the functions of the kidneys. It is possible that the remaining kidney does not take over all functionality. A patient has to stay in the hospital between 2 and 7 days depending on the procedure and complications. # Links and Sources Drawings of the steps of the procedure MedlinePlus Medical Encyclopedia: Nephrectomy Explanation of the surgery, the risks and the recovery	Nephrectomy Template:Interventions infobox Template:Search infobox Steven C. Campbell, M.D., Ph.D. # Overview Nephrectomy is the surgical removal of a kidney. # Indications There are various indications for this procedure, such as renal cell carcinoma, a non-functioning kidney (which may cause high blood pressure) and a congenitally small kidney (in which the kidney is swelling, causing it to press on nerves which can cause pain in unrelated areas such as the back). Nephrectomy for renal cell carcinoma is rapidly being modified to allow partial removal of the kidney. When one is donating a kidney for a kidney transplant, a nephrectomy is also performed on the patient. # Procedure The surgery is performed with the patient under general anesthesia. The surgeon makes an incision in the side of the abdomen to reach the kidney. Depending on circumstances, the incision can also be made midline. The ureter and blood vessels are disconnected, and the kidney is then removed. The surgery can be done as open surgery, with one incision, or as a laparoscopic procedure, with three or four small cuts in the abdominal and flank area. Recently, this procedure is performed through a single incision in the patient's belly-button. This advanced technique is called as Single Port Access Surgery. # After Care Pain medication is often given to the patient after the surgery because of the painful location. An IV with fluids is administered. Electrolyte balace and fluids are carefully monitored, because these are the functions of the kidneys. It is possible that the remaining kidney does not take over all functionality. A patient has to stay in the hospital between 2 and 7 days depending on the procedure and complications. # Links and Sources Drawings of the steps of the procedure MedlinePlus Medical Encyclopedia: Nephrectomy Explanation of the surgery, the risks and the recovery Template:Urogenital surgical procedures Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Complete_nephrectomy
b673087f256480fe2cfc62b10053e0a0520c78a8	wikidoc	Cortexolone	Cortexolone Cortexolone or cortodoxone or 11-deoxycortisol or 11-desoxycortisol or 11-deoxyhydrocortisone or 11-desoxyhydrocortisone or Reichstein's Substance S or, most commonly, Compound S, is a steroid that can be oxygenated to cortisol (hydrocortisone). It was first synthesized by Tadeusz Reichstein. On April 5, 1952, biochemist Durey Peterson and microbiologist Herbert Murray at Upjohn published the first report of a breakthrough fermentation process for the microbial 11α-oxygenation of steroids (e.g. progesterone) in a single step by common molds of the order Mucorales. 11α-oxygenation of Compound S produces 11α-hydrocortisone, which can be chemically oxidized to cortisone, or converted by further chemical steps to 11β-hydrocortisone (cortisol). Subsequent fermentation processes for the microbial 11β-oxygenation of steroids in a single step were developed that could convert Compound S directly to 11β-hydrocortisone (cortisol).	Cortexolone Template:Chembox new Cortexolone or cortodoxone or 11-deoxycortisol or 11-desoxycortisol or 11-deoxyhydrocortisone or 11-desoxyhydrocortisone or Reichstein's Substance S or, most commonly, Compound S, is a steroid that can be oxygenated to cortisol (hydrocortisone). It was first synthesized by Tadeusz Reichstein. On April 5, 1952, biochemist Durey Peterson and microbiologist Herbert Murray at Upjohn published the first report of a breakthrough fermentation process for the microbial 11α-oxygenation of steroids (e.g. progesterone) in a single step by common molds of the order Mucorales.[1] 11α-oxygenation of Compound S produces 11α-hydrocortisone, which can be chemically oxidized to cortisone, or converted by further chemical steps to 11β-hydrocortisone (cortisol). Subsequent fermentation processes for the microbial 11β-oxygenation of steroids in a single step were developed that could convert Compound S directly to 11β-hydrocortisone (cortisol).	https://www.wikidoc.org/index.php/Compound_S
e4996a3d3688f8c1f707a4cfba2c7b6af3a2a4c8	wikidoc	Compounding	Compounding Compounding pharmacy is the long-standing process of mixing drugs by a pharmacist or physician to fit the unique needs of a patient. For example, a patient allergic to the dyes used in a pill can obtain a doctor’s prescription for the necessary medicine to be compounded without the offending dye. # History The art of pharmaceutical compounding began with the birth of the first humans. All ancient hunter-gatherer societies had some knowledge of the medicinal properties of the animals, plants, molds, fungus and bacteria as well as inorganic minerals within their environment. Ancient civilizations utilized pharmaceutical compounding for religion, grooming, keeping the healthy well, treating the ill and preparing the dead. These ancient compounders produced the first oils from plants and animals. They discovered poisons and the antidotes. They made ointments for a wounded patients as well as perfumes for a customer. The earliest druggists were familiar with the various natural substances and their uses. These drug artisans compounded a variety of preparations from medications, dyes, incense, perfumes and ceremonial compounds to preservatives and cosmetics. The Bible lists many drugs that were compounded in biblical times in the Middle East. Drug compounders seeking gold and the fountain of youth drove the Alchemy movement. Alchemy eventually contributed to the creation of modern pharmacy and the principles of pharmacy compounding. The modern age of pharmacy and pharmacy compounding began in the nineteenth century with the isolation of various compounds from coal tar for the purpose of producing synthetic dyes. From this one natural product came the earliest antibacterial sulfa drugs, phenolic compounds made famous by Joseph Lister, and plastics. During 1800s pharmacists specialized in the raising, preparation and compounding of crude drugs. Crude drugs, like opium, are from natural sources and usually contain multiple chemical compounds. The compounding pharmacist often extracted these crude drugs using water or alcohol to form extracts, concoctions and decoctions. Pharmacists began isolating and identifying the active ingredients contained within these crude drugs concoctions. Using fractionation or recrystallization, the compounding pharmacist would separate the active ingredients, like morphine, and use it in place of the crude drug. During this time modern medicine began. With the isolation of medications from the “raw materials” or crude drugs came the birth of the modern pharmaceutical company. Pharmacists were trained to compound the preparations made by the drug companies but they weren’t able to do it as efficiently on a small basis. So economies of scale, not lack of skill or knowledge, produced a market niche for the modern pharmaceutical drug companies, (Pharma). With the turn of the twentieth century came the government involvement and subsequent regulation into the practice of medicine. In 1938 the Government of the United States imposed new regulations on the drug companies forming the Food and Drug Administration (FDA) when several people died from a poorly prepared sulfa drug that used ethylene glycol as a base. These new regulations forced the drug companies to prove any new medication they brought to market was safe. Pharmacy compounding was still going strong in the 1930s with over 80% of the prescriptions dispensed being compounded by the compounding pharmacist. With the discovery of penicillin and the modern marketing techniques and brand promotion, the drug manufacturing industry came of age. Pharmacists continued to compound most prescriptions until the early 1950’s when the majority of dispensed drugs came directly from the large pharmaceutical companies. From the 1950s to the 1980s pharmaceutical compounding became almost obsolete and a lost art. Pharmaceutical compounding continued losing favor as the big drug companies became larger and more powerful until they eventually dominated the practice of medicine. It was during this time that patients and physician became dissatisfied with the “one size fits all” attitude of the large Pharma companies. Physicians searching for drugs to treat their patients, lead to the reawakening of the ancient art of prescription compounding. Today many pharmacists specialize in the ancient art of pharmaceutical compounding. In 2006 over 30 million compounded prescriptions were dispensed not counting all the admixtures and injectable drugs compounded in America’s hospitals. Pharmaceutical compounding has been responsible for the health of millions of individual patients, has given birth the modern pharmaceutical companies and continues to be a vital link in the search for new drugs and dosage forms. Throughout history, there has always been a need for pharmacists to compound drugs for individualized dosages. When the pharmaceutical industry began mass-producing drugs and dosage forms for patients in the 1950s, compounding became less widespread. In recent years, many patients’ unique health needs have driven more business to compounding pharmacists. # Uses Compounding is one of the pillars of new drug development. Most medications have gained widespread usage throughout the entire medical community thanks to the practice of pharmaceutical compounding and the compounding pharmacist. Every major pharmaceutical company ever in existence or currently operating started in a compounding pharmacy with a compounding pharmacist. Without the practice of pharmaceutical compounding and compounding pharmacists none of the drugs we have today would have been discovered. This facet of pharmacy has been the greatest developer of drugs and the most positive influence within the entire allopathic, osteopathic, naturopathic and homeopathic, medical communities. Pharmaceutical compounding is a branch of pharmacy that continues to play the crucial role of new drug research and development. Physicians often prescribe compounded medicines for patients with unique health needs, because they are able to tailor a prescription to each individual. Compounding preparations are especially prevalent for: - Patients requiring limited dosage strengths and dosage forms (i.e., infants) - Those with allergies to certain ingredients in manufactured drugs - Veterinary medicine - Pediatrics (i.e., making a medicine more palatable to children with flavor additives) - Home health care - Hospice patients - Bioidentical hormone replacement therapy, specifically the Wiley Protocol - Patients who need drugs that have been discontinued by pharmaceutical manufacturers because of low profitability # Regulation Compounding pharmacies are licensed and regulated by state Boards of Pharmacy in the 50 states and the District of Columbia. Additionally, pharmacies follow guidelines from U.S. Pharmacopeia. Compounding pharmacists must work within the jurisdiction of the FDA, they are simply exempt from many FDA requirements so long as they are state-compliant and compound pursuant to a valid prescription. However, the FDA registers and inspects the facilities that supply manufacturers with active pharmaceutical ingredients. The Pharmacy Compounding Accreditation Board was created in 2006 as a voluntary accreditation body by pharmacy organizations to establish high quality standards for compounding pharmacies. # Controversies There is currently a controversy over who should regulate compounding pharmacies. The FDA is concerned that many compounders are acting as large-scale manufacturers of new drugs, and are subject to the numerous rules that apply to drug makers. The FDA has repeatedly asserted that all compounded drugs are new drugs and are thus illegal, but it will exercise its “enforcement discretion.” The Agency has issued numerous warning letters to compounding pharmacies, threatening actions including, but "not limited to, seizure of your products or injunction against you or your firm." The International Academy of Compounding Pharmacists states that "Congress, the U.S. Supreme Court, and each of the 50 state boards of pharmacy that regulate compounding have long recognized the value of pharmacy compounding, yet the FDA has contended for nearly 20 years that compounded medications are illegal. Compounded medications are not new, unapproved drugs and pharmacies dispensing them act only under a doctor’s prescription. To the extent that there are patient safety issues, state boards of pharmacy are well-equipped to deal with them.” Recent court rulings, such as Medical Center Pharmacy v. Gonzales (2006) support the position taken by IACP. Compounding pharmacy has been caught up in the recent controversy over hormone replacement therapy. Synthetic hormones, manufactured by large drug companies such as Wyeth Pharmaceuticals, were found to lead to increased rates of heart disease, breast cancer and stroke in the Women’s Health Initiative study, halted in 2002. As an alternative to synthetics, many physicians prescribe bioidentical hormones for patients suffering from menopausal symptoms. These hormones are mixed in a compounding pharmacy. Groups such as the North American Menopause Society have raised concerns about the marketing of these drugs. The compounding pharmacy profession purports to make no claims about the safety and efficacy of bioidentical hormones, and believes it should be up to a patient and her doctor to decide on the best course of treatment for menopausal symptoms. The stance of the FDA has been that each time a drug is compounded it creates a “new drug”. Since that “new drug” has not received FDA approval, the FDA then claims the compound is adulterated and therefore illegal. The illogic of such a position is clarified when one considers the actual practice of medicine in the United States, which uses multiple medications simultaneously (polypharmacy). While many people take two or more medications daily, very few prescription drugs are studied when combined together. This polypharmacy is impossible to study because of the difficulty and the cost of conducting a full-scale study of each drug combination. For example say there are three hundred drugs available for a doctor to choose from. If a patient is taking an average of six prescription drugs daily, there would be over 10^14 possible drug combinations that individual patient could take. It would be impossible to study that many drug combinations. Yet the polypharmacy is practiced universally and the FDA accepts it. Using the FDA’s own logic, combining various medications together is illegal if the patient swallows all the drugs after they have been compounded into one capsule… but let that same patient individually take the same multiple prescription drugs and swallow them one at a time… then the FDA has no problem with it.	Compounding Compounding pharmacy is the long-standing process of mixing drugs by a pharmacist or physician to fit the unique needs of a patient. For example, a patient allergic to the dyes used in a pill can obtain a doctor’s prescription for the necessary medicine to be compounded without the offending dye. # History The art of pharmaceutical compounding began with the birth of the first humans. All ancient hunter-gatherer societies had some knowledge of the medicinal properties of the animals, plants, molds, fungus and bacteria as well as inorganic minerals within their environment. Ancient civilizations utilized pharmaceutical compounding for religion, grooming, keeping the healthy well, treating the ill and preparing the dead. These ancient compounders produced the first oils from plants and animals. They discovered poisons and the antidotes. They made ointments for a wounded patients as well as perfumes for a customer. The earliest druggists were familiar with the various natural substances and their uses. These drug artisans compounded a variety of preparations from medications, dyes, incense, perfumes and ceremonial compounds to preservatives and cosmetics. The Bible lists many drugs that were compounded in biblical times in the Middle East. Drug compounders seeking gold and the fountain of youth drove the Alchemy movement. Alchemy eventually contributed to the creation of modern pharmacy and the principles of pharmacy compounding. The modern age of pharmacy and pharmacy compounding began in the nineteenth century with the isolation of various compounds from coal tar for the purpose of producing synthetic dyes. From this one natural product came the earliest antibacterial sulfa drugs, phenolic compounds made famous by Joseph Lister, and plastics. During 1800s pharmacists specialized in the raising, preparation and compounding of crude drugs. Crude drugs, like opium, are from natural sources and usually contain multiple chemical compounds. The compounding pharmacist often extracted these crude drugs using water or alcohol to form extracts, concoctions and decoctions. Pharmacists began isolating and identifying the active ingredients contained within these crude drugs concoctions. Using fractionation or recrystallization, the compounding pharmacist would separate the active ingredients, like morphine, and use it in place of the crude drug. During this time modern medicine began. With the isolation of medications from the “raw materials” or crude drugs came the birth of the modern pharmaceutical company. Pharmacists were trained to compound the preparations made by the drug companies but they weren’t able to do it as efficiently on a small basis. So economies of scale, not lack of skill or knowledge, produced a market niche for the modern pharmaceutical drug companies, (Pharma). With the turn of the twentieth century came the government involvement and subsequent regulation into the practice of medicine. In 1938 the Government of the United States imposed new regulations on the drug companies forming the Food and Drug Administration (FDA) when several people died from a poorly prepared sulfa drug that used ethylene glycol as a base. These new regulations forced the drug companies to prove any new medication they brought to market was safe. Pharmacy compounding was still going strong in the 1930s with over 80% of the prescriptions dispensed being compounded by the compounding pharmacist. With the discovery of penicillin and the modern marketing techniques and brand promotion, the drug manufacturing industry came of age. Pharmacists continued to compound most prescriptions until the early 1950’s when the majority of dispensed drugs came directly from the large pharmaceutical companies. From the 1950s to the 1980s pharmaceutical compounding became almost obsolete and a lost art. Pharmaceutical compounding continued losing favor as the big drug companies became larger and more powerful until they eventually dominated the practice of medicine. It was during this time that patients and physician became dissatisfied with the “one size fits all” attitude of the large Pharma companies. Physicians searching for drugs to treat their patients, lead to the reawakening of the ancient art of prescription compounding. Today many pharmacists specialize in the ancient art of pharmaceutical compounding. In 2006 over 30 million compounded prescriptions were dispensed not counting all the admixtures and injectable drugs compounded in America’s hospitals. Pharmaceutical compounding has been responsible for the health of millions of individual patients, has given birth the modern pharmaceutical companies and continues to be a vital link in the search for new drugs and dosage forms. Throughout history, there has always been a need for pharmacists to compound drugs for individualized dosages. When the pharmaceutical industry began mass-producing drugs and dosage forms for patients in the 1950s, compounding became less widespread. In recent years, many patients’ unique health needs have driven more business to compounding pharmacists. # Uses Compounding is one of the pillars of new drug development. Most medications have gained widespread usage throughout the entire medical community thanks to the practice of pharmaceutical compounding and the compounding pharmacist. Every major pharmaceutical company ever in existence or currently operating started in a compounding pharmacy with a compounding pharmacist. Without the practice of pharmaceutical compounding and compounding pharmacists none of the drugs we have today would have been discovered. This facet of pharmacy has been the greatest developer of drugs and the most positive influence within the entire allopathic, osteopathic, naturopathic and homeopathic, medical communities. Pharmaceutical compounding is a branch of pharmacy that continues to play the crucial role of new drug research and development. Physicians often prescribe compounded medicines for patients with unique health needs, because they are able to tailor a prescription to each individual. Compounding preparations are especially prevalent for: - Patients requiring limited dosage strengths and dosage forms (i.e., infants) - Those with allergies to certain ingredients in manufactured drugs - Veterinary medicine - Pediatrics (i.e., making a medicine more palatable to children with flavor additives) - Home health care - Hospice patients - Bioidentical hormone replacement therapy, specifically the Wiley Protocol - Patients who need drugs that have been discontinued by pharmaceutical manufacturers because of low profitability # Regulation Compounding pharmacies are licensed and regulated by state Boards of Pharmacy in the 50 states and the District of Columbia. Additionally, pharmacies follow guidelines from U.S. Pharmacopeia. Compounding pharmacists must work within the jurisdiction of the FDA, they are simply exempt from many FDA requirements so long as they are state-compliant and compound pursuant to a valid prescription. However, the FDA registers and inspects the facilities that supply manufacturers with active pharmaceutical ingredients. The Pharmacy Compounding Accreditation Board was created in 2006 as a voluntary accreditation body by pharmacy organizations to establish high quality standards for compounding pharmacies. # Controversies There is currently a controversy over who should regulate compounding pharmacies. The FDA is concerned that many compounders are acting as large-scale manufacturers of new drugs, and are subject to the numerous rules that apply to drug makers. The FDA has repeatedly asserted that all compounded drugs are new drugs and are thus illegal, but it will exercise its “enforcement discretion.” The Agency has issued numerous warning letters to compounding pharmacies, threatening actions including, but "not limited to, seizure of your products or injunction against you or your firm." The International Academy of Compounding Pharmacists states that "Congress, the U.S. Supreme Court, and each of the 50 state boards of pharmacy that regulate compounding have long recognized the value of pharmacy compounding, yet the FDA has contended for nearly 20 years that compounded medications are illegal. Compounded medications are not new, unapproved drugs and pharmacies dispensing them act only under a doctor’s prescription. To the extent that there are patient safety issues, state boards of pharmacy are well-equipped to deal with them.” Recent court rulings, such as Medical Center Pharmacy v. Gonzales (2006) support the position taken by IACP. Compounding pharmacy has been caught up in the recent controversy over hormone replacement therapy.[1] Synthetic hormones, manufactured by large drug companies such as Wyeth Pharmaceuticals, were found to lead to increased rates of heart disease, breast cancer and stroke in the Women’s Health Initiative study, halted in 2002. As an alternative to synthetics, many physicians prescribe bioidentical hormones for patients suffering from menopausal symptoms. These hormones are mixed in a compounding pharmacy. Groups such as the North American Menopause Society have raised concerns about the marketing of these drugs. The compounding pharmacy profession purports to make no claims about the safety and efficacy of bioidentical hormones, and believes it should be up to a patient and her doctor to decide on the best course of treatment for menopausal symptoms. Template:POV section The stance of the FDA has been that each time a drug is compounded it creates a “new drug”. Since that “new drug” has not received FDA approval, the FDA then claims the compound is adulterated and therefore illegal. The illogic of such a position is clarified when one considers the actual practice of medicine in the United States, which uses multiple medications simultaneously (polypharmacy). While many people take two or more medications daily, very few prescription drugs are studied when combined together. This polypharmacy is impossible to study because of the difficulty and the cost of conducting a full-scale study of each drug combination. For example say there are three hundred drugs available for a doctor to choose from. If a patient is taking an average of six prescription drugs daily, there would be over 10^14 possible drug combinations that individual patient could take. It would be impossible to study that many drug combinations. Yet the polypharmacy is practiced universally and the FDA accepts it. Using the FDA’s own logic, combining various medications together is illegal if the patient swallows all the drugs after they have been compounded into one capsule… but let that same patient individually take the same multiple prescription drugs and swallow them one at a time… then the FDA has no problem with it.	https://www.wikidoc.org/index.php/Compounding
6ddccbdd4e9b1223f3f0df32ffb6b5d9ec000aa9	wikidoc	Growth cone	Growth cone # Overview A growth cone is a dynamic, actin-supported extension of a developing axon seeking its synaptic target. Their existence was originally proposed by Spanish histologist Santiago Ramón y Cajal based upon stationary images he observed under the microscope. Neuronal growth cones are situated on the very tips of nerve cells on structures called axons and dendrites. The most crucial roles of the neuronal growth cone are to explore its surroundings ultimately establishing synaptic contacts. # Structure The morphology of the growth cone can be easily described by using the hand as an analogy. The fine extensions of the growth cone are known as "filopodia". The filopodia are like the "fingers" of the growth cone; they contain actin filaments that give them shape and support. In between filopodia--much like the webbing of the hands--are the "lamellipodia". The filopodia contain receptors that are important for axon guidance. # Movement The growth cones are continually being built up through construction of the actin microfilaments and extension of the plasma membrane via vesicle fusion. The actin filaments depolymerize and disassamble on one end to allow free monomers to migrate to the leading edge of the actin filament where it can polymerize and thus reattach. Actin filaments thus do not actually grow but rather migrate. The growth capacity of the axons lies in the microtubules which are located just beyond the actin filaments. Laminins of the basal membrane interact with the integrins of the growth cone to promote the forward movement of the growth cone. # Axon guidance Movement of the axons is controlled by an integration of its sensory and motor function (described above) which is established through second messengers such as calcium and cyclic nucleotides. The sensory function of axons is dependent on cues from the extracellular matrix which can be either attractive or repulsive, thus helping to guide the axon away from certain paths and attracting them to their proper target destinations. Attractive cues inhibit retrograde flow of the actin filaments and promote their assembly whereas repulsive cues have the exact opposite effect. Growth cone receptors detect the presence of axon guidance molecules such as Netrin, Slit, Ephrins, and Semaphorins. It has more recently been shown that cell fate determinants such as Wnt can also act as guidance cues. Quite interestingly, the same guidance cue can act as an attractant or a repellent, depending on context. A prime example of this is Netrin-1, which signals attraction through the DCC receptor and repulsion through the Unc-5 receptor. Furthermore, it has been discovered that these same molecules are involved in guiding vessel growth. Axon guidance directs the initial wiring of the nervous system and is also important in axonal regeneration following an injury.	Growth cone # Overview A growth cone is a dynamic, actin-supported extension of a developing axon seeking its synaptic target. Their existence was originally proposed by Spanish histologist Santiago Ramón y Cajal based upon stationary images he observed under the microscope. Neuronal growth cones are situated on the very tips of nerve cells on structures called axons and dendrites. The most crucial roles of the neuronal growth cone are to explore its surroundings ultimately establishing synaptic contacts. # Structure The morphology of the growth cone can be easily described by using the hand as an analogy. The fine extensions of the growth cone are known as "filopodia". The filopodia are like the "fingers" of the growth cone; they contain actin filaments that give them shape and support. In between filopodia--much like the webbing of the hands--are the "lamellipodia". The filopodia contain receptors that are important for axon guidance. # Movement The growth cones are continually being built up through construction of the actin microfilaments and extension of the plasma membrane via vesicle fusion. The actin filaments depolymerize and disassamble on one end to allow free monomers to migrate to the leading edge of the actin filament where it can polymerize and thus reattach. Actin filaments thus do not actually grow but rather migrate. The growth capacity of the axons lies in the microtubules which are located just beyond the actin filaments. Laminins of the basal membrane interact with the integrins of the growth cone to promote the forward movement of the growth cone. # Axon guidance Movement of the axons is controlled by an integration of its sensory and motor function (described above) which is established through second messengers such as calcium and cyclic nucleotides. The sensory function of axons is dependent on cues from the extracellular matrix which can be either attractive or repulsive, thus helping to guide the axon away from certain paths and attracting them to their proper target destinations. Attractive cues inhibit retrograde flow of the actin filaments and promote their assembly whereas repulsive cues have the exact opposite effect. Growth cone receptors detect the presence of axon guidance molecules such as Netrin, Slit, Ephrins, and Semaphorins. It has more recently been shown that cell fate determinants such as Wnt can also act as guidance cues. Quite interestingly, the same guidance cue can act as an attractant or a repellent, depending on context. A prime example of this is Netrin-1, which signals attraction through the DCC receptor and repulsion through the Unc-5 receptor. Furthermore, it has been discovered that these same molecules are involved in guiding vessel growth. Axon guidance directs the initial wiring of the nervous system and is also important in axonal regeneration following an injury.	https://www.wikidoc.org/index.php/Cone_of_origin
c66d68d834eec98cfef7d4f8c7b340b719decf46	wikidoc	Confounding	Confounding # Overview A confounding variable (also confounding factor, lurking variable, a confound, or confounder) is an extraneous variable in a statistical model that correlates (positively or negatively) with both the dependent variable and the independent variable. The methodologies of scientific studies therefore need to control for these factors to avoid what is known as a type 1 error: A 'false positive' conclusion that the dependent variables are in a causal relationship with the independent variable. Such a relation between two observed variables is termed a spurious relationship. Thus, confounding is a major threat to the validity of inferences made about cause and effect, i.e. internal validity, as the observed effects should be attributed to the confounder rather than the independent variable. For example, assume that a child's weight and a country's gross domestic product (GDP) rise with time. A person carrying out an experiment could measure weight and GDP, and conclude that a higher GDP causes children to gain weight, or that children's weight gain boosts the GDP. However, the confounding variable, time, was not accounted for, and is the real cause of both rises. By definition, a confounding variable is associated with both the probable cause and the outcome. The confounder is not allowed to lie in the causal pathway between the cause and the outcome: If A is thought to be the cause of disease C, the confounding variable B may not be solely caused by behaviour A; and behaviour B shall not always lead to behaviour C. An example: Being female does not always lead to smoking tobacco, and smoking tobacco does not always lead to cancer. Therefore, in any study that tries to elucidate the relation between being female and cancer should take smoking into account as a possible confounder. In addition, a confounder is always a risk factor that has a different prevalence in two risk groups (e.g. females/males). (Hennekens, Buring & Mayrent, 1987). Though criteria for causality in statistical studies have been researched intensely, Judea Pearl has shown that confounding variables cannot be defined in terms of statistical notions alone; some causal assumptions are necessary. In a 1965 paper, Austin Bradford Hill proposed a set of causal criteria.. Many working epidemiologists take these as a good place to start when considering confounding and causation. However, these are of heuristic value at best. When causal assumptions are articulated in the form of causal graph, a simple criterion is available, called backdoor, to identify sets of confounding variables. # How to remove confounding in a study There are various ways to modify a study design to actively exclude or control confounding variables: - Case-control studies assign confounders to both groups, cases and controls, equally. For example if somebody wanted to study the cause of myocardial infarct and thinks that the age is a probable confounding variable, each 67 years old infarct patient will be matched with a healthy 67 year old "control" person. In case-control studies, matched variables most often are the age and sex. - Cohort studies: A degree of matching is also possible and it is often done by only admitting certain age groups or a certain sex into the study population, and thus all cohorts are comparable in regard to the possible confounding variable. For example, if age and sex are thought to be a confounders, only 40 to 50 years old males would be involved in a cohort study that would assess the myocardial infarct risk in cohorts that either are physically active or inactive. - Stratification: As in the example above, physical activity is thought to be a behaviour that protects from myocardial infarct; and age is assumed to be a possible confounder. The data sampled is then stratified by age group – this means, the association between activity and infarct would be analyzed per each age group. If the different age groups (or age strata) yield much different risk ratios, age must be viewed as a confounding variable. There are statistical tools like Mantel-Haenszel methods that deal with stratified data. All these methods have their drawbacks. This can be clearly seen in this example: A 45 years old Afro-American from Alaska, avid football player and vegetarian, working in education, suffers from a disease and is enrolled into a case-control study. Proper matching would call for a person with the same characteristics, with the sole difference of being healthy – but finding such one would be an enormous task. Additionally, there is always the risk of over- and undermatching of the study population. In cohort studies, too many people can be excluded; and in stratification, single strata can get too thin and thus contain only a small, non-significant number of samples. - Controlling for confounding by measuring the known confounders and including them as covariates in multivariate analyses. A drawback of these is that they give little information about the strength of the confounding variable compared to stratification methods. One major problem is that confounding variables are not always known or measurable. This leads to 'residual confounding' - epidemiological jargon for incompletely controlled confounding. Hence, randomization is often the best solution as, if performed successfully on sufficiently large numbers, all confounding variables (known and unknown) will be equally distributed across all study groups.	Confounding # Overview A confounding variable (also confounding factor, lurking variable, a confound, or confounder) is an extraneous variable in a statistical model that correlates (positively or negatively) with both the dependent variable and the independent variable. The methodologies of scientific studies therefore need to control for these factors to avoid what is known as a type 1 error: A 'false positive' conclusion that the dependent variables are in a causal relationship with the independent variable. Such a relation between two observed variables is termed a spurious relationship. Thus, confounding is a major threat to the validity of inferences made about cause and effect, i.e. internal validity, as the observed effects should be attributed to the confounder rather than the independent variable. For example, assume that a child's weight and a country's gross domestic product (GDP) rise with time. A person carrying out an experiment could measure weight and GDP, and conclude that a higher GDP causes children to gain weight, or that children's weight gain boosts the GDP. However, the confounding variable, time, was not accounted for, and is the real cause of both rises. By definition, a confounding variable is associated with both the probable cause and the outcome. The confounder is not allowed to lie in the causal pathway between the cause and the outcome: If A is thought to be the cause of disease C, the confounding variable B may not be solely caused by behaviour A; and behaviour B shall not always lead to behaviour C. An example: Being female does not always lead to smoking tobacco, and smoking tobacco does not always lead to cancer. Therefore, in any study that tries to elucidate the relation between being female and cancer should take smoking into account as a possible confounder. In addition, a confounder is always a risk factor that has a different prevalence in two risk groups (e.g. females/males). (Hennekens, Buring & Mayrent, 1987). Though criteria for causality in statistical studies have been researched intensely, Judea Pearl has shown that confounding variables cannot be defined in terms of statistical notions alone; some causal assumptions are necessary.[1] In a 1965 paper, Austin Bradford Hill proposed a set of causal criteria.[2]. Many working epidemiologists take these as a good place to start when considering confounding and causation. However, these are of heuristic value at best. When causal assumptions are articulated in the form of causal graph, a simple criterion is available, called backdoor, to identify sets of confounding variables. # How to remove confounding in a study There are various ways to modify a study design to actively exclude or control confounding variables:[3] - Case-control studies assign confounders to both groups, cases and controls, equally. For example if somebody wanted to study the cause of myocardial infarct and thinks that the age is a probable confounding variable, each 67 years old infarct patient will be matched with a healthy 67 year old "control" person. In case-control studies, matched variables most often are the age and sex. - Cohort studies: A degree of matching is also possible and it is often done by only admitting certain age groups or a certain sex into the study population, and thus all cohorts are comparable in regard to the possible confounding variable. For example, if age and sex are thought to be a confounders, only 40 to 50 years old males would be involved in a cohort study that would assess the myocardial infarct risk in cohorts that either are physically active or inactive. - Stratification: As in the example above, physical activity is thought to be a behaviour that protects from myocardial infarct; and age is assumed to be a possible confounder. The data sampled is then stratified by age group – this means, the association between activity and infarct would be analyzed per each age group. If the different age groups (or age strata) yield much different risk ratios, age must be viewed as a confounding variable. There are statistical tools like Mantel-Haenszel methods that deal with stratified data. All these methods have their drawbacks. This can be clearly seen in this example: A 45 years old Afro-American from Alaska, avid football player and vegetarian, working in education, suffers from a disease and is enrolled into a case-control study. Proper matching would call for a person with the same characteristics, with the sole difference of being healthy – but finding such one would be an enormous task. Additionally, there is always the risk of over- and undermatching of the study population. In cohort studies, too many people can be excluded; and in stratification, single strata can get too thin and thus contain only a small, non-significant number of samples. - Controlling for confounding by measuring the known confounders and including them as covariates in multivariate analyses. A drawback of these is that they give little information about the strength of the confounding variable compared to stratification methods. One major problem is that confounding variables are not always known or measurable. This leads to 'residual confounding' - epidemiological jargon for incompletely controlled confounding. Hence, randomization is often the best solution as, if performed successfully on sufficiently large numbers, all confounding variables (known and unknown) will be equally distributed across all study groups. # External links These sites contain descriptions or examples of lurking variables: - Linear Regression (Yale University) - Scatterplots (Simon Fraser University) - Pearl, J. "Why there is no statistical test for counfounding, why many think there is, and why they are almost right," UCLA Computer Science Department, Technical Report R-256, January 1998	https://www.wikidoc.org/index.php/Confounding
3aa647d1e0ac48b66a72edf3ab58cbeda3272e98	wikidoc	Conjunctiva	Conjunctiva The conjunctiva is a membrane that covers the sclera (white part of the eye) and lines the inside of the eyelids. # Function It helps lubricate the eye by producing mucus and tears, although a smaller volume of tears than the lacrimal gland. It also contributes to immune surveillance and helps to prevent the entrance of microorganisms into the eye. # Histology The conjunctiva is typically divided into three parts: - Palpebral or tarsal conjunctiva: The conjunctiva lining the eyelids. - Fornix conjunctiva: The conjunctiva where the inner part of the eyelids and the eyeball meet, the palpebral conjunctiva is reflected at the superior fornix and the inferior fornix to become the bulbar conjunctiva. - Bulbar or ocular conjunctiva: The conjunctiva covering the eyeball, over the sclera. This region of the conjunctiva is bound tightly and moves with the eyeball movements. # Diseases and disorders Disorders of the conjunctiva and cornea are a common source of eye complaints. The surface of the eye is exposed to various external influences and is especially suspectible to trauma, infections, and allergic reactions. The conjunctiva is best known because of its inflamed state, conjunctivitis (more commonly known as pinkeye). Conjunctival irritation is one of the adverse health effects that can take place after overexposure to VOCs (Volatile organic compounds).	Conjunctiva Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The conjunctiva is a membrane that covers the sclera (white part of the eye) and lines the inside of the eyelids. # Function It helps lubricate the eye by producing mucus and tears, although a smaller volume of tears than the lacrimal gland.[1] It also contributes to immune surveillance and helps to prevent the entrance of microorganisms into the eye. # Histology The conjunctiva is typically divided into three parts: - Palpebral or tarsal conjunctiva: The conjunctiva lining the eyelids. - Fornix conjunctiva: The conjunctiva where the inner part of the eyelids and the eyeball meet, the palpebral conjunctiva is reflected at the superior fornix and the inferior fornix to become the bulbar conjunctiva. - Bulbar or ocular conjunctiva: The conjunctiva covering the eyeball, over the sclera. This region of the conjunctiva is bound tightly and moves with the eyeball movements. # Diseases and disorders Disorders of the conjunctiva and cornea are a common source of eye complaints. The surface of the eye is exposed to various external influences and is especially suspectible to trauma, infections, and allergic reactions. The conjunctiva is best known because of its inflamed state, conjunctivitis (more commonly known as pinkeye). Conjunctival irritation is one of the adverse health effects that can take place after overexposure to VOCs (Volatile organic compounds).	https://www.wikidoc.org/index.php/Conjuctiva
0415a95552fd9e7fc7387d569e3ff373b3bb2a06	wikidoc	Contactin 4	Contactin 4 Contactin-4 is a protein that in humans is encoded by the CNTN4 gene. The protein encoded by this gene is a member of the immunoglobulin superfamily. It is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. It may play a role in the formation of axon connections in the developing nervous system. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. # Genomics The gene is located on the short arm of chromosome 3 (3p26.3). It is a single copy gene within the Watson (plus) strand, 957,399 bases in length and encodes a protein of 1026 amino acids (molecular weight 113.454 kDa) # Clinical relevance Abnormal expression of this gene has been implicated in some cases of autism. It has also been associated with cerebellar degeneration in spinocerebellar ataxia type 16.	Contactin 4 Contactin-4 is a protein that in humans is encoded by the CNTN4 gene.[1][2][3] The protein encoded by this gene is a member of the immunoglobulin superfamily. It is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. It may play a role in the formation of axon connections in the developing nervous system. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[3] # Genomics The gene is located on the short arm of chromosome 3 (3p26.3). It is a single copy gene within the Watson (plus) strand, 957,399 bases in length and encodes a protein of 1026 amino acids (molecular weight 113.454 kDa) # Clinical relevance Abnormal expression of this gene has been implicated in some cases of autism.[4] It has also been associated with cerebellar degeneration in spinocerebellar ataxia type 16.	https://www.wikidoc.org/index.php/Contactin_4
3147715c458e3a8b56309fb35afca31d325cba99	wikidoc	Contrayerva	Contrayerva In botany, the contrayerva, or contrajerva, is the root and scaly rhizome of various tropical American species of Dorstenia in the family Moraceae (D. contrayerva and D. braziliensis), a South American plant, the aromatic root of which is sometimes used in medicine as a gentle stimulant and tonic. It was previously used as an antidote to snake bites. The name is used in Jamaica to refer to a species of Birthwort (Aristolochia odoratissima) still believed to have antidotal properties. The root is smaller than that of the iris, reddish outside and white inside, knotty, and fibrous. To be of use, it must be new, heavy, and of a dusky red color. Its odor resembles that of fig leaves. Its taste is aromatic, accompanied with some acrimony. The contrayerva root was formerly considered by many writers to be one of the best anti-epidemics known. Dr. Nathaniel Hodges (1629–1688), in his treatise of the Great Plague of London (Loimologia; published in 1672), had a recipe which he said was very successful, and of which this root was one of the chief ingredients.	Contrayerva In botany, the contrayerva, or contrajerva, is the root and scaly rhizome of various tropical American species of Dorstenia in the family Moraceae (D. contrayerva and D. braziliensis[1]), a South American plant, the aromatic root of which is sometimes used in medicine as a gentle stimulant and tonic[2]. It was previously used as an antidote to snake bites.[3] The name is used in Jamaica to refer to a species of Birthwort (Aristolochia odoratissima) still believed to have antidotal properties.[1] The root is smaller than that of the iris, reddish outside and white inside, knotty, and fibrous. To be of use, it must be new, heavy, and of a dusky red color. Its odor resembles that of fig leaves. Its taste is aromatic, accompanied with some acrimony.[3] The contrayerva root was formerly considered by many writers to be one of the best anti-epidemics known. Dr. Nathaniel Hodges (1629–1688), in his treatise of the Great Plague of London (Loimologia; published in 1672), had a recipe which he said was very successful, and of which this root was one of the chief ingredients.[3]	https://www.wikidoc.org/index.php/Contrayerva
543bc3e16b57ba598e4decbe57cd5c0fb0fb2ee6	wikidoc	Coprophagia	Coprophagia # Overview Coprophagia is the consumption of feces, from the Greek copros (feces) and phagein (eat). Many animal species have evolved to practice coprophagia; other species do not normally consume feces but may do so under unusual conditions. Only in rare cases is it practiced by humans. # Evolved coprophagia Coprophagous insects consume and redigest the feces of large animals; these feces contain substantial amounts of semi-digested food. (Herbivore digestive systems are especially inefficient.) The most famous feces-eating insect is dung-beetle and the most ubiquitous being the fly. Pigs are most commonly associated with eating not only their own dung, but those of other animals and humans. In parts of the third world, where village dwellers excrete in the open, pigs are known to eat it. Rabbits, cavies (guinea pigs) and related species do not have the complicated ruminant digestive system. Instead they extract more nutrition from grass by giving their food a second pass through the gut. Soft caecal pellets of partially digested food are excreted and generally consumed immediately. They also produce normal droppings, which are not eaten. Young elephants, panda bears, koala bears and hippos eat the feces of their mother to obtain the necessary bacteria for the proper digestion of the vegetation found on the savannah and in the jungle. When they are born, their intestines do not contain these bacteria (they are completely sterile). Without them, these youngs would be unable to get any nutritional value from plants. Gorillas eat their own feces and the feces of other gorillas. Hamsters eat their own droppings; this is thought to be a source of vitamins B and K, produced by bacteria in the gut. Apes have been observed eating horse feces for the salt. Monkeys have been observed to eat elephant feces. # Theories on dogs Coprophagia is a behavior sometimes observed by dog owners. Hofmeister, Cumming, and Dhein (2001) wrote that this behavior in dogs has not been well-researched, and are currently preparing a study. In a preliminary paper, they write that there are various hypotheses for this, although none have been proven: - To get attention from their owners. - From anxiety, stress, or having been punished for bad behaviors. - They had been punished for having defecated in the past, and attempt to clean up out of fear to be punished again. - From boredom. - In an attempt to clean up in crowded conditions. - When dogs observe their owners picking up feces, and imitate this behavior (allelomimetic behavior). This is highly improbable because the behaviour has also been observed in environments where owners never picked up the dog's (or other) feces. - Because puppies taste everything and discover that feces are edible and, perhaps, tasty, especially when fed a high fat content diet. - Because dogs are, by nature, scavengers, and this is within the range of scavenger behavior. - To prevent the scent from attracting predators, especially mother dogs eating their offspring's feces. - Because the texture and temperature of fresh feces approximates that of regurgitated food, which is how canine mothers in the wild would provide solid food. - Because of the protein content of the feces (particularly cat feces), or over-feeding, leading to large concentrations of undigested matter in the feces. - Due to assorted health problems, including: Pancreatitis Intestinal infections Food allergies, creating mal-absorption - Pancreatitis - Intestinal infections - Food allergies, creating mal-absorption - Because they are hungry, such as when eating routines are changed, food is withheld, or nutrients are not properly absorbed. - Carnivores may sometimes eat or roll in the feces of their prey to ingest and exude scents which camouflage their own. The most obvious reason--desperate hunger--is rarely considered. Some veterinarians recommend putting meat tenderizer in dogfood, since this makes the feces taste excessively bad to dogs. Several companies produce food additives that can also be added to the animal's food to make feces taste bad. Due to the attraction of dogs to their feces, a popular Chinese idiom goes "A dog cannot change its habit of eating feces", which usually refers to a habit that is hard to correct. # Humans Coprophagia is extremely uncommon in humans. It is generally thought to be the result of the paraphilia known as coprophilia, although it is only diagnosable in extreme cases where it disturbs one's functioning. From the medical literature, coprophagia has been observed in a small number of patients with dementia, schizophrenia and depression. Consuming other people's feces carries the risk of contracting diseases spread through fecal matter, such as hepatitis. Hepatitis A, Hepatitis E, pneumonia, and influenza vaccinations are generally recommended for those who engage in this practice. Consuming one's own feces potentially involves risk, as the bowel bacteria and eggs of parasitic worms are not safe to ingest. Similar risk can apply to related sexual practices, such as anilingus or inserting an object into the mouth that has recently been in the anus (see ass to mouth). The practice of coprophagia in humans is also depicted in a handful of motion pictures. For examples see section Coprophagia in motion pictures below. Lewin (2001) reports that "... consumption of fresh, warm camel feces has been recommended by Bedouins as a remedy for bacterial dysentery; its efficacy (probably attributable to the antibiotic subtilisin from Bacillus subtilis) was confirmed by German soldiers in Africa during World War II." Coprophagia is also depicted in porn sometimes.	Coprophagia # Overview Coprophagia is the consumption of feces, from the Greek copros (feces) and phagein (eat). Many animal species have evolved to practice coprophagia; other species do not normally consume feces but may do so under unusual conditions. Only in rare cases is it practiced by humans. # Evolved coprophagia Coprophagous insects consume and redigest the feces of large animals; these feces contain substantial amounts of semi-digested food. (Herbivore digestive systems are especially inefficient.) The most famous feces-eating insect is dung-beetle and the most ubiquitous being the fly. Pigs are most commonly associated with eating not only their own dung, but those of other animals and humans. In parts of the third world, where village dwellers excrete in the open, pigs are known to eat it. Rabbits, cavies (guinea pigs) and related species do not have the complicated ruminant digestive system. Instead they extract more nutrition from grass by giving their food a second pass through the gut. Soft caecal pellets of partially digested food are excreted and generally consumed immediately. They also produce normal droppings, which are not eaten. Young elephants, panda bears, koala bears and hippos eat the feces of their mother to obtain the necessary bacteria for the proper digestion of the vegetation found on the savannah and in the jungle. When they are born, their intestines do not contain these bacteria (they are completely sterile). Without them, these youngs would be unable to get any nutritional value from plants. Gorillas eat their own feces and the feces of other gorillas. Hamsters eat their own droppings; this is thought to be a source of vitamins B and K, produced by bacteria in the gut. Apes have been observed eating horse feces for the salt. Monkeys have been observed to eat elephant feces. # Theories on dogs Coprophagia is a behavior sometimes observed by dog owners. Hofmeister, Cumming, and Dhein (2001) wrote that this behavior in dogs has not been well-researched, and are currently preparing a study. In a preliminary paper, they write that there are various hypotheses for this, although none have been proven: - To get attention from their owners. - From anxiety, stress, or having been punished for bad behaviors. - They had been punished for having defecated in the past, and attempt to clean up out of fear to be punished again. - From boredom. - In an attempt to clean up in crowded conditions. - When dogs observe their owners picking up feces, and imitate this behavior (allelomimetic behavior). This is highly improbable because the behaviour has also been observed in environments where owners never picked up the dog's (or other) feces. - Because puppies taste everything and discover that feces are edible and, perhaps, tasty, especially when fed a high fat content diet. - Because dogs are, by nature, scavengers, and this is within the range of scavenger behavior. - To prevent the scent from attracting predators, especially mother dogs eating their offspring's feces. - Because the texture and temperature of fresh feces approximates that of regurgitated food, which is how canine mothers in the wild would provide solid food. - Because of the protein content of the feces (particularly cat feces), or over-feeding, leading to large concentrations of undigested matter in the feces. - Due to assorted health problems, including: Pancreatitis Intestinal infections Food allergies, creating mal-absorption - Pancreatitis - Intestinal infections - Food allergies, creating mal-absorption - Because they are hungry, such as when eating routines are changed, food is withheld, or nutrients are not properly absorbed. - Carnivores may sometimes eat or roll in the feces of their prey to ingest and exude scents which camouflage their own. The most obvious reason--desperate hunger--is rarely considered. Some veterinarians recommend putting meat tenderizer in dogfood, since this makes the feces taste excessively bad to dogs. Several companies produce food additives that can also be added to the animal's food to make feces taste bad. Due to the attraction of dogs to their feces, a popular Chinese idiom goes "A dog cannot change its habit of eating feces", which usually refers to a habit that is hard to correct. # Humans Coprophagia is extremely uncommon in humans. It is generally thought to be the result of the paraphilia known as coprophilia, although it is only diagnosable in extreme cases where it disturbs one's functioning. From the medical literature, coprophagia has been observed in a small number of patients with dementia, schizophrenia[1] and depression[2]. Consuming other people's feces carries the risk of contracting diseases spread through fecal matter, such as hepatitis. Hepatitis A, Hepatitis E, pneumonia, and influenza vaccinations are generally recommended for those who engage in this practice. Consuming one's own feces potentially involves risk, as the bowel bacteria and eggs of parasitic worms are not safe to ingest. Similar risk can apply to related sexual practices, such as anilingus or inserting an object into the mouth that has recently been in the anus (see ass to mouth). The practice of coprophagia in humans is also depicted in a handful of motion pictures. For examples see section Coprophagia in motion pictures below. Lewin (2001) reports that "... consumption of fresh, warm camel feces has been recommended by Bedouins as a remedy for bacterial dysentery; its efficacy (probably attributable to the antibiotic subtilisin from Bacillus subtilis) was confirmed by German soldiers in Africa during World War II." Coprophagia is also depicted in porn sometimes.	https://www.wikidoc.org/index.php/Coprophagia
457a510760d1c01681be6f58dee6f2a3d7705c91	wikidoc	Cor bovinum	Cor bovinum Cor bovinum refers to a massive hypertrophy of the left ventricle of the heart due to volume overload, usually in the context of syphilis infection. # Pathophysiology Due to Syphilitic aortitis (a complication of tertiary syphilis) the aortic valve ring becomes dilated. The free margins of ] no longer approximate leading to aortic valve insufficiency. As blood regurgitates into the left ventricle between each systole, volume overload ensues and the ventricular wall hypertrophies in an attempt to maintain cardiac output and blood pressure. The massive ventricle can lead to a heart weighing over 1000 grams (the weight of a normal heart is about 350 grams), referred to as "Cor Bovinum" A Medline search of articles published since 1950 revealed seven articles on "cor bovinum" (in the earlier part of this period only the titles could be searched), of which only one is in English. Searching for the synonyms revealed no mention of "bucardia," and all 101 articles mentioning "ox heart" related to oxen. Fluri and Gebbers define cor bovinum as a heart exceeding 500 g in weight. Looking through autopsies on Internal Medicine patients at the Kantonsspital Luzern, they found 415 cases out of 1181 autopsies in the two periods 1978-81 and 1997-2000. Cor bovinum was found in 25.3% of cases in the earlier period, with mean age at death 67.7 years, and in the later period 20.6% with mean age 74.3 years. The male female ratio was 4:1. "In 93% of all patients with CB, we found coronary atherosclerosis as a sign of high blood pressure and in 79% a COPD." In 84% of cases the cause of death was directly related to the cor bovinum, but in 37% the cause of death was still unclear. They concluded that cor bovinum was a decreasing but still frequent autopsy finding. High blood pressure, COPD and male sex were the main risk factors. The decreasing incidence was ascribed to improved medical management: they mention treatments for high blood pressure and coronary artery disease, which suggests that "COPD" in their abstract refers to the latter.	Cor bovinum Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Cor bovinum refers to a massive hypertrophy of the left ventricle of the heart due to volume overload, usually in the context of syphilis infection. # Pathophysiology Due to Syphilitic aortitis (a complication of tertiary syphilis) the aortic valve ring becomes dilated. The free margins of [[\|valve cusps\|valve cusps]] no longer approximate leading to aortic valve insufficiency. As blood regurgitates into the left ventricle between each systole, volume overload ensues and the ventricular wall hypertrophies in an attempt to maintain cardiac output and blood pressure. The massive ventricle can lead to a heart weighing over 1000 grams (the weight of a normal heart is about 350 grams), referred to as "Cor Bovinum" [latin Cow's heart.][1] A Medline search of articles published since 1950 revealed seven articles on "cor bovinum" (in the earlier part of this period only the titles could be searched), of which only one is in English. Searching for the synonyms revealed no mention of "bucardia," and all 101 articles mentioning "ox heart" related to oxen. Fluri and Gebbers[2] define cor bovinum as a heart exceeding 500 g in weight. Looking through autopsies on Internal Medicine patients at the Kantonsspital Luzern, they found 415 cases out of 1181 autopsies in the two periods 1978-81 and 1997-2000. Cor bovinum was found in 25.3% of cases in the earlier period, with mean age at death 67.7 years, and in the later period 20.6% with mean age 74.3 years. The male female ratio was 4:1. "In 93% of all patients with CB, we found coronary atherosclerosis as a sign of high blood pressure and in 79% a COPD." In 84% of cases the cause of death was directly related to the cor bovinum, but in 37% the cause of death was still unclear. They concluded that cor bovinum was a decreasing but still frequent autopsy finding. High blood pressure, COPD and male sex were the main risk factors. The decreasing incidence was ascribed to improved medical management: they mention treatments for high blood pressure and coronary artery disease, which suggests that "COPD" in their abstract refers to the latter.	https://www.wikidoc.org/index.php/Cor_bovinum
b90576ab7959db461c8bde3a8e84b8ed7b425c35	wikidoc	Glans penis	Glans penis The glans penis (or simply glans) is the sensitive tip of the penis. It is also commonly referred to as the "head" of the penis. Slang terms include "helmet" and "bell end". When the penis is flaccid it is wholly or partially covered by the foreskin, except in men who have been circumcised. # Medical considerations The meatus (opening) of the urethra is at the tip of the glans penis. In circumcised infants who wear diapers, the meatal area of the glans penis is without the protection of the foreskin and at slight risk of meatitis, meatal ulceration, and meatal stenosis. The epithelium of the glans penis is mucocutaneous tissue. Birley et al. report that excessive washing with soap may dry the mucous membrane that covers the glans penis and cause non-specific dermatitis. Inflammation of the glans penis is known as balanitis. It occurs in 3–11% of males, and up to 35% of diabetic males. It has many causes, including irritation, or infection with a wide variety of pathogens. Careful identification of the cause with the aid of patient history, physical examination, swabs and cultures, and biopsy are essential in order to determine the proper treatment. # Anatomical details The glans penis is the expanded cap of the corpus spongiosum. It is moulded on the rounded ends of the Corpora cavernosa penis, extending farther on their upper than on their lower surfaces. At the summit of the glans is the slit-like vertical external urethral orifice. The circumference of the base of the glans forms a rounded projecting border, the corona glandis, overhanging a deep retroglandular sulcus (the coronal sulcus), behind which is the neck of the penis. The proportional size of the glans penis can vary greatly. The foreskin maintains the mucosa in a moist environment. In males who have been circumcised, but have not undergone restoration, the glans is permanently exposed and dry. Szabo and Short found that the glans of the circumcised penis does not develop a thicker keratinization layer. Studies have suggested that the glans is equally sensitive in circumcised and uncircumcised males. Halata & Munger (1986) report that the density of genital corpuscles is greatest in the corona glandis, while Yang & Bradley (1998) report that their study "showed no areas in the glans to be more densely innervated than others." Halata & Spathe (1997) reported that "the glans penis contains a predominance of free nerve endings, numerous genital end bulbs and rarely Pacinian and Ruffinian corpuscles. Merkel nerve endings and Meissner corpuscles are not present." Yang & Bradley argue that "The distinct pattern of innervation of the glans emphasizes the role of the glans as a sensory structure". An anatomycal variant of glans is showed: Hirsuties papillaris genitalis # Additional images - Diagram of the arteries of the penis. - Penis - An uncircumcised glans penis - Side view circumcised glans penis - An anterior view of a flaccid uncircumcised glans penis	Glans penis Template:Infobox Anatomy The glans penis (or simply glans) is the sensitive tip of the penis. It is also commonly referred to as the "head" of the penis. Slang terms include "helmet" and "bell end". When the penis is flaccid it is wholly or partially covered by the foreskin, except in men who have been circumcised. # Medical considerations The meatus (opening) of the urethra is at the tip of the glans penis. In circumcised infants who wear diapers, the meatal area of the glans penis is without the protection of the foreskin and at slight risk of meatitis, meatal ulceration, and meatal stenosis.[1] The epithelium of the glans penis is mucocutaneous tissue.[2] Birley et al. report that excessive washing with soap may dry the mucous membrane that covers the glans penis and cause non-specific dermatitis.[3] Inflammation of the glans penis is known as balanitis. It occurs in 3–11% of males, and up to 35% of diabetic males. It has many causes, including irritation, or infection with a wide variety of pathogens. Careful identification of the cause with the aid of patient history, physical examination, swabs and cultures, and biopsy are essential in order to determine the proper treatment.[4] # Anatomical details The glans penis is the expanded cap of the corpus spongiosum. It is moulded on the rounded ends of the Corpora cavernosa penis, extending farther on their upper than on their lower surfaces. At the summit of the glans is the slit-like vertical external urethral orifice. The circumference of the base of the glans forms a rounded projecting border, the corona glandis, overhanging a deep retroglandular sulcus (the coronal sulcus), behind which is the neck of the penis. The proportional size of the glans penis can vary greatly. The foreskin maintains the mucosa in a moist environment.[5] In males who have been circumcised, but have not undergone restoration, the glans is permanently exposed and dry. Szabo and Short found that the glans of the circumcised penis does not develop a thicker keratinization layer.[6] Studies have suggested that the glans is equally sensitive in circumcised and uncircumcised males.[7] [8] Halata & Munger (1986) report that the density of genital corpuscles is greatest in the corona glandis,[9] while Yang & Bradley (1998) report that their study "showed no areas in the glans to be more densely innervated than others."[10] Halata & Spathe (1997) reported that "the glans penis contains a predominance of free nerve endings, numerous genital end bulbs and rarely Pacinian and Ruffinian corpuscles. Merkel nerve endings and Meissner corpuscles are not present."[2] Yang & Bradley argue that "The distinct pattern of innervation of the glans emphasizes the role of the glans as a sensory structure".[10] An anatomycal variant of glans is showed: Hirsuties papillaris genitalis # Additional images - Diagram of the arteries of the penis. - Penis - An uncircumcised glans penis - Side view circumcised glans penis - An anterior view of a flaccid uncircumcised glans penis	https://www.wikidoc.org/index.php/Coronal_sulcus
cc3025b3fb07846556fc5e61eefc1583d26678af	wikidoc	QT interval	QT interval Synonyms and keywords: QT; QTc; corrected QT interval; corrected QT # Overview The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval is a general measure of how long it takes for the heart to recharge or repolarize itself electrically. The QT interval is dependent on the heart rate such that the faster the heart rate, the shorter the QT interval. As a result, the QT interval must be adjusted for the heart rate for accurate interpretation. This adjustment is called the corrected QT interval or QTc. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias such as torsades de pointes and is a risk factor for sudden cardiac death. # Historical Perspective The standard clinical correction is to use Bazett's formula, named after physiologist Henry Cuthbert Bazett, calculating the heartrate-corrected QT interval QTc. The formula is as follows: QTc = \frac{QT}{\sqrt {RR} }, where QTc is the QT interval corrected for rate, and RR is the interval from the onset of one QRS complex to the onset of the next QRS complex, measured in seconds. However, this formula tends to not be accurate, and over-corrects at high heart rates and under-corrects at low heart rates. In the same year, Fridericia published an alternative adjustment: QT_F = \frac{QT}{RR^{1/3} } . There are several other methods, but a regression based approach is the most accurate according to the current knowledge. An example of the regression-based approach is that developed by Sagie et al., as follows: QT_S = QT + 0.154(1-RR). # Measurement Normal values for the QT interval are between 0.30 and 0.44 (0.45 for women) seconds. QT interval can be measured by different methods such as the threshold method in which the end of the T wave is determined by the point at which the component of the T wave merges with the isoelectric baseline or the tangent method in which the end of the T wave is determined by the intersection of a line extrapolated from the isoelectric baseline and the tangent line which touches the terminal part of the T wave at the point of maximium downslope. Shown below is an example of normal QT interval. The QT interval is an important ECG parameter and the identification of ECGs with long QT syndrome is of clinical importance. Considering the required standards for precision, the measurement of QT interval is subjective. This is because the end of the T wave is not always clearly defined and usually merges gradually with the baseline. QT interval in an ECG complex can be measured manually by different methods such as the threshold method, in which the end of the T wave is determined by the point at which the component of the T wave merges with the isoelectric baseline or the tangent method, in which the end of the T wave is determined by the intersection of a line extrapolated from the isoelectric baseline and the tangent line, which touches the terminal part of the T wave at the point of maximum downslope. With the increased availability of digital ECGs with simultaneous 12-channel recording, QT measurement may also be done by the 'superimposed median beat' method. In the superimposed median beat method, a median ECG complex is constructed for each of the 12 leads. The 12 median beats are superimposed on each other and the QT interval is measured either from the earliest onset of the Q wave to the latest offset of the T wave or from the point of maximum convergence for the Q wave onset to the T wave offset. # Natural History, Complications and Prognosis If the QT interval is abnormally prolonged or shortened, there is a risk of developing ventricular arrhythmias. ## Genetic Causes An abnormal prolonged QT interval could be due to Long QT syndrome, whereas an abnormal shortened QT interval could be due to Short QT syndrome. ## Due to adverse drug reactions Prolongation of the QT interval may be due to an adverse drug reaction. Many drugs such as haloperidol can prolong the QT interval. # Prolongation of the QT Interval: - Represents an excess time required for completion of ventricular depolarization and repolarization. - Abnormal when the QTc is > 0.44 seconds. Shown below are examples of prolonged QY interval. Shown below is an example of prolonged QT interval with bradycardia. Shown below is an example of torsades de pointes ## Drug Causes Ofloxacin ## Differential Diagnosis: - Idiopathic long QT syndrome - Jervell and Lange-Nielsen syndrome is associated with congenital deafness, syncope, and sudden death. autosomal recessive inheritance heterozygotes may be normal or have a slightly prolonged QT interval incidence among deaf mute children is .25% - is associated with congenital deafness, syncope, and sudden death. - autosomal recessive inheritance - heterozygotes may be normal or have a slightly prolonged QT interval - incidence among deaf mute children is .25% - Romano-Ward syndrome clinically similar to the Jervell and Lange-Nielsen syndrome except the hearing is normal autosomal dominant heterozygotes and homozygotes persons may have similar symptoms - clinically similar to the Jervell and Lange-Nielsen syndrome except the hearing is normal - autosomal dominant - heterozygotes and homozygotes persons may have similar symptoms - Sporadic long QT syndrome females:males = 2:1 57% had a history of syncope there was a strong association between syncopal episodes and emotions, vigorous activities and loud noises. - females:males = 2:1 - 57% had a history of syncope - there was a strong association between syncopal episodes and emotions, vigorous activities and loud noises. - Pathogenesis imbalance between various components of the cardiac sympathetic innervation. - imbalance between various components of the cardiac sympathetic innervation. - Treatment to shorten the QT syndrome: left stellate ganglion block right stellate ganglion stimulation the administration of propranolol - left stellate ganglion block - right stellate ganglion stimulation - the administration of propranolol # Short QT Interval Shown below is an example of short QT interval. ## Causes - Digoxin therapy - Hypercalcemia - Secondary (acquired) types of QT prolongation - Coronary artery disease: Ischemia, infarction - MVP, cardiomyopathy - CNS disease, especially hemorrhage - Autonomic nervous system dysfunction secondary to radical neck dissection, carotid endarterectomy, transabdominal truncal vagotomy. - Metabolic disturbances. Electrolyte imbalance (such as hypocalcemia), liquid protein diet, intracoronary injection of contrast agents. - Cardiac medications: Quinidine, PCA, disopyramide, encainide, flecainide, propafenone, amiodarone. - Psychotropic drugs. Phenothiazines, tricyclic antidepressants. - Miscellaneous. Severe bradycardia, high degree AV block, post Stokes-Adams attacks, hypothyroidism, hypothermia, pheochromocytoma, organophosphate poisoning.	QT interval Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: QT; QTc; corrected QT interval; corrected QT # Overview The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval is a general measure of how long it takes for the heart to recharge or repolarize itself electrically. The QT interval is dependent on the heart rate such that the faster the heart rate, the shorter the QT interval. As a result, the QT interval must be adjusted for the heart rate for accurate interpretation. This adjustment is called the corrected QT interval or QTc. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias such as torsades de pointes and is a risk factor for sudden cardiac death. # Historical Perspective The standard clinical correction is to use Bazett's formula,[1] named after physiologist Henry Cuthbert Bazett, calculating the heartrate-corrected QT interval QTc. The formula is as follows: <math>QTc = \frac{QT}{\sqrt {RR} }</math>, where QTc is the QT interval corrected for rate, and RR is the interval from the onset of one QRS complex to the onset of the next QRS complex, measured in seconds. However, this formula tends to not be accurate, and over-corrects at high heart rates and under-corrects at low heart rates. In the same year, Fridericia [2] published an alternative adjustment: <math>QT_F = \frac{QT}{RR^{1/3} } </math>. There are several other methods, but a regression based approach is the most accurate according to the current knowledge. An example of the regression-based approach is that developed by Sagie et al.,[3] as follows: <math>QT_S = QT + 0.154(1-RR)</math>. # Measurement Normal values for the QT interval are between 0.30 and 0.44 (0.45 for women) seconds. QT interval can be measured by different methods such as the threshold method in which the end of the T wave is determined by the point at which the component of the T wave merges with the isoelectric baseline or the tangent method in which the end of the T wave is determined by the intersection of a line extrapolated from the isoelectric baseline and the tangent line which touches the terminal part of the T wave at the point of maximium downslope.[4] Shown below is an example of normal QT interval. The QT interval is an important ECG parameter and the identification of ECGs with long QT syndrome is of clinical importance. Considering the required standards for precision, the measurement of QT interval is subjective.[5] This is because the end of the T wave is not always clearly defined and usually merges gradually with the baseline. QT interval in an ECG complex can be measured manually by different methods such as the threshold method, in which the end of the T wave is determined by the point at which the component of the T wave merges with the isoelectric baseline or the tangent method, in which the end of the T wave is determined by the intersection of a line extrapolated from the isoelectric baseline and the tangent line, which touches the terminal part of the T wave at the point of maximum downslope.[4] With the increased availability of digital ECGs with simultaneous 12-channel recording, QT measurement may also be done by the 'superimposed median beat' method. In the superimposed median beat method, a median ECG complex is constructed for each of the 12 leads. The 12 median beats are superimposed on each other and the QT interval is measured either from the earliest onset of the Q wave to the latest offset of the T wave or from the point of maximum convergence for the Q wave onset to the T wave offset.[6] # Natural History, Complications and Prognosis If the QT interval is abnormally prolonged or shortened, there is a risk of developing ventricular arrhythmias. ## Genetic Causes An abnormal prolonged QT interval could be due to Long QT syndrome, whereas an abnormal shortened QT interval could be due to Short QT syndrome. ## Due to adverse drug reactions Prolongation of the QT interval may be due to an adverse drug reaction.[7] Many drugs such as haloperidol[8] can prolong the QT interval. # Prolongation of the QT Interval: - Represents an excess time required for completion of ventricular depolarization and repolarization. - Abnormal when the QTc is > 0.44 seconds. Shown below are examples of prolonged QY interval. Shown below is an example of prolonged QT interval with bradycardia. Shown below is an example of torsades de pointes ## Drug Causes Ofloxacin ## Differential Diagnosis: - Idiopathic long QT syndrome - Jervell and Lange-Nielsen syndrome is associated with congenital deafness, syncope, and sudden death. autosomal recessive inheritance heterozygotes may be normal or have a slightly prolonged QT interval incidence among deaf mute children is .25% - is associated with congenital deafness, syncope, and sudden death. - autosomal recessive inheritance - heterozygotes may be normal or have a slightly prolonged QT interval - incidence among deaf mute children is .25% - Romano-Ward syndrome clinically similar to the Jervell and Lange-Nielsen syndrome except the hearing is normal autosomal dominant heterozygotes and homozygotes persons may have similar symptoms - clinically similar to the Jervell and Lange-Nielsen syndrome except the hearing is normal - autosomal dominant - heterozygotes and homozygotes persons may have similar symptoms - Sporadic long QT syndrome females:males = 2:1 57% had a history of syncope there was a strong association between syncopal episodes and emotions, vigorous activities and loud noises. - females:males = 2:1 - 57% had a history of syncope - there was a strong association between syncopal episodes and emotions, vigorous activities and loud noises. - Pathogenesis imbalance between various components of the cardiac sympathetic innervation. - imbalance between various components of the cardiac sympathetic innervation. - Treatment to shorten the QT syndrome: left stellate ganglion block right stellate ganglion stimulation the administration of propranolol [9] - left stellate ganglion block - right stellate ganglion stimulation - the administration of propranolol [9] # Short QT Interval Shown below is an example of short QT interval. ## Causes - Digoxin therapy - Hypercalcemia - Secondary (acquired) types of QT prolongation - Coronary artery disease: Ischemia, infarction - MVP, cardiomyopathy - CNS disease, especially hemorrhage - Autonomic nervous system dysfunction secondary to radical neck dissection, carotid endarterectomy, transabdominal truncal vagotomy. - Metabolic disturbances. Electrolyte imbalance (such as hypocalcemia), liquid protein diet, intracoronary injection of contrast agents. - Cardiac medications: Quinidine, PCA, disopyramide, encainide, flecainide, propafenone, amiodarone. - Psychotropic drugs. Phenothiazines, tricyclic antidepressants. - Miscellaneous. Severe bradycardia, high degree AV block, post Stokes-Adams attacks, hypothyroidism, hypothermia, pheochromocytoma, organophosphate poisoning.	https://www.wikidoc.org/index.php/Corrected_QT
d718d21e86b9a44a7e87e35b7661cd9e0f706914	wikidoc	Correlation	Correlation In probability theory and statistics, correlation, (often measured as a correlation coefficient), indicates the strength and direction of a linear relationship between two random variables. In general statistical usage, correlation or co-relation refers to the departure of two variables from independence. In this broad sense there are several coefficients, measuring the degree of correlation, adapted to the nature of data. A number of different coefficients are used for different situations. The best known is the Pearson product-moment correlation coefficient, which is obtained by dividing the covariance of the two variables by the product of their standard deviations. Despite its name, it was first introduced by Francis Galton. # Pearson's product-moment coefficient ## Mathematical properties The correlation coefficient ρX, Y between two random variables X and Y with expected values μX and μY and standard deviations σX and σY is defined as: where E is the expected value operator and cov means covariance. Since μX = E(X), σX2 = E(X2) − E2(X) and likewise for Y, we may also write The correlation is defined only if both of the standard deviations are finite and both of them are nonzero. It is a corollary of the Cauchy-Schwarz inequality that the correlation cannot exceed 1 in absolute value. The correlation is 1 in the case of an increasing linear relationship, −1 in the case of a decreasing linear relationship, and some value in between in all other cases, indicating the degree of linear dependence between the variables. The closer the coefficient is to either −1 or 1, the stronger the correlation between the variables. If the variables are independent then the correlation is 0, but the converse is not true because the correlation coefficient detects only linear dependencies between two variables. Here is an example: Suppose the random variable X is uniformly distributed on the interval from −1 to 1, and Y = X2. Then Y is completely determined by X, so that X and Y are dependent, but their correlation is zero; they are uncorrelated. However, in the special case when X and Y are jointly normal, uncorrelatedness is equivalent to independence. A correlation between two variables is diluted in the presence of measurement error around estimates of one or both variables, in which case disattenuation provides a more accurate coefficient. ## The sample correlation If we have a series of n measurements of X and Y written as xi and yi where i = 1, 2, ..., n, then the Pearson product-moment correlation coefficient can be used to estimate the correlation of X and Y . The Pearson coefficient is also known as the "sample correlation coefficient". The Pearson correlation coefficient is then the best estimate of the correlation of X and Y . The Pearson correlation coefficient is written: r_{xy}=\frac{\sum x_iy_i-n \bar{x} \bar{y}}{(n-1) s_x s_y}=\frac{n\sum x_iy_i-\sum x_i\sum y_i} {\sqrt{n\sum x_i^2-(\sum x_i)^2}~\sqrt{n\sum y_i^2-(\sum y_i)^2}}. r_{xy}=\frac{\sum (x_i-\bar{x})(y_i-\bar{y})}{(n-1) s_x s_y}, where \bar{x} and \bar{y} are the sample means of X and Y , sx and sy are the sample standard deviations of X and Y and the sum is from i = 1 to n. As with the population correlation, we may rewrite this as r_{xy}=\frac{\sum x_iy_i-n \bar{x} \bar{y}}{(n-1) s_x s_y}=\frac{n\sum x_iy_i-\sum x_i\sum y_i} {\sqrt{n\sum x_i^2-(\sum x_i)^2}~\sqrt{n\sum y_i^2-(\sum y_i)^2}}. Again, as is true with the population correlation, the absolute value of the sample correlation must be less than or equal to 1. Though the above formula conveniently suggests a single-pass algorithm for calculating sample correlations, it is notorious for its numerical instability (see below for something more accurate). The square of the sample correlation coefficient, which is also known as the coefficient of determination, is the fraction of the variance in yi that is accounted for by a linear fit of xi to yi . This is written where sy\|x2 is the square of the error of a linear regression of xi on yi by the equation y = a + bx: and sy2 is just the variance of y: Note that since the sample correlation coefficient is symmetric in xi and yi , we will get the same value for a fit of yi to xi : This equation also gives an intuitive idea of the correlation coefficient for higher dimensions. Just as the above described sample correlation coefficient is the fraction of variance accounted for by the fit of a 1-dimensional linear submanifold to a set of 2-dimensional vectors (xi , yi ), so we can define a correlation coefficient for a fit of an m-dimensional linear submanifold to a set of n-dimensional vectors. For example, if we fit a plane z = a + bx + cy to a set of data (xi , yi , zi ) then the correlation coefficient of z to x and y is The distribution of the correlation coefficient has been examined by R. A. Fisher and A. K. Gayen. ## Geometric Interpretation of correlation The correlation coefficient can also be viewed as the cosine of the angle between the two vectors of samples drawn from the two random variables. Caution: This method only works with centered data, i.e., data which have been shifted by the sample mean so as to have an average of zero. Some practitioners prefer an uncentered (non-Pearson-compliant) correlation coefficient. See the example below for a comparison. As an example, suppose five countries are found to have gross national products of 1, 2, 3, 5, and 8 billion dollars, respectively. Suppose these same five countries (in the same order) are found to have 11%, 12%, 13%, 15%, and 18% poverty. Then let x and y be ordered 5-element vectors containing the above data: x = (1, 2, 3, 5, 8) and y = (0.11, 0.12, 0.13, 0.15, 0.18). By the usual procedure for finding the angle between two vectors (see dot product), the uncentered correlation coefficient is: Note that the above data were deliberately chosen to be perfectly correlated: y = 0.10 + 0.01 x. The Pearson correlation coefficient must therefore be exactly one. Centering the data (shifting x by E(x) = 3.8 and y by E(y) = 0.138) yields x = (−2.8, −1.8, −0.8, 1.2, 4.2) and y = (−0.028, −0.018, −0.008, 0.012, 0.042), from which as expected. ## Motivation for the form of the coefficient of correlation Another motivation for correlation comes from inspecting the method of simple linear regression. As above, X is the vector of independent variables, x_i, and Y of the dependent variables, y_i, and a simple linear relationship between X and Y is sought, through a least-squares method on the estimate of Y: Then, the equation of the least-squares line can be derived to be of the form: (Y - \bar{Y}) = \frac{n\sum x_iy_i-\sum x_i\sum y_i} {n\sum x_i^2-(\sum x_i)^2} (X - \bar{X}) which can be rearranged in the form: (Y - \bar{Y})=\frac{r s_y}{s_x} (X-\bar{X}) where r has the familiar form mentioned above : \frac{n\sum x_iy_i-\sum x_i\sum y_i} {\sqrt{n\sum x_i^2-(\sum x_i)^2}~\sqrt{n\sum y_i^2-(\sum y_i)^2}}. ## Interpretation of the size of a correlation Several authors have offered guidelines for the interpretation of a correlation coefficient. Cohen (1988), As Cohen himself has observed, however, all such criteria are in some ways arbitrary and should not be observed too strictly. This is because the interpretation of a correlation coefficient depends on the context and purposes. A correlation of 0.9 may be very low if one is verifying a physical law using high-quality instruments, but may be regarded as very high in the social sciences where there may be a greater contribution from complicating factors. Along this vein, it is important to remember that "large" and "small" should not be taken as synonyms for "good" and "bad" in terms of determining that a correlation is of a certain size. For example, a correlation of 1.0 or −1.0 indicates that the two variables analyzed are equivalent modulo scaling. Scientifically, this more frequently indicates a trivial result than an earth-shattering one. For example, consider discovering a correlation of 1.0 between how many feet tall a group of people are and the number of inches from the bottom of their feet to the top of their heads. # Non-parametric correlation coefficients Pearson's correlation coefficient is a parametric statistic and when distributions are not normal it may be less useful than non-parametric correlation methods, such as Chi-square, Point biserial correlation, Spearman's ρ, Kendall's τ, and Goodman and Kruskal's lambda. They are a little less powerful than parametric methods if the assumptions underlying the latter are met, but are less likely to give distorted results when the assumptions fail. # Other measures of dependence among random variables To get a measure for more general dependencies in the data (also nonlinear) it is better to use the correlation ratio which is able to detect almost any functional dependency, or the entropy-based mutual information/total correlation which is capable of detecting even more general dependencies. The latter are sometimes referred to as multi-moment correlation measures, in comparison to those that consider only 2nd moment (pairwise or quadratic) dependence. The polychoric correlation is another correlation applied to ordinal data that aims to estimate the correlation between theorised latent variables. # Copulas and correlation The information given by a correlation coefficient is not enough to define the dependence structure between random variables; to fully capture it we must consider a copula between them. The correlation coefficient completely defines the dependence structure only in very particular cases, for example when the cumulative distribution functions are the multivariate normal distributions. In the case of elliptic distributions it characterizes the (hyper-)ellipses of equal density, however, it does not completely characterize the dependence structure (for example, the a multivariate t-distribution's degrees of freedom determine the level of tail dependence). # Correlation matrices The correlation matrix of n random variables X1, ..., Xn is the n × n matrix whose i,j entry is corr(Xi, Xj). If the measures of correlation used are product-moment coefficients, the correlation matrix is the same as the covariance matrix of the standardized random variables Xi /SD(Xi) for i = 1, ..., n. Consequently it is necessarily a positive-semidefinite matrix. The correlation matrix is symmetric because the correlation between X_i and X_j is the same as the correlation between X_j and X_i. # Removing correlation It is always possible to remove the correlation between zero-mean random variables with a linear transform, even if the relationship between the variables is nonlinear. Suppose a vector of n random variables is sampled m times. Let X be a matrix where X_{i,j} is the jth variable of sample i. Let Z_{r,c} be an r by c matrix with every element 1. Then D is the data transformed so every random variable has zero mean, and T is the data transformed so all variables have zero mean, unit variance, and zero correlation with all other variables. The transformed variables will be uncorrelated, even though they may not be independent. where an exponent of -1/2 represents the matrix square root of the inverse of a matrix. The covariance matrix of T will be the identity matrix. If a new data sample x is a row vector of n elements, then the same transform can be applied to x to get the transformed vectors d and t: # Common misconceptions about correlation ## Correlation and causality The conventional dictum that "correlation does not imply causation" means that correlation cannot be validly used to infer a causal relationship between the variables. This dictum should not be taken to mean that correlations cannot indicate causal relations. However, the causes underlying the correlation, if any, may be indirect and unknown. Consequently, establishing a correlation between two variables is not a sufficient condition to establish a causal relationship (in either direction). Here is a simple example: hot weather may cause both a reduction in purchases of warm clothing and an increase in ice-cream purchases. Therefore warm clothing purchases are correlated with ice-cream purchases. But a reduction in warm clothing purchases does not cause ice-cream purchases and ice-cream purchases do not cause a reduction in warm clothing purchases. A correlation between age and height in children is fairly causally transparent, but a correlation between mood and health in people is less so. Does improved mood lead to improved health; or does good health lead to good mood; or both? Or does some other factor underlie both? Or is it pure coincidence? In other words, a correlation can be taken as evidence for a possible causal relationship, but cannot indicate what the causal relationship, if any, might be. ## Correlation and linearity While Pearson correlation indicates the strength of a linear relationship between two variables, its value alone may not be sufficient to evaluate this relationship, especially in the case where the assumption of normality is incorrect. The image on the right shows scatterplots of Anscombe's quartet, a set of four different pairs of variables created by Francis Anscombe. The four y variables have the same mean (7.5), standard deviation (4.12), correlation (0.81) and regression line (y = 3 + 0.5x). However, as can be seen on the plots, the distribution of the variables is very different. The first one (top left) seems to be distributed normally, and corresponds to what one would expect when considering two variables correlated and following the assumption of normality. The second one (top right) is not distributed normally; while an obvious relationship between the two variables can be observed, it is not linear, and the Pearson correlation coefficient is not relevant. In the third case (bottom left), the linear relationship is perfect, except for one outlier which exerts enough influence to lower the correlation coefficient from 1 to 0.81. Finally, the fourth example (bottom right) shows another example when one outlier is enough to produce a high correlation coefficient, even though the relationship between the two variables is not linear. These examples indicate that the correlation coefficient, as a summary statistic, cannot replace the individual examination of the data. # Computing correlation accurately in a single pass The following algorithm (in pseudocode) will calculate Pearson correlation with good numerical stability.	Correlation In probability theory and statistics, correlation, (often measured as a correlation coefficient), indicates the strength and direction of a linear relationship between two random variables. In general statistical usage, correlation or co-relation refers to the departure of two variables from independence. In this broad sense there are several coefficients, measuring the degree of correlation, adapted to the nature of data. A number of different coefficients are used for different situations. The best known is the Pearson product-moment correlation coefficient, which is obtained by dividing the covariance of the two variables by the product of their standard deviations. Despite its name, it was first introduced by Francis Galton.[1] # Pearson's product-moment coefficient ## Mathematical properties The correlation coefficient ρX, Y between two random variables X and Y with expected values μX and μY and standard deviations σX and σY is defined as: where E is the expected value operator and cov means covariance. Since μX = E(X), σX2 = E(X2) − E2(X) and likewise for Y, we may also write The correlation is defined only if both of the standard deviations are finite and both of them are nonzero. It is a corollary of the Cauchy-Schwarz inequality that the correlation cannot exceed 1 in absolute value. The correlation is 1 in the case of an increasing linear relationship, −1 in the case of a decreasing linear relationship, and some value in between in all other cases, indicating the degree of linear dependence between the variables. The closer the coefficient is to either −1 or 1, the stronger the correlation between the variables. If the variables are independent then the correlation is 0, but the converse is not true because the correlation coefficient detects only linear dependencies between two variables. Here is an example: Suppose the random variable X is uniformly distributed on the interval from −1 to 1, and Y = X2. Then Y is completely determined by X, so that X and Y are dependent, but their correlation is zero; they are uncorrelated. However, in the special case when X and Y are jointly normal, uncorrelatedness is equivalent to independence. A correlation between two variables is diluted in the presence of measurement error around estimates of one or both variables, in which case disattenuation provides a more accurate coefficient. ## The sample correlation If we have a series of n measurements of X and Y written as xi and yi where i = 1, 2, ..., n, then the Pearson product-moment correlation coefficient can be used to estimate the correlation of X and Y . The Pearson coefficient is also known as the "sample correlation coefficient". The Pearson correlation coefficient is then the best estimate of the correlation of X and Y . The Pearson correlation coefficient is written: r_{xy}=\frac{\sum x_iy_i-n \bar{x} \bar{y}}{(n-1) s_x s_y}=\frac{n\sum x_iy_i-\sum x_i\sum y_i} {\sqrt{n\sum x_i^2-(\sum x_i)^2}~\sqrt{n\sum y_i^2-(\sum y_i)^2}}. </math> r_{xy}=\frac{\sum (x_i-\bar{x})(y_i-\bar{y})}{(n-1) s_x s_y}, </math> where <math>\bar{x}</math> and <math>\bar{y}</math> are the sample means of X and Y , sx and sy are the sample standard deviations of X and Y and the sum is from i = 1 to n. As with the population correlation, we may rewrite this as r_{xy}=\frac{\sum x_iy_i-n \bar{x} \bar{y}}{(n-1) s_x s_y}=\frac{n\sum x_iy_i-\sum x_i\sum y_i} {\sqrt{n\sum x_i^2-(\sum x_i)^2}~\sqrt{n\sum y_i^2-(\sum y_i)^2}}. </math> Again, as is true with the population correlation, the absolute value of the sample correlation must be less than or equal to 1. Though the above formula conveniently suggests a single-pass algorithm for calculating sample correlations, it is notorious for its numerical instability (see below for something more accurate). The square of the sample correlation coefficient, which is also known as the coefficient of determination, is the fraction of the variance in yi that is accounted for by a linear fit of xi to yi . This is written where sy\|x2 is the square of the error of a linear regression of xi on yi by the equation y = a + bx: and sy2 is just the variance of y: Note that since the sample correlation coefficient is symmetric in xi and yi , we will get the same value for a fit of yi to xi : This equation also gives an intuitive idea of the correlation coefficient for higher dimensions. Just as the above described sample correlation coefficient is the fraction of variance accounted for by the fit of a 1-dimensional linear submanifold to a set of 2-dimensional vectors (xi , yi ), so we can define a correlation coefficient for a fit of an m-dimensional linear submanifold to a set of n-dimensional vectors. For example, if we fit a plane z = a + bx + cy to a set of data (xi , yi , zi ) then the correlation coefficient of z to x and y is The distribution of the correlation coefficient has been examined by R. A. Fisher[2][3] and A. K. Gayen.[4] ## Geometric Interpretation of correlation The correlation coefficient can also be viewed as the cosine of the angle between the two vectors of samples drawn from the two random variables. Caution: This method only works with centered data, i.e., data which have been shifted by the sample mean so as to have an average of zero. Some practitioners prefer an uncentered (non-Pearson-compliant) correlation coefficient. See the example below for a comparison. As an example, suppose five countries are found to have gross national products of 1, 2, 3, 5, and 8 billion dollars, respectively. Suppose these same five countries (in the same order) are found to have 11%, 12%, 13%, 15%, and 18% poverty. Then let x and y be ordered 5-element vectors containing the above data: x = (1, 2, 3, 5, 8) and y = (0.11, 0.12, 0.13, 0.15, 0.18). By the usual procedure for finding the angle between two vectors (see dot product), the uncentered correlation coefficient is: Note that the above data were deliberately chosen to be perfectly correlated: y = 0.10 + 0.01 x. The Pearson correlation coefficient must therefore be exactly one. Centering the data (shifting x by E(x) = 3.8 and y by E(y) = 0.138) yields x = (−2.8, −1.8, −0.8, 1.2, 4.2) and y = (−0.028, −0.018, −0.008, 0.012, 0.042), from which as expected. ## Motivation for the form of the coefficient of correlation Another motivation for correlation comes from inspecting the method of simple linear regression. As above, X is the vector of independent variables, <math>x_i</math>, and Y of the dependent variables, <math>y_i</math>, and a simple linear relationship between X and Y is sought, through a least-squares method on the estimate of Y: Then, the equation of the least-squares line can be derived to be of the form: (Y - \bar{Y}) = \frac{n\sum x_iy_i-\sum x_i\sum y_i} {n\sum x_i^2-(\sum x_i)^2} (X - \bar{X}) </math> which can be rearranged in the form: (Y - \bar{Y})=\frac{r s_y}{s_x} (X-\bar{X}) </math> where r has the familiar form mentioned above :<math> \frac{n\sum x_iy_i-\sum x_i\sum y_i} {\sqrt{n\sum x_i^2-(\sum x_i)^2}~\sqrt{n\sum y_i^2-(\sum y_i)^2}}. </math> ## Interpretation of the size of a correlation Several authors have offered guidelines for the interpretation of a correlation coefficient. Cohen (1988),[5] As Cohen himself has observed, however, all such criteria are in some ways arbitrary and should not be observed too strictly. This is because the interpretation of a correlation coefficient depends on the context and purposes. A correlation of 0.9 may be very low if one is verifying a physical law using high-quality instruments, but may be regarded as very high in the social sciences where there may be a greater contribution from complicating factors. Along this vein, it is important to remember that "large" and "small" should not be taken as synonyms for "good" and "bad" in terms of determining that a correlation is of a certain size. For example, a correlation of 1.0 or −1.0 indicates that the two variables analyzed are equivalent modulo scaling. Scientifically, this more frequently indicates a trivial result than an earth-shattering one. For example, consider discovering a correlation of 1.0 between how many feet tall a group of people are and the number of inches from the bottom of their feet to the top of their heads. # Non-parametric correlation coefficients Pearson's correlation coefficient is a parametric statistic and when distributions are not normal it may be less useful than non-parametric correlation methods, such as Chi-square, Point biserial correlation, Spearman's ρ, Kendall's τ, and Goodman and Kruskal's lambda. They are a little less powerful than parametric methods if the assumptions underlying the latter are met, but are less likely to give distorted results when the assumptions fail. # Other measures of dependence among random variables To get a measure for more general dependencies in the data (also nonlinear) it is better to use the correlation ratio which is able to detect almost any functional dependency, or the entropy-based mutual information/total correlation which is capable of detecting even more general dependencies. The latter are sometimes referred to as multi-moment correlation measures, in comparison to those that consider only 2nd moment (pairwise or quadratic) dependence. The polychoric correlation is another correlation applied to ordinal data that aims to estimate the correlation between theorised latent variables. # Copulas and correlation The information given by a correlation coefficient is not enough to define the dependence structure between random variables; to fully capture it we must consider a copula between them. The correlation coefficient completely defines the dependence structure only in very particular cases, for example when the cumulative distribution functions are the multivariate normal distributions. In the case of elliptic distributions it characterizes the (hyper-)ellipses of equal density, however, it does not completely characterize the dependence structure (for example, the a multivariate t-distribution's degrees of freedom determine the level of tail dependence). # Correlation matrices The correlation matrix of n random variables X1, ..., Xn is the n × n matrix whose i,j entry is corr(Xi, Xj). If the measures of correlation used are product-moment coefficients, the correlation matrix is the same as the covariance matrix of the standardized random variables Xi /SD(Xi) for i = 1, ..., n. Consequently it is necessarily a positive-semidefinite matrix. The correlation matrix is symmetric because the correlation between <math>X_i</math> and <math>X_j</math> is the same as the correlation between <math>X_j</math> and <math>X_i</math>. # Removing correlation It is always possible to remove the correlation between zero-mean random variables with a linear transform, even if the relationship between the variables is nonlinear. Suppose a vector of n random variables is sampled m times. Let X be a matrix where <math>X_{i,j}</math> is the jth variable of sample i. Let <math>Z_{r,c}</math> be an r by c matrix with every element 1. Then D is the data transformed so every random variable has zero mean, and T is the data transformed so all variables have zero mean, unit variance, and zero correlation with all other variables. The transformed variables will be uncorrelated, even though they may not be independent. where an exponent of -1/2 represents the matrix square root of the inverse of a matrix. The covariance matrix of T will be the identity matrix. If a new data sample x is a row vector of n elements, then the same transform can be applied to x to get the transformed vectors d and t: # Common misconceptions about correlation ## Correlation and causality The conventional dictum that "correlation does not imply causation" means that correlation cannot be validly used to infer a causal relationship between the variables. This dictum should not be taken to mean that correlations cannot indicate causal relations. However, the causes underlying the correlation, if any, may be indirect and unknown. Consequently, establishing a correlation between two variables is not a sufficient condition to establish a causal relationship (in either direction). Here is a simple example: hot weather may cause both a reduction in purchases of warm clothing and an increase in ice-cream purchases. Therefore warm clothing purchases are correlated with ice-cream purchases. But a reduction in warm clothing purchases does not cause ice-cream purchases and ice-cream purchases do not cause a reduction in warm clothing purchases. A correlation between age and height in children is fairly causally transparent, but a correlation between mood and health in people is less so. Does improved mood lead to improved health; or does good health lead to good mood; or both? Or does some other factor underlie both? Or is it pure coincidence? In other words, a correlation can be taken as evidence for a possible causal relationship, but cannot indicate what the causal relationship, if any, might be. ## Correlation and linearity While Pearson correlation indicates the strength of a linear relationship between two variables, its value alone may not be sufficient to evaluate this relationship, especially in the case where the assumption of normality is incorrect. The image on the right shows scatterplots of Anscombe's quartet, a set of four different pairs of variables created by Francis Anscombe.[6] The four <math>y</math> variables have the same mean (7.5), standard deviation (4.12), correlation (0.81) and regression line (<math>y = 3 + 0.5x</math>). However, as can be seen on the plots, the distribution of the variables is very different. The first one (top left) seems to be distributed normally, and corresponds to what one would expect when considering two variables correlated and following the assumption of normality. The second one (top right) is not distributed normally; while an obvious relationship between the two variables can be observed, it is not linear, and the Pearson correlation coefficient is not relevant. In the third case (bottom left), the linear relationship is perfect, except for one outlier which exerts enough influence to lower the correlation coefficient from 1 to 0.81. Finally, the fourth example (bottom right) shows another example when one outlier is enough to produce a high correlation coefficient, even though the relationship between the two variables is not linear. These examples indicate that the correlation coefficient, as a summary statistic, cannot replace the individual examination of the data. # Computing correlation accurately in a single pass The following algorithm (in pseudocode) will calculate Pearson correlation with good numerical stability.	https://www.wikidoc.org/index.php/Correlate

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